ANTIBODY CONSTRUCT CONJUGATES

PRIORITY

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S.

Provisional Application No. 62/516,667, filed June 7, 2017, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] One of the leading causes of death in the United States is cancer. The conventional methods of cancer treatment, like chemotherapy, surgery, or radiation therapy, tend to be either highly toxic or nonspecific to a cancer, or both, resulting in limited efficacy and harmful side effects. However, the immune system has the potential to be a powerful, specific tool in fighting cancers. In many cases tumors can specifically express genes whose products are required for inducing or maintaining the malignant state. These proteins may serve as antigen markers for the development and establishment of more specific anti-cancer immune response. The immune response may include the recruitment of immune cells that target tumors expressing these antigen markers. Additionally, the immune cells may express genes whose products are important to proper immune function and may serve as markers for specific types of immune cells. The boosting of this specific immune response has the potential to be a powerful anti-cancer treatment that can be more effective than conventional methods of cancer treatment and can have fewer side effects.

INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

SUMMARY

[0004] Provided herein are immune-modulatory and immune- stimulatory conjugates. In certain embodiments, an immune-modulatory conjugate is provided comprising: (a) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to a first antigen; (b) a proteolysis targeting module, comprising: (i) a protein targeting moiety that binds to a target protein; (ii) an E3 ubiquitin ligase binding moiety; and (iii) a spacer S that is covalently bound to the protein targeting moiety and to the E3 ubiquitin ligase binding moiety, wherein the spacer is optionally has 1-25 consecutive non-hydrogen atoms; and (c) a linker L that is covalently attached to the antibody construct and to the proteolysis targeting module. The conjugate can be represented by one of the following formulae:

(IX),

wherein: Ab is the antibody construct; L is the linker; ULM is the E3 ubiquitin ligase binding moiety; IMC is the protein targeting moiety and comprises an immune-modulatory compound; S is the spacer; n is selected from 1 to 20; and z is selected from 1 to 20. In some embodiments, the Fc domain of the conjugate is an Fc null.

[0005] In some embodiments, the E3 ubiquitin ligase is selected from the group consisting of

Von Hippel-Lindaue E3 ubiquitin ligase (VHL), cereblon, mouse double minute 2 homolog

(MDM2), AMFR, APC/Cdc20, APC/Cdhl, C6orfl57, Cbl, CBLL1, CHFR, CHIP, DTL (Cdt2),

E6-AP, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC2, HERC3, HERC4,

HERC5, HUWE1, HYD, ITCH, LNX1, mahogunin, MARCH-I, MARCH-II, MARCH-III,

MARCH-IV, MARCH- VI, MARCH- VII, MARCH- VIII, MARCH-X, MEKK1, MIB 1, MIB2,

MycBP2, NEDD4, NEDD4L, Parkin, PELIl, Pirh2, PJAl, PJA2, RFFL, RFWD2, Rictor, RNF5,

RNF8, RNF19, RNF190, RNF20, RNF34, RNF40, RNF125, RNF128, RNF138, RNF168,

SCF/?-TrCP, SCF/FBW7, SCF/Skp2, SHPRH, SIAH1, SIAH2, SMURF1, SMURF2, TOPORS, TRAF6, TRAF7, TRIM63, UBE3B, UBE3C, UBR1, UBR2, UHRF2, WWP1, WWP2, and ZNRF1. In some further embodiments, the E3 ubiquitin ligase binding moiety binds to VHL, cereblon or MDM2.

[0006] In some embodiments, the protein targeting moiety binds to a protein selected from one of the groups consisting of: a) an aryl hydrocarbon receptor, androgen receptor, estrogen receptor, FK506-binding protein 12, fibroblast growth factor receptor substrate 2,

phosphatidylinositol -4,5-biphosphate 3-kinase, SMAD family member 3, bromodomain and extra-territorial family of proteins (BET), bromodomain-containing protein 4 member of the BET family, Abelson tyrosine kinase, receptor- interacting serine/threonine-protein kinase 1, estrogen- related receptor, and transforming growth factor beta (TGFP); or b) ALK, Bcr-Abl, BRAF, BTK, c-KIT, EGFR, ErbB2, JAK, MEK, MET, PDGFRB, RET, ROS 1, Syk, SRC, TNIK, TNKS, TNKS2, TrkA, TrkB, TrkC, VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, FGFR4, CSF1R, RON/MS T1R, TYR03, MERTK, AXL, PI3K, PI3K, MAP4K1, PERK, and KIT; or c) TGFpR2, TGFpRl, SMAD2, SMAD3, SMAD4, beta-catenin, CREBB2, Beta catenin/TCF4, beta catenin/LEF, beta catenin/CREBBP, YAP, TAZ, YAP/TAZ, TNKS 1, TNKS2, MST1, MST2, NRAS, HRAS, KRAS, RASmutl2, RASmutl3, PERK (EIF2AK3), RON/MS T1R, STAT3, MCT1, MCT2 and MCT4; or d) CSFR1, RON/MST1, PI3Kd, PI3Kg, PARP1, PD-L1, PP2A, A2ar, TYR03, AXL and MER.

[0007] In some embodiments, the first antigen is a tumor antigen. The tumor antigen can be MUC16, CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC, HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Ley, CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, v 3, WT1, LMP2, HPV E6, HPV E7, EGFRvIII, Her-2/neu, MAGE A3, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyronsinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint fusion protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, MUC15, CA6,

NAPI2B, TROP2, CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, LIV1, ROR1, or Fos-related antigen 1. [0008] In some embodiments, the first antigen is an immune cell antigen, and can be an antigen present on the surface of an antigen presenting cell such as a dendritic cell or a macrophage. In some embodiments, the immune cell antigen is selected from the group consisting of CD40, DEC-205, PD-Ll, PD-1, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, and CD32B.

[0009] In some embodiments, the protein targeting moiety can be a peptide or a non- proteinaceous molecule. In some embodiments, the proteolysis targeting module is selected from compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and 2-1, as disclosed herein. In some embodiments, the linker L is a cleavable linker. In some embodiments, the linker L is a non-cleavable linker. In some embodiments, the linker L is covalently bound to the antibody construct at a cysteine residue, an engineered cysteine residue, a lysine residue, a glutamate residue, or a glutamine residue of the antibody construct or is covalently bound to the antibody construct using a Sortase linker.

[0010] In some embodiments, the spacer S is an optionally substituted Ci-25 alkylene or optionally substituted Ci- ₂₅ heteroalkylene, wherein the hetero alkylene is a Ci-24 alkylene chain interspersed with one or more groups independently selected from: -0-, -S-, -NH ₂ -, and - C(0)NH-; and optionally substituted with a reactive group, R , that can form a functional group selected from an amide bond, an ester bond, an ether bond, a carbonate bond, a carbamate bond, or a thioether bond. The spacer can be optionally substituted with Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - C ₈ alkynyl, -(CH ₂ 0) _n iH, -(CH ₂ CH ₂ 0) _n iH, -(CH ₂ 0) _n iCH ₃ , -C(0)OH or -NH ₂ , wherein nl is from 1 to 8. In some embodiments the spacer is substituted with R ^x . In some embodiments, the linker is unsubstituted.

[0011] In some embodiments, the antibody construct further comprises a second binding domain. The second binding domain can specifically bind to an antigen on an immune cell. The immune cell antigen is selected from the group consisting of CD40, PD-1, PD-Ll, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, and CD32B. In some embodiments, the second binding domain is attached to the antibody construct at a C-terminal end of the Fc domain.

[0012] In some embodiments, the Fc domain is an Fc domain variant comprising at least one amino acid residue change as compared to a wild type sequence of the Fc domain. In some embodiments, the Fc domain is an Fc domain variant that decreases binding of the Fc domain to an Fc receptor. In some embodiments, the at least one amino acid residue change in the Fc domain is: a) F243L, R292P, Y300L, L235V, and P396L, wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898; b) S239D and I332E, wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898; or c) S298A, E333A, and K334A, wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898. In some embodiments, the at least one amino acid residue change in the Fc domain is: a) N297A, N297G, N297Q, N297D as in Eu index of Kabat numbering and relative to SEQ ID NO: 898; or b) K322A/L234A/L235A N296A as in the EU index of Kabat numbering and relative to SEQ ID NO: 898; or c) L234F/L235E/P331S N296A as in the EU index of Kabat numbering and relative to SEQ ID NO: 898; or d) P329G/L234A/L235A as in the EU index of Kabat numbering and relative to SEQ ID NO: 898.

[0013] Also provided is a pharmaceutical composition comprising a conjugate as described herein along with a pharmaceutically acceptable excipient. In the pharmaceutical composition, the average ratio of proteolysis targeting modules to antibody construct in the conjugate can be from 2 to 6, from 3 to 5 or 1 to 3. The pharmaceutical composition can be lyophilized.

[0014] Also provided are methods of treating cancer comprising administering a conjugate as described herein, or a pharmaceutical composition of a conjugate as described herein, to a subject in need thereof. In some embodiments, the cancer is a solid tumor, such as breast cancer, pancreatic cancer, colorectal cancer, renal cell cancer, gastric cancer, or lung cancer. In some embodiments, the pharmaceutical composition is administered parenterally. In some

embodiments, the pharmaceutical composition is administered intravenously.

[0015] In certain aspects, the disclosure also provides immune- stimulatory conjugates comprising: (a) an immune- stimulatory compound that binds to a target protein to stimulate an immune response by stimulating the activity of the target protein, reducing immune inhibition by the target protein or increasing degradation of the target protein; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to at least a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound of the conjugate (i.e, attached to the conjugate) to the target protein is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the target protein active site or wherein the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 300-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound of the conjugate (i.e, attached to the conjugate) to the target protein is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the target protein active site or wherein the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 300- fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the Fc domain is an Fc null.

[0016] In certain embodiments, the disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site to stimulate an immune response; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to at least a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of immune- stimulatory compound of the conjugate to the protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate (attached to the conjugate )is no greater than 300-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of immune- stimulatory compound of the conjugate to the protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate (attached to the conjugate) is no greater than 300-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

[0017] In certain embodiments, the disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site of a binding protein to stimulate an immune response by inhibition of the activity of the binding protein; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to at least a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound of the conjugate (attached to the conjugate) to the protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC ₅₀ of the immune- stimulatory compound of the conjugate (attached to the conjugate) is no greater than 300-fold the IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound of the conjugate (attached to the conjugate) to the protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC ₅₀ of the immune- stimulatory compound of the conjugate (attached to the conjugate) is no greater than 300-fold the IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the Fc domain is an Fc null.

[0018] In certain embodiments, the disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site of a binding protein to stimulate an immune response by increasing degradation of the binding protein; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to at least a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound of the conjugate

(attached to the conjugate) to the protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 300-fold the IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound of the conjugate (attached to the conjugate) to the protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 300-fold the IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the Fc domain is an Fc null.

[0019] In certain embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 100-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. The EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate may be no greater than 10-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. The EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate may be equivalent to or less than the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

[0020] In certain embodiments, the EC ₅₀ or IC ₅₀ of the immune stimulatory compound on an antigen bearing cell is equivalent to or less than the EC ₅₀ or IC ₅₀ of a control compound on the antigen bearing cell and the EC ₅₀ or IC ₅₀ of the immune- stimulatory conjugate is 5-fold greater or more than the EC ₅₀ or IC ₅₀ of the control compound for a non-antigen bearing cell.

[0021] The immune- stimulatory compound of the conjugate may have a K _d for binding to the protein active site of no greater than 50 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory

compound. The immune- stimulatory compound of the conjugate may have a K _d for binding to the protein active site of no greater than 10 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory

compound. The immune- stimulatory compound of the conjugate may have a K _d for binding to the protein active site of equivalent to or less than the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound.

[0022] In certain aspects, the disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site to stimulate an immune response; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker comprising 5- 100 consecutive atoms attachment sites, wherein one attachment site of the linker is covalently bound to the antibody construct and another attachment site of the linker is covalently bound to the immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound when bound to a the linker to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 300-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the dissociation constant (K _d ) for binding of the Fc domain of the conjugate to an Fc receptor is greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct; and wherein the K _d for binding of the immune- stimulatory compound when bound to a the linker to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 300-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In some embodiments, the Fc domain is an Fc null.

[0023] In certain embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound when bound to the 5- 100 atom linker is no greater than 100-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In certain embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound when bound to the 5- 100 atom linker is no greater than 10-fold the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. The EC ₅₀ or IC ₅₀ of the immune- stimulatory compound when bound to the 5- 100 atom linker may be equivalent to or less than the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

[0024] In certain embodiments, the K _d for binding of the immune- stimulatory compound when bound to the 5- 100 atom linker to the protein active site may be no greater than 50 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. The K _d for binding of the of the immune- stimulatory compound when bound to a 5-100 atom linker to the protein active site may be no greater than 10 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. The K _d for binding of the immune- stimulatory compound when bound to a 5-100 atom linker to the protein active site may be equivalent to or less than the K _d for binding of a control compound to the protein active site wherein the control compound is the unbound immune- stimulatory compound.

[0025] In certain embodiments, the immune- stimulatory conjugate described herein comprises moiety that binds to the binding protein and an E3 ubiquitin ligase binding moiety. The E3 ubiquitin ligase binding moiety may bind to, for example, VHL, cereblon or MDM2. The E3 ubiquitin ligase binding moiety may be selected from among E3 targeting compounds. The E3 ubiquitin ligase binding moiety may be attached to the linker or may be part of the linker. In certain embodiments, the E3 ubiquitin ligase binding moiety attached to the linker, wherein the E3 ubiquitin ligase binding moiety is bound through a first linker having 5-100 consecutive atoms between attachment sites to the immune- stimulatory compound and the E3 ubiquitin ligase binding moiety is bound through a second linker having 5-100 consecutive atoms between attachment points to the antibody construct.

[0026] In certain embodiments, the immune- stimulatory compound is a kinase inhibitor and the protein active site is a kinase active site. In certain embodiments, the linker is covalently bound to the kinase inhibitor at a position on the kinase inhibitor that is at or near the solvent interface of the kinase active site as determined by modeling of the kinase inhibitor in the kinase active site. In certain embodiments, the linker is covalently bound to the kinase inhibitor at a position on the kinase inhibitor such that when the kinase inhibitor is bound to the active site, the linker extends out from the kinase active site into the solvent, as determined by modeling of the kinase inhibitor in the kinase active site. In certain embodiments, the kinase inhibitor may be selected from an inhibitor of ALK, Bcr-Abl, BRAF, BTK, c-KIT, EGFR, ErbB2, JAK, MEK, MET, PDGFRB, RET, ROS 1, Syk, SRC, TGFpR2, TNIK, TNKS, TNKS2, TrkA, TrkB, TrkC, VEGF, VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, FGFR4, CSF1R, RON/MS T1R, TYR03, MERTK, AXL, PDKdelta PDKgamma, MAP4K1, PERK, and combinations thereof.

[0027] In certain embodiments, the immune- stimulatory compound is selected from a to 11- like receptor agonist, STING agonist, or RIG-I agonist. The immune- stimulatory compound may be a toll-like receptor (TLR) agonist selected from a TLR1 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a TLR10 agonist. The immune- stimulatory compound may be selected from a pyrimidine, a purine, a guanine nucleoside, an 8-oxoadenine, an imidazoquinoline, a

thiazoquinoline, a 2-aminoimidazole, a furo[2,3-c]pyridine, a furo[2,3-c]quinoline, a 2- aminobenzimidazole, a 2-aminoquinoline, and a 2-aminobenzazepine. The immune- stimulatory compound may bind to a G protein-coupled receptor (GCPR), an ion channel, a membrane transporter, a phosphatase or an endoplasmic reticulum (ER) protein.

[0028] In certain embodiments, the immune- stimulatory compound is an antagonist of the GPCR A2aR, the sphingosine 1-phosphate receptor 1, prostaglandin receptor EP3, prostanglandin receptor E2, Frizzled, CXCR4 or an LPA receptor. The immune- stimulatory compound may be an ion channel agonist for CRAC, Kvl.3 or KCa3.1. The immune- stimulatory compound may be an inhibitor of HSP90 or AAA-ATPase p97.

[0029] In certain embodiments, the immune- stimulatory conjugate has immune- stimulatory activity while attached to the conjugate or the linker and without undergoing cell processing such as by endosomal or lysosomal degradation, e.g., to release the immune- stimulatory compound or a modified form of the compound from the conjugate or linker. In certain embodiments, the linker is a non-cleavable linker. The linker may be selected from the group consisting of

Fleximer linkers. The linker may comprise one or more carbamate or amide linkages when attached to an immune- stimulatory compound. The linker ma be selected from a linker is

represented by one of the following formula:

, wherein R ^x is a reactive moiety and wherein R is selected from the group consisting of hydrogen, alkyl (e.g., d- C ₈ alkyl), sulfonate and methyl sulfonate. The linker may be attached to the antibody construct at a cysteine or lysine residue of the antibody construct.

[0030] In certain embodiments, the first antigen is a tumor antigen. The first antigen may be at least 80% or 100% homologous to CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, folate-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1,

MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GMl, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, , TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD-L1, VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof.

[0031] In certain embodiments, the antibody construct further comprises a second target binding domain. In certain embodiments, the target binding domain specifically binds an antigen on an immune cell. The target binding domain may be attached (e.g., conjugated or linked) to the antibody construct at a C-terminal end of the Fc domain. The antigen binding domain may be from an antibody or non-antibody scaffold. The antigen binding domain may be at least 97% homologous to an antigen binding domain from an antibody or non-antibody scaffold. The antibody construct may be a human antibody or a humanized antibody. The Fc domain may be an Fc domain variant comprising at least one amino acid residue change as compared to a wild type sequence of the Fc domain. The Fc domain may be at least about 80% homologous to an Fc domain from an antibody, wherein the Fc domain from an antibody comprises amino acid residues 216 to 447 of an IgGl (within SEQ ID NO: 898), amino acid residues 216 to 443 of an IgG2 (within SEQ ID NO: 899), or amino acid residues 216 to 444 of an IgG4 (within SEQ ID NO: 900).

[0032] In certain embodiments, the Fc domain may have at least one amino acid residue change as compared to a wildtype Fc domain. In certain embodiments, the Fc domain may have at least one amino acid residue change as compared to a wildtype Fc domain, wherein the Fc domain is at least 80% homologous to SEQ ID NO: 898. The at least one amino acid residue change may be in an IgG Fc domain: a) F243L, R292P, Y300L, L235V, and P396L, wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO:898; b) S239D and I332E, wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898; or c)

S298A, E333A, and K334A, wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 296. The Fc domain may have at least one amino acid residue change as compared to wildtype, wherein the Fc domain is at comprises at least 80% homologous to SEQ ID NO: 898, and wherein the at least one amino acid residue change is: (a) N296A wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898; or (b) N296G N296A wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898; or (c) K322A/L234A/L235A N296A wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898; or (d) L234F/L235E/P331S N296A wherein numbering of amino acid residues in the Fc domain is relative to SEQ ID NO: 898.

[0033] In certain embodiments, the IQ for binding of the antigen binding domain to the first antigen in the presence of the immune- stimulatory compound is less than about 100 nM and is equal to, or up to no greater than about 10 times the IQ of the binding of the antigen binding domain to the first antigen in the absence of the immune- stimulatory compound; and the IQ for binding of the Fc domain to the Fc receptor in the presence of the immune- stimulatory compound is equal to, or up to no greater than about 10 times the IQ for the binding of the Fc domain to the Fc receptor in the absence of the immune- stimulatory compound.

[0034] In certain embodiments, the molar ratio of immune- stimulatory compound to antibody in a conjugate is less than 5. In certain embodiments, the average molar ratio of immune- stimulatory compound to antibody construct in a composition of conjugates is less than 5. In certain embodiments, the average molar ratio of immune- stimulatory compound to antibody construct in a composition of conjugates from 1 to 3, 3 to 5, or about 2.

[0035] The linker may be bound to the antibody construct at an amino acid residue that does not interfere with the Fc domain binding to the Fc receptor. The linker may not be attached to an amino acid residue of an IgG Fc domain selected from a group consisting of: 221, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 275, 276, 278, 280, 281, 283, 285, 286, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 318, 323, 324, 325, 327, 328, 329, 330, 331, 332, 333, 335, 336, 396, or 428, wherein numbering of amino acid residues in the Fc domain is according to the EU index as in Kabat.

[0036] The linker is bound to the antibody construct at an amino acid of an IgG Fc domain selected from a group consisting of: 221, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 275, 276, 278, 280, 281, 283, 285, 286, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 318, 323, 324, 325, 327, 328, 329, 330, 331, 332, 333, 335, 336, 396, or 428, wherein numbering of amino acid residues in the Fc domain is according to the EU index as in Kabat. [0037] In certain embodiments, the Fc domain is an IgG Fc domain selected from a group consisting of a human IgGl Fc domain, a human IgG2 Fc domain, a human IgG3 Fc domain, and a human IgG4 Fc domain. In certain aspects, the immune- stimulatory conjugate induces the secretion of cytokines by an antigen presenting cell.

[0038] In certain aspects, the disclosure provides a pharmaceutical composition comprising immune- stimulatory conjugates as described herein and a pharmaceutically acceptable excipient. In certain aspects, the disclosure provides a method of treating cancer, comprising administering to a subject in need thereof an immune- stimulatory conjugate described herein. In certain aspects, the disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising immune- stimulatory conjugates as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative aspects, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0040] FIGURE 1 illustrates a schematic of a conjugate comprising an antibody and a second binding domain. The antibody contains two heavy chains as shown in gray and two light chains as shown in light gray. A portion of the heavy chains contain Fc domains (705 and 720). The antibody comprises a binding domain comprising two antigen binding sites (710 and 715). The second binding domain is attached to the antibody (780 and 785), for example, at the C-terminus of the heavy chains.

[0041] FIGURE 2 illustrates a schematic of an exemplary conjugate. The conjugate comprises an antibody, which contains two heavy chains as shown in gray and two light chains as shown in light gray. The antibody comprises a binding domain comprising two antigen binding sites (910 and 915), and a portion of the heavy chains contain Fc domains (905 and 920). The immune- stimulatory compounds (930 and 940) are attached to the antibody by linkers (960 and 970). A second binding domain is attached to the antibody (980 and 985), for example, at the C-terminus of the heavy chains.

[0042] FIGURE 3 illustrates a schematic of an exemplary conjugate. The conjugate comprises the Fc region of an antibody with the heavy chains shown in gray, and two scaffolds as shown in light gray. The conjugate comprises a first binding domain comprising two antigen binding sites (1110 and 1115) in the scaffolds, and a portion of the heavy chains contain Fc domains (1105 and 1120). The immune- stimulatory compounds (1130 and 1140) are conjugated to the Fc domains by linkers (1160 and 1170). A second binding domain is attached to the conjugate (1180 and 1185), for example, at the C-terminus of the heavy chains.

[0043] FIGURE 4 illustrates a schematic of an exemplary conjugate. The conjugate comprises the F(ab') ₂ region of an antibody with the Fab portions of heavy chains shown in gray and light chains shown in light gray, and two scaffolds as shown in dark gray. The conjugate comprises a first binding domain comprising two antigen binding sites (1310 and 1315), and a portion of two scaffolds contain Fc domains (1340 and 1345). The immune- stimulatory compounds (1330 and 1340) are attached to the conjugate by linkers (1360 and 1370). A second binding domain is attached to the Fc domains (1380 and 1385).

[0044] FIGURE 5 illustrates a schematic of an exemplary conjugate. The conjugate contains two scaffolds as shown in light gray and two scaffolds as shown in dark gray. The conjugate comprises a first binding domain comprising two antigen binding sites (1510 and 1515), and a portion of the two dark gray scaffolds contain Fc domains (1540 and 1545). The immune- stimulatory compounds (1530 and 1540) are conjugated to the conjugate by linkers (1560 and 1570). A second binding domain is attached to the conjugate (1580 and 1585).

[0045] FIGURE 6 illustrates a schematic of a conjugate comprising an antibody and a second binding domain. The antibody contains two heavy chains as shown in gray and two light chains as shown in light gray. A portion of the heavy chains contain Fc domains (1705 and 1720). The antibody comprises a binding domain comprising two antigen binding sites (1710 and 1715). The second binding domain is attached to the antibody (1780 and 1785), for example, at the C- terminus of the light chains.

[0046] FIGURE 7 illustrates a schematic of an exemplary conjugate. The conjugate comprises an antibody, which contains two heavy chains as shown in gray and two light chains as shown in light gray. The antibody comprises a binding domain comprising two antigen binding sites (1910 and 1915), and a portion of the heavy chains contain Fc domains (1905 and 1920). The immune- stimulatory compounds (1930 and 1940) are conjugated to the antibody by linkers (1960 and 1970). A second binding domain is attached to the antibody (1980 and 1985), for example, at the C-terminus of the light chains.

[0047] FIGURE 8 illustrates a schematic of an exemplary conjugate. The conjugate comprises an Fc region of an antibody shown in gray, and two scaffolds as shown in light gray. The conjugate comprises a first binding domain comprising two antigen binding sites (2110 and 2115) in the scaffolds, and a portion containing Fc domains (2105 and 2120). The immune- stimulatory compounds (2130 and 2140) are conjugated to the antibody construct by linkers (2160 and 2170). A second binding domain is attached to the antibody (2180 and 2185). [0048] FIGURE 9 illustrates a schematic of an exemplary conjugate. The conjugate comprises the F(ab')2 region of an antibody with heavy chains shown in gray and light chains shown in light gray, and two scaffolds as shown in dark gray. The conjugate comprises a first binding domain comprising two antigen binding sites (2310 and 2315), and a portion of two scaffolds contain Fc domains (2340 and 2345). The immune- stimulatory compounds (2330 and 2340) are conjugated to the antibody by linkers (2360 and 2370). A second binding domain is attached to the antibody (2380 and 2385), for example, at the C-terminus of the light chains.

[0049] FIGURE 10 illustrates a schematic of an exemplary conjugate. The conjugate contains two scaffolds as shown in light gray and two scaffolds as shown in dark gray. The conjugate comprises a first binding domain comprising two antigen binding sites (2510 and 2515), and a portion of the two dark gray scaffolds contain Fc domains (2540 and 2545). The immune- stimulatory compounds (2530 and 2540) are conjugated to the antibody construct by linkers (2560 and 2570). A second binding domain is attached to the conjugate (2580 and 2585).

[0050] FIGURE 11 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (2705 and 2720). The antibody comprises a binding domain comprising two antigen binding sites shown in black (2710 and 2715).

[0051] FIGURE 12 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (2925 and 2930). The antibody comprises a first binding domain comprising two antigen binding sites shown in black (2910 and 2915). The antibody comprises a second binding domain comprising two single chain variable fragments (2905 and 2920) attached to a C- terminus of the light chains. A single chain variable fragment can be attached to a light chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a light chain at a light chain variable domain of the single chain variable fragment.

[0052] FIGURE 13 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (3120 and 3125). The antibody comprises a first binding domain comprising two antigen binding sites shown in black (3110 and 3115). The antibody comprises a second binding domain comprising two single chain variable fragments (3130 and 3135) attached to a C- terminus of the heavy chains. A single chain variable fragment can be attached to a heavy chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a heavy chain at a light chain variable domain of the single chain variable fragment. [0053] FIGURE 14 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (3330 and 3335). The antibody comprises a first binding domain comprising two antigen binding sites shown in black (3310 and 3315). The antibody comprises a second binding domain comprising two single chain variable fragments (3320 and 3325) attached to a C- terminus of the light chains. A single chain variable fragment can be attached to a light chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a light chain at a light chain variable domain of the single chain variable fragment. The antibody comprises a third binding domain comprising two single chain variable fragments (3340 and 3345) attached to a C-terminus of the heavy chains. A single chain variable fragment can be attached to a heavy chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a heavy chain at a light chain variable domain of the single chain variable fragment.

[0054] FIGURE 15A sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with an amine handle (right top).

[0055] FIGURE 15B shows the x-ray crystal structure and binding orientation (pdb code 5D7A) of the immune- stimulatory compound as described in FIGURE 15A in a TNIK (TRAF2 and NCK- interacting protein kinase) active site. Specific interactions between the inhibitor and the TNIK active site are described in Masuda et al., TNIK inhibition abrogates colorectal cancer sternness, (2016) Nat Commun 7: 12586-12586.

[0056] FIGURE 15C shows a close up of the binding orientation of the immune- stimulatory compound as described in FIGURE 15A in a TNIK active site, where the linker and antibody portions are pointing away and sitting outside of the active site.

[0057] FIGURE 16 sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with an amine handle and linker surrogate (right). The structure on the right illustrates that the immune- stimulatory compound is predicted to sit in the enzyme active site, whereas the amine handle and linker surrogate are predicted to sit outside of the enzyme active site, in the solvent.

[0058] FIGURE 17A sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with a linker surrogate (left side of molecule on right).

[0059] FIGURE 17B shows the x-ray crystal structure and binding orientation (pdb code 5E91) of the immune- stimulatory compound as described in FIGURE 17 A in a TGFPR2 (transforming growth factor, beta receptor II) active site. Specific interactions between the inhibitor and the TGFpRII active site are described in Tebben et al., Crystal structures of apo and inhibitor-bound TGFbetaR2 kinase domain: insights into TGFbetaR isoform selectivity, (2016) Acta Crystallogr., Sect.D 72: 658-674.

[0060] FIGURE 17C shows a close up of the binding orientation of the immune- stimulatory compound as described in FIGURE 17 A in a TGFPR2 active site, where the linker and antibody construct portions are pointing away and sitting outside of the active site.

[0061] FIGURE 18A sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with an amine handle (upper left in molecule on right).

[0062] FIGURE 18B shows the x-ray crystal structure and binding orientation (pdb code 3KR8) of the immune- stimulatory compound as described in FIGURE 18A in a TNKS (tankyrase) active site.

[0063] FIGURE 18C shows a close up of the binding orientation of the immune- stimulatory compound as described in FIGURE 18A in a TNKS active site, where the linker and antibody construct portions are pointing away and sitting outside of the active site. Specific interactions between the inhibitor and the human tankyrase 2 - catalytic PARP domain active site are described in Karlberg et al., Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor, (2010) J.Med.Chem. 53: 5352-5355.

[0064] FIGURE 19A shows a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with two amine handles (on right side of molecule on the right).

[0065] FIGURE 19B shows the x-ray crystal structure and binding orientation (pdb code 4191) of the immune- stimulatory compound as described in FIGURE 19A with dual site binding in the TNKS (tankyrase) active site. Specific interactions between the inhibitor and human tankyrase 1 are described in Bregman et al, Discovery of a class of novel tankyrase inhibitors that bind to both the nicotinamide pocket and the induced pocket, (2013) J.Med.Chem. 56: 1341-1345.

[0066] FIGURE 19C shows a close up of the binding orientation of the immune- stimulatory compound as described in FIGURE 19A in a TNKS active site, where the linker and antibody portions are pointing away and sitting outside of the active site.

[0067] FIGURE 20A illustrates a schematic of an exemplary conjugate and its molecular target. The conjugate comprises an antibody (3405) attached to a linker (3410) that is attached to a drug (3415) at the opposite end of the antibody (3405). The molecular target (3420) has an active site (3425) that is complementary to the drug (3415).

[0068] FIGURE 20B illustrates a schematic of an active exemplary conjugate that is bound to the the molecular target's active site. The drug (3415) sits within the active site of the molecular target (3420). The linker (3410) and antibody (3405) sit outside of the active site (3430).

[0069] FIGURE 20C illustrates a schematic of an active drug (3415) and linker (3410) that is bound to the molecular target (3420). [0070] FIGURE 20D illustrates a schematic of an active drug (3415) that is bound to the molecular target (3420).

[0071] FIGURE 21A, FIGURE 21B, and FIGURE 21C show the results of an assay for degradation of TFGpR2 by a TGFpR2-VHL PROTAC anti-HER2 antibody conjugate.

[0072] FIGURE 22A and FIGURE 22B show the results of an assay for antigen targeted degradation of TGFPR2 by an antibody conjugate with a PROTAC having VHL or Cereblon E3 binding moieties.

[0073] FIGURE 23A and FIGURE 23B show the results of an assay for cellular levels of TGFpR2 and TGFpRl in the presence of a TGFpR2/TGFpRl-VHL PROTAC with or without the addition of a proteasome inhibitor.

DETAILED DESCRIPTION

[0074] Additional aspects and advantages of the present disclosure will become apparent to those skilled in this art from the following detailed description, wherein illustrative aspects of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different aspects, and its several details are capable of modifications in various respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0075] As used herein, "potency" generally refers to measured bioactivity and may be quantified as an EC50 or IC50. Potency refers to the amount of a compound or conjugate needed to give an effect. For example, the potency of an immune- stimulatory compound which requires a lower amount of the immune- stimulatory compound compared with a different immune- stimulatory compound can be considered to have greater potency. Furthermore, the different immune- stimulatory compound requires a greater amount of the different immune- stimulatory compound to generate a response, and can therefore be considered lower potency. Potencies of bioactive compounds or conjugates may be measured over a concentration range and can be reported as those molar concentrations required to elicit or inhibit a percentage of the measured bioresponse. For example, a concentration required to stimulate 50% of observed maximal activity in the assay may be reported as an effective concentration 50 (EC50), to stimulate 90% activity as an EC90, or to stimulate 10% activity as an EC 10. For example, a concentration of an antagonist required to give 50% maximal inhibition of a biological activity may be reported as an inhibitory concentration 50 (IC50), to inhibit 90% as an IC90, or to inhibit 10% as an ICIO. This may allow for a comparison of the potencies of bioactive compounds on a molar basis by comparison of their EC or IC values for a given bioassay. For example, an immune- stimulatory conjugate or an immune- stimulatory compound with an EC50 or IC50 that is greater than 300 times the EC50 or IC50 of a control requires 300-fold higher, or more than 300-fold higher, concentration compared to the control to achieve a 50% bioresponse and has a potency weaker than the control by at least 300-fold. Therefore, an immune- stimulatory compound or conjugate that has an EC50 or IC50 not greater than about 300 times the EC50 or IC50 of a control compound may require no more than a 300-fold higher concentration than the control compound to achieve a 50% maximal bioresponse, no greater than 100 times the EC50 or IC50 requires no more than 100-fold higher concentration and no greater than 10 times the EC50 or IC50 requires no more than 10 times the concentration of the control. The potency of the immune- stimulatory compound or conjugate may be within 300-fold or better, 100-fold or better, or 10-fold or better the potency of the control.

[0076] As used herein, "control compound" refers to, in a case of an immune- stimulatory compound, the compound before attachment to a linker and antibody construct; in the case of an antibody construct, the construct before attachment of the linker and immune- stimulatory compound; or, in the case of a conjugate including an E3 ubiquitin ligase binding moiety, control compound refers to the immune- stimulatory compound attached to a linker that is attached to an E3 ubiquitin ligase binding moiety.

[0077] An "immune- stimulatory compound" as described herein, also referred to herein as an immune- stimulatory agent or molecule, refers to a molecule that stimulates the immune system by inducing activation or increasing activity of any of its components. For example, an immune stimulatory compound may bind directly to a component of the immune system and activate or increase an activity of the immune system or a component thereof. An immune stimulatory compound may also bind to an inhibitory component of the immune system and inactivate or decrease the activity of that component, thereby increasing an activity of the immune system. Immune- stimulatory compounds may have or cause antigenic specificity. In certain embodiments, an immune- stimulatory compound activates macrophages. In certain embodiments, an immune- stimulatory compound induces the secretion of cytokines by an antigen presenting cell. The increased activity or activation of the immune system may be evaluated using methods known in the field for evaluating an immune response (see, for example, J. Gratama, Cytometry A. 2008 Nov: 73(11): 971-4, the contents of which are incorporated herein in its entirety).

[0078] A "protein active site" as described herein, refers to a region of a protein target where a molecule (such as a substrate molecule or allosteric effector) binds to the target protein. The molecule may trigger a response upon binding to the the binding protein, e.g., inhibition of the activity of the binding protein or degradation of the binding protein. The protein active site includes the residues that interact with, e.g., bind covalently or non-covalently, a molecule such as an immune- stimulatory compound or a portion thereof. The protein active site may define a groove or pocket in the target protein wherein the interface between the groove or pocket and surrounding solvent is the solvent/active site interface of the protein active site.

[0079] The phrase "stimulate an immune response" refers to stimulating a response from immune cells that increases the activity or responsiveness of the immune system or a part thereof, such as, for example, inducing secretion of cytokines and/or chemokines, activating immune cells, e.g., T cells, B cells, macrophages, dendritic cells, etc., enhancing antigen presenting cell presentation of antigen, inducing antibody-dependent cell-mediated phagocytosis (ADCP), inducing antibody-dependent cell-mediated cytotoxicity (ADCC), NK cell or CD8+ T cell cytolytic activity, and/or blocking immune suppression.

[0080] As used herein, "homologous" or "homology" refer to the similarity or identity between a DNA, RNA, nucleotide, amino acid, or protein sequence to another DNA, RNA, nucleotide, amino acid, or protein sequence, respectively. Homology can be expressed in terms of a percentage of sequence identity of a first sequence to a second sequence. Percent (%) sequence identity with respect to a reference DNA sequence is the percentage of DNA nucleotides in a candidate sequence that are identical with the DNA nucleotides in the reference DNA sequence after aligning the sequences and introducing gaps, as necessary. Percent (%) sequence identity with respect to a reference amino acid sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference amino acid sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.

[0081] As used herein, the abbreviations for the natural 1- enantiomeric amino acids are conventional and can be as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gin); glycine (G, Gly); histidine (H, His); isoleucine (I, He); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). Unless otherwise specified, X can indicate any amino acid. In some aspects, X can be asparagine (N), glutamine (Q), histidine (H), lysine (K), or arginine (R).

[0082] As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive toward, a specific antigen. The term antibody can include, for example, polyclonal, monoclonal, genetically engineered, and antigen binding fragments thereof. An antibody can be, for example, murine, chimeric, humanized, bispecific, a heteroconjugate, a diabody, a triabody, a tetrabody or a hcAb (heavy chain antibody). An antigen binding fragment can include, for example, a Fab', F(ab') ₂ , Fab, Fv, rlgG, scFv, a single domain antibody, V _HH , V _NAR , sdAb, or nanobody. [0083] As used herein, the term "antigen" refers to a molecule that can be bound by an antibody or a antibody construct. An antigen may elicit an immune response. An antigen can be a protein, polysaccharide, lipid, glycolipid or the like, which can be recognized by an antibody or an immune cell, such as a T cell or a B cell. Exposure of immune cells to one or more of these antigens can elicit a rapid cell division and differentiation response resulting in the formation of clones of the exposed T cells and B cells. B cells can differentiate into plasma cells which in turn can produce antibodies which selectively bind to the antigens.

[0084] As used herein, the terms "recognize," "bind," and "specifically bind" refer to the specific association or specific binding between an antigen binding domain and a corresponding antigen, or an immune stimulatory compound and a protein, as compared to the non-specific association or non-specific binding of the antigen binding domain or immune- stimulatory compound with a non-target antigen or protein.

[0085] As used herein, a "tumor antigen" is an antigen that can be expressed by or is present on, a cancer cell, a neoplastic tumor cell and/or within a tumor microenvironment.

[0086] As used herein, an "antibody construct" refers to a construct that contains an antigen binding domain and an Fc domain.

[0087] As used herein, an "antigen binding domain" refers to an antigen binding domain from an antibody or from a non-antibody that can specifically bind to the antigen. Antigen binding domains can be numbered when there is more than one antigen binding domain in a given conjugate or construct (e.g., first binding domain, second antigen binding domain, third antigen binding domain, etc.). Different antigen binding domains in the same conjugate or construct can target the same antigen or different antigens (e.g., first binding domain that can bind a tumor antigen, second antigen binding domain that can bind to a tumor antigen or an antigen presenting cell (APC) antigen, and third antigen binding domain that can bind an APC antigen).

[0088] As used herein, a "Fc domain" is an Fc domain from an antibody or from a non-antibody that can bind to an Fc receptor.

[0089] As used herein, an "Fc null" refers to an Fc domain that exhibits weak to no binding to any of the Fcgamma receptors. In some embodiments, an Fc null domain or region exhibits a reduction in binding affinity (e.g., increase in Kd) to Fc gamma receptors of at least 1000-fold.

[0090] As used herein, a "target binding domain" refers to a construct that contains an antigen binding domain from an antibody or from a non-antibody that can bind to the antigen.

[0091] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as

isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0092] As used herein, "agonism" is the binding of a chemical to a receptor to induce a biological response. A chemical can be, for example, a small molecule, a compound, or a protein. An agonist causes a response, an antagonist can block the action of an agonist, and an inverse agonist can cause a response that is opposite to that of the agonist. A receptor can be activated by either endogenous or exogenous agonists.

[0093] The term "C _x-y " when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term "C _x - _y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0094] The terms "C _x - _y alkenyl" and "C _x - _y alkynyl" refer to substituted or unsubstituted

unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0095] The term "carbocycle" as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.

Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. [0096] The term "heterocycle" as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings wherein at least one of the rings includes a heteroatom. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. The term "heteroaryl" includes aromatic single ring structures, preferably 5- to 7- membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0097] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0098] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N0 ₂ ), imino (=N-H), oximo (=N-OH), hydrazino (=N-

NH ₂ ), -R ^b -OR ^a , -R ^b -OC(0)-R ^a , -R ^b -OC(0)-OR ^a , -R ^b -OC(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(0)R ^a , -R ^b -C(0)OR ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)OR ^a , -R ^b -N(R ^a )C(0)R ^a , -R ^b -N (R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2), and -R ^b -S(0) _t N(R ) ₂ (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocyclo alkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N0 ₂ ), imino (=N-H), oximo (=N-OH), hydrazine (=N-

NH ₂ ), -R ^b -OR ^a , -R ^b -OC(0)-R ^a , -R ^b -OC(0)-OR ^a , -R ^b -OC(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(0)R ^a , -R ^b -C(0)OR ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)OR ^a , -R ^b -N(R ^a )C(0)R ^a , -R ^b -N (R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ) ₂ (where t is 1 or 2); wherein each R is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R , valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N0 ₂ ), imino (=N-H), oximo (=N-OH), hydrazine (=N-

NH ₂ ), -R ^b -OR ^a , -R ^b -OC(0)-R ^a , -R ^b -OC(0)-OR ^a , -R ^b -OC(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(0)R ^a , -R ^b -C(0)OR ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)OR ^a , -R ^b -N(R ^a )C(0)R ^a , -R ^b -N (R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ) ₂ (where t is 1 or 2); and wherein each R ^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R ^c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0099] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0100] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0101] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state temperature, solvent, and pH. Some examples of tautomeric

equilibrium include:

[0102] The compounds, constructs and conjugates disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or ¹⁴ C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, or as otherwise known in the art. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0103] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

[0104] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine- 125 ( ¹²⁵ I) or carbon- 14 ( ¹⁴ C). Isotopic substitution with ² H, ^U C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ 0, ¹⁷ 0, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ C1, ³⁷ C1, ⁷⁹ Br, ⁸¹ Br, and ¹²⁵ I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0105] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0106] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0107] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein or otherwise known to provide for the synthesis of deuterium- containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0108] Compounds also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0109] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal,

intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0110] The phrase "pharmaceutically acceptable" is employed herein to refer to those

compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0111] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0112] As used herein, "attached" refers to a covalent bond, between two or more groups.

Alternatively, attached may refer to the connection of two or more groups via a linker, e.g., a linker connecting a second binding domain to an antibody construct. A fusion may refer to a nucleic acid sequence of two separate domains being expressed in frame. For example, a binding domain can be attached as a fusion or by attachment (e.g., conjugation) via a linker to an antibody construct or other portion of a conjugate. For example, an antibody can be fused with an additional binding domain to create an antibody construct containing a fusion of the antibody and the additional binding domain. The antibody construct can be the result of the nucleic acid sequence of the binding domain being expressed in frame with the nucleic acid sequence of the antibody construct. The fusion can be the result of an in- frame nucleotide sequence encoding the antibody construct with the binding domain. As another example, an additional binding domain can be attached to an antibody construct via a linker, wherein the linker is attached (i.e., conjugated) to the binding domain and the linker is attached to the antibody construct. The binding domain can be linked to the linker by a chemical conjugation and the antibody construct can be linked to the linker by a chemical conjugation. The additional binding domain can be a second binding domain and/or a third binding domain as described herein. Furthermore, a binding domain can be a first binding domain attached to an Fc domain to produce the antibody construct as described herein, which may produce the first binding domain as a fusion with the Fc domain or a conjugate wherein the first binding domain can be linked to a linker and the linker can be linked to the Fc domain.

Immune-Stimulatory Conjugates

[0113] Disclosed herein are conjugates of antibody constructs, immune- stimulatory compounds and linkers, referred to as antibody construct- immune- stimulatory compound conjugates (also referred to as immune- stimulatory compound-conjugates, antibody conjugates or conjugates). The conjugates may be used in the treatment of various diseases and disorders, including cancers. Also disclosed pharmaceutical compositions of the conjugates. In certain embodiments, immune- stimulatory compounds are attached either directly or through a linker to an antibody construct to form antibody construct-immune- stimulatory compound conjugates.

[0114] In some embodiments, the immune- stimulatory compound stimulates the immune system, or a component thereof. In some embodiments, the immune- stimulatory compound has an immune-modulatory activity. In some embodiments, the immune- stimulatory compound has an inhibitory effect on a component of the immune system, thereby stimulating an immune- modulatory activity.

[0115] In certain embodiments, conjugates are represented by the following formula:

wherein A is an antibody construct, L is a linker, D is an immune- stimulatory compound, x may be from 1 to 20 (wherein each x denotes a separate compound), n may be from 1 to 20, and z may be from 1 to 20. In some embodiments, L is a cleavable linker. In some embodiments, L is a non-cleavable linker.

[0116] In some embodiments, x is 1, n is 1 and z may be from 1 to 10, such as from 1 to 9, such as from 1 to 8, such as from 2 to 8, such as from 1 to 6, such as from 3 to 5 or such as about 2.

[0117] In some embodiments, x is 1, n is 2, and z may be from 1 to 10, such as from 1 to 9, such as from 1 to 8, such as from 2 to 8, such as from 1 to 6 or such as from 3 to 5. In certain embodiments, z is 4.

[0118] In some embodiments, x may be from 1-20, n may be from 1-20, and z may be from 1 to

20.

[0119] In certain embodiments, conjugates are represented by the following formula:

wherein A is an antibody construct, L is a linker having the structure -A _a -W _w -Y _y -, where A is a spacer, a is 0 or 1, W is a cleavable unit, w may be from 0 to 10, Y is a stretcher, y may be from 0 to 3, D is an immunomodulatory compound, x may be from 1 to 20 (wherein each x denotes a distinct compound), n may be from 1 to 20, and z may be from 1 to 20. [0120] In some embodiments, a is 1, w is 0, y is 0, x is 1, n is 1, and z may be from 1 to 20, 1 to 10, 1 to 9, 1 to 8, 2 to 8, 1 to 6 or 3 to 5. In certain embodiments, z is 4.

[0121] In some embodiments, a isl, w is 1, y is from 1, x is 1, n is 1 and z may be from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 1 to 6, 3 to 5, 2 or 4.

[0122] In some embodiments, a is 0 or 1, w is from 0 to 10, y is from 0-3, where at least one of a, w or y is present, x may be from 1 to 20, n may be from 1-20, and z may be from 1 to 20.

[0123] In some embodiments, the immune- stimulatory conjugates include a linker (L) that may comprise from 5 to 100 linear non-hydrogen atoms that is covalently attached to an antibody construct (A) and may be:

i) covalently attached to an immune- stimulatory compound (CO as in the following formula:

ii) covalently attached to an immune- stimulatory compound (CO which itself may be covalently attached to a spacer (S) comprising from 5 to 100 linear no n- hydrogen atoms covalently attached to a second immune- stimulatory compound (C ₂ ) as in the following formula:

iii) covalently attached an immune- stimulatory compound (C ₂ ) that may be covalently attached to a spacer (S) comprising from 5 to 100 linear non-hydrogen atoms covalently attached to a formula: , or

iv) covalently attached to a spacer (S) comprising from 5 to 100 linear non- hydrogen atoms that is covalently attached immune- stimulatory compounds (Ci and C ₂ ) as in the following formula:

[0124] In some embodiments, an immune- stimulatory conjugate is provided that includes a proteolysis targeting module (PTM; also referred to as a proteolysis-targetting chimera or PROTAC) that includes an immune-modulatory compound (IMC) that is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and wherein a linker (L) is covalently attached to the protein targeting molecule and to the antibody construct ^as

represented by the formula < A>-(L-PTM _n ) _z , where n is from 1-20 and z is from 1 to 20. In some embodiments, L is a cleavable linker. In some embodiments, S is a non-cleavable spacer.

[0125] Referring to the previous formula, in some embodiments, Ci is a target protein targeting moiety, such as an immodulatory compound, C2 is an E3 ubiquitin ligase binding moiety such that together C ₁ -S-C ₂ may form a PTM.

[0126] In some embodiments, an immune-modulatory compound or other protein targeting moiety (IMC) is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and a linker (L) is covalently attached to the spacer, n is from 1-20 and z is from 1 to 20 as represented by the for

[0127] In some embodiments, L is a cleavable linker. In some embodiments, L is a non- cleavable linker. In some embodiments, S is non-cleavable.

[0128] In some embodiments, an immune-modulatory compound or other protein targeting moiety (IMC) is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and a linker (L) is covalently attached to the IMC, n is from 1-20 and z is from 1 to 20 as represented by the formula:

[0129] In some embodiments, L is a cleavable linker. In some embodiments, L is a non- cleavable linker.

[0130] In some embodiments, an immune-modulatory compound or other protein targeting moiety (IMC) is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and linker L is covalently attached to the ubiquitin E3 ligase moiety (ULM), n is from 1-20 and z is from 1 to 20 as represented by the formula:

[0131] In some embodiments, L is a cleavable linker. In some embodiments, L is a non- cleavable linker. In some embodiments, S is non-cleavable.

Tumor and Immune Cell Antigens

[0132] In cancer, there are several general groups of tumor antigens, including but not limited to: (i) viral tumor antigens which can be identical for any viral tumor of this type, (ii) carcinogenic tumor antigens which can be specific for patients and for the tumors, (iii) isoantigens of the transplantation type or tumor- specific transplantation antigens which can be different in all individual types of tumor but can be the same in different tumors caused by the same inciting biological event; and (iv) embryonic antigens.

[0133] As a result of the discovery of tumor antigens, tumor antigens have become important in the development of new cancer treatments that can specifically target the cancer. This has led to the development of antibodies directed against these tumor antigens. Such tumor antigens include the following: CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, prostate- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6- AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES l, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page 4, VEGFR2, MAD- CT-1, PDGFR-B, MAD-CT-2, ROR2, TRAILl, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, and gpNMB.

[0134] In addition to the development of antibodies against tumor antigens for cancer treatment, antibodies that target immune cells to boost the immune response have also been developed, including the following: an anti-CD40 antibody, an anti-CD47 antibody, anti-TNFR2 antibody, an anti-DEC205 antibody, an anti-CD36 mannose scavenger receptor 1 antibody, an anti- CLEC9A antibody, an anti-CLEC12A antibody, an anti-DC-SIGN antibody, an anti-BDCA-2 antibody, an anti-OX40L antibody, an anti-41BBL antibody, an anti-CD204 antibody, an anti- MARCO antibody, an anti-CLEC5A antibody, an anti-Dectin 1 antibody, and anti-Dectin 2 antibody, an anti-CLEClOA antibody, an anti-CD206 antibody, an anti-CD64 antibody, an anti- CD32A antibody, an anti-CD 16A antibody, an anti-HVEM antibody, an anti-CD38 antibody, an anti-PD-Ll antibody, an anti-TREM2 antibody, an anti-CSFIR antibody, or an anti-CD32B antibody can be used to target, respectively, cell surface CD40, CD47, TNFR2, DEC-205, CD36 mannose scavenger receptor 1, CLEC9A, CLEC12A, DC-SIGN, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, CD38, PD-L1, TREM2, CSF1R, or CD32B molecules expressed by antigen presenting cells.

[0135] Cluster of Differentiation 40 (CD40) is a member of the Tumor Necrosis Factor Receptor (TNF-R) family. CD40 can be a 50 kDa cell surface glycoprotein that can be constitutively expressed in normal cells, such as monocytes, macrophages, B lymphocytes, dendritic cells, endothelial cells, smooth muscle cells, fibroblasts and epithelium, and in tumor cells, including B-cell lymphomas and many types of solid tumors. Expression of CD40 can be increased in antigen presenting cells in response to IL-Ιβρ, IFN-γ, GM-CSF, and LPS induced signaling events.

[0136] Examples of agonistic CD40 monoclonal antibodies include CP-870,893, dacetuzumab, Chi Lob 7/4, SEA-CD40, ADC- 1013, 3C3, or 3G5.

[0137] Cluster of Differentiation 205 (CD205 or DEC-205) is a member of the C-type multilectin family of endocytic receptors, which can include the macrophage mannose receptor (MMR) and the phospholipase A2 receptor (PLA ₂ R). DEC-205 can be a 205 kDa endocytic receptor highly expressed in cortical thymic epithelial cells, thymic medullary dendritic cells (CDl lc ⁺ CD8 ⁺ ), subpopulations of peripheral dendritic cells (CDl lc ⁺ CD8 ⁺ ). The DEC-205 ⁺ CDl lc ⁺ CD8 ⁺ dendritic cells (DCs) can function in cross-presentation of antigens derived from apoptotic cells. Additionally, DEC-205 can be significantly upregulated during DC maturation. DEC-205 can also be expressed at moderate levels in B cells and low levels in macrophages and T cells.

[0138] After antigen binding to DEC-205, the receptor- antigen complex can be internalized whereupon the antigen can be processed and be presented on the DC surface by a major histocompatibility complex class II (MHC II) or MHC class I. DEC-205 can deliver antigen to DCs for antigen presentation on MHC class II and cross-presentation on MHC class I. DEC-205 mediated antigen delivery for antigen presentation in DCs without an inflammatory stimulus can result in tolerance. Conversely, DEC-205 mediated antigen delivery in DCs in the presence of a maturational stimulus (e.g., a CD40 agonist) can result in long-term immunity via activation of antigen- specific CD4 ⁺ and CD8 ⁺ T cells.

[0139] CD36 mannose scavenger receptor 1 is an oxidized LDL receptor with two

transmembrane domains located in the caveolae of the plasma membrane. It can be classified as a Class B scavenger receptor, which can be characterized by involvement in the removal of foreign substances and waste materials. This receptor can also be involved in cell adhesion, phagocytosis of apoptotic cells, and metabolism of long-chain fatty acids.

[0140] TNFR2 (tumor necrosis factor receptor 2), also known as TNFRSF1B (tumor necrosis factor receptor super family IB) and CD 120b, is a single-pass type I membrane protein and the member of TNFR superfamily containing 4 cysteine-rich domains (CRD) repeats. In addition to the full length membrane- anchored form, soluble TNFR2 can be generated via two distinct mechanisms: (1) shedding via proteolytic processing of the full membrane anchored from, and (2) translation from an alternatively spliced message encoding the extracellular domains of TNFR2. TNFR2 is the receptor with high affinity for TNF-alpha and approximately 5-fold lower affinity for homotrimeric lymphotoxin-alpha. TNFR2 (Tumor Necrosis Factor Receptor Type II) and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti- apoptotic proteins, c-IAPl and C-IAP2, which possess E3 ubiquitin ligase activity. c-IAPl can potentiate TNF- induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti- apoptotic signals. Knockout studies in mice suggest a role of TNFR2 in protecting neurons from apoptosis by stimulating antioxidative pathways.

[0141] CLEC9A is a group V C-type lectin receptor. This receptor can be expressed as on myeloid lineage cells, and can be characterized as an activation receptor.

[0142] CLEC12A is a member of the C-type lectin/C-type lectin like domain super family that can be a negative regulator of granulocyte and monocyte function. It can also be involved in cell adhesion, cell-cell signaling, and glycoprotein turnover, and can play a role in the inflammatory response. [0143] Dendritic cell-specific inter cellular adhesion molecule-3-grabbing non-integrin (DC- SIGN) or CD209, is a C-type lectin receptor that can be expressed on the surface of macrophages and dendritic cells. This receptor can recognize and bind to mannose type carbohydrates and be involved in activating phagocytosis, can mediate dendritic cell rolling, and can be involved in CD4+ T cell activation.

[0144] BDCA-2 is a C-type lectin that is a membrane protein of plasmacytoid dendritic cells. It can be involved in plasmacytoid dendritic cell function, such as ligand internalization and presentation.

[0145] OX40L, which is also referred to as CD252, is the ligand for CD 134 that can be expressed on dendritic cells. It can be involved in T cell activation.

[0146] 41BBL, which is also referred to as CD137L, is a member of the TNF superfamily, and can be expressed on B cells, dendritic cells, activated T cells, and macrophages. It can provide co-stimulatory signal for T cell activation and expansion.

[0147] CD204, which is also referred to as macrophage scavenger receptor 1, is a macrophage scavenger receptor receptor. The gene for CD204 can encode three different class A macrophage scavenger receptor isoforms. The type 1 and type 2 isoforms can be involved in binding, internalizing, and processing negatively charged macromolecules, such as low density lipoproteins. The type 3 isoform can undergo altered intracellular processing in which it can be retained within the endoplasmic reticulum, and has been shown to have a dominant negative effect on the type 1 and type 2 isoforms.

[0148] Macrophage receptor with collagenous structure (MARCO), which is also referred to as SCARA2, is a class A scavenger receptor with collagen-like and cysteine-rich domains. It can be expressed in macrophages, and can bind to modified low density lipoproteins. It can be involved in the removal of foreign substances and waste materials.

[0149] C-type lectin domain family 5 member A (CLEC5A) is a C-type lectin. It can be involved in the myeloid lineage activating pathway.

[0150] Dendritic cell-associated c-type lectin- 1 (Dectin 1), which is also referred to as CLEC7A, is member of the C-type lectin/C-type lectin- like super family. It can be expressed by myeloid dendritic cells, monocytes, macrophages, and B cells, and can be involved in antifungal immunity.

[0151] Dendritic cell-associated c-type lectin-2 (Dectin 2), which is also referred to as CLEC6A, is member of the C-type lectin/C-type lectin- like super family. It can be expressed by dendritic cells, macrophages, monocytes and neutrophils. It can be involved in antifungal immunity. [0152] CLECIOA, which is also referred to as CD301, is member of the C-type lectin/C-type lectin-like super family. It can be expressed by dendritic cells, monocytes, and CD33+ myeloid cells, and can be involved in macrophage adhesion and migration.

[0153] CD206, which is also referred to as macrophage mannose receptor, is a C-type lectin type I membrane glycoprotein. It can be expressed on dendritic cells, macrophages and endothelial cells, and can act as a pattern recognition receptor and bind high-mannose structures of viruses, bacteria, and fungi.

[0154] CD64, which is also referred to as FcyRI, is a high affinity Fc receptor for IgG. It can be expressed by monocytes and macrophages. It can be involved in mediating phagocytosis, antigen capture, and antibody dependent cell-mediated cytoxicity.

[0155] CD32A, which is also referred to as FcyRIIa, is a low affinity Fc receptor. It can be expressed on monocytes, granulocytes, B cells, and eosinophils. It can be involved in

phagocytosis, antigen capture, and antibody dependent cell-mediated cytoxicity.

[0156] CD 16 A, which is also referred to as FcyRIIIa, is low affinity Fc receptor. It can be expressed on NK cells, and can be involved in phagocytosis and antibody dependent cell- mediated cytotoxicity.

[0157] Herpesvirus entry mediator (HVEM), which is also referred to as CD270, is a member of the TNF-receptor superfamily. It can be expressed on B cells, dendritic cells, T cells, NK cells, CD33+ myeloid cells, and monocytes. It can be involved in activating the immune response.

[0158] CD32B, which is also referred to as FcyRIIb, is a low affinity Fc receptor. It can be expressed on B cells and myeloid dendritic cells. It can be involved in inhibiting maturation and cell activation of dendritic cells.

[0159] The HER2/neu (human epidermal growth factor receptor 2/receptor tyro sine-protein kinase erbB-2) is part of the human epidermal growth factor family. Overexpression of this protein can be shown to play an important role in the progression of cancer, for example, breast cancer. The HER2/neu protein can function as a receptor tyrosine kinase and autophosphorylates upon dimerization with binding partners. HER2/neu can activate several signaling pathways including, for example, mitogen-activated protein kinase, phosphoinositide 3-kinase,

phospholipase Cy, protein kinase C, and signal transducer and activator of transcription (STAT). Examples of antibodies that can target and inhibit HER2/neu can include trastuzumab and pertuzumab.

[0160] EGFR (epidermal growth factor receptor) encodes a member of the human epidermal growth factor family. Mutations that can lead to EGFR overexpression or over activity can be associated with a number of cancers, including squamous cell carcinoma and glioblastomas. EGFR can function as a receptor tyrosine kinase and ligand binding can trigger dimerization with binding partners and autophosphorylation. The phosphorylated EGFR can then activate several downstream signaling pathways including mitogen-activated protein kinase, phosphoinositide 3- kinase, phospholipase Cy, protein kinase C, and signal transducer and activator of transcription (STAT). Examples of antibodies that can target and inhibit EGFR can include cetuximab, panutumumab, nimotuzumab, and zalutumumab. One mutant variant of EGFR is EGFRvIII (epidermal growth factor receptor variant III, also referred to as de2-7EGFR). EGFRvIII is the result of an EGFR gene rearrangement in which exons 2-7 of the extracellular domain are deleted. This mutation can result in a mutant receptor incapable of binding to any known ligand. The resulting receptor can engage in a constitutive low-level signaling and can be implicated in tumor progression. Examples of antibodies that can target EGFRvIII can include AMG595 and ABT806.

[0161] C-Met (hepatocyte growth factor receptor) encodes a member of the receptor tyrosine kinase family of proteins. C-Met overexpression and over activity can be implicated in various cancers including lung adenocarcinomas, and high c-Met levels can be associated with poor patient outcome. Binding of hepatocyte growth factor can induce dimerization and

autophosphorylation of c-Met. The c-Met receptor can activate various downstream signaling pathways including mitogen-activated protein kinase, phosphoinositide 3-kinase, and protein kinase C pathways. The antibody onartuzumab can target and inhibit c-Met.

[0162] HER3 (human epidermal growth factor receptor 3) encodes a member of the human epidermal growth factor receptor family. Ligand binding can induce dimerization and autophosphorylation of cytoplasmic tyrosine residues that then can recruit signaling proteins for downstream signaling pathway activation including mitogen-activated protein kinase and phosphoinoside 3-kinase pathways. HER3 can play an active role in cell proliferation and survival, and can be overexpressed, overactive, and/or mutated in various cancers. For example, HER3 can be overexpressed in breast, ovarian, prostate, colon, pancreas, stomach, oral, and lung cancers. The antibody patritumab can target and inhibit HER3.

[0163] MUC1 (mucin 1, cell surface associated) encodes a member of the mucin family of glycosylated proteins that can play an important role in cell adhesion and forming protective mucosal layers on epithelial surfaces. MUC1 can be proteolytically cleaved into alpha and beta subunits that form a heterodimeric complex with the N-terminal alpha subunit providing cell- adhesion functionality and the C-terminal beta subunit modulating cell signaling pathways including the mitogen activated map kinase pathway. MUC1 can play a role in cancer progression, for example, by regulating TP53-mediated transcription. MUC1 overexpression, aberrant intracellular localization, and glycosylation changes can all be associated with carcinomas including pancreatic cancer cells. The antibody clivatuzumab can target MUC1. [0164] MUC16 (mucin 16, cell surface associated) encodes the largest member of the mucin family of glycosylated proteins that can play an important role in cell adhesion and forming protective mucosal layers on epithelial surfaces. MUC16 can be a highly glycosylated 2.5MDa transmembrane protein that can provide a hydrophilic lubricating barrier on epithelial cells. The cytoplasmic tail of MUC16 can be involved with various signaling pathways including the JAK2-STAT3 and Src kinase pathways. A peptide epitope of MUC16 can be used as biomarker for detecting ovarian cancer. Elevated expression of MUC16 can be present in advanced ovarian cancers and pancreatic cancers. The antibody sofituzumab can target MUC16.

[0165] EPCAM (epithelial cell adhesion molecule) encodes a transmembrane glycoprotein that can be frequently and highly expressed in carcinomas and tumor- initiating cells. EPCAM can also be a pluripotent stem cell marker. EPCAM can modulate a variety of pathways including cell-cell adhesion, cellular proliferation, migration, invasion, maintenance of a pluripotent state, and differentiation in the context of tumor cells. The antibodies edrecolomab and adecatumumab can target EPCAM.

[0166] MSLN (mesothelin) encodes a 40 kDa cell GPI-anchored membrane surface protein believed to function in cell adhesion. MSLN is overexpressed in mesothelioma and certain types of pancreatic, lung, and ovarian cancers. MSLN-related peptides that circulate in serum of patients suffering from pleural mesothelioma are used as biomarkers for monitoring the disease. MSLN may promote metastasis by inducing matrix metalloproteinase 7 and 9 expression. The monoclonal antibody anetumab has been developed to target MSLN.

[0167] CA6 (carbonic anhydrase VI) encodes one of several isozymes of carbonic anhydrase. CA6 is found in salivary glands and may play a role in the reversible hydration of carbon dioxide. CA6 is expressed in human serous ovarian adenocarcinomas. The monoclonal antibody huDS6 has been developed to target CA6.

[0168] NAPI2B (sodium/phosphate cotransporter 2B) encodes a type II sodium-phosphate cotransporter. NAPI2B is highly expressed on the tumor surface in lung, ovarian, and thyroid cancers as well as in normal lung pneumocytes. The monoclonal antibody lifastuzumab has been developed to target NAPI2B.

[0169] TROP2 (trophoblast antigen 2) encodes a transmembrane glycoprotein that acts as an intracellular calcium signal transducer. TROP2 binds to multiple factors such as IGF-1, claudin- 1, claudin-7, cyclin Dl, and PKC. TROP2 including intracellular calcium signaling and the mitogen activated protein kinase pathway. TROP 2 plays a role in cell self-renewal, proliferation, invasion, and survival. Discovered first in trophoblast cells that have the ability to invade uterine decidua during placental implantation, TROP2 overexpression has been shown to be capable of stimulating cancer growth. TROP2 overexpression has been observed in breast, cervix, colorectal, esophagus, lung, non-Hodgkin' s lymphoma, chronic lymphocytic lymphoma, Raji Burkitt lymphoma, oral squamous cell, ovarian, pancreatic, prostate, stomach, thyroid, urinary bladder, and uterine carcinomas. The monoclonal antibody sacituzumab has been developed to target TROP2.

[0170] CEA (carcinoembryonic antigen; also referred to as CEACAM5) is a member of a family of related glycoproteins involved in cell adhesion. CEA is a biomarker for gastrointestinal cancers and may promote tumor development by means of its cell adhesion function. CEA levels have been found to be elevated in serum of individuals with colorectal carcinoma. CEA levels have also been found to be elevated in gastric carcinoma, pancreatic carcinoma, lung carcinoma, breast carcinoma, and medullary thyroid carcinoma. The monoclonal antibodies PR1A3 and Ab2-3 have been developed to target CEA.

[0171] CLDN18.2 (claudin 18) encodes a member of the claudin family of integral membrane proteins. CLDN18.2 is a component of tight junctions that create a physical barrier to prevent diffusion of solutes and water through the paracellular space between epithelial cells. CLDN18.2 is overexpressed in infiltrating ductal adenocarcinomas, but is reduced in some gastric carcinomas. The monoclonal antibody claudiximab has been developed to target CLDN18.2.

[0172] FAP (fibroblast activation protein, alpha) encodes a homodimeric integral membrane protein from a family of serine proteases. FAP is believed to play a role in many processes including tissue remodeling, fibrosis, wound healing, inflammation, and tumor growth. FAP enhances tumor growth and invasion by promoting angiogenesis, collagen fiber degradation and apoptosis, and by downregulating the immune response. FAP is selectively expressed on fibroblasts within the tumor stroma. The monoclonal antibody sibrotuzumab has been developed to target FAP.

[0173] EphA2 (EPH Receptor A2) encodes a member of the ephrin receptor subfamily of the protein- tyro sine kinase family. EphA2 binds to ephrin-A ligands. Activation of EphA2 receptor upon ligand binding can result in modulation of migration, integrin- mediated adhesion, proliferation, and differentiation. EphA2 is overexpressed in various cancers including breast, prostate, urinary bladder, skin, lung, ovarian, and brain cancers. High EphA2 expression is also correlated with poor prognosis. The monoclonal antibodies DS-8895a optl, DS-8895 opt2, and the 1C1 antibody in MEDI-547 have been developed to target EphA2.

[0174] RON (macrophage stimulating 1 receptor) encodes a cell surface receptor for macrophage stimulating protein (MSP) with tyrosine kinase activity and belongs to the MET proto-oncogene family. RON has significant structural similarity and sequence identity with the cancer-related gene C-MET. RON plays a significant role in KRAS oncogene addiction and has also been shown to be overexpressed in pancreatic cancers. Altered Ron expression and activation has been associated with decreased survival and cancer progression in various cancers including gastric, colon, breast, bladder, renal cell, ovarian, and hepatocellular cancers. The monoclonal antibody narnatumab has been developed to target RON.

[0175] LY6E (lymphocyte antigen 6 complex, locus E) encodes an interferon alpha-inducible GPI-anchored cell membrane protein. LY6E is overexpressed in numerous cancers including lung, gastric, ovarian, breast, kidney, pancreatic, and head and neck carcinomas. The monoclonal antibody in RG7841 has been developed to target LY6E.

[0176] FRA (folate receptor alpha) encodes a GPI-anchored cell surface glycoprotein. FRA binds folic acid, a molecule needed for cell growth and DNA synthesis, and mediates its internalization via receptor-mediated endocytosis. FRA is overexpressed in various cancers including prostate, breast, ovarian, pancreatic, mesothelioma, non-small cell lung carcinoma, and head and neck cancer. FRA expression has also been found to enhance tumor cell proliferation. The monoclonal antibodies farletuzumab and mirvetuximab have been developed to target FRA.

[0177] PSMA (prostate specific membrane antigen) is a type II transmembrane glycoprotein belonging to the M28 peptidase family that is expressed in all types of prostate tissues. PSMA is upregulated in cancer cells within the prostate and is used as a marker for prostate cancer. PSMA expression may also serve as a predictor of disease recurrence in prostate cancer patients. The monoclonal antibodies J591 variant 1 and J591 variant 2 have been developed to target PSMA.

[0178] DLL3 (delta-like 3) encodes a ligand in the Notch signaling pathway that is associated with neuroendocrine cancer. DLL3 is most highly expressed in the fetal brain and is involved in somitogenesis in the paraxial mesoderm. DLL3 is expressed on tumor cell surfaces but not in normal tissues. The monoclonal antibody rovalpituzumab has been developed to target DLL3.

[0179] PTK7 (tyrosine protein kinase-like 7) encodes a receptor tyrosine kinase that lacks catalytic tyrosine kinase activity but is nevertheless capable of signal transduction. PTK7 interacts with the WNT signaling pathway, which itself has important roles in epithelial mesenchymal transition and various cancers such as breast cancer. PTK7 overexpression has been associated with patient prognosis depending on the cancer type. The monoclonal antibodies in PF-06647020 and the anti-PTK7 antibody described by SEQ ID NOs: 440 and 445 have been developed to target PTK7.

[0180] LIVl (LIV-1 protein, estrogen regulated) encodes a member of the LIV-1 subfamily of ZIP (Zrt-, Irt-like proteins) zinc transporters. LIVl is an estrogen regulated protein that transports zinc and/or other ions across the cell membrane. Elevated levels of LIVl have been shown in estrogen receptor positive breast cancers, and LIVl is used as a marker of ER-positive cancers. LIVl has also been implicated as a downstream target of the STAT3 transcription factor and as playing an essential role in the nuclear localization of the Snail transcription factor that modulates epithelial-to-mesenchymal transition. The monoclonal antibody in SGN-LIV1A has been developed to target LIV1.

[0181] RORl (receptor tyrosine kinase-like orphan receptor 1) encodes a member of the ROR family of orphan receptors. RORl has been found to bind Wnt5a, a non-canonical Wnt via a Frizzled domain (FZD), and plays an important role in skeletal, cardiorespiratory, and

neurological development. RORl expression is predominantly restricted to embryonic

development and is absent in most mature tissues. In contrast, RORl expression is upregulated in B-Cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, and myeloid malignancies. The monoclonal antibody cirmtuzumab has been developed to target RORl.

[0182] MAGE-A3 (melanoma-associated antigen 3) encodes a member of the melanoma- associated antigen gene family. The function of MAGE-A3 is not known, but its elevated expression has been observed in various cancers including melanoma, non-small cell lung cancer, and in putative cancer stem cell populations in bladder cancer. The monoclonal antibody described by SEQ ID NOs: 479 and 484 has been developed to target MAGE- A3.

[0183] NY-ESO-1 (New York esophageal squamous cell carcinoma 1) encodes a member of the cancer-testis family of proteins. Cancer-testis antigen expression is normally restricted to testicular germ cells in adult tissues, but has been found to be aberrantly expressed in various tumors including soft tissue sarcomas, melanoma, epithelial cancers, and myxoid and round cell liposarcomas. The monoclonal antibody described by SEQ ID Nos: 492 and 497 has been developed to target NY-ESO-1.

Binding Domain

[0184] The binding domain of an antibody construct is selected to recognize an antigen or molecule. For example, an antigen can be a cell surface marker on target cells associated with a disease or condition. An antigen can be a peptide or fragment thereof. An antigen can be expressed on an immune cell. An antigen can be expressed on an antigen-presenting cell. An antigen can be expressed on a dendritic cell, a macrophage, or a B cell. An antigen on an antigen presenting cell can be a cell lineage marker or a cell surface protein expressed preferentially on antigen presenting cells or a subset of antigen presenting cells. An antigen can be a peptide presented in a major histocompatibility complex by cell. As another example, a cell surface marker recognized by the antigen binding domain can include macromolecules associated with viral and bacterial diseases or infections, autoimmune diseases and cancerous diseases. An antigen can be a tumor antigen or fragment thereof. A tumor antigen can be any antigen listed on tumor antigen databases, such as TANTIGEN, or peptide databases for T cell-defined tumor antigens, such as the Cancer Immunity Peptide database. A tumor antigen can also be any antigen listed in the review by Chen (Chen, Cancer Immun 2004 [updated 2004 Mar 10; cited 2004 Apr 1]). An antigen can be or can be at least 80% homologous CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page 4, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, , TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6

(CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, or gpNMB.

[0185] In some embodiments, an antigen binding domain recognizes a single antigen. In some embodiments, an antigen binding domain recognizes two or more different antigens.

[0186] An antibody construct can include one or more binding domains. For example, an antibody construct can comprise a first binding domain. An antibody construct can also comprise a second binding domain. A binding domain can specifically bind to an antigen on a cell surface. A binding domain can specifically bind to an antigen on a cell surface, for example, of a tumor or cancer cell, an immune cell, or of an antigen presenting cell, such as a dendritic cell or macrophage. A binding domain can be a cell surface receptor agonist. A binding domain can be an antigen binding domain. An antigen binding domain can be a cell surface receptor agonist. An antigen binding domain can be a domain that can specifically bind to an antigen. An antigen binding domain can specifically bind to a tumor antigen. An antigen binding domain can be an antigen-binding portion of an antibody or an antigen binding fragment thereof. A binding domain can recognize a single antigen.

[0187] An antibody construct can include, for example, one, two, three, four, five, six, seven, eight, nine, ten, or more antigen binding domains. An antibody construct, such as an antibody, can include two antigen binding domains in which each antigen binding domain can recognize the same antigen. An antibody construct, such as a bi- specific antibody, can include two antigen binding domains in which each antigen binding domain can recognize different antigens. An antibody construct can include three antigen binding domains in which each antigen binding domain can recognize different antigens. An antibody construct can include three antigen binding domains in which two of the antigen binding domains can recognize the same antigen. An antigen binding domain can be in a scaffold, in which a scaffold is a supporting framework for the antigen binding domain. An antigen binding domain can be in a non-antibody scaffold. An antigen binding domain can be in an antibody scaffold. An antibody construct can comprise an antigen binding domain in a scaffold. The antibody construct can further comprise an Fc fusion protein product. In some embodiments, the antibody construct is an Fc fusion protein.

[0188] In some embodiments, an antibody construct can comprise an antigen binding domain that can specifically bind to a tumor antigen. A tumor antigen, also referred to as a tumor associated antigen, is an antigen that can be expressed by a cancer cell, a neoplastic tumor cell and/or within a tumor microenvironment. It is preferably not expressed or expressed at low levels on normal (non-cancerous) cells. For example, a tumor antigen can be an antigen expressed on a cell associated within a tumor, such as a neoplastic cell, or a tumor associated cell such as a stromal cell, endothelial cell, fibroblast, or tumor- infiltrating immune cell. For example, the tumor antigen Her2/Neu can be overexpressed by certain types of breast and ovarian cancer. A tumor antigen can also be ectopically expressed by a tumor and contribute to deregulation of the cell cycle, reduced apoptosis, metastasis, or escape from immune surveillance. Tumor antigens can generally be proteins or polypeptides derived therefrom, but also can be glycans, lipids, or other small organic molecules. Additionally, a tumor antigen can arise through increases or decreases in post-translational processing exhibited by a cancer cell compared to a normal cell, for example, protein glycosylation, protein lipidation, protein phosphorylation, or protein acetylation.

[0189] In certain embodiments, a binding domain specifically can bind to a tumor associated antigen, such as CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH- 1 antigen, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, prostate- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6- AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT- 1, PDGFR-B, MAD-CT-2, ROR2, TRAILl, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, or gpNMB.

[0190] In some embodiments, a binding domain specifically can bind to a tumor associated antigen having at least 80%, 90%, 95%, 97%, 98%, 99% or 100% sequence identity to CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH- 1 antigen, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUCl, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen

(PSMA), ferritin, CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor,

EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WTl, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, MYCN, RhoC, TRP-2, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, CYP1B 1, PLAV1, BORIS, GloboH, ETV6- AML, NY-BR-1, RGS5, SART3, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, TRAILl, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, or gpNMB.

[0191] In certain embodiments, a binding domain specifically binds to an antigen selected from the group consisting of comprising Her2/Neu (CD340), EGFR, CMET, HER3, MUCl, MUCl 6,

EPCAM, MSLN, CA6, NAPI2B, TROP2, CEA, CLDN18.2, EGFRvIII, FAP, EphA2, RON,

LY6E, FRA, PSMA, DLL3, PTK7, LIV1, ROR1, MAGE- A3, and NY-ESO-1.

[0192] A binding domain of an antibody construct can be selected from any domain that specifically binds to an antigen, including but not limited to, from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, or a functional fragment thereof, for example, a heavy chain variable domain (V _H ) and a light chain variable domain (V _L ), or from a non-antibody such as a DARPin, an affimer, an avimer, a knottin, a monobody, an affinity clamp, an ectodomain, a receptor ectodomain, a receptor, a cytokine, a ligand, an immunocytokine, a T-cell receptor, a VNAR, an anticalin, or a recombinant T-cell receptor. In some embodiments, a binding domain of an antibody construct is from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, or a functional fragment thereof, for example, a heavy chain variable domain (V _H ) and a light chain variable domain (V _L ).

[0193] The antigen binding domain of an antibody construct can be at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% homologous to an antigen binding domain selected from, but not limited to, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, or a functional fragment thereof, for example, a heavy chain variable domain (V _H ) and a light chain variable domain (V _L ), or from a non-antibody, such as a DARPin, an affimer, an avimer, a knottin, a monobody, an affinity clamp, an ectodomain, a receptor ectodomain, a receptor, a cytokine, a ligand, an immunocytokine, a T-cell receptor, a VNAR, an anticalin, or a

recombinant T-cell receptor.

[0194] A binding domain, for example an antigen binding domain from a monoclonal antibody, can comprise a light chain and a heavy chain. In one aspect, the monoclonal antibody binds to an antigen present on the surface of an antigen presenting cell (APC antigen) and comprises the light chain of an anti-APC antigen antibody and the heavy chain of an anti-APC antigen antibody, which bind an APC antigen. In another aspect, the monoclonal antibody binds to a tumor antigen comprises the light chain of a tumor antigen (anti-tumor) antibody and the heavy chain of a tumor antigen (anti-tumor) antibody, which bind to the tumor antigen.

[0195] An antibody construct can be an antibody. An antibody molecule can include of two identical light protein chains (light chains) and two identical heavy protein chains (heavy chains), all held together covalently by interchain disulfide linkages. Structurally, various functions of an antibody can be confined to discrete protein regions or domains. The sites that can recognize and can bind to antigen consist of three complementarity determining regions (CDRs; also referred to as hyper- variable regions) that lie within the variable heavy chain regions and within the variable light chain regions at the N-terminal ends of the two heavy and two light chains. The constant domains can provide the general framework of the antibody and may not be involved directly in binding the antibody to an antigen, but can be involved in various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC).

[0196] The variable domains of natural light and heavy chains can have the same general structures, and each domain can comprise four framework regions, whose sequences can be somewhat conserved, connected by three CDRs. The four framework regions can largely adopt a β-sheet conformation and the CDRs can form loops connecting, and in some aspects forming part of, the β -sheet structure. The CDRs in each chain can be held in close proximity by the framework regions and, with the CDRs from the other chain, can contribute to the formation of the antigen binding site.

[0197] An antibody can include an antibody of any type, which can be assigned to different classes of immunoglobins, e.g., IgA, IgD, IgE, IgG, and IgM. Several different classes can be further divided into isotypes, e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. Exemplary heavy chain sequences of reference antibodies can be used to identify residue variants and mutants.

[0198] An exemplary heavy chain sequence for human IgGl heavy chain is that of the human IgGl antibody, and can comprise:

ASTKGPS VFPLAPS S KSTS GGT AALGCLVKD YFPEPVT VS WNS G ALTS GVHTFP AVLQS S

GLYS LS S V VT VPS S S LGTQT YICN VNHKPS NTKVD KKVEPKS CD KTHTCPPCP APELLGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QY

NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SR

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 898).

[0199] An exemplary heavy chain reference sequence for human IgG2 heavy chain can comprise:

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYS LS S V VT VPS S NFGTQT YTCN VDHKPS NTKVD KT VERKCC VECPPCP APP V AGPS VF

LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TF

RVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREE MT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR WQ

QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 899).

[0200] An exemplary heavy chain reference sequence for human IgG4 heavy chain can comprise:

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYS LS S V VT VPS S S LGTKT YTCN VDHKPS NTKVD KRVES KYGPPCPS CP APEFLGGPS V FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 900).

[0201] The heavy-chain constant regions (Fc) that corresponds to the different classes of immunoglobulins can be α, δ, ε, γ, and μ. The light chains can be one of either kappa or κ and lambda or λ, based on the amino acid sequences of the constant domains. The Fc region can contain an Fc domain. An Fc receptor can bind an Fc domain. An Fc domain can comprise amino acid residues 216 to 447 of an IgGl, which are part of SEQ ID NO: 898. An Fc domain can comprise amino acid residues 216 to 442 of an IgG2, which are part of SEQ ID NO: 899. An Fc domain can comprise amino acid residues 216 to 444 of an IgG4, which are part of SEQ ID NO: 900. Antibody constructs can also include any fragment or recombinant forms thereof (e.g., scFVs and domain antibodies). Antibody constructs can also include any fragment or

recombinant forms thereof (e.g., scFVs and domain antibodies) of non-antibody scaffolds, including but not limited to anti-calins, affibodies, affilins, atrimers, avimers, bicyclic peptides, centyrins, Cys-knots, Darpins, fibronections, Kunitz domains, O-bodies, or peptibodies.

[0202] An antibody construct can comprise an antigen binding domain of an antibody. An antigen binding domain of an antibody can comprise one or more light chain CDRs (LCDRs) and one or more heavy chain CDRs (HCDRs), or one or more LCDRs or one or more HCDRs. For example, an antibody binding domain of an antibody construct can comprise one or more of the following: a light chain complementary determining region 1 (LCDR1), a light chain

complementary determining region 2 (LCDR2), or a light chain complementary determining region 3 (LCDR3). For another example, an antibody binding domain can comprise one or more of the following: a heavy chain complementary determining region 1 (HCDR1), a heavy chain complementary determining region 2 (HCDR2), or a heavy chain complementary determining region 3 (HCDR3). In some embodiments, an antigen binding domain comprises LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3. Unless stated otherwise, the CDRs described herein can be defined according to the IMGT (the international ImMunoGeneTics information system).

[0203] An antigen binding domain can comprise only the heavy chain of an antibody. An antigen binding domain can comprise only the variable domain of the heavy chain of an antibody.

Alternatively, an antigen binding domain can comprise only the light chain of an antibody. An antigen binding domain can comprise only the variable light chain of an antibody.

[0204] An antibody construct can comprise an antibody fragment. An antibody fragment can include (i) a Fab fragment, a monovalent fragment consisting of the V _L , V _H, C _L and C _HI domains; (ii) a F(ab') ₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; and (iii) a Fv fragment consisting of the V _L and V _H domains of a single arm of an antibody. Although the two domains of the Fv fragment, V _L and V _H , can be coded for by separate genes, they can be linked by a synthetic linker to be made as a single protein chain in which the V _L and V _H regions pair to form monovalent molecules. F(ab') ₂ and Fab' moieties can be produced recombinantly. [0205] An Fv can be the minimum antibody fragment which contains a complete antigen- recognition and antigen-binding site. This region can consist of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. In this configuration the three hypervariable regions of each variable domain can interact to define an antigen-binding site on the surface of the V _H -V _L dimer. A single variable domain (or half of an Fv comprising only CDRs specific for an antigen) can recognize and bind antigen, although at a lower affinity than the entire binding site.

[0206] An antibody used herein can be chimeric or "humanized." Chimeric and humanized forms of non-human (e.g., murine) antibodies can be chimeric immunoglobulins,

immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') ₂ or other target- binding subdomains of antibodies), which can contain minimal sequences derived from non- human immunoglobulin. In general, the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the frame work regions (FR) are those of a human immunoglobulin sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence.

[0207] An antibody described herein can be a human antibody. As used herein, "human antibodies" can include antibodies having, for example, the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulins that do not express endogenous immunoglobulins. Human antibodies can be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. Completely human antibodies that recognize a selected epitope can be generated using guided selection. In this approach, a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope

[0208] An antibody described herein can be a bispecific antibody or a dual variable domain antibody (DVD). Bispecific and DVD antibodies are monoclonal, often human or humanized, antibodies that have binding specificities for at least two different antigens.

[0209] An antibody described herein can be a derivatized antibody. For example, derivatized antibodies can be modified by glycosylation, deglycosylation, defucosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or linkage to a cellular ligand or other protein. [0210] An antibody described herein can have a sequence that has been modified to alter at least one constant region-mediated biological effector function relative to the corresponding wild type sequence. For example, in some embodiments, the antibody can be modified to reduce at least one constant region-mediated biological effector function relative to an unmodified antibody, e.g., reduced binding or increased binding to the Fc receptor (FcR). FcR binding can be reduced or increased by, for example, mutating the immunoglobulin constant region segment of the antibody at particular regions necessary for FcR interactions.

[0211] An antibody described herein can be modified to acquire or improve at least one constant region-mediated biological effector function relative to an unmodified antibody, e.g., to enhance FcyR interactions. For example, an antibody with a constant region that binds FcyRIIA, FcyRIIB and/or FcyRIIIA with greater affinity than the corresponding wild type constant region can be produced according to the methods described herein.

[0212] An antibody described herein can bind to tumor cells, such as an antibody against a cell surface receptor or a tumor antigen.

[0213] An antibody construct can comprise a first binding domain. An antibody construct can comprise a first binding domain that specifically binds an antigen. An antibody construct can comprise a first binding domain that specifically binds a tumor antigen. A first binding domain can specifically bind a tumor antigen, wherein the tumor antigen is selected from the group consisting CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-Ll, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYPIB I, PLAVl, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK,

HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1,

PDGFR-B, MAD-CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof. An antibody construct can comprise a first binding domain that specifically binds a tumor antigen on a tumor cell, a tumor fragment, an immune cell or an antigen presenting cell.

[0214] An antibody construct can comprise a first binding domain that specifically binds a tumor antigen. The construct can comprise a first binding domain comprising one or more CDRs, typically a set of six CDRs. A first binding domain can comprise at least 80% sequence identity to any sequence in TABLE 1. An antibody construct can comprise a first binding domain that binds a tumor antigen, wherein the first binding domain comprises at least 80% sequence identity to: a) HCDR1 comprising an amino acid sequence of SEQ ID NO: 13, HCDR2 comprising an amino acid sequence of SEQ ID NO: 14, HCDR3 comprising an amino acid sequence of SEQ ID NO: 15, LCDR1 comprising an amino acid sequence of SEQ ID NO: 18, LCDR2 comprising an amino acid sequence of SEQ ID NO: 19, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 20; b) HCDR1 comprising an amino acid sequence of SEQ ID NO: 26, HCDR2 comprising an amino acid sequence of SEQ ID NO: 27, HCDR3 comprising an amino acid sequence of SEQ ID NO: 28, LCDR1 comprising an amino acid sequence of SEQ ID NO: 31, LCDR2 comprising an amino acid sequence of SEQ ID NO: 32, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 33; c) HCDR1 comprising an amino acid sequence of SEQ ID NO: 39, HCDR2 comprising an amino acid sequence of SEQ ID NO: 40, HCDR3 comprising an amino acid sequence of SEQ ID NO: 41, LCDR1 comprising an amino acid sequence of SEQ ID NO: 44, LCDR2 comprising an amino acid sequence of SEQ ID NO: 45, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 46; d) HCDR1 comprising an amino acid sequence of SEQ ID NO: 52, HCDR2 comprising an amino acid sequence of SEQ ID NO: 53, HCDR3 comprising an amino acid sequence of SEQ ID NO: 54, LCDR1 comprising an amino acid sequence of SEQ ID NO: 57, LCDR2 comprising an amino acid sequence of SEQ ID NO: 58, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 59; e) HCDR1 comprising an amino acid sequence of SEQ ID NO: 65, HCDR2 comprising an amino acid sequence of SEQ ID NO: 66, HCDR3 comprising an amino acid sequence of SEQ ID NO: 67, LCDR1 comprising an amino acid sequence of SEQ ID NO: 70, LCDR2 comprising an amino acid sequence of SEQ ID NO: 71, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 72; f) HCDR1 comprising an amino acid sequence of SEQ ID NO: 78, HCDR2 comprising an amino acid sequence of SEQ ID NO: 79, HCDR3 comprising an amino acid sequence of SEQ ID NO: 80, LCDR1 comprising an amino acid sequence of SEQ ID NO: 83, LCDR2 comprising an amino acid sequence of SEQ ID NO: 84, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 85; g) HCDR1 comprising an amino acid sequence of SEQ ID NO: 91, HCDR2 comprising an amino acid sequence of SEQ ID NO: 92, HCDR3 comprising an amino acid sequence of SEQ ID NO: 93, LCDRl comprising an amino acid sequence of SEQ ID NO: 96, LCDR2 comprising an amino acid sequence of SEQ ID NO: 97, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 98; h) HCDRl comprising an amino acid sequence of SEQ ID NO: 104, HCDR2 comprising an amino acid sequence of SEQ ID NO: 105, HCDR3 comprising an amino acid sequence of SEQ ID NO: 106, LCDRl comprising an amino acid sequence of SEQ ID NO: 109, LCDR2 comprising an amino acid sequence of SEQ ID NO: 110, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 111; i) HCDRl comprising an amino acid sequence of SEQ ID NO: 117, HCDR2 comprising an amino acid sequence of SEQ ID NO: 118, HCDR3 comprising an amino acid sequence of SEQ ID NO: 119, LCDRl comprising an amino acid sequence of SEQ ID NO: 122, LCDR2 comprising an amino acid sequence of SEQ ID NO: 123, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 124; j) HCDRl comprising an amino acid sequence of SEQ ID NO: 130, HCDR2 comprising an amino acid sequence of SEQ ID NO: 131, HCDR3 comprising an amino acid sequence of SEQ ID NO: 132, LCDRl comprising an amino acid sequence of SEQ ID NO: 135, LCDR2 comprising an amino acid sequence of SEQ ID NO: 136, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 137; k) HCDRl comprising an amino acid sequence of SEQ ID NO: 143, HCDR2 comprising an amino acid sequence of SEQ ID NO: 144, HCDR3 comprising an amino acid sequence of SEQ ID NO: 145, LCDRl comprising an amino acid sequence of SEQ ID NO: 148, LCDR2 comprising an amino acid sequence of SEQ ID NO: 149, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 150; 1) HCDRl comprising an amino acid sequence of SEQ ID NO: 156, HCDR2 comprising an amino acid sequence of SEQ ID NO: 157, HCDR3 comprising an amino acid sequence of SEQ ID NO: 158, LCDRl comprising an amino acid sequence of SEQID NO: 161, LCDR2 comprising an amino acid sequence of SEQ ID NO: 162, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 163; m) HCDRl comprising an amino acid sequence of SEQ ID NO: 169, HCDR2 comprising an amino acid sequence of SEQ ID NO: 170, HCDR3 comprising an amino acid sequence of SEQ ID NO: 171, LCDRl comprising an amino acid sequence of SEQ ID NO: 174, LCDR2 comprising an amino acid sequence of SEQ ID NO: 175, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 176; n) HCDRl comprising an amino acid sequence of SEQ ID NO: 182, HCDR2 comprising an amino acid sequence of SEQ ID NO: 183, HCDR3 comprising an amino acid sequence of SEQ ID NO: 184, LCDRl comprising an amino acid sequence of SEQ ID NO: 187, LCDR2 comprising an amino acid sequence of SEQ ID NO: 188, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 189; o) HCDRl comprising an amino acid sequence of SEQ ID NO: 195, HCDR2 comprising an amino acid sequence of SEQ ID NO: 196, HCDR3 comprising an amino acid sequence of SEQ ID NO: 197, LCDRl comprising an amino acid sequence of SEQ ID NO: 200, LCDR2 comprising an amino acid sequence of SEQ ID NO: 201, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 202; p) HCDRl comprising an amino acid sequence of

SEQ ID NO: 208, HCDR2 comprising an amino acid sequence of SEQ ID NO: 209, HCDR3 comprising an amino acid sequence of SEQ ID NO: 210, LCDR1 comprising an amino acid sequence of SEQ ID NO: 213, LCDR2 comprising an amino acid sequence of SEQ ID NO: 214, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 215; q) HCDRl comprising an amino acid sequence of SEQ ID NO: 805, HCDR2 comprising an amino acid sequence of SEQ

ID NO: 806, HCDR3 comprising an amino acid sequence of SEQ ID NO: 807, LCDR1 comprising an amino acid sequence of SEQ ID NO: 808, LCDR2 comprising an amino acid sequence of SEQ ID NO: 809, and LCDR3 comprising an amino acid sequence of SEQ ID NO:

810; r) HCDRl comprising an amino acid sequence of SEQ ID NO: 823, HCDR2 comprising an amino acid sequence of SEQ ID NO: 824, HCDR3 comprising an amino acid sequence of SEQ

ID NO: 825, LCDR1 comprising an amino acid sequence of SEQ ID NO: 826, LCDR2 comprising an amino acid sequence of SEQ ID NO: 827, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 828; s) HCDRl comprising an amino acid sequence of SEQ ID NO:

221, HCDR2 comprising an amino acid sequence of SEQ ID NO: 222, HCDR3 comprising an amino acid sequence of SEQ ID NO: 223, LCDR1 comprising an amino acid sequence of SEQ

ID NO: 226, LCDR2 comprising an amino acid sequence of SEQ ID NO: 227, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 228; t) HCDRl comprising an amino acid sequence of SEQ ID NO: 260, HCDR2 comprising an amino acid sequence of SEQ ID NO: 261,

HCDR3 comprising an amino acid sequence of SEQ ID NO: 262, LCDR1 comprising an amino acid sequence of SEQ ID NO: 265, LCDR2 comprising an amino acid sequence of SEQ ID NO:

266, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 267; u) HCDRl comprising an amino acid sequence of SEQ ID NO: 273, HCDR2 comprising an amino acid sequence of SEQ ID NO: 274, HCDR3 comprising an amino acid sequence of SEQ ID NO: 275,

LCDR1 comprising an amino acid sequence of SEQ ID NO: 278, LCDR2 comprising an amino acid sequence of SEQ ID NO: 279, and LCDR3 comprising an amino acid sequence of SEQ ID

NO: 280; v) HCDRl comprising an amino acid sequence of SEQ ID NO: 286, HCDR2 comprising an amino acid sequence of SEQ ID NO: 287, HCDR3 comprising an amino acid sequence of SEQ ID NO: 288, LCDR1 comprising an amino acid sequence of SEQ ID NO: 291,

LCDR2 comprising an amino acid sequence of SEQ ID NO: 292, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 293; w) HCDRl comprising an amino acid sequence of

SEQ ID NO: 299, HCDR2 comprising an amino acid sequence of SEQ ID NO: 300, HCDR3 comprising an amino acid sequence of SEQ ID NO: 301, LCDR1 comprising an amino acid sequence of SEQ ID NO: 304, LCDR2 comprising an amino acid sequence of SEQ ID NO: 305, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 306; x) HCDRl comprising an amino acid sequence of SEQ ID NO: 312, HCDR2 comprising an amino acid sequence of SEQ ID NO: 313, HCDR3 comprising an amino acid sequence of SEQ ID NO: 314, LCDR1 comprising an amino acid sequence of SEQ ID NO: 317, LCDR2 comprising an amino acid sequence of SEQ ID NO: 318, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 319; y) HCDRl comprising an amino acid sequence of SEQ ID NO: 325, HCDR2 comprising an amino acid sequence of SEQ ID NO: 326, HCDR3 comprising an amino acid sequence of SEQ ID NO: 327, LCDR1 comprising an amino acid sequence of SEQ ID NO: 330, LCDR2 comprising an amino acid sequence of SEQ ID NO: 331, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 332; z) HCDRl comprising an amino acid sequence of SEQ ID NO: 338, HCDR2 comprising an amino acid sequence of SEQ ID NO: 339, HCDR3 comprising an amino acid sequence of SEQ ID NO: 340, LCDR1 comprising an amino acid sequence of SEQ ID NO: 343, LCDR2 comprising an amino acid sequence of SEQ ID NO: 344, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 345; aa) HCDRl comprising an amino acid sequence of SEQ ID NO: 351, HCDR2 comprising an amino acid sequence of SEQ ID NO: 352, HCDR3 comprising an amino acid sequence of SEQ ID NO: 353, LCDR1 comprising an amino acid sequence of SEQ ID NO: 356, LCDR2 comprising an amino acid sequence of SEQ ID NO: 357, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 358; bb) HCDRl comprising an amino acid sequence of SEQ ID NO: 364, HCDR2 comprising an amino acid sequence of SEQ ID NO: 365, HCDR3 comprising an amino acid sequence of SEQ ID NO: 366, LCDR1 comprising an amino acid sequence of SEQ ID NO: 369, LCDR2 comprising an amino acid sequence of SEQ ID NO: 370, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 371; cc) HCDRl comprising an amino acid sequence of SEQ ID NO: 377, HCDR2 comprising an amino acid sequence of SEQ ID NO: 378, HCDR3 comprising an amino acid sequence of SEQ ID NO: 379, LCDR1 comprising an amino acid sequence of SEQ ID NO: 382, LCDR2 comprising an amino acid sequence of SEQ ID NO: 383, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 384; dd) HCDRl comprising an amino acid sequence of SEQ ID NO: 390, HCDR2 comprising an amino acid sequence of SEQ ID NO: 391, HCDR3 comprising an amino acid sequence of SEQ ID NO: 392, LCDR1 comprising an amino acid sequence of SEQ ID NO: 395, LCDR2 comprising an amino acid sequence of SEQ ID NO: 396, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 397; ee) HCDRl comprising an amino acid sequence of SEQ ID NO: 403, HCDR2 comprising an amino acid sequence of SEQ ID NO: 404, HCDR3 comprising an amino acid sequence of SEQ ID NO: 405, LCDR1 comprising an amino acid sequence of SEQ ID NO: 408, LCDR2 comprising an amino acid sequence of SEQ ID NO: 409, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 410; ff) HCDRl comprising an amino acid sequence of SEQ ID NO: 416, HCDR2 comprising an amino acid sequence of SEQ ID NO: 417, HCDR3 comprising an amino acid sequence of SEQ

ID NO: 418, LCDR1 comprising an amino acid sequence of SEQ ID NO: 421, LCDR2 comprising an amino acid sequence of SEQ ID NO: 422, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 423; gg) HCDRl comprising an amino acid sequence of SEQ ID NO:

429, HCDR2 comprising an amino acid sequence of SEQ ID NO: 430, HCDR3 comprising an amino acid sequence of SEQ ID NO: 431, LCDR1 comprising an amino acid sequence of SEQ

ID NO: 434, LCDR2 comprising an amino acid sequence of SEQ ID NO: 435, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 436; hh) HCDRl comprising an amino acid sequence of SEQ ID NO: 442, HCDR2 comprising an amino acid sequence of SEQ ID NO: 443,

HCDR3 comprising an amino acid sequence of SEQ ID NO: 444, LCDR1 comprising an amino acid sequence of SEQ ID NO: 447, LCDR2 comprising an amino acid sequence of SEQ ID NO:

448, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 449; ii) HCDRl comprising an amino acid sequence of SEQ ID NO: 455, HCDR2 comprising an amino acid sequence of SEQ ID NO: 456, HCDR3 comprising an amino acid sequence of SEQ ID NO: 457,

LCDR1 comprising an amino acid sequence of SEQ ID NO: 460, LCDR2 comprising an amino acid sequence of SEQ ID NO: 461, and LCDR3 comprising an amino acid sequence of SEQ ID

NO: 462; jj) HCDRl comprising an amino acid sequence of SEQ ID NO: 468, HCDR2 comprising an amino acid sequence of SEQ ID NO: 469, HCDR3 comprising an amino acid sequence of SEQ ID NO: 470, LCDR1 comprising an amino acid sequence of SEQ ID NO: 473,

LCDR2 comprising an amino acid sequence of SEQ ID NO: 474, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 475; kk) HCDRl comprising an amino acid sequence of

SEQ ID NO: 481, HCDR2 comprising an amino acid sequence of SEQ ID NO: 482, HCDR3 comprising an amino acid sequence of SEQ ID NO: 483, LCDR1 comprising an amino acid sequence of SEQ ID NO: 486, LCDR2 comprising an amino acid sequence of SEQ ID NO: 487, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 488; 11) HCDRl comprising an amino acid sequence of SEQ ID NO: 494, HCDR2 comprising an amino acid sequence of SEQ

ID NO: 495, HCDR3 comprising an amino acid sequence of SEQ ID NO: 496, LCDR1 comprising an amino acid sequence of SEQ ID NO: 499, LCDR2 comprising an amino acid sequence of SEQ ID NO: 500, and LCDR3 comprising an amino acid sequence of SEQ ID NO:

501; mm) HCDRl comprising an amino acid sequence of SEQ ID NO: 673, HCDR2 comprising an amino acid sequence of SEQ ID NO: 674, HCDR3 comprising an amino acid sequence of

SEQ ID NO: 675, LCDR1 comprising an amino acid sequence of SEQ ID NO: 676, LCDR2 comprising an amino acid sequence of SEQ ID NO: 677, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 678; nn) HCDRl comprising an amino acid sequence of SEQ ID NO: 850, HCDR2 comprising an amino acid sequence of SEQ ID NO: 851, HCDR3 comprising an amino acid sequence of SEQ ID NO: 852, LCDR1 comprising an amino acid sequence of SEQ ID NO: 853, LCDR2 comprising an amino acid sequence of SEQ ID NO: 854, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 855; oo) HCDR1 comprising an amino acid sequence of SEQ ID NO: 856, HCDR2 comprising an amino acid sequence of SEQ ID NO: 857, HCDR3 comprising an amino acid sequence of SEQ ID NO: 858, LCDR1 comprising an amino acid sequence of SEQ ID NO: 859, LCDR2 comprising an amino acid sequence of SEQ ID NO: 860, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 861 ; pp) HCDR1 comprising an amino acid sequence of SEQ ID NO: 862, HCDR2 comprising an amino acid sequence of SEQ ID NO: 863, HCDR3 comprising an amino acid sequence of SEQ ID NO: 864, LCDR1 comprising an amino acid sequence of SEQ ID NO: 865, LCDR2 comprising an amino acid sequence of SEQ ID NO: 866, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 867; qq) HCDR1 comprising an amino acid sequence of SEQ ID NO: 868, HCDR2 comprising an amino acid sequence of SEQ ID NO: 869, HCDR3 comprising an amino acid sequence of SEQ ID NO: 870, LCDR1 comprising an amino acid sequence of SEQ ID NO: 871 , LCDR2 comprising an amino acid sequence of SEQ ID NO: 872, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 873 ; rr) HCDR1 comprising an amino acid sequence of SEQ ID NO: 874, HCDR2 comprising an amino acid sequence of SEQ ID NO: 875, HCDR3 comprising an amino acid sequence of SEQ ID NO: 876, LCDR1 comprising an amino acid sequence of SEQ ID NO: 877, LCDR2 comprising an amino acid sequence of SEQ ID NO: 878, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 879; or ss) HCDR1 comprising an amino acid sequence of SEQ ID NO: 880, HCDR2 comprising an amino acid sequence of SEQ ID NO: 881, HCDR3 comprising an amino acid sequence of SEQ ID NO: 882, LCDR1 comprising an amino acid sequence of SEQ ID NO: 883, LCDR2 comprising an amino acid sequence of SEQ ID NO: 884, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 885.

[0215] An antibody construct can comprise a first binding domain that specifically binds a tumor antigen. An antibody construct can comprise a first binding domain comprising one or more variable domains. An antibody construct can comprise a first binding domain comprising a light chain variable domain (V _L domain). A first binding domain can have at least 80% or 100% sequence identity to any V _L sequence in TABLE 2. An antibody construct can comprise a first binding domain comprising a heavy chain variable domain (V _H domain). A first binding domain can comprise at least 80% or 100% sequence identity to any V _H sequence in TABLE 2. A first binding domain can comprise at least 80% sequence identity to any sequence in TABLE 2. A first binding domain can have a pair of V _H and V _L regions, having sequence selected from the pairs in TABLE 2.

[0216] An antibody construct can comprise a first binding domain that specifically binds a tumor antigen, wherein the first binding domain comprises: a) a V _H sequence having at least 80% or 100% sequence identity to an amino acid sequence of SEQ ID NO: 12, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 17; b) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 25, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 30; c) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 38, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 43; d) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 51, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 56; e) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 64, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 69; f) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 77, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 82; g) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 90, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 95; h) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 103, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 108; i) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 116, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 121; j) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 129, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 134; k) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 142, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 147; 1) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 155, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 160; m) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 168, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 173; n) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 181, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 186; o) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 194, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 199; p) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 207, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 212; q) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 811, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 812; r) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 829, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 830; s) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO:

220, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ

ID NO: 225; t) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 259, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 264; u) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 272, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 277; v) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 285, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 290; w) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 298, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 303; x) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO:

311, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ

ID NO: 316; y) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 324, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 328; z) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 337, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 342; aa) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 350, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 355; bb) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 363, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 368; cc) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID

NO: 376, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of

SEQ ID NO: 381; dd) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 389, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 394; ee) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 402, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 407; ff) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 415, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 420; gg) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 428, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 433; hh) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 441, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 446; ii) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 454, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 459; jj) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 467, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 472; kk) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 480, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 485; 11) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 493, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 498; mm) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 679, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 680; nn) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 886, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 887; oo) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 888, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 889; pp) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 890, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 891; qq) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 892, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 893; rr) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 894, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO:895; ss) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 896, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 897.

[0217] An antibody construct can comprise a first binding domain and an Fc domain, wherein the first binding domain and the Fc domain comprise an antibody. A first binding domain can specifically bind a tumor antigen. An antibody construct can comprise an antibody light chain wherein the antibody construct specifically binds to an antigen. An antibody construct can comprise a light chain comprising at least 80% or 100% sequence identity to a light chain sequence in TABLE 3, wherein the antibody construct specifically binds to an antigen. An antibody construct can comprise an antibody heavy chain, wherein the antibody construct specifically binds to an antigen. An antibody construct can comprise a heavy chain comprising at least 80% or 100% sequence identity to a heavy chain sequence in TABLE 3, wherein the antibody construct specifically binds to an antigen. An antibody construct can comprise at least 80% sequence identity to any sequence in TABLE 3, wherein the antibody construct specifically binds to an antigen. An antibody construct can have a pair of heavy and light chains having sequences selected from the pairs of sequences in TABLE 3, wherein the antibody construct specifically binds to an antigen.

[0218] An antibody construct can comprise an anti-tumor antibody, wherein the antibody comprises: a) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 11, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 16; b) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 24, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 29; c) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 37, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 42; d) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 50, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 55; e) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 63, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 68; f) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 76, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 81; g) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 89, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 94; h) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 102, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 107; i) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 115, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 120; j) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 128, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 133; k) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 141, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 146; 1) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 154, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 159; m) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 167, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 172; n) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 180, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 185; o) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 193, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 198; p) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 206, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 211; q) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 813, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 814; r) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 831, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 832; s) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 219, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 224; t) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 258, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 263; u) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 271, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 276; v) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 284, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 289; w) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 297, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 302; x) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 310, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 315; y) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 323, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 328; z) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 336, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 341; aa) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 349, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 354; bb) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 362, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 367; cc) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 375, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 380; dd) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 388, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 393; ee) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 401, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 406; ff) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 414, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 419; gg) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 427, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 432; hh) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 440, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 445; ii) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 453, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 458; jj) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 466, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 471; kk) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 479, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 484; 11) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 492, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 497; or mm) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 681, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 682.

[0219] An antibody construct can comprise a second binding domain that specifically binds to an antigen. An antibody construct can comprise a second binding domain that specifically binds to an antigen on an antigen presenting cell. An antigen presenting cell can be a dendritic cell or a macrophage. A second binding domain can specifically bind to an antigen on an immune cell such as an antigen presenting cell, wherein the molecule comprises at least 80% sequence identity to a group consisting of CD40, CD47, TNFR2, DEC-205, PD-L1, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, CD38, TREM2, CSF1R, or CD32B.

[0220] An antibody construct can further comprise an Fc domain. An antibody construct can comprise, for example, a first binding domain, a second binding domain, and an Fc domain, wherein the first binding domain is attached to the Fc domain. An antibody construct can comprise a first binding domain, a second binding domain, and an Fc domain, wherein the second binding domain is attached to the Fc domain. A first binding domain can be attached to an Fc domain as a fusion protein. A second binding domain can be attached to an Fc domain as a fusion protein. A first binding domain can be attached to an Fc domain via a linker. A second binding domain can be attached to an Fc domain via a linker.

[0221] An antibody construct can comprise a second binding domain comprising one or more CDRs. A second binding domain can comprise at least 80% sequence identity to any sequence in TABLE 5. A second binding domain can comprise a set of CDRs having the sequences set forth in any sete of sequence in TABLE 5.

[0222] An antibody construct can comprise a second binding domain that specifically binds to

CD40. An antibody construct can comprise a second binding domain that is a CD40 agonist. An antibody construct can comprise a second binding domain that binds to CD40, wherein the second binding domain comprises at least 80% sequence identity to: a) HCDR1 comprising an amino acid sequence of SEQ ID NO: 3, HCDR2 comprising an amino acid sequence of SEQ ID

NO: 4, HCDR3 comprising an amino acid sequence of SEQ ID NO: 5, LCDR1 comprising an amino acid sequence of SEQ ID NO: 8, LCDR2 comprising an amino acid sequence of SEQ ID

NO: 9, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 10; b) HCDR1 comprising an amino acid sequence of SEQ ID NO: 582, HCDR2 comprising an amino acid sequence of SEQ ID NO: 583, HCDR3 comprising an amino acid sequence of SEQ ID NO: 584,

LCDR1 comprising an amino acid sequence of SEQ ID NO: 587, LCDR2 comprising an amino acid sequence of SEQ ID NO: 588, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 589; c) HCDRl comprising an amino acid sequence of SEQ ID NO: 592, HCDR2 comprising an amino acid sequence of SEQ ID NO: 593, HCDR3 comprising an amino acid sequence of SEQ ID NO: 594, LCDR1 comprising an amino acid sequence of SEQ ID NO: 597, LCDR2 comprising an amino acid sequence of SEQ ID NO: 598, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 599; d) HCDRl comprising an amino acid sequence of SEQ ID NO: 602, HCDR2 comprising an amino acid sequence of SEQ ID NO: 603, HCDR3 comprising an amino acid sequence of SEQ ID NO: 604, LCDR1 comprising an amino acid sequence of SEQ ID NO: 607, LCDR2 comprising an amino acid sequence of SEQ ID NO: 608, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 609; e) HCDRl comprising an amino acid sequence of SEQ ID NO: 612, HCDR2 comprising an amino acid sequence of SEQ ID NO: 613, HCDR3 comprising an amino acid sequence of SEQ ID NO: 614, LCDR1 comprising an amino acid sequence of SEQ ID NO: 617, LCDR2 comprising an amino acid sequence of SEQ ID NO: 618, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 619; f) HCDRl comprising an amino acid sequence of SEQ ID NO: 622, HCDR2 comprising an amino acid sequence of SEQ ID NO: 623, HCDR3 comprising an amino acid sequence of SEQ ID NO: 624, LCDR1 comprising an amino acid sequence of SEQ ID NO: 627, LCDR2 comprising an amino acid sequence of SEQ ID NO: 628, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 629; or g) HCDRl comprising an amino acid sequence of SEQ ID NO: 632, HCDR2 comprising an amino acid sequence of SEQ ID NO: 633, HCDR3 comprising an amino acid sequence of SEQ ID NO: 634, LCDR1 comprising an amino acid sequence of SEQ ID NO: 637, LCDR2 comprising an amino acid sequence of SEQ ID NO: 638, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 639.

[0223] An antibody construct can comprise a second binding domain that specifically binds DC- SIGN. An antibody construct can comprise a second binding domain that binds DC-SIGN, wherein the second binding domain comprises at least 80% sequence identity to: a) HCDRl comprising an amino acid sequence of SEQ ID NO: 640, HCDR2 comprising an amino acid sequence of SEQ ID NO: 641, HCDR3 comprising an amino acid sequence of SEQ ID NO: 642, LCDR1 comprising an amino acid sequence of SEQ ID NO: 643, LCDR2 comprising an amino acid sequence of SEQ ID NO: 644, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 645; b) HCDRl comprising an amino acid sequence of SEQ ID NO: 646, HCDR2 comprising an amino acid sequence of SEQ ID NO: 647, HCDR3 comprising an amino acid sequence of SEQ ID NO: 648, LCDR1 comprising an amino acid sequence of SEQ ID NO: 649, LCDR2 comprising an amino acid sequence of SEQ ID NO: 650, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 651; or c) HCDRl comprising an amino acid sequence of SEQ ID NO: 652, HCDR2 comprising an amino acid sequence of SEQ ID NO: 653, HCDR3 comprising an amino acid sequence of SEQ ID NO: 654, LCDR1 comprising an amino acid sequence of SEQ ID NO: 655, LCDR2 comprising an amino acid sequence of SEQ ID NO: 656, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 657.

[0224] An antibody construct can comprise a second binding domain that specifically binds DEC-205. An antibody construct comprising a second binding domain that binds DEC-205 can comprise at least 80% sequence identity to: a) HCDR1 comprising an amino acid sequence of SEQ ID NO: 234, HCDR2 comprising an amino acid sequence of SEQ ID NO: 235, HCDR3 comprising an amino acid sequence of SEQ ID NO: 236, LCDR1 comprising an amino acid sequence of SEQ ID NO: 239, LCDR2 comprising an amino acid sequence of SEQ ID NO: 240, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 241 ; or b) HCDR1 comprising an amino acid sequence of SEQ ID NO: 247, HCDR2 comprising an amino acid sequence of SEQ ID NO: 248, HCDR3 comprising an amino acid sequence of SEQ ID NO: 249, LCDR1 comprising an amino acid sequence of SEQ ID NO: 252, LCDR2 comprising an amino acid sequence of SEQ ID NO: 253, and LCDR3 comprising an amino acid sequence of SEQ ID NO: 254.

[0225] An antibody construct can comprise a second binding domain comprising one or more variable domains. An antibody construct can comprise a second binding domain comprising a light chain variable domain (V _L domain). A second binding domain can comprise at least 80% sequence identity to any V _L sequence in TABLE 6. An antibody construct can comprise a second binding domain comprising a heavy chain variable domain. A second binding domain can comprise at least 80% sequence identity to any V _H sequence in TABLE 6. A second binding domain can comprise at least 80% sequence identity to any sequence in TABLE 6. A second binding domain can comprise at a pair of V _H and V _L domains having a pair of sequences in

TABLE 6.

[0226] An antibody construct can comprise a second binding domain that specifically binds

CD40. An antibody construct can comprise a second binding domain that is a CD40 agonist. An antibody construct can comprise a second binding domain that binds CD40, wherein the second binding domain comprises: a) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 2, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 7; b) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 581, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 586; c) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 591 , and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 596; d) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 601 , and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 606; e) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 611, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 616; f) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 621, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 626; g) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 631, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 636.

[0227] An antibody construct can comprise a second binding domain that specifically binds DEC-205. An antibody construct can comprise a second binding domain that binds DEC-205, wherein the second binding domain comprises: a) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 233, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 238; or b) a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 246, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 251.

[0228] An antibody construct can comprise a second binding domain that specifically binds to CD36 mannose scavenger receptor 1. An antibody construct can comprise a second binding domain that binds CD36 mannose scavenger receptor 1, wherein the second binding domain comprises a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 658, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 659.

[0229] An antibody construct can comprise a second binding domain that specifically binds to CLEC9A. An antibody construct can comprise a second binding domain that binds CLEC9A, wherein the second binding domain comprises a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 660, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 661.

[0230] An antibody construct can comprise a second binding domain that specifically binds to PD-Ll. An antibody construct can comprise a second binding domain that binds PD-Ll, wherein the second binding domain comprises a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 901, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 902; or wherein the second binding domain comprises a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 890, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 891; or wherein the second binding domain comprises a V _H sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 892, and a V _L sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 893.

[0231] An antibody construct can comprise a second binding domain and an Fc domain, wherein the second binding domain and the Fc domain comprise an antibody. An antibody construct can comprise a heavy chain and a light chain that target an antigen expressed by an antigen presenting cell. An antibody construct can comprise an antibody light chain. An antibody construct can comprise a light chain comprising at least 80% sequence identity to any light chain sequence in TABLE 7. An antibody construct can comprise an antibody heavy chain. An antibody construct can comprise a heavy chain comprising at least 80% sequence identity to any heavy chain sequence in TABLE 7. An antibody construct can comprise at least 80% sequence identity to any sequence in TABLE 7. An antibody construct can comprise a heavy and light chains having a pair of sequences in TABLE 7.

[0232] An antibody construct can comprise a heavy chain and a light chain that target an antigen expressed by an antigen presenting cell. An antibody construct can comprise a first binding domain and an Fc domain, wherein the first binding domain and the Fc domain comprise an antibody. An antibody construct may comprise an anti-CD40 antibody, the antibody construct comprising: a) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 1 and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 6; b) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 577 or SEQ ID NO: 578, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 579; c) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 580, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 585; d) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 590, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 595; e) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 600, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 605; f) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 610, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 615; g) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 620, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 625; or h) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 630, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 635.

[0233] An antibody construct can comprise a first binding domain and an Fc domain, wherein the first binding domain and the Fc domain comprise an antibody. An antibody construct may comprise an anti-DEC-205 antibody, the construct comprising: a) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 232, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 237; or b) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 245, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 250.

[0234] An antibody construct can comprise a first binding domain and an Fc domain, wherein the first binding domain and the Fc domain comprise an antibody. A composition may comprise an anti-CLEC12A antibody, the construct comprising: a) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 662, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 665; b) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 663, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 665; or c) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 664, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 665.

[0235] An antibody construct can comprise a first binding domain and an Fc domain, wherein the first binding domain and the Fc domain comprise an antibody. An antibody construct may comprise an anti-BDCA-2 antibody, the construct comprising: a) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 666, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 669; b) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 667, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 670; or c) a heavy chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 668, and a light chain sequence having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 671.

Antibody-ScFv Fusion Protein Products

[0236] An antibody construct can comprise a first binding domain, a second binding domain, and an Fc domain, wherein the first binding domain and the second binding domain are attached to the Fc domain. The first binding domain and the second binding domain can be attached to the Fc domain as a fusion protein. The first binding domain can be attached to the Fc domain at an N- terminal end of the Fc domain, wherein the second binding domain can be attached to the Fc domain at a C-terminal end. The first binding domain can be attached to the Fc domain at an N- terminal end of the Fc domain, wherein the second binding domain can be attached to the Fc domain at a C-terminal end via a polypeptide linker ranging from 10 to 25 amino acids. In some embodiments, the polypeptide linker has the sequence [G ₄ S]n where n = 2 to 5. Alternatively, the first binding domain can be attached to the Fc domain at a C-terminal end of the Fc domain, wherein the second binding domain can be attached to the Fc domain at an N-terminal end. A second binding domain and an Fc domain can comprise an antibody and a first binding domain can comprise a single chain variable fragment (scFv). A single chain variable fragment can comprise a heavy chain variable domain and a light chain variable domain of an antibody. The first binding domain of the fusion protein can be attached to the second binding domain at a heavy chain variable domain of the single chain variable fragment of the first binding domain (HL orientation). Alternatively, the first binding domain of the fusion protein can be attached to the second binding domain at a light chain variable domain of the single chain variable fragment of the first binding domain (LH orientation). In either orientation, the first binding domain and the second binding domain can be attached via a polypeptide linker varying in length from 15 to 25 amino acids. In some embodiments, the polypeptide linker has the sequence [G ₄ S]n where n = 3 to 5.

[0237] Alternatively, an antibody construct can comprise an antibody (having two antigen binding domains and an Fc domain) and the second binding domain can comprise a single chain variable fragment (scFv). The second binding domain of the fusion protein can be attached to the first binding domain at a heavy chain variable domain of the single chain variable fragment of the first binding domain (HL orientation). Alternatively, the second binding domain of the fusion protein can be attached to the first binding domain at a light chain variable domain of the single chain variable fragment of the first binding domain (LH orientation).

[0238] An antibody construct can comprise a first binding domain and a second binding domain, wherein the second binding domain can be attached to the first binding domain. The antibody construct can comprise an antibody comprising a light chain and a heavy chain or pair of heavy and light chains. The first binding domain can comprise an Fab fragment of the light and heavy chains. The second binding domain can be attached to the light chain at a C-terminus or C- terminal end of the light chain as a fusion protein. The second binding domain can comprise a single chain variable fragment (scFv). In some embodiments, a first binding domain can be specific for any of the tumor antigens, e.g., CEA, HER2, TROP2, Claudin-6 (CLDN6), Claudin- 16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, or gpNMB, and an scFv can be a binding domain with a specificity selected from a group consisting of antigens on antigen presenting cells, such as CD40, DEC205, and PD-L1.

[0239] An antibody construct can comprise a first binding domain, a second binding domain, and an Fc domain, wherein the first binding domain and the second binding domain are attached to the Fc domain as a fusion protein. The second binding domain of the fusion protein can specifically target an antigen with at least 80% sequence identity to CD40. The second binding domain of the fusion protein can be a CD40 agonist. The first binding domain of the fusion protein can target a tumor antigen. The construct can comprise a fusion protein comprising a heavy chain (HC) attached to a single chain variable fragment. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence in TABLE 4. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a heavy chain CD40 monoclonal antibody (mAb) with tumor ScFv in TABLE 4. The construct can comprise a fusion protein comprising at least 80% sequence identity to any sequence of a heavy chain CD40 mAb with tumor ScFv in TABLE 4 and a light chain comprising at least 80% sequence identity to SEQ ID NO: 6. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a heavy chain tumor mAb with CD40 ScFv in TABLE 4. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a heavy chain tumor antigen mAb with CD40 ScFv in TABLE 4, and at least 80% sequence identity to a light chain mAb for the tumor antigen in

TABLE 3.

[0240] An antibody construct can comprise a first binding domain and a second binding domain, wherein the second binding domain can be attached to the first binding domain. An antibody construct can comprise a first binding domain, a second binding domain, and an Fc domain, wherein the second binding domain can be attached to the first binding domain. The second binding domain can be attached at a C-terminal end of the first binding domain as a fusion protein. The first binding domain can comprise a Fab fragment comprising a light chain, wherein the second binding domain can be attached at a C-terminal end of the light chain as a fusion protein. The second binding domain of the fusion protein can comprise a single chain variable fragment (scFv). The second binding domain of the fusion protein can be attached to the first binding domain at a heavy chain variable domain of the single chain variable fragment of the first binding domain (HL orientation). Alternatively, the second binding domain of the fusion protein can be attached to the first binding domain at a light chain variable domain of the single chain variable fragment of the first binding domain (LH orientation). For example, a fusion protein comprising a light chain of an anti-CEA antibody attached to an anti-CD40 scFv in the LH orientation can be illustrated by SEQ ID NO: 842. The fusion sequences comprising an scFv sequence are in the HL orientation unless indicated otherwise (e.g., sequence name recites "(LH)" indicating light heavy orientation).

[0241] The first binding domain of the fusion protein can target a tumor antigen. The second binding domain of the fusion protein can target an APC antigen. The second binding domain of the fusion protein can target CD40. The first binding domain can comprise a Fab fragment comprising a light chain, wherein the second binding domain is attached at a C-terminal end of the light chain as a fusion protein. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence in TABLE 9. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a light chain CD40 mAb with tumor ScFv in TABLE 9. The construct can comprise a fusion protein comprising at least 80% sequence identity to any sequence of a light chain CD40 mAb with tumor ScFv in TABLE 9 and a heavy chain comprising at least 80% sequence identity to SEQ ID NO: 1. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a light chain tumor mAb with CD40 ScFv in TABLE 9. The construct can comprise a fusion protein comprising at least 80% sequence identity to any sequence of a light chain tumor antigen mAb with CD40 ScFv in TABLE 9, and at least 80% sequence identity to a heavy chain mAb for the tumor antigen in TABLE 3.

[0242] An antibody construct can comprise a first binding domain, a second binding domain, and an Fc domain, wherein the first binding domain and the second binding domain are attached to the Fc domain as a fusion protein. The first binding domain of the fusion protein can specifically target an antigen with at least 80% sequence identity to DEC-205. The second binding domain of the fusion protein can target a tumor antigen. The construct can comprise a fusion protein comprising a heavy chain attached to a single chain variable fragment. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence in TABLE 8. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a heavy chain DEC-205 mAb with tumor ScFv in TABLE 8. The construct can comprise a fusion protein comprising at least 80% sequence identity to any sequence of a heavy chain DEC-205 mAb with tumor ScFv in TABLE 8 and a peptide comprising at least 80% sequence identity to SEQ ID NO: 237. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a heavy chain tumor antigen mAb with CD40 ScFv in TABLE 8. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a heavy chain tumor antigen mAb with CD40 ScFv in TABLE 8, and at least 80% sequence identity to a heavy chain rnAb for the tumor antigen in TABLE 3.

[0243] The second binding domain of the fusion protein can target DEC-205. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence in

TABLE 10. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a light chain DEC-205 rnAb with tumor ScFv in TABLE 10. The construct comprising a fusion protein can comprise at least 80% sequence identity to any sequence of a light chain DEC-205 rnAb with tumor ScFv in TABLE 10 and at least 80% sequence identity to SEQ ID NO: 237. The construct comprising the fusion protein can comprise at least 80% sequence identity to any sequence of a light chain tumor mAb with DEC-205 ScFv in TABLE 10. The construct comprising a fusion protein can comprise at least 80% sequence identity to any sequence of a light chain tumor antigen mAb with DEC-205 ScFv in TABLE 10, and at least 80% sequence identity to a heavy chain mAb for the tumor antigen in TABLE 3.

[0244] The second binding domain of the fusion protein can specifically bind to an antigen of an

Antigen Presenting Cell (APC) or other immune cell. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD40. The second binding domain of the fusion protein can be a CD40 agonist. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to

DEC-205. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to DC-SIGN. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD36 mannose scavenger receptor. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CLEC12A. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to BDCA-2.

The second binding domain of the fusion protein can specifically bind to an antigen with at least

80% sequence identity to PD-L1. The second binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD40, CD47, TNFR2,

DEC-205, PD-L1, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A,

BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206,

CD64, CD32A, CD 16 A, HVEM, CD38, TREM2, CSF1R, or CD32B. The first binding domain of the fusion protein can specifically bind to a tumor antigen. The first binding domain of the fusion protein can specificall bind to an antigen with at least 80% sequence identity to CD5,

CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3,

B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1,

MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WTl, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, MYCN, RhoC, TRP-2, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, CYP1B 1, PLAV1, BORIS, ETV6-AML, NY-BR-1, RGS5, SART3, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1,

PDGFR-B, MAD-CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD- Ll, VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof.

[0245] Alternatively, the second binding domain of the fusion protein can target a tumor antigen. The second binding domain of the fusion protein can specifically bind to an antigen selected from CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD- Ll, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WTl, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1, PDGFR-B, MAD- CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4,

TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD-L1, VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof. The first binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD40. The first binding domain of the fusion protein can be a CD40 agonist. The first binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to DEC-205. The first binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CEA, HER2, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA or gpNMB. The first binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD40, CD47, TNFR2, DEC-205, PD-L1, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, CD38, TREM2, CSF1R, or CD32B.

[0246] An antibody construct can comprise a first binding domain, a second binding domain, and a third binding domain. An antibody construct can comprise a first binding domain, a second binding domain, a third binding domain, and an Fc domain. The first binding domain and the second binding domain can be attached to the Fc domain. The first and second binding domains are described herein throughout the specification. The first binding domain can be attached to the Fc domain at an N-terminal end of the Fc domain. The second binding domain can be attached at a C-terminal end of the Fc domain. The second binding domain can be attached at a C-terminal end of the Fc domain via a polypeptide linker having a length of 10 to 25 amino acid. In some embodiments, the polypeptide linker has the sequence [G ₄ S]n where n = 2 to 5. The third binding domain can be attached to a C-terminal end of the first binding domain. The third binding domain can be attached at a C-terminal end of the Fc domain via a polypeptide linker having a length of 10 to 25 amino acid. In some embodiments, the polypeptide linker has the sequence [G ₄ S]n where n = 2 to 5. The third binding domain can be attached to a C-terminal end of a light chain of the first binding domain. One or more of the first binding domain, the second binding domain, the third binding domain, and the Fc domain can be attached as a fusion protein. The first binding domain can comprise a Fab fragment comprising a light chain, wherein the second binding domain is attached at a C-terminal end of the light chain as a fusion protein. The second binding domain of the fusion protein can comprise a single chain variable fragment (scFv). The second binding domain of the fusion protein can be attached to the Fc domain at a heavy chain variable domain of the single chain variable fragment of the second binding domain (HL orientation). The second binding domain of the fusion protein can be attached to the Fc domain at a light chain variable domain of the single chain variable fragment of the second binding domain (LH orientation). The third binding domain of the fusion protein can comprise a single chain variable fragment (scFv). The antibody construct can comprise a fusion protein comprising the third binding domain attached to the first binding domain having at least 80% sequence identity to any sequence in TABLE 9 or TABLE 10. The third binding domain of the fusion protein can be attached to the first binding domain at a heavy chain variable domain of the single chain variable fragment of the first binding domain (HL orientation). Alternatively, the third binding domain of the fusion protein can be attached to the first binding domain at a light chain variable domain of the single chain variable fragment of the first binding domain (LH orientation). The third binding domain of the fusion protein can target an antigen of an immune cell, such as an antigen presenting cell (APC). The third binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD40. The third binding domain of the fusion protein can be a CD40 agonist. The third binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to DEC-205. The third binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD40, CD47, TNFR2, DEC-205, PD-Ll, CD36 mannose scavenger receptor 1, CLEC9A, DC-SIGN, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, CD38, TREM2, CSF1R, or CD32B.

[0247] Alternatively, the third binding domain can target a tumor antigen. The third binding domain of the fusion protein can specifically bind to an antigen with at least 80% sequence identity to CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1,

PD-Ll, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM,

MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor,

EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WTl, LMP2, HPV E6, HPV E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP,

ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, MYCN, RhoC, TRP-2, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, CYP1B 1, PLAV1, BORIS, GloboH, ETV6-

AML, NY-BR-1, RGS5, SART3, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17,

LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, PAGE4, VEGFR2, MAD-CT-1,

PDGFR-B, MAD-CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET,

HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6,

TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin,

VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof. In additional embodiments, the third binding domain of the fusion protein can specifically bind to an antigen selected from CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin B l, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B 1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, PAGE4, VEGFR2, MAD-CT-1, PDGFR-B, MAD- CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4,

TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof.

[0248] An antibody construct can comprise a first binding domain targeting CD40 and a second binding domain targeting DEC-205. Alternatively, an antibody construct can comprise a first binding domain targeting DEC-205 and a second binding domain targeting CD40. An antibody construct can comprise a first binding domain, a second binding domain, and an Fc domain. The first binding domain and the second binding domain can be attached to the Fc domain. The first binding domain can be attached to the Fc domain at an N-terminal end of the Fc domain, wherein the second binding domain is attached to the Fc domain at a C-terminal end of the Fc domain. Alternatively, the second binding domain can be attached to the Fc domain at an N-terminal end of the Fc domain, wherein the first binding domain is attached to the Fc domain at a C-terminal end of the Fc domain. An antibody construct can comprise a fusion protein comprising a first binding domain targeting CD40 and a second binding domain targeting DEC-205. The fusion protein can comprise at least 80% sequence identity to any sequence in TABLE 11.

[0249] Additionally, antibody constucts expressing proteins having the sequences referenced in Tables 1-11 can have a dissociation constant (IQ) that is less than 10 nM for the antigen of the first binding domain. The antibody constructs expressing proteins having the sequences referenced in Tables 1-11 can have a dissociation constant (IQ) that is less than 10 nM for the antigen of the second binding domain. The antibody constructs expressing the sequences referenced in Tables 1-11 can have a dissociation constant (K _d ) that is less than 10 nM for the antigen of the third binding domain. The antibody constructs can have a dissociation constant (K _d ) for the antigen of the first binding domain that is less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM, or less than 0.1 pM. The antibody constructs can have a dissociation constant (K _d ) for the antigen of the second binding domain that is less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM, or less than 0.1 pM. The antibody constructs can have a dissociation constant (K _d ) for the antigen of the third binding domain that is less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM, or less than 0.1 pM.

[0250] An anti-CD40 light chain can be expressed with an anti-CD40 heavy chain or fragment thereof, wherein the light and heavy chains specifically bind to CD40. The anti-CD40 light chain can also be expressed with an anti-CD40 heavy chain or fragment thereof to form an anti-CD40 antibody or fragment thereof, wherein the antibody or antibody fragment specifically binds to CD40. The anti-CD40 antibody or fragment thereof can be purified, and can be combined with a pharmaceutically acceptable carrier.

[0251] An anti-DEC-205 light chain can be expressed with any anti-DEC-205 heavy chain or fragment thereof, wherein the light and heavy chains specifically bind to DEC-205. The anti- DEC-205 light chain can also be expressed with an anti-DEC-205 heavy chain or fragment thereof to form an anti-DEC-205 antibody or fragment thereof, wherein the antibody or antibody fragment specifically binds to DEC-205. The anti-DEC-205 antibody or fragment thereof can be purified, and can be combined with a pharmaceutically acceptable carrier.

[0252] An anti-PD-Ll light chain can be expressed with any anti-PD-Ll heavy chain or fragment thereof, wherein the light and heavy chains specifically bind to PD-L1. The anti-PD-Ll light chain can also be expressed with an anti-PD-Ll heavy chain or fragment thereof to form an anti- PD-Ll antibody or fragment thereof, wherein the antibody or antibody fragment specifically binds to PD-L1. The anti-PD-Ll antibody or fragment thereof can be purified, and can be combined with a pharmaceutically acceptable carrier.

[0253] An anti-tumor antigen light chain can be expressed with any anti-tumor antigen heavy chain or fragment thereof, wherein the antibody or antibody fragment specifically binds to tumor antigen. The anti-tumor antigen light chain can also expressed with any anti-tumor antigen heavy chain or fragment thereof to form an anti-tumor antigen antibody or fragment thereof. The antitumor antibody or fragment thereof can be purified, and can be combined with a

pharmaceutically acceptable carrier.

[0254] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be an IgGl isotype. A heavy chain of an anti-CD40 antibody can be dacetuzumab.

[0255] An antibody construct can comprise an antibody light chain. A light chain can be a light chain of an anti-CD40 antibody which can bind a CD40 antigen. A light chain of an anti-CD40 antibody can be dacetuzumab.

[0256] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be an IgG4 isotype. A heavy chain of an anti-CD40 antibody can be bleselumab.

[0257] An antibody construct can comprise an antibody light chain. A light chain can be a light chain of an anti-CD40 antibody which can bind a CD40 antigen. A light chain of an anti-CD40 antibody can be bleselumab.

[0258] An antibody constructcan comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be an IgGl isotype. A heavy chain of an anti-CD40 antibody can be lucatumumab.

[0259] An antibody construct can comprise an antibody light chain. A light chain can be a light chain of an anti-CD40 antibody which can bind a CD40 antigen. A light chain of an anti-CD40 antibody can be lucatumumab.

[0260] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be an IgGl isotype. A heavy chain of an anti-CD40 antibody can be ADC- 1013.

[0261] An antibody construct can comprise an antibody light chain. A light chain can be a light chain of an anti-CD40 antibody which can bind a CD40 antigen. A light chain of an anti-CD40 antibody can be ADC- 1013.

[0262] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be the humanized rabbit antibody APX005.

[0263] An antibody construct can comprise an antibody light chain. A light chain can be a light chain of an anti-CD40 antibody which can bind a CD40 antigen. A light chain of an anti-CD40 antibody can be the humanized rabbit antibody APX005.

[0264] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be Chi Lob 7/4. [0265] An antibody construct can comprise an antibody light chain. A light chain can be a light chain of an anti-CD40 antibody which can bind a CD40 antigen. A light chain of an anti-CD40 antibody can be Chi Lob 7/4.

[0266] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be an IgGl isotype. A heavy chain of an anti-CD40 antibody can be SBT- 040-G1WT.

[0267] An antibody construct can comprise an antibody heavy chain. A heavy chain can be a heavy chain of an anti-CD40 antibody which can bind a CD40 antigen. A heavy chain of an anti- CD40 antibody can be an IgGl isotype. A heavy chain of an anti-CD40 antibody can be SBT- 040 VH-hlgGl wt.

[0268] A heavy chain of an anti-CD40 antibody can be an IgG2 isotype. A heavy chain of an anti-CD40 antibody can be SBT-040-G2.

[0269] An antibody construct can comprise an antibody with modifications occurring at least at one amino acid residue. Modifications can be substitutions, additions, mutations, deletions, or the like. An antibody modification can be an insertion of an unnatural amino acid.

[0270] An antibody construct can comprise a light chain of an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine, or ten modifications but not more than 40, 35, 30, 25, 20, 15, or 10 modifications of the amino acid sequence relative to the natural or original amino acid sequence. An antibody construct can comprise a heavy chain with an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine or ten

modifications but not more than 40, 35, 30, 25, 20, 15, or 10 modifications of the amino acid sequence relative to the natural or original amino acid sequence.

[0271] An antibody construct can have an Fc domain of an IgGl isotype. An antibody construct can have an Fc domain of an IgG2 isotype. An antibody construct can have an Fc domain of an IgG3 isotype. An antibody construct can have an Fc domainof an IgG4 isotype. An antibody construct can have an Fc domain of a hybrid isotype comprising constant regions from two or more isotypes. An antibody construct can be an anti-CD40 antibody, in which the anti-CD40 antibody can be a monoclonal human antibody comprising a wild-type sequence of an IgGl isoform, in particular, at an Fc region of the antibody.

[0272] An antibody constructs disclosed herein can be non-natural, designed, and/or engineered. Antibody constructs disclosed herein can be non-natural, designed, and/or engineered scaffolds comprising an antigen binding domain. Antibody constructs disclosed herein can be no n- natural, designed, and/or engineered antibodies. Antibody constructs can be monoclonal antibodies. Antibody constructs can be human antibodies. Antibody constructs can be humanized antibodies. Antibody constructs can be monoclonal humanized antibodies. Antibody construct can be recombinant antibodies.

[0273] The K _d for binding of the Fc domain to an Fc receptor of an antibody construct as described herein can increase when the tumor antigen binding domain is bound to its tumor antigen as compared to the K _d for binding of the Fc domain to an Fc receptor of a construct as described herein when the tumor antigen binding domain is not bound to its tumor antigen. For example, an antibody construct as described herein can have a K _d for binding of the Fc domain to an Fc receptor in the presence of the binding domain that binds to an antigen on an immune cell, such as an antigen presenting cell, and the tumor target binding domain when the tumor target binding domain is bound to its tumor antigen that can be greater than or greater than about 100 nM. The K _d for binding of the Fc domain to an Fc receptor in the presence of the binding domain that binds to an antigen on an immune cell, such as an antigen presenting cell, and the tumor target binding domain when the tumor target binding domain is bound to its tumor antigen can be or can be about 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, or 1000 nM. The ¾ for binding of the Fc domain to an Fc receptor in the presence of the binding domain that binds to an antigen on an immune cell, such as an antigen presenting cell, and the tumor target binding domain when the tumor target binding domain is bound to its tumor antigen can be from 100 nM to 200 nM, 100 nM to 300 nM, 100 nM to 400 nM, 100 nM to 500 nM, or 100 nM to 1000 nM. Additionally, the antibody construct as described herein can have a K _d for binding of the Fc domain to an Fc receptor in the presence of the binding domain that binds to an antigen on an immune cell, such as an antigen presenting cell, and a tumor antigen binding domain when the tumor antigen binding domain is not bound to the tumor antigen is no greater than about 100 nM and is no greater than about 100 times a K _d for binding of the Fc domain to the Fc receptor in an absence of the binding domain that binds to an antigen on an immune cell and a tumor antigen binding domain.

[0274] The K _d for binding of the binding domain of an antibody construct as described herein that binds to an antigen on an immune cell, such as an antigen presenting cell, can increase when the tumor antigen binding domain is bound to its tumor antigen as compared to the K _d for binding of the binding domain that binds to an antigen on an immune cell when the tumor antigen binding domain is not bound to its tumor antigen. For example, an antibody construct can comprise a K _d for binding of the binding domain that binds to an antigen on an antigen presenting cell when the tumor antigen binding domain is bound to its tumor antigen can be greater than or greater than about ΙΟΟηΜ. The K _d for binding of the binding domain that binds to an antigen on an immune cell, such as an antigen presenting cell, when the tumor antigen binding domain is bound to its tumor antigen can be or can be about 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, or 1000 nM. IQ for binding of the binding domain that binds to an antigen on an immune cell when the tumor antigen binding domain is bound to its tumor antigen can be from 100 nM to 200 nM, 100 nM to 300 nM, 100 nM to 400 nM, 100 nM to 500 nM, or 100 nM to 1000 nM.

[0275] The effect of the tumor antigen binding domain and the binding domain that binds to an antigen on the immune cell together can be to cluster the antibody constructs or conjugates on cells expressing tumor antigen, and thus clustering immune cells such as antigen presenting cells around cancerous cells and at tumor sites resulting in activation of the antigen presenting cell effector functions. This can include the activation of the antigen on the antigen presenting cell when a an antibody construct is bound to its antigen, such as activation of CD40, CD47, TNFR2, DEC-205, PD-L1, CD36 mannose scavenger receptor 1, DC-SIGN, CLEC9A, CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2, CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, CD38, TREM2, CSFIR, or CD32B. In some embodiments, this activation of the antigen on the antigen presenting cell only occurs when the tumor targeting antibody construct is bound to its tumor antigen. An antigen presenting cell effector function can include antibody dependent cellular cytotoxicity (ADCC) of the tumor antigen expressing cell, which can occur when a bispecific tumor targeting antibody construct is bound to its tumor antigen. In some embodiments, ADCC of the tumor antigen expressing cell only occurs with a bispecific tumor targeting antibody construct is bound to its tumor antigen. In certain

embodiments, a bispecific tumor targeting antibody construct density of greater than 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000 or more per cell, resulting from the bispecific tumor targeting antibody construct binding to the tumor antigen, induces signaling in the antigen presenting cell. Signaling can suitably be measured in vitro using a cell line expressing the tumor antigen bound by the target antigen binding domain, and primary antigen presenting cells isolated from a human subject. Signaling can be assessed as cytokine release, chemokine release, or increased expression of cell surface markers. In certain embodiments, a bispecific tumor targeting antibody construct density of greater than 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000 or more per cell, resulting from the bispecific tumor targeting antibody construct binding to the tumor antigen, induces ADCC of the cells expressing tumor antigen. ADCC can suitably be measured in vitro using a cell line expressing the tumor antigen bound by the target antigen binding domain, and cells such as NK cells and/or macrophages isolated from a human subject. ADCC can be determined by the frequency of remaining tumor antigen expressing cells in the co-culture.

[0276] In some embodiments, the antibody constructs as described herein can specifically bind to a tumor antigen in a cluster of constructs or conjugates, and this clustering can induce a signal in an antigen presenting cell. The constructs as described herein can specifically bind to a tumor antigen in a cluster of constructs, and this clustering can induce antibody dependent cellular cytotoxicity. The constructs as described herein can specifically bind to a tumor antigen in a cluster of constructs and this clustering can result in an increased avidity for an antigen on an antigen presenting cell. The antibody constructs as described herein can specifically bind to a tumor antigen in a cluster of constructs and this clustering can result in an increased avidity of the Fc domain for an Fc receptor.

[0277] Sequences that can be used to produce antibodies for antibody constructs can include leader sequences. Leader sequences can include signal sequences. Leader sequences useful with the antibody construct and methods described herein can include, but are not limited to, an amino acid sequence comprising MRLP AQLLGLLLLWFPGS RC (SEQ ID NO: 847),

MDWTWRILFLVAAATGAHS (SEQ ID NO: 848), and MRAWIFFLLCLAGRALA (SEQ ID NO: 849).

[0278] An antibody construct can comprise an Fc region with an Fc domain. An Fc domain is a structure that can bind to Fc receptors. An antibody construct can comprise an Fc domain. Fc domains can be bound by Fc receptors (FcRs). Fc domains can be from antibodies. An Fc domain can be at least 80% homologous to an Fc domain from an antibody. An Fc region can be in a scaffold. An Fc region with an Fc domain can be in an antibody scaffold. An Fc region with an Fc domain can be in a non-antibody scaffold. An antibody construct can comprise an Fc region with an Fc domain in an antibody scaffold. An antibody construct can comprise an Fc region with an Fc domain in a non-antibody scaffold. An Fc domain can be in a scaffold. An Fc domain can be in an antibody scaffold. An Fc domain can be in a non-antibody scaffold. An antibody construct can comprise an Fc domain in an antibody scaffold. An antibody construct can comprise an Fc domain in a non-antibody scaffold. Fc domains of antibodies, including those of the present disclosure, can be bound by Fc receptors (FcRs). An Fc domain can be a portion of the Fc region of an antibody. FcRs can bind to an Fc domain of an antibody. FcRs can bind to an Fc domain of an antibody bound to an antigen. FcRs are organized into classes (e.g. , gamma (γ), alpha (a) and epsilon (ε)) based on the class of antibody that the FcR recognizes. The FcaR class can bind to IgA and includes several isoforms, FcaRI (CD89) and Fco jR. The FcyR class can bind to IgG and includes several isoforms, FcyRI (CD64), FcyRIIA (CD32a), FcyRIIB (CD32b), FcyRIIIA (CD 16a), and FcyRIIIB (CD 16b). An FcyRIIIA (CD 16a) can be an FcyRIIIA (CD 16a) F158 variant. An FcyRIIIA (CD 16a) can be an FcyRIIIA (CD 16a) V158 variant. Each FcyR isoform can differ in affinity to the Fc region of the IgG antibody. For example, FcyRI can bind to IgG with greater affinity than FcyRII or FcyRIII. The affinity of a particular FcyR isoform to IgG can be controlled, in part, by a glycan (e.g., oligosaccharide) at position CH ₂ 84.4 of the IgG antibody. For example, fucose containing CH ₂ 84.4 glycans can reduce IgG affinity for FcyRIIIA. In addition, GO glucans can have increased affinity for FcyRIIIA due to the lack of galactose and terminal GlcNAc moiety.

[0279] Binding of an Fc domain to an FcR can enhance an immune response. FcR-mediated signaling that can result from an Fc region binding to an FcR can lead to the maturation of immune cells. FcR-mediated signaling that can result from an Fc domain binding to an FcR can lead to the maturation of dendritic cells. FcR-mediated signaling that can result from an Fc domain binding to an FcR can lead to antibody dependent cellular cytotoxicity. FcR-mediated signaling that can result from an Fc domain binding to an FcR can lead to more efficient immune cell antigen uptake and processing. FcR-mediated signaling that can result from an Fc region binding to an FcR can lead to more efficient dendritic cell antigen uptake and processing. FcR- mediated signaling that can result from an Fc region binding to an FcR can increase antigen presentation. FcR-mediated signaling that can result from an Fc region binding to an FcR can increase antigen presentation by immune cells. FcR-mediated signaling that can result from an Fc region binding to an FcR can increase antigen presentation by antigen presenting cells. FcR- mediated signaling that can result from an Fc domain binding to an FcR can increase antigen presentation by dendritic cells. FcR-mediated signaling that can result from an Fc domain binding to an FcR can promote the expansion and activation of T cells. FcR-mediated signaling that can result from an Fc domain binding to an FcR can promote the expansion and activation of CD8 ⁺ T cells. FcR-mediated signaling that can result from an Fc domain binding to an FcR can influence immune cell regulation of T cell responses. FcR-mediated signaling that can result from an Fc domain binding to an FcR can influence immune cell regulation of T cell responses. FcR-mediated signaling that can result from an Fc domain binding to an FcR can influence dendritic cell regulation of T cell responses. FcR-mediated signaling that can result from an Fc domain binding to an FcR can influence functional polarization of T cells (e.g., polarization can be toward a ¾1 cell response).

[0280] The profile of FcRs on a dendritic cell (DC) can impact the ability of the DC to respond upon stimulation. For example, most DC can express both CD32A and CD32B, which can have opposing effects on IgG-mediated maturation and function of DCs: binding of IgG to CD32A can mature and activate DCs in contrast with CD32B, which can mediate inhibition due to phosphorylation of immunoreceptor tyro sine-based inhibition motif (ITIM), after CD32B binding of IgG. Therefore, the activity of these two receptors can establish a threshold of DC activation. Furthermore, the difference in functional avidity of these receptors for IgG can shift their functional balance. Hence, altering the Fc domain binding to FcRs can also shift their functional balance, allowing for manipulation (either enhanced activity or enhanced inhibition) of the DC immune response.

[0281] A modification in the amino acid sequence of the Fc domain of an antibody construct can alter the recognition of an FcR for the Fc domain. However, such modifications can still allow for FcR-mediated signaling. A modification can be a substitution of an amino acid at a residue (e.g., wildtype) for a different amino acid at that residue. A modification can permit binding of an FcR to a site on the Fc domain or region that the FcR may not otherwise bind to. A modification can increase the binding affinity of an FcR to the Fc domain that the FcR may have reduced binding affinity for. A modification can decrease binding affinity of an FcR to a site on the Fc domain that the FcR may have increased binding affinity for. A modification can increase the subsequent FcR-mediated signaling after Fc binding to an FcR.

[0282] An antibody construct can comprise an Fc region with at least one amino acid change as compared to the sequence of the wild-type Fc region. An antibody construct can comprise an Fc domain with at least one amino acid change as compared to the sequence of the wild-type Fc domain. An amino acid change in an Fc region can allow the construct to bind to at least one Fc receptor with greater affinity compared to a wild-type Fc region. An amino acid change in an Fc domain can allow the antibody construct to bind to at least one Fc receptor with greater affinity compared to a wild-type Fc domain. An Fc region can comprise an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine or ten modifications but not more than 40, 35, 30, 25, 20, 15, or 10 modifications of the amino acid sequence relative to the natural or original amino acid sequence. An Fc domain can comprise an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine or ten modifications but not more than 40, 35, 30, 25, 20, 15, or 10 modifications of the amino acid sequence relative to the natural or original amino acid sequence. An Fc region can be an Fc region of an IgGl antibody. An Fc region can contain an Fc domain. An Fc region can be an Fc domain.

[0283] An antibody construct can be an antibody comprising a sequence of the IgGl isoform that has been modified from the wildtype IgGl sequence. A modification can comprise a substitution at more than one amino acid residue such as at 5 different amino acid residues including

L235V/F243L/R292P/Y300L/P396L (IgGlVLPLL). The numbering of amino acids residues is according to the EU index of Kabat. The 5 amino acid residues can be located in a portion of an antibody sequence which can encode an Fc region of the antibody and in particular, can be located in portions of the Fc region that can bind to Fc receptors (i.e., the Fc domain). A modification can comprise a substitution at more than one amino acid residue such as at 3 different amino acid residues including S298A/E333A/K334A (IgGl AAA), according to the EU index of Kabat. The 3 amino acid residues can be located in a portion of an antibody sequence which can encode an Fc region of the antibody and in particular, can be located in portions of the Fc region that can bind Fc receptors (i.e., the Fc domain).

[0284] In some embodiments, the Fc domain or region can comprise a sequence of an IgG isoform that has been modified from the wild-type IgG sequence. In some embodiments, the Fc domain or region can comprise a sequence of the IgGl isoform that has been modified from the wild-type IgGl sequence. In some embodiments, the modification comprises substitution of one or more amino acids that reduce binding affinity of an IgG Fc domain or region to all Fey receptors. A modification can be substitution of E233, L234 and L235, such as

E233P/L234V/L235A or E233P/L234V/L235A/AG236, according to the EU index of Kabat. A modification can be substitution of L235, F243, R292, Y300 and P396, such as

L235V/F243L/R292P/Y300L/P396L (IgGlVLPLL) according to the EU index of Kabat. A modification can be a substitution of P238, such as P238A, according to the EU index of Kabat. A modification can be a substitution of D265, such as D265A, according to the EU index of Kabat. A modification can be a substitution of N297, such as N297A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A327Q, according to the EU index of Kabat. A modification can be a substitution of P329, such as P239A, according to the EU index of Kabat.

[0285] In some embodiments, an IgG Fc domain or region comprises at least one amino acid substitution that reduces its binding affinity to FcyRl, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at F241, such as F241A, according to the EU index of Kabat. A modification can comprise a substitution at F243, such as F243A, according to the EU index of Kabat. A modification can comprise a substitution at V264, such as V264A, according to the EU index of Kabat. A modification can comprise a substitution at D265, such as D265A according to the EU index of Kabat.

[0286] In some embodiments, an IgG Fc domain or region comprises at least one amino acid substitution that increases its binding affinity to FcyRl, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at A327 and P329, such as

A327Q/P329A, according to the EU index of Kabat.

[0287] In some embodiments, the modification comprises substitution of one or more amino acids that reduce binding affinity of an IgG Fc domain or region to FcyRII and FcyRIIIA receptors. A modification can be a substitution of D270, such as D270A, according to the EU index of Kabat. A modification can be a substitution of Q295, such as Q295A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A237S, according to the EU index of Kabat. [0288] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRII and FcyRIIIA receptors. A modification can be a substitution of T256, such as T256A, according to the EU index of Kabat. A modification can be a substitution of K290, such as K290A, according to the EU index of Kabat.

[0289] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRII receptor. A modification can be a substitution of R255, such as R255A, according to the EU index of Kabat. A modification can be a substitution of E258, such as E258A, according to the EU index of Kabat. A modification can be a substitution of S267, such as S267A, according to the EU index of Kabat. A modification can be a substitution of E272, such as E272A, according to the EU index of Kabat. A modification can be a substitution of N276, such as N276A, according to the EU index of Kabat. A modification can be a substitution of D280, such as D280A, according to the EU index of Kabat. A modification can be a substitution of H285, such as H285A, according to the EU index of Kabat. A modification can be a substitution of N286, such as N286A, according to the EU index of Kabat. A modification can be a substitution of T307, such as T307A, according to the EU index of Kabat. A modification can be a substitution of L309, such as L309A, according to the EU index of Kabat. A modification can be a substitution of N315, such as N315A, according to the EU index of Kabat. A modification can be a substitution of K326, such as K326A, according to the EU index of Kabat. A modification can be a substitution of P331, such as P331A, according to the EU index of Kabat. A modification can be a substitution of S337, such as S337A, according to the EU index of Kabat. A modification can be a substitution of A378, such as A378A, according to the EU index of Kabat. A modification can be a substitution of E430, such as E430, according to the EU index of Kabat.

[0290] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRII receptor and reduces the binding affinity to FcyRIIIA receptor. A modification can be a substitution of H268, such as H268A, according to the EU index of Kabat. A modification can be a substitution of R301, such as R301A, according to the EU index of Kabat. A modification can be a substitution of K322, such as K322A, according to the EU index of Kabat.

[0291] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain or region to FcyRII receptor but does not affect the binding affinity to FcyRIIIA receptor. A modification can be a substitution of R292, such as R292A, according to the EU index of Kabat. A modification can be a substitution of K414, such as K414A, according to the EU index of Kabat. [0292] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain or region to FcyRII receptor and increases the binding affinity to FcyRIIIA receptor. A modification can be a substitution of S298, such as S298A, according to the EU index of Kabat. A modification can be substitution of S239, 1332 and A330, such as S239D/I332E/A330L. A modification can be substitution of S239 and 1332, such as S239D/I332E.

[0293] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain or region to FcyRIIIA receptor and does not affect the binding affinity to FcyRII receptor. A modification can be a substitution of S239, such as S239A, according to the EU index of Kabat. A modification can be a substitution of E269, such as E269A, according to the EU index of Kabat. A modification can be a substitution of E293, such as E293A, according to the EU index of Kabat. A modification can be a substitution of Y296, such as Y296F, according to the EU index of Kabat. A modification can be a substitution of V303, such as V303A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A327G, according to the EU index of Kabat. A

modification can be a substitution of K338, such as K338A, according to the EU index of Kabat. A modification can be a substitution of D376, such as D376A, according to the EU index of Kabat.

[0294] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRIIIA receptor and does not affect the binding affinity to FcyRII receptor. A modification can be a substitution of E333, such as E333A, according to the EU index of Kabat. A modification can be a substitution of K334, such as K334A, according to the EU index of Kabat. A modification can be a substitution of A339, such as A339T, according to the EU index of Kabat. A modification can be substitution of S239 and 1332, such as S239D/I332E.

[0295] In some embodiments, an IgG Fc domain or region comprises at least one amino acid substitution that reduces the binding affinity to FcRn, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at H435, such as H435A according to the EU index of Kabat. A modification can comprise a substitution at 1253, such as 1253 A according to the EU index of Kabat. A modification can comprise a substitution at H310, such as H310A according to the EU index of Kabat. A modification can comprise substitutions at 1253, H310 and H435, such as I253A/H310A/H435A according to the EU index of Kabat.

[0296] A modification can comprise a substitution of one amino acid residue that increases the binding affinity of an IgG Fc domain for FcRn, relative to a wildtype or reference IgG Fc domain. A modification can comprise a substitution at V308, such as V308P according to the EU index of Kabat. A modification can comprise a substitution at M428, such as M428L according to the EU index of Kabat. A modification can comprise a substitution at N434, such as N434A according to the EU index of Kabat or N434H according to the EU index of Kabat. A modification can comprise substitutions at T250 and M428, such as T250Q and M428L according to the EU index of Kabat. A modification can comprise substitutions at M428 and N434, such as M428L and N434S, N434A or N434H according to the EU index of Kabat. A modification can comprise substitutions at M252, S254 and T256, such as M252Y/S254T/T256E according to the EU index of Kabat. A modification can be a substitution of one or more amino acids selected from P257L, P257N, P257I, V279E, V279Q, V279Y, A281S, E283F, V284E, L306Y, T307V, V308F, Q311V, D376V, and N434H. Other substitutions in an IgG Fc domain that affect its interaction with FcRn are disclosed in U.S. Patent No. 9,803,023 (the disclosure of which is incorporated by reference herein).

[0297] An antibody construct can be a monoclonal anti-CD40 human antibody comprising a sequence of the IgGl isoform that has been modified from the wildtype IgGl sequence. A modification can comprise a substitution at more than one amino acid residue such as at 5 different amino acid residues including L235V/F243L/R292P/Y300L/P396L (SBT-040- G1VLPLL). The numbering of amino acids residues is according to the EU index. The 5 amino acid residues can be located in a portion of an antibody sequence which can encode an Fc region of the antibody and in particular, can be located in portions of the Fc region that can bind to Fc receptors (i.e., the Fc domain). A modification can comprise a substitution at more than one amino acid residue such as at 3 different amino acid residues including S298A/E333A/K334A (SBT-040-G1AAA). The 3 amino acid residues can be located in a portion of an antibody sequence which can encode an Fc region of the antibody and in particular, can be located in portions of the Fc region that can bind Fc receptors (i.e., the Fc domain).

[0298] Binding of Fc receptors to an Fc region can be affected by amino acid substitutions. For example, SBT-040-VLPLL is an antibody with an amino acid sequence of a heavy chain of human anti-CD40 monoclonal antibody with modifications to a wild-type IgGl Fc domain (L235V/F243L/R292P/Y300L/P396L). Binding of some Fc receptors to the Fc region of SBT- 040-VLPLL can be enhanced compared to wild-type by as result of the

L235V/F243L/R292P/Y300L/P396L amino acid modifications. However, binding of other Fc receptors to the Fc region of SBT-040-VLPLL can be reduced compared to wild-type by the L235V/F243L/R292P/Y300L/P396L amino acid modifications. For example, the binding affinities of SBT-040-VLPLLto FcyRIIIA and to FcyRIIA can be enhanced compared to wild- type whereas the binding affinity of SBT-040-VLPLL to FcyRIIB can be reduced compared to wild-type. Binding of Fc receptors to an Fc region of are affected by amino acid substitutions. SBT-040-G1AAA antibody is an antibody with an amino acid sequence of a heavy chain of a human anti-CD40 monoclonal antibody with modifications to a wild-type IgGl Fc domain (S298A/E333A/K334A). Binding of Fc receptors to an Fc region of SBT-040-G1AAA can be enhanced compared to wild-type as a result of the S298A/E333A/K334A amino acid

modification. However, binding of some Fc receptors to the Fc region of SBT-040-G1AAA can be reduced compared to wild-type by S298A/E333A/K334A amino acid modification. Binding affinities of SBT-040-G1AAA to FcyRIIIA can be enhanced compared to wild-type whereas the binding affinity of SBT-040-G1AAA to FcyRIIB can be reduced compared to wildtype.

[0299] In some embodiments, the heavy chain of a human IgG2 antibody can be mutated at cysteines as positions 127, 232, or 233. In some embodiments, the light chain of a human IgG2 antibody can be mutated at a cysteine at position 214. The mutations in the heavy and light chains of the human IgG2 antibody can be from a cysteine residue to a serine residue.

[0300] While an antibody construct of the present disclosure can comprise a first binding domain and a second binding domain (or, in some cases, a third binding domain) with wild-type or modified amino acid sequences encoding the Fc region or Fc domain, the modifications of the Fc region or the Fc domain from the wild-type sequence may not significantly alter binding and/or affinity of the binding domains. For example, binding and/or affinity of an antibody

constructcomprising a first binding domain and a second binding domain (or, in some cases, a third binding domain) and having the Fc domain modifications of SBT-040-G1WT, SBT-040- G1VLPLL, or SBT-040-G1AAA may not be significantly altered by modification of an Fc region or Fc domain amino acid sequence compared to a wild-type sequence. Modifications of an Fc region or Fc domain from a wild-type sequence may not alter binding and/or affinity of a first binding domain that binds, for example, to CD40 or DEC-205. Additionally, the binding and/or affinity of the binding domains described herein, for example, a first binding domain, a second binding domain (or, in some cases, a third binding domain), and an Fc domain modification selected from SBT-040-G1WT, SBT-040-G1VLPLL, and SBT-040-G1AAA, may be comparable to the binding and/or affinity of wild-type antibodies.

[0301] In some embodiments, the binding profile of the Fc domain for Fey receptors can be retained in the antibody construct or conjugate, which can allow for delivery of the antibody construct or conjugate into immune cell types comprising the Fey receptors and can further immune activation by Fey receptor signaling. In some embodiments, APCs can be activated by an antibody construct or conjugate as described herein when the antibody construct or conjugate is bound to a tumor cell, undergoes Fey receptor mediated uptake, or undergoes Fey receptor mediated Antibody Dependent Cellular Phagocytosis (ADCP). In some embodiments, the antibody construct or conjugate can retain weak or no Fey receptor binding to allow for maximal immune activation or decreased toxicity of the immune- stimulatory compound due to the primary delivery of the antibody construct or conjugate into tumor cells by antibody antigen mediated endocytosis.

[0302] In some embodiments, the antibody construct or conjugate can comprise an IgGl Fc domain variant comprising N297A, N297G, K322A/L234A/L235A, or L234F/L235E/P331S, and lacks binding to an Fey receptor but can retain binding to FcRN in the presence of the immune-modulatory compound to allow for lower delivery of the conjugate into tumor cells or immune cells.

[0303] In some embodiments, an antibody construct or conjugate can comprise an Fc domain with higher affinity to one or more Fey receptors, which can result in greater immune activation than for an antibody construct or conjugate with an Fc domain that can bind to one or more Fey receptors with lower affinity.

TABLE 1. Tumor Antibody CDRs

Antibody Region SEQ ID Sequence

NO:

Pertuzumab HCDR1 13 GFTFTDYT

HCDR2 14 VNPNSGGS

HCDR3 15 ARNLGPSFYFDY

LCDR1 18 QDVSIG

LCDR2 19 SAS

LCDR3 20 QQYYIYPYT

Cetuximab HCDR1 26 GFSLTNYG

HCDR2 27 IWSGGNT

HCDR3 28 ARALTYYDYEFAY

LCDR1 31 QSIGTN

LCDR2 32 YAS

LCDR3 33 QQNNNWPTT

Panitumumab HCDR1 39 GGSVSSGDYY

HCDR2 40 IYYSGNT

HCDR3 41 VRDRVTGAFDI

LCDR1 44 QDISNY

LCDR2 45 DAS

LCDR3 46 QHFDHLPLA

Nimotuzumab HCDR1 52 GYTFTNYY

HCDR2 53 INPTSGGS

HCDR3 54 ARQGLWFDSDGRGFDF

LCDR1 57 QNIVHSNGNTY

LCDR2 58 KVS

LCDR3 59 FQYSHVPWT

Zalutumumab HCDR1 65 GFTFSTYG

HCDR2 66 IWDDGSYK

HCDR3 67 ARDGITMVRGVMKDYFDY

LCDR1 70 QDISSA

LCDR2 71 DAS

LCDR3 72 QQFNSYPLT

Onartuzumab HCDR1 78 GYTFTSYW

HCDR2 79 IDPSNSDT

HCDR3 80 ATYRSYVTPLDY

LCDR1 83 QSLLYTSSQKNY

LCDR2 84 WAS Antibody Region SEQ ID Sequence

NO:

LCDR3 85 QQYYAYPWT

Patritumab HCDR1 91 GGSFSGYY

HCDR2 92 INHSGST

HCDR3 93 ARDKWTWYFDL

LCDR1 96 QSVLYSSSNRNY

LCDR2 97 WAS

LCDR3 98 QQYYSTPRT

Clivatuzumab HCDR1 104 GYTFPSYV

HCDR2 105 INPYNDGT

HCDR3 106 ARGFGGSYGFAY

LCDR1 109 SSVSSSY

LCDR2 110 STS

LCDR3 111 HQWNRYPYT

Sofituzumab HCDR1 117 GYSITNDYA

HCDR2 118 ISYSGYT

HCDR3 119 ARWT SGLDY

LCDR1 122 DLIHNW

LCDR2 123 GAT

LCDR3 124 QQYWTTPFT

Edrecolomab HCDR1 130 GYAFTNYL

HCDR2 131 INPGSGGT

HCDR3 132 ARDGPWFAY

LCDR1 135 ENVVTY

LCDR2 136 GAS

LCDR3 137 GQGYSYPYT

Adecatumumab HCDR1 143 GFTFSSYG

HCDR2 144 ISYDGSNK

HCDR3 145 AKDMGWGSGWRPYYYYGMDV

LCDR1 148 QSISSY

LCDR2 149 WAS

LCDR3 150 QQSYDIPYT

Anetumab HCDR1 156 GYSFTSYW

HCDR2 157 IDPGDSRT

HCDR3 158 ARGQLYGGTYMDG

LCDR1 161 SSDIGGYNS

LCDR2 162 GVN

LCDR3 163 SSYDIESATPV huDS6 HCDR1 169 GYTFTSYN

HCDR2 170 IYPGNGAT

HCDR3 171 ARGDSVPFAY

LCDR1 174 SSVSF

LCDR2 175 STS

LCDR3 176 QQRSSFPLT

Lifastuzumab HCDR1 182 GFSFSDFA

HCDR2 183 IGRVAFHT

HCDR3 184 ARHRGFDVGHFDF

LCDR1 187 ETLV HSSGNTY

LCDR2 188 RVS

LCDR3 189 FQGSFNPLT

Sacituzumab HCDR1 195 GYTFTNYG

HCDR2 196 INTYTGEP

HCDR3 197 ARGGFGSSYWYFDV

LCDR1 200 QDVSIA

LCDR2 201 SAS

LCDR3 202 QQHYITPLT

PR1A3 HCDR1 208 GYTFTEFG

HCDR2 209 INTKTGEA

HCDR3 210 ARWDFYDYVEAMDY Antibody Region SEQ ID Sequence

NO:

LCDR1 213 QNVGTN

LCDR2 214 SAS

LCDR3 215 HQYYTYPLFT

Humanized PR1A3 HCDR1 805 GYTFTEFG

HCDR2 806 INTKTGEA

HCDR3 807 ARWDFAYYVEAMDY

LCDR1 808 AAVGTY

LCDR2 809 SAS

LCDR3 810 HQYYTYPLFT

Humanized Ab2-3 HCDR1 823 GFVFSSYD

HCDR2 824 YISSGGGIT

HCDR3 825 AAHYFGSSGPFAY

LCDR1 826 ENIFSY

LCDR2 827 NTR

LCDR3 828 QHHYGTPFT

IMAB362, HCDR1 221 GYTFTSYW

CLAUDIXIMAB HCDR2 222 IYPSDSYT

HCDR3 223 TRSWRGNSFDY

LCDR1 226 QSLLNSGNQKNY

LCDR2 227 WAS

LCDR3 228 QNDYSYPFT

AMG595 HCDR1 260 GFTFRNYG

HCDR2 261 IWYDGSDK

HCDR3 262 ARDGYDILTGNPRDFDY

LCDR1 265 QSLVHSDGNTY

LCDR2 266 RIS

LCDR3 267 MQSTHVPRT

ABT806 HCDR1 273 GYSISRDFA

HCDR2 274 ISYNGNT

HCDR3 275 VTASRGFPY

LCDR1 278 QDINSN

LCDR2 279 HGT

LCDR3 280 VQYAQFPWT

Sibrotuzumab HCDR1 286 RYTFTEYT

HCDR2 287 INPNNGIP

HCDR3 288 ARRRIAYGYDEGHAMDY

LCDR1 291 QSLLYSRNQKNY

LCDR2 292 WAS

LCDR3 293 QQYFSYPLT

DS-8895a variant 1 HCDR1 299 GYTFIDYS

HCDR2 300 INTYTGEP

HCDR3 301 ATYYRYERDFDY

LCDR1 304 QSIVHSSGITY

LCDR2 305 KVS

LCDR3 306 FQGSHVPYT

DS-8895a variant 2 HCDR1 312 GYTFIDYS

HCDR2 313 INTYTGEP

HCDR3 314 ATYYRYERDFDY

LCDR1 317 QSIVHSSGITY

LCDR2 318 KVS

LCDR3 319 FQGSHVPYT

MEDI-547 HCDR1 325 GFTFSHYM

HCDR2 326 IGPSGGPT

HCDR3 327 AGYDSGYDYVAVAGPAEYFQH

LCDR1 330 QSISTW

LCDR2 331 KAS

LCDR3 332 QQYNSYSRT

Narnatumab HCDR1 338 GFTFSSYL Antibody Region SEQ ID Sequence

NO:

HCDR2 339 IKQDGSEK

HCDR3 340 TRDGYSSGRHYGMDV

LCDR1 343 QSVSRY

LCDR2 344 DAS

LCDR3 345 QQRSNWPRT

RG7841 HCDR1 351 GFSLTGYS

HCDR2 352 IWGDGST

HCDR3 353 ARDYYFNYASWFAY

LCDR1 356 QGISNYL

LCDR2 357 YTS

LCDR3 358 QQYSELPWT

Farletuzumab HCDR1 364 GFTFSGYG

HCDR2 365 ISSGGSYT

HCDR3 366 ARHGDDPAWFAY

LCDR1 369 SSISSNN

LCDR2 370 GTS

LCDR3 371 QQWSSYPYMYT

Mirvetuximab HCDR1 377 GYTFTGYF

HCDR2 378 IHPYDGDT

HCDR3 379 TRYDGSRAMDY

LCDR1 382 QSVSFAGTSL

LCDR2 383 RAS

LCDR3 384 QQSREYPYT

J591 variant 1 HCDR1 390 GYTFTEYT

HCDR2 391 INPNNGGT

HCDR3 392 AAGWNFDY

LCDR1 395 QDVGTA

LCDR2 396 WAS

LCDR3 397 QQYNSYPLT

J591 variant 2 HCDR1 403 GYTFTEYT

HCDR2 404 INPNNGGT

HCDR3 405 AAGWNFDY

LCDR1 408 ENVVTY

LCDR2 409 GAS

LCDR3 410 GQGYSYPYT

Rovalpituzumab HCDR1 416 GYTFTNYG

HCDR2 417 INTYTGEP

HCDR3 418 ARIGDSSPSDY

LCDR1 421 QSVSND

LCDR2 422 YAS

LCDR3 423 QQDYTSPWT

PF-06647020 HCDR1 429 GYTFTDYA

HCDR2 430 ISTYNDYT

HCDR3 431 ARGNSYFYALDY

LCDR1 434 ESVDSYGKSF

LCDR2 435 RAS

LCDR3 436 QQSNEDPWT

Antibody to PTK7 HCDR1 442 GFTFSSYA

HCDR2 443 ISYDGSIK

HCDR3 444 ARTYYFDY

LCDR1 447 QSIGSS

LCDR2 448 YAS

LCDR3 449 HQSSSLPIT

Ladiratuzumab HCDR1 455 GLTIEDYY

HCDR2 456 IDPENGDT

HCDR3 457 AVHNAHYGTWFAY

LCDR1 460 QSLLHS SGNT Y

LCDR2 461 KIS Antibody Region SEQ ID Sequence

NO:

LCDR3 462 FQGSHVPYT

Cirmtuzumab HCDR1 468 GYAFTAYN

HCDR2 469 FDPYDGGS

HCDR3 470 ARGWYYFDY

LCDR1 473 KSISKY

LCDR2 474 SGS

LCDR3 475 QQHDESPYT

Antibody to HCDR1 481 GFRFRSHG

MAGE-A3 HCDR2 482 SYDGNNK

HCDR3 483 ASPYTSDWQYFQY

LCDR1 486 QNISTT

LCDR2 487 DTS

LCDR3 488 QQSNSWPLT

Antibody to NY- HCDR1 494 GFSFIDYG

ESO-1 HCDR2 495 MNWSGDKK

HCDR3 496 ARGEYSNRFDP

LCDR1 499 QSLVFTDGNTY

LCDR2 500 KVS

LCDR3 501 MQGTHWPPI

Trastuzumab HCDR1 673 GFNIKDTY

HCDR2 674 IYPTNGYT

HCDR3 675 SRWGGDGFYAMDY

LCDR1 676 QDVNTA

LCDR2 677 SAS

LCDR3 678 QQHYTTPPT

Ipilumumab HCDR1 850 GFTFSSYT

HCDR2 851 ISYDGNNK

HCDR3 852 ARTGWLGPFDY

LCDR1 853 QSVGSSY

LCDR2 854 SSY

LCDR3 855 QQYGSSPWT

Vonlerolizumab HCDR1 856 GYTFTDSY

HCDR2 857 MYPDNGDS

HCDR3 858 VLAPRWYFSV

LCDR1 859 QDISNY

LCDR2 860 YTS

LCDR3 861 QQGHTLPPT

Anti-CD27 HCDR1 862 GFTFSSYD

Antibody HCDR2 863 IWYDGSNK

HCDR3 864 ARGSGNWGFFDY

LCDR1 865 QGISRW

LCDR2 866 AAS

LCDR3 867 QQYNTYPRT

Atezolizumab HCDR1 868 GFTFSDSW

HCDR2 869 ISPYGGST

HCDR3 870 ARRHWPGGFDY

LCDR1 871 QDVSTA

LCDR2 872 SAS

LCDR3 873 QQYLYHPAT

Durvalumab HCDR1 874 GFTFSRYW

HCDR2 875 IKQDGSEK

HCDR3 876 AREGGWFGELAFDY

LCDR1 877 QRVSSSY

LCDR2 878 DAS

LCDR3 879 QQYGSLPWT

MDX-1106 HCDR1 880 GDTFSTYA

HCDR2 881 IIPIFGKA

HCDR3 882 ARKFHFVSGSPFGMDV Antibody Region SEQ ID Sequence

NO:

LCDR1 883 QSVSSY

LCDR2 884 DAS

LCDR3 885 QQRSNWPT

TABLE 2. Tumor Antibody V _H sequences and V _L sequences

Antibody Region SEQ Sequence

ID

NO:

Pertuzumab V _H 12 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVA

DVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARN LGPSFYFDYWGQGTLVTVSS

V _L 17 DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSAS

YRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKV EIK

Cetuximab V _H 25 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI

WSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYY DYEFAYWGQGTLVTVSA

V _L 30 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES

ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK

Panitumumab V _H 38 QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIG fflYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTG AFDIWGQGTMVTVSS

V _L 43 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDA

SNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKV EIK

Nimotuzumab V _H 51 QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIG

GINPTSGGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAFYFCARQGL

WFDSDGRGFDFWGQGSTVTVSS

V _L 56 DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAPKL

LIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQYSHVPWTFG QGTKLEIK

Zalutumumab V _H 64 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVA

VIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DGITMVRGVMKDYFDYWGQGTLVTVSS

V _L 69 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDAS

SLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVE IK

Onartuzumab V _H 77 EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVG

MIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYR SYVTPLDYWGQGTLVTVSS

V _L 82 DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPK

LLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWT FGQGTKVEIK

Patritumab V _H 90 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGE

INHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWT WYFDLWGRGTLVTVSS Antibody Region SEQ Sequence

ID

NO:

v _L 95 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPK

LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRT FGQGTKVEIK

Clivatuzumab V _H 103 QVQLQQSGAEVKKFGASVKVSCEASGYTFPSYVLHWVKQAPGQGLEWIG

YINPYNDGTQTNKKFKGKATLTRDTSINTAYMELSRLRSDDTAVYYCARG FGGSYGFAYNGQGTLVTVSS

V _L 108 DIQLTQSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGKAPKLWIYS

TSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQWNRYPYTFGGGT

RLEIK

Sofituzumab V _H 116 EVQLVESGGGLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGLEWV

GYISYSGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARWT SGLDYWGQGTLVTVSS

V _L 121 DIQMTQSPSSLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKLLIYGA

TSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTTPFTFGQGTK VEIK

Edrecolomab V _H 129 QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGV

INPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARDGP WFAYWGQGTLVTVSA

V _L 134 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYG

ASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGG

TKLEIK

Adecatumum V _H 142 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVA ab VISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD

MGWGSGWRPYYYYGMDVWGQGTTVTVSS

V _L 147 ELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWAS

TRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIPYTFGQGTKLE IK

Anetumab V _H 155 QVELVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLEWMGII

DPGDSRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGQLY GGTYMDGWGQGTLVTVSS

V _L 160 DIALTQPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKLMIYG

VNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDIESATPVFGG

GTKLTVL

huDS6 V _H 168 QAQLVQSGAEVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIG

YIYPGNGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDSAVYFCARGD SVPFAYWGQGTLVTVSA

V _L 173 EIVLTQSPATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLWIYSTSS

LASGVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFPLTFGAGTKLE

LK

Lifastuzumab V _H 181 EVQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLEWVAT

IGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHR

GFDVGHFDFWGQGTLVTVSS

V _L 186 DIQMTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGKAPKL Antibody Region SEQ Sequence

ID

NO:

LIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSFNPLTFG QGTKVEIK

Sacituzumab V _H 194 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWM

GWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARG GFGSSYWYFDVWGQGSLVTVSS

V _L 199 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSAS

YRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKV EIK

PR1A3 V _H 207 QVKLQQSGPELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGLKWMG

WINTKTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDTAKYFCARW

DFYDYVEAMDYWGQGTTVTVSS

V _L 212 DIVMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYS

ASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCHQYYTYPLFTFGSG TKLEMK

Humanized V _H 811 QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWM PR1A3 GWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCAR

WDFAYYVEAMDYWGQGTTVTVSS

V _L 812 DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPKLLIYSA

SYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYTYPLFTFGQGT

KLEIK

Humanized V _H 829 EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYI Ab2-3 SSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYF

GSSGPFAYWGQGTLVTVSS

V _L 830 DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNT

RTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKL

EIK

IMAB362, V _H 220 QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGN

CLAUDIXIM IYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWR

AB GNSFDYWGQGTTLTVSS

V _L 225 DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPP

KLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPF

TFGSGTKLEIK

AMG595 V _H 259 QVQLVESGGGVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEWVA

VIWYDGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD GYDILTGNPRDFDYWGQGTLVTVSS

V _L 264 DTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQPPRL

LIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEAEDVGVYYCMQSTHVPRTF GQGTKVEIK

ABT806 V _H 272 EVQLQESGPGLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWMG

YISYNGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTASRG

FPYWGQGTLVTVSS

V _L 277 DIQMTQSPSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGT

NLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTK LEIK

Sibrotuzumab V _H 285 QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGG

INPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIA YGYDEGHAMDYWGQGTLVTVSS

V _L 290 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPK

LLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLT Antibody Region SEQ Sequence

ID

NO:

FGQGTKVEIK

DS-8895a V _H 298 QVQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLEWM variant 1 GWINTYTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDTAVYYCATY

YRYERDFDYWGQGTLVTVSS

V _L 303 DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIY

KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQ GTKVEIK

DS-8895a V _H 311 QIQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLKWMG variant 2 WINTYTGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDTAVYYCATYY

RYERDFDYWGQGTLVTVSS

V _L 316 DVLMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLI

YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFG QGTKVEIK

MEDI-547 V _H 324 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVS

RIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGY DSGYDYVAVAGPAEYFQHWGQGTLVTVSS

V _L 329 DIQMTQSPSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKAS

NLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKV EIK

Narnatumab V _H 337 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLEWVA

NIKQDGSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDTAVYYCTRD

GYSSGRHYGMDVWGQGTTVIVSS

V _L 342 EIVLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKPGQAPRLLIYDAS

NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKV EIK

RG7841 V _H 350 EVQLVESGPALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALEWLGMI

WGDGSTDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYY FNYASWFAYWGQGTLVTVSS

V _L 355 DIQMTQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKTVKLLIYYTS

NLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSELPWTFGQGTKV EIK

Farletuzumab V _H 363 EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVA

MISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARH GDDPAWFAYWGQGTPVTVSS

V _L 368 DIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYGTS

NLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSYPYMYTFGQGT KVEIK

Mirvetuximab V _H 376 QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGR

IHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYD

GSRAMDYWGQGTTVTVSS

V _L 381 DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLI

YRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFG GGTKLEIK Antibody Region SEQ Sequence

ID

NO:

J591 variant 1 V _H 389 EVQLQQSGPELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNIN

PNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWNF DYWGQGTTLTVSS

V _L 394 DIVMTQSHKFMSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPKLLIYW

ASTRHTGVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQYNSYPLTFGAG TMLDLK

J591 variant 2 V _H 402 EVQLQQSGPELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNIN

PNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWNF DYWGQGTTLTVSS

V _L 407 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYG

ASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGG

TKLEIK

Rovalpituzum V _H 415 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWM ab GWINTYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR

IGDSSPSDYWGQGTLVTVSS

V _L 420 EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYYA

SNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTK LEIK

PF-06647020 V _H 428 QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIG

VISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCARG NSYFYALDYWGQGTSVTVSS

V _L 433 EIVLTQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQAPRLLI

YRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDPWTFGG

GTKLEIK

Antibody to V _H 441 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGLEWVA PTK7 VISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTY

YFDYWGQGTLVTVSS

V _L 446 EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQ

SFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPITFGQGTRLEI

K

Ladiratuxuma V _H 454 QVQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWM b GWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAV

HNAHYGTWFAYWGQGTLVTVSS

V _L 459 DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEYFQQRPGQSPRPLI

YKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGG GTKVEIK

Cirmtuzumab V _H 467 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGS

FDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARG

WYYFDYWGHGTLVTVSS

V _L 472 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGST

LQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEI K

Antibody to V _H 480 QVQLVESGGGVVQPGRSLRLSCTASGFRFRSHGMHWVRQAPGKGLEWVA MAGE-A3 VISYDGNNKLYADSVKGRITISRDNSKNTLFLQMNNVRAEDTAVYYCASP

YTSDWQYFQYWGQGTLVIVSS Antibody Region SEQ Sequence

ID

NO:

v _L 485 EIVMTQSPATLSVSPGERATFSCRASQNISTTLAWYQQKPGQAPRLLIYDTS

TRATGIPARFSGSGSGTEFTLTISSLQSEDLAVYYCQQSNSWPLTFGGGTKV EIK

Antibody to V _H 493 QVQLVQSGGGVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLEWVA NY-ESO-1 GMNWSGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVEDTALYFCARG

EYSNRFDPRGRGTLVTVSS

V _L 498 DIVMTQTPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPGQSPRRL

IYKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYCMQGTHWPPIFG

QGTKVEIK

Trastuzumab V _H 679 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR

IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWG GDGFYAMDYWGQGTLVTVSS

V _L 680 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSA

SFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKV EIK

Vonlerolizum V _H 886 EVQLVQSGAEVKKPGASVKVSCKASGYTFTDSYMSWVRQAPGQGLEWIG ab DMYPDNGDSSYNQKFRERVTITRDTSTSTAYLELSSLRSEDTAVYYCVLAP

RWYFSVWGQGTLVTVSS

V _L 887 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTS

RLRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPPTFGQGTKV

EIK

Varlilumab V _H 888 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

GSGNWGFFDYWGQGTLVTVSS

V _L 889 DIQMTQSPSSLSASVGDRVTITCRASQGISRWLAWYQQKPEKAPKSLIYAAS

SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNTYPRTFGQGTKV

EIK

Atezolizumab V _H 890 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVA

WISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARR

HWPGGFDYWGQGTLVTVSS

V _L 891 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA

SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTK VEIK

Durvalumab V _H 892 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVA

NIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARE GGWFGELAFDYWGQGTLVTVSS

V _L 893 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDA

SSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTK VEIK

MDX-1106 V _H 894 QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMG

GIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFH FVSGSPFGMDVWGQGTTVTVSS

V _L 895 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS

NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVE IK

Ipilumumab V _H 896 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVT

FISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTG

WLGPFDYWGQGTLVTVSS

V _L 897 EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGA

FSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTK VEIK

MDX-1105 V _H 901 QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMG

GIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFH Antibody Region SEQ Sequence

ID

NO:

FVSGSPFGMDVWGQGTTVTVSS

V _L 902 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS

NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVE IK

TABLE 3. Tumor Antibody Heavy Chain and Light Chain sequences

Antibody Region SEQ Sequence

ID

NO:

Pertuzumab Heavy 11 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVA

Chain DVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARN

LGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

Light 16 DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSAS Chain YRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

Cetuximab Heavy 24 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI

Chain WSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYY

DYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN

HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS

VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 29 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES Chain ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK

RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF

NRGEC

Panitumumab Heavy 37 QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIG

Chain HIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTG

AFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHK

PSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTC

VVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVH

QDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKN

QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 42 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDA Chain SNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC Antibody Region SEQ Sequence

ID

NO:

Nimotuzumab Heavy 50 QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIG

Chain GINPTSGGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAFYFCARQGL

WFDSDGRGFDFWGQGSTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY

ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 55 DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAPKL Chain LIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQYSHVPWTFG

QGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

Zalutumumab Heavy 63 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVA

Chain VIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF

PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE

EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP

REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT

PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP

GK

Light 68 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDAS Chain SLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVE

IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC

Onartuzumab Heavy 76 EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVG

Chain MIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYR

SYVTPLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI

SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV

VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF

FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 81 DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPK Chain LLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWT

FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC

Patritumab Heavy 89 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGE

Chain INHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWT

WYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE

PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 94 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPK Chain LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRT

FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW

KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

Clivatuzumab Heavy 102 QVQLQQSGAEVKKPGASVKVSCEASGYTFPSYVLHWVKQAPGQGLEWIG Antibody Region SEQ Sequence

ID

NO:

Chain YINPYNDGTQYNEKFKGKATLTRDTSINTAYMELSRLRSDDTAVYYCARG

FGGSYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 107 DIQLTQSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGKAPKLWIYS Chain TSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQWNRYPYTFGGGT

RLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA

LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP

VTKSFNRGEC

Sofituzumab Heavy 115 EVQLVESGGGLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGLEWV

Chain GYISYSGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARWT

SGLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE

PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 120 DIQMTQSPSSLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKLLIYGA Chain TSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTTPFTFGQGTK

VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC

Edrecolomab Heavy 128 QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGV

Chain INPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARDGP

WFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP

VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 133 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYG Chain ASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGG

TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN

ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS

PVTKSFNRGEC

Adecatumum Heavy 141 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVA ab Chain VISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD

MGWGSGWRPYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGG

TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF

LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP

REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK

TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK

Light 146 ELQMTQSPSS LSASVGDRVT ITCRTSQSIS SYLNWYQQKP GQPPKLLIYW Chain ASTRESGVPD RFSGSGSGTD FTLTISSLQP EDSATYYCQQ SYDIPYTFGQ

GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC

Anetumab Heavy 154 QVELVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLEWMGII Antibody Region SEQ Sequence

ID

NO:

Chain DPGDSRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGQLY

GGTYMDGWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI

SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV

VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF

FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 159 DIALTQPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKLMIYG Chain VNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDIESATPVFGG

GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKG DSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKT VAPTECS

huDS6 Heavy 167 QAQLVQSGAEVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIG

Chain YIYPGNGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDSAVYFCARGD

SVPFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN

HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR

TPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD

ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 172 EIVLTQSPATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLWIYSTSS Chain LASGVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFPLTFGAGTKLE

LKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS

GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK

SFNRGEC

Lifastuzumab Heavy 180 EVQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLEWVAT

Chain IGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHR

GFDVGHFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 185 DIQMTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGKAPKL Chain LIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSFNPLTFG

QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

Sacituzumab Heavy 193 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWM

Chain GWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARG

GFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY

ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 198 DIQLTQSPSS LSASVGDRVS ITCKASQDVS IAVAWYQQKP GKAPKLLIYS Chain ASYRYTGVPD RFSGSGSGTD FTLTISSLQP EDFAVYYCQQ HYITPLTFGA

GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC

PR1A3 Heavy 206 QVKLQQSGPELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGLKWMG

Chain WINTKTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDTAKYFCARW

DFYDYVEAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL Antibody Region SEQ Sequence

ID

NO:

VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD

TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 211 DIVMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYS Chain ASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCHQYYTYPLFTFGSG

TKLEMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD

NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS

SPVTKSFNRGEC

Humanized Heavy 813 QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWM PR1A3 Chain GWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCAR

WDFAYYVEAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC

LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK

DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS

TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD

SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 814 DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPKLLIYSA Chain SYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYTYPLFTFGQGT

KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA

LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP

VTKSFNRGEC

Humanized Heavy 831 EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYI Ab2-3 Chain SSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYF

GSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI

SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV

VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF

FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 832 DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNT Chain RTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKL

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

IMAB362, Heavy 219 QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGN

CLAUDIXIM Chain IYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWR

AB GNSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN

HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS

VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 224 DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPP Chain KLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPF

TFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW

KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

AMG595 Heavy 258 QVQLVESGGGVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEWVA

Chain VIWYDGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD

GYDILTGNPRDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT

QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP

KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY Antibody Region SEQ Sequence

ID

NO:

NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP

QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV

LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 263 DTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQPPRL Chain LIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEAEDVGVYYCMQSTHVPRTF

GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

ABT806 Heavy 271 EVQLQESGPGLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWMG

Chain YISYNGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTASRG

FPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT

VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM

TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 276 DIQMTQSPSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGT Chain NLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTK

LEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC

Sibrotuzumab Heavy 284 QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGG

Chain INPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIA

YGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL

VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD

TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 289 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPK Chain LLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLT

FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW

KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

DS-8895a Heavy 297 QVQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLEWM variant 1 Chain GWINTYTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDTAVYYCATY

YRYERDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 302 DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIY Chain KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQ

GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD

NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS

SPVTKSFNRGEC

DS-8895a Heavy 310 QIQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLKWMG variant 2 Chain WINTYTGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDTAVYYCATYY

RYERDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI

SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV

VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF

FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Antibody Region SEQ Sequence

ID

NO:

Light 315 DVLMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLI Chain YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFG

QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC

MEDI-547 Heavy 323 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVS

Chain RIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGY

DSGYDYVAVAGPAEYFQHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG

TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF

LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP

REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK

TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK

Light 328 DIQMTQSPSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKAS Chain NLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

Narnatumab Heavy 336 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLEWVA

Chain NIKQDGSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDTAVYYCTRD

GYSSGRHYGMDVWGQGTTVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCL

VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD

TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 341 EIVLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKPGQAPRLLIYDAS Chain NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC

RG7841 Heavy 349 EVQLVESGPALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALEWLGMI

Chain WGDGSTDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYY

FNYASWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 354 DIQMTQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKTVKLLIYYTS Chain NLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSELPWTFGQGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

Farletuzumab Heavy 362 EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVA

Chain MISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARH

GDDPAWFAYWGQGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 367 DIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYGTS Antibody Region SEQ Sequence

ID

NO:

Chain NLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSYPYMYTFGQGT

KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC

Mirvetuximab Heavy 375 QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGR

Chain IHPYDGDTFY

NQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWG QGTTVTVSSAS

TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGL

YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNST

YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQ

GNVFSCSVMHEALHNHYTQKSLSLSPG

Light 380 DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLI Chain YRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFG

GGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

J591 variant 1 Heavy 388 EVQLQQSGPELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNIN

Chain PNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWNF

DYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT

VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS

NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL

TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 393 DIVMTQSHKFMSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPKLLIYW Chain ASTRHTGVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQYNSYPLTFGAG

TMLDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD

NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS

SPVTKSFNRGEC

J591 variant 2 Heavy 401 EVQLQQSGPELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNIN

Chain PNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWNF

DYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT

VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS

NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL

TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 406 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYG Chain ASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGG

TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN

ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS

PVTKSFNRGEC

Rovalpituzum Heavy 414 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWM ab Chain GWINTYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR

IGDSSPSDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Antibody Region SEQ Sequence

ID

NO:

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

Light 419 EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYYA Chain SNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTK

LEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL

QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV

TKSFNRGEC

PF-06647020 Heavy 427 QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIG

Chain VISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCARG

NSYFYALDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 432 EIVLTQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQAPRLLI Chain YRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDPWTFGG

GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD

NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS

SPVTKSFNRGEC

Antibody to Heavy 440 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGLEWVA PTK7 Chain VISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTY

YFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP

VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 445 EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQ Chain SFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPITFGQGTRLEI

KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG

NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS

FNRGEC

Ladiratuzuma Heavy 453 QVQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWM b Chain GWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAV

HNAHYGTWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL

VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD

TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 458 DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEYFQQRPGQSPRPLI Chain YKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGG

GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC

Cirmtuzumab Heavy 466 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGS

Chain FDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARG

WYYFDYWGHGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF

PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS

RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV

SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF Antibody Region SEQ Sequence

ID

NO:

LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 471 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGST Chain LQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEI

KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG

NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS

FNRGEC

Antibody to Heavy 479 QVQLVESGGGVVQPGRSLRLSCTASGFRFRSHGMHWVRQAPGKGLEWVA MAGE-A3 Chain VISYDGNNKLYADSVKGRITISRDNSKNTLFLQMNNVRAEDTAVYYCASP

YTSDWQYFQYWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 484 EIVMTQSPATLSVSPGERATFSCRASQNISTTLAWYQQKPGQAPRLLIYDTS Chain TRATGIPARFSGSGSGTEFTLTISSLQSEDLAVYYCQQSNSWPLTFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC

Antibody to Heavy 492 QVQLVQSGGGVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLEWVA NY-ESO-1 Chain GMNWSGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVEDTALYFCARG

EYSNRFDPRGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF

PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS

RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV

SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF

LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 497 DIVMTQTPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPGQSPRRL Chain IYKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYCMQGTHWPPIFG

QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC

Trastuzumab Heavy 681 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR

Chain IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWG

GDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 682 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSA Chain SFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

TABLE 4. Fusion Sequences - CD40 fusions via the heavy chain

Antibody Region SEQ Sequence

ID

NO:

Pertuzumab HC CD40 21 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS Antibody Region SEQ Sequence

ID

NO:

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRF

KGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTI

TCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTD

FTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK

HC tumor 22 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEW mAb with VADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYY CD40 mAb CARNLGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL ScFv GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKAS

GYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMT

RDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTI

TCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTD

FTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

HC tumor 845 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEW mAb with VADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYY CD40 mAb CARNLGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL scFv (LH) GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRAS

QGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTIS

SLQPEDFATYYCQQANIFPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGG

GSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQG

LEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDT

AVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSS

Cetuximab HC CD40 34 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLKQSGPGLVQPSQ

SLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTS

RLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGT

LVTVSAGGGGSGGGGSGGGGSGGGGSDILLTQSPVILSVSPGERVSFSCR

ASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSIN

SVESEDIADYYCQQNNNWPTTFGAGTKLELK

HC tumor 35 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWL mAb with GVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR CD40 mAb ALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALG Antibody Region SEQ Sequence

ID

NO:

ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Panitumuma HC CD40 47 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQESGPGLVKPSE

TLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSL

KSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMV

TVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQA

SQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTI

SSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK

HC tumor 48 QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLE mAb with WIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVR CD40 mAb DRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV ScFv KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK

SLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTG

YYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIS

TAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTV

SSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQ

GIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISS

LQPEDFATYYCQQANIFPLTFGGGTKVEIK

Nimotuzuma HC CD40 60 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQQSGAEVKKPG

SSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIGGINPTSGGSNFNEKF

KTRVTITVDESTNTAYMELSSLRSEDTAFYFCARQGLWFDSDGRGFDF

WGQGSTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGD

RVTITCRSSQNIVHSNGNTYLDWYQQTPGKAPKLLIYKVSNRFSGVPSRF

SGSGSGTDFTFTISSLQPEDIATYYCFQYSHVPWTFGQGTKLEIK

HC tumor 61 QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWI mAb with GGINPTSGGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAFYFCAR Antibody Region SEQ Sequence

ID

NO:

CD40 mAb QGLWFDSDGRGFDFWGQGSTVTVSSASTKGPSVFPLAPSSKSTSGGTAA ScFv LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS

SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Zalutumuma HC CD40 73 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVESGGGVVQPG

RSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGD

SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMK

DYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSAIQLTQSPSSLS

ASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRF

SGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK

HC tumor 74 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEW mAb with VAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY CD40 mAb YCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP

ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG

VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL

PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGAS

VKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQK

FQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCS

YFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSA

SVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRF

SGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Onartuzuma HC CD40 86 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRFNPNF

KDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTI

TCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSG

SGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIK

HC tumor 87 EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEW Antibody Region SEQ Sequence

ID

NO:

mAb with VGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYC CD40 mAb ATYRSYVTPLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Patritumab HC CD40 99 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQQWGAGLLKPS

ETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLK

SRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIEMTQSPDSLAVSLGERATINCR

SSQSVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSGSGS

GTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIK

HC tumor 100 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWI mAb with GEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARD CD40 mAb KWTWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV ScFv KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK

SLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTG

YYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIS

TAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTV

SSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQ

GIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISS

LQPEDFATYYCQQANIFPLTFGGGTKVEIK

Clivatuzuma HC CD40 112 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQQSGAEVKKPG

ASVKVSCEASGYTFPSYVLHWVKQAPGQGLEWIGYINPYNDGTQYNEK

FKGKATLTRDTSINTAYMELSRLRSDDTAVYYCARGFGGSYGFAYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDRVT

MTCSASSSVSSSYLYWYQQKPGKAPKLWIYSTSNLASGVPARFSGSGSG

TDFTLTISSLQPEDSASYFCHQWNRYPYTFGGGTRLEIK Antibody Region SEQ Sequence

ID

NO:

HC tumor 113 QVQLQQSGAEVKKPGASVKVSCEASGYTFPSYVLHWVKQAPGQGLEW mAb with IGYINPYNDGTQYNEKFKGKATLTRDTSINTAYMELSRLRSDDTAVYYC CD40 mAb ARGFGGSYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Sofituzumab HC CD40 125 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGYSITNDYAWNWVRQAPGKGLEWVGYISYSGYTTYNPSL

KSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARWTSGLDYWGQGTLV

TVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKA

SDLIHNWLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTI

SSLQPEDFATYYCQQYWTTPFTFGQGTKVEIK

HC tumor 126 EVQLVESGGGLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGLE mAb with WVGYISYSGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYC CD40 mAb ARWTSGLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL ScFv VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT

QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP

KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE

EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN

YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

KSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFT

GYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSI

STAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVT

VSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRAS

QGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTIS

SLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Edrecoloma HC CD40 138 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQQSGAELVRPGT

SVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKF

KGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARDGPWFAYWGQGTL

VTVSAGGGGSGGGGSGGGGSGGGGSNIVMTQSPKSMSMSVGERVTLT

CKASENVVTYVSWYQQKPEQSPKLLIYGASNRYTGVPDRFTGSGSATD Antibody Region SEQ Sequence

ID

NO:

FTLTISSVQAEDLADYHCGQGYSYPYTFGGGTKLEIK

HC tumor 139 QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWI mAb with GVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCA CD40 mAb RDGPWFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLV ScFv KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK

SLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTG

YYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIS

TAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTV

SSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQ

GIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISS

LQPEDFATYYCQQANIFPLTFGGGTKVEIK

Adecatumu HC CD40 151 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mab mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGVVQPGR

SLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADS

VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDMGWGSGWRPYY

YYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSELQMTQSPSS

LSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWASTRESGVPD

RFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIPYTFGQGTKLEIK

HC tumor 152 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEW mAb with VAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CD40 mAb CAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPG

ASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYA

QKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGV

CSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSV

SASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Anetumab HC CD40 164 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVELVQSGAEVKKPGE

SLKISCKGSGYSFTSYWIGWVRQAPGKGLEWMGIIDPGDSRTRYSPSFQ

GQVTISADKSISTAYLQWSSLKASDTAMYYCARGQLYGGTYMDGWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIALTQPASVSGSPGQSITISC Antibody Region SEQ Sequence

ID

NO:

TGTSSDIGGYNSVSWYQQHPGKAPKLMIYGVNNRPSGVSNRFSGSKSG NTASLTISGLQAEDEADYYCSSYDIESATPVFGGGTKLTVL

HC tumor 165 QVELVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLEWM mAb with GIIDPGDSRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCAR CD40 mAb GQLYGGTYMDGWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

huDS6 HC CD40 177 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQAQLVQSGAEVVKPG

ASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGYIYPGNGATNYNQ

KFQGKATLTADPSSSTAYMQISSLTSEDSAVYFCARGDSVPFAYWGQGT

LVTVSAGGGGSGGGGSGGGGSGGGGSEIVLTQSPATMSASPGERVTITC

SAHSSVSFMHWFQQKPGTSPKLWIYSTSSLASGVPARFGGSGSGTSYSL

TISSMEAEDAATYYCQQRSSFPLTFGAGTKLELK

HC tumor 178 QAQLVQSGAEVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLE mAb with WIGYIYPGNGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDSAVYF CD40 mAb CARGDSVPFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGC ScFv LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP

PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR

EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK

GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTF

TGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTS

ISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLV

TVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRA

SQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTI

SSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Lifastuzuma HC CD40 190 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGFSFSDFAMSWVRQAPGKGLEWVATIGRVAFHTYYPDSM

KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHRGFDVGHFDFWG Antibody Region SEQ Sequence

ID

NO:

QGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRV TITCRSSETLVHSSGNTYLEWYQQKPGKAPKLLIYRVSNRFSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCFQGSFNPLTFGQGTKVEIK

HC tumor 191 EVQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLEWV mAb with ATIGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC CD40 mAb ARHRGFDVGHFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL ScFv GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKAS

GYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMT

RDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTI

TCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTD

FTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Sacituzumab HC CD40 203 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQQSGSELKKPGA

SVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTD

DFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDV

WGQGSLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGD

RVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSG

SGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK

HC tumor 204 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLK mAb with WMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYF CD40 mAb CARGGFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTA ScFv ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

PR1A3 HC CD40 216 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVKLQQSGPELKKPGE

TVKISCKASGYTFTEFGMNWVKQAPGKGLKWMGWINTKTGEATYVEE Antibody Region SEQ Sequence

ID

NO:

FKGRFAFSLETSATTAYLQINNLKNEDTAKYFCARWDFYDYVEAMDY WGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSQRFMSTSVG DRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTG SGSGTDFTLTISNVQSEDLAEYFCHQYYTYPLFTFGSGTKLEMK

HC tumor 217 QVKLQQSGPELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGLKW mAb with MGWINTKTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDTAKYFC CD40 mAb ARWDFYDYVEAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTA ScFv ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Humanized HC CD40 815 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE PR1A3 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPG

ASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWINTKTGEATYV

EEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCARWDFAYYVEAM

DYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASV

GDRVTITCKASAAVGTYVAWYQQKPGKAPKLLIYSASYRKRGVPSRFS

GSGSGTDFTLTISSLQPEDFATYYCHQYYTYPLFTFGQGTKLEIK

HC tumor 816 QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLE mAb with WMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVY CD40 mAb YCARWDFAYYVEAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGG ScFv TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT

VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE

SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSC

KASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRV

TMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDY

WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGD

RVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

HC tumor 843 QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLE mAb with WMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVY CD40 mAb YCARWDFAYYVEAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGG scFv (LH) TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT

VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE

SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITC Antibody Region SEQ Sequence

ID

NO:

RASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFT

LTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIKGGGGSGGGGSGGGGS

GGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAP

GQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRS

DDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSS

Humanized HC CD40 833 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE Ab2-3 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLQESGPGLVKPGG

SLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVK

GRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGDRVTI

TCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTD

FSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK

HC tumor 834 EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWV mAb with AYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCA CD40 mAb AHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

HC tumor 841 EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWV mAb with AYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCA CD40 mAb AHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG scFv (LH) CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIY

SWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQANIFPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEW

MGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVY

YCARDQPLGYCTNGVCSYFDYWGQGTLVTVSS

IMAB362, HC CD40 229 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE

CLAUDIXI mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

MAB tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS

ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS Antibody Region SEQ Sequence

ID

NO:

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQQPGAELVRPG

ASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQK

FKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQG

TTLTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPSSLTVTAGEKVTM

SCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTG

SGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIK

HC tumor 230 QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWI mAb with GNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYM

CD40 mAb QLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFPLA ScFv PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG

LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS

NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

FSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKP

GASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNY

AQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNG

VCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSS

VSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVP

SRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

AMG595 HC CD40 268 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVESGGGVVQSG

RSLRLSCAASGFTFRNYGMHWVRQAPGKGLEWVAVIWYDGSDKYYA

DSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGYDILTGNPR

DFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDTVMTQTPLSSH

VTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQPPRLLIYRISRRFSGV

PDRFSGSGAGTDFTLEISRVEAEDVGVYYCMQSTHVPRTFGQGTKVEIK

HC tumor 269 QVQLVESGGGVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEW mAb with VAVIWYDGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CD40 mAb CARDGYDILTGNPRDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSG ScFv GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV

TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE

SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSC

KASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRV

TMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDY

WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGD

RVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

ABT806 HC CD40 281 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD Antibody Region SEQ Sequence

ID

NO:

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLQESGPGLVKPSQ

TLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWMGYISYNGNTRYQPSLK

SRITISRDTSKNQFFLKLNSVTAADTATYYCVTASRGFPYWGQGTLVTV

SSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSMSVSVGDRVTITCHSSQ

DINSNIGWLQQKPGKSFKGLIYHGTNLDDGVPSRFSGSGSGTDYTLTISS

LQPEDFATYYCVQYAQFPWTFGGGTKLEIK

HC tumor 282 EVQLQESGPGLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWM mAb with GYISYNGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTA CD40 mAb SRGFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY ScFv FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK

DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY

NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR

EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL

SLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYY

MHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTA

YMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSS

GGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGI

YSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQ

PEDFATYYCQQANIFPLTFGGGTKVEIK

Sibrotuzuma HC CD40 294 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPG

ASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKF

KGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMD

YWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSL

GERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGV

PDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK

HC tumor 295 QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWI mAb with GGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCA CD40 mAb RRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG ScFv TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT

VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE

SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSC

KASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRV

TMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDY

WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGD

RVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

DS-8895a HC CD40 307 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE variant 1 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK Antibody Region SEQ Sequence

ID

NO:

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPG

ASVKVSCKASGYTFIDYSMHWVRQAPGQGLEWMGWINTYTGEPTYSD

DFKGRVTITADTSTSTAYLELSSLRSEDTAVYYCATYYRYERDFDYWG

QGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPLSLPVTPGEPAS

ISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSG

SGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKVEIK

HC tumor 308 QVQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLEW mAb with MGWINTYTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDTAVYYC CD40 mAb ATYYRYERDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

DS-8895a HC CD40 320 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE variant 2 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQIQLVQSGAEVKKPGA

SVKVSCKASGYTFIDYSMHWVRQAPGQGLKWMGWINTYTGEPTYSDD

FKGRFAFSLDTSTSTAYLELSSLRSEDTAVYYCATYYRYERDFDYWGQ

GTLVTVSSGGGGSGGGGSGGGSGGGGSDVLMTQSPLSLPVTPGEPASIS

CRSSQSIVHSSGITYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGS

GTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKVEIK

HC tumor 321 QIQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLKW mAb with MGWINTYTGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDTAVYYC CD40 mAb ATYYRYERDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

MEDI-547 HC CD40 333 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV Antibody Region SEQ Sequence

ID

NO:

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGG

SLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSV

KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGP

AEYFQHWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSL

SASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASNLHTGVPS

RFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKVEIK

HC tumor 334 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEW mAb with VSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC CD40 mAb AGYDSGYDYVAVAGPAEYFQHWGQGTLVTVSSASTKGPSVFPLAPSSK ScFv STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP

ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG

VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL

PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGAS

VKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQK

FQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCS

YFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSA

SVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRF

SGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Narnatumab HC CD40 346 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGFTFSSYLMTWVRQAPGKGLEWVANIKQDGSEKYYVDSV

KGRFTISRDNAKNSLNLQMNSLRAEDTAVYYCTRDGYSSGRHYGMDV

WGQGTTVIVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGER

ATLSCRASQSVSRYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGS

GTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKVEIK

HC tumor 347 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLEWV mAb with ANIKQDGSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDTAVYYC CD40 mAb TRDGYSSGRHYGMDVWGQGTTVIVSSASTKGPSVFPLAPSSKSTSGGTA ScFv ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

RG7841 HC CD40 359 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP Antibody Region SEQ Sequence

ID

NO:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGPALVKPTQ

TLTLTCTVSGFSLTGYSVNWIRQPPGKALEWLGMIWGDGSTDYNSALK

SRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYYFNYASWFAYWG

QGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRV

TITCSASQGISNYLNWYQQKPGKTVKLLIYYTSNLHSGVPSRFSGSGSGT

DYTLTISSLQPEDFATYYCQQYSELPWTFGQGTKVEIK

HC tumor 360 EVQLVESGPALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALEWLG mAb with MIWGDGSTDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCA CD40 mAb RDYYFNYASWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA ScFv LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS

SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Farletuzuma HC CD40 372 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGVVQPG

RSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVAMISSGGSYTYYADS

VKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARHGDDPAWFAYWG

QGTPVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDRVT

ITCSVSSSISSNNLHWYQQKPGKAPKPWIYGTSNLASGVPSRFSGSGSGT

DYTFTISSLQPEDIATYYCQQWSSYPYMYTFGQGTKVEIK

HC tumor 373 EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWV mAb with AMISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCA CD40 mAb RHGDDPAWFAYWGQGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Mirvetuxima HC CD40 385 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS Antibody Region SEQ Sequence

ID

NO:

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVVKPG

ASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQK

FQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQ

GTTVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPLSLAVSLGQPAIIS

CKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSG

SKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIK

HC tumor 386 QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWI mAb with GRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYC CD40 mAb TRYDGSRAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG ScFv CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL

FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYT

FTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDT

SISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTL

VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCR

ASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTL

TISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

J591 HC CD40 398 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE variantl mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLQQSGPELKKPGT

SVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNINPNNGGTTYNQKFE

DKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWNFDYWGQGTTLT

VSSGGGGSGGGGSGGGGSGGGGSDIVMTQSHKFMSTSVGDRVSIICKAS

QDVGTAVDWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLT

ITNVQSEDLADYFCQQYNSYPLTFGAGTMLDLK

HC tumor 399 EVQLQQSGPELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIG mAb with NINPNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCA CD40 mAb AGWNFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK ScFv DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP

KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ

YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP

REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK

TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS

LSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGY

YMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIST

AYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVS

SGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQG

IYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQANIFPLTFGGGTKVEIK

J591 variant HC CD40 411 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE 2 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS Antibody Region SEQ Sequence

ID

NO:

ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLQQSGPELVKPGT

SVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNINPNNGGTTYNQKFE

DKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWNFDYWGQGTTLT

VSSGGGGSGGGGSGGGGSGGGGSNIVMTQSPKSMSMSVGERVTLTCKA

SENVVTYVSWYQQKPEQSPKLLIYGASNRYTGVPDRFTGSGSATDFTLT

ISSVQAEDLADYHCGQGYSYPYTFGGGTKLEIK

HC tumor 412 EVQLQQSGPELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIG mAb with NINPNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCA CD40 mAb AGWNFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK ScFv DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP

KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ

YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP

REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK

TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS

LSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGY

YMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIST

AYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVS

SGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQG

IYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQANIFPLTFGGGTKVEIK

Rovalpituzu HC CD40 424 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mab mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPG

ASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYA

DDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARIGDSSPSDYWG

QGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERAT

LSCKASQSVSNDVVWYQQKPGQAPRLLIYYASNRYTGIPARFSGSGSGT

EFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTKLEIK

HC tumor 425 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLE mAb with WMGWINTYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAV CD40 mAb YYCARIGDSSPSDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL ScFv GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKAS

GYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMT

RDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTI

TCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTD

FTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

PF- HC CD40 437 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE

06647020 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV Antibody Region SEQ Sequence

ID

NO:

tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGPEVKKPG

ASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIGVISTYNDYTYNNQ

DFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCARGNSYFYALDYW

GQGTSVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERA

TLSCRASESVDSYGKSFMHWYQQKPGQAPRLLIYRASNLESGIPARFSG

SGSGTDFTLTISSLEPEDFAVYYCQQSNEDPWTFGGGTKLEIK

HC tumor 438 QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEW mAb with IGVISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYY CD40 mAb CARGNSYFYALDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAAL ScFv GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKAS

GYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMT

RDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQ

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTI

TCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTD

FTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Antibody to HC CD40 450 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE PTK7 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVESGGGVVQPG

RSLRLSCAASGFTFSSYAFHWVRQAPGKGLEWVAVISYDGSIKYYADSV

KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTYYFDYWGQGTLV

TVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDFQSVTPKEKVTITCRA

SQSIGSSLHWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTIN

SLEAEDAAAYYCHQSSSLPITFGQGTRLEIK

HC tumor 451 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGLEWV mAb with AVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA CD40 mAb RTYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD ScFv YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY

ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK

DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY

NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR

EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL

SLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYY

MHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTA

YMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSS

GGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGI

YSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQ

PEDFATYYCQQANIFPLTFGGGTKVEIK

SGN-LIV1A HC CD40 463 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE Antibody Region SEQ Sequence

ID

NO:

mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPG

ASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWMGWIDPENGDTEYGP

KFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAVHNAHYGTWFAY

WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPLSLPVTLG

QPASISCRSSQSLLHSSGNTYLEYFQQRPGQSPRPLIYKISTRFSGVPDRFS

GSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK

HC tumor 464 QVQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEW mAb with MGWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYY CD40 mAb CAVHNAHYGTWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA ScFv ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Cirmtuzuma HC CD40 476 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE b mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLQESGPGLVKPSQ

TLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSYNQKF

KDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGWYYFDYWGHGT

LVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTPLSLPVTPGEPASISC

RASKSISKYLAWYQQKPGQAPRLLIYSGSTLQSGIPPRFSGSGYGTDFTL

TINNIESEDAAYYFCQQHDESPY TFGEGTKVEIK

HC tumor 477 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWM mAb with GSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYC CD40 mAb ARGWYYFDYWGHGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL ScFv VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT

QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP

KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE

EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN

YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

KSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFT

GYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSI

STAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVT

VSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRAS

QGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTIS

SLQPEDFATYYCQQANIFPLTFGGGTKVEIK Antibody Region SEQ Sequence

ID

NO:

Antibody to HC CD40 489 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE MAGE-A3 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVESGGGVVQPG

RSLRLSCTASGFRFRSHGMHWVRQAPGKGLEWVAVISYDGNNKLYAD

SVKGRITISRDNSKNTLFLQMNNVRAEDTAVYYCASPYTSDWQYFQYW

GQGTLVIVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERA

TFSCRASQNISTTLAWYQQKPGQAPRLLIYDTSTRATGIPARFSGSGSGT

EFTLTISSLQSEDLAVYYCQQSNSWPLTFGGGTKVEIK

HC tumor 490 QVQLVESGGGVVQPGRSLRLSCTASGFRFRSHGMHWVRQAPGKGLEW mAb with VAVISYDGNNKLYADSVKGRITISRDNSKNTLFLQMNNVRAEDTAVYY CD40 mAb CASPYTSDWQYFQYWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAA ScFv LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS

SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Antibody to HC CD40 502 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE NY-ESO-1 mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGGGVVRPG

GSLRLSCAASGFSFIDYGMSWVRQVPGKGLEWVAGMNWSGDKKGHA

ESVKGRFIISRDNAKNTLYLEMSSLRVEDTALYFCARGEYSNRFDPRGR

GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTPLSLPVTLGQPASL

SCRSSQSLVFTDGNTYLNWFQQRPGQSPRRLIYKVSSRDPGVPDRFSGT

GSGTDFTLEISRVEAEDIGVYYCMQGTHWPPIFGQGTKVEIK

HC tumor 503 QVQLVQSGGGVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLEW mAb with VAGMNWSGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVEDTALYF CD40 mAb CARGEYSNRFDPRGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC ScFv LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP

PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR

EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK

GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTF

TGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTS

ISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLV

TVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRA

SQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTI Antibody Region SEQ Sequence

ID

NO:

SSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

Trastuzumab HC CD40 683 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSV

KGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDR

VTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRS

GTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

HC tumor 684 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWV mAb with ARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC CD40 mAb SRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA ScFv LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS

SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCK

ASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVT

MTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYW

GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDR

VTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGS

GTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKVEIK

HC CD40 796 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE mAb with WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV tumor mAb YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

(LH,25mer) LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVG

DRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGS

RSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGG

GSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKD

TYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTA

YLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

TABLE 5. APC Antibody CDRs

Antibody Region SEQ ID NO: Sequence

CP-8709893 HCDR1 3 GYTFTGYY

HCDR2 4 INPDSGGT

HCDR3 5 ARDQPLGYCTNGVCSYFDY

LCDR1 8 QGIYSW

LCDR2 9 TAS

LCDR3 10 QQANIFPLT

SBT-040 (G1/G2) HCDR1 3 GYTFTGYY

HCDR2 4 INPDSGGT Antibody Region SEQ ID NO: Sequence

HCDR3 5 ARDQPLGYCTNGVCSYFDY

LCDR1 8 QGIYSW

LCDR2 9 TAS

LCDR3 10 QQANIFPLT

Dacetuzumab HCDR1 582 GYSFTGYY

HCDR2 583 VIPNAGGT

HCDR3 584 AREGIYW

LCDR1 587 QSLVHSNGNTF

LCDR2 588 TVS

LCDR3 589 SQTTHVPWT

Bleselumab HCDR1 592 GGSISSPGYY

HCDR2 593 IYKSGST

HCDR3 594 TRPVVRYFGWFDP

LCDR1 597 QGISSA

LCDR2 598 DAS

LCDR3 599 QQFNSYPT

lucatumumab HCDR1 602 GFTFSSYG

HCDR2 603 ISYEESNR

HCDR3 604 ARDGGIAAPGPDY

LCDR1 607 QSLLYSNGYNY

LCDR2 608 LGS

LCDR3 609 MQARQTPFT

ADC-1013 HCDR1 612 GFTFSTYG

HCDR2 613 ISGGSSYI

HCDR3 614 ARILRGGSGMDL

LCDR1 617 SSNIGAGYN

LCDR2 618 GNI

LCDR3 619 AAWDKSISGLV

APX005 HCDR1 622 GFSFSSTY

HCDR2 623 IYTGDGTN

HCDR3 624 ARPDITYGFAINFW

LCDR1 627 QSISSR

LCDR2 628 RAS

LCDR3 629 QCTGYGISWP

Chi Lob 7/4 HCDR1 632 GYTFTEYI

HCDR2 633 IIPNNGGT

HCDR3 634 TRREVYGRNYYALDY

LCDR1 637 QGINNY

LCDR2 638 YTS

LCDR3 639 QQYSNLPYT

DEC-205 variant 1 HCDR1 234 GFTFSNYG

HCDR2 235 IWYDGSNK

HCDR3 236 ARDLWGWYFDY

LCDR1 239 QSVSSY

LCDR2 240 DAS

LCDR3 241 QQRRNWPLT

DEC-205 variant 2 HCDR1 247 GDSFTTYW

HCDR2 248 IYPGDSDT

HCDR3 249 TRGDRGVDY

LCDR1 252 QGISRW

LCDR2 253 AAS

LCDR3 254 QQYNSYPRT

DC-SIGN variant 1 HCDR1 640 QHFWNTPWT

HCDR2 641 QQGHTLPYT

HCDR3 642 SNDGYYS

LCDR1 643 RYYLGVD

LCDR2 644 DDSGRFP

LCDR3 645 YGYAVDY

DC-SIGN variant 2 HCDR1 646 YYGIYVDY Antibody Region SEQ ID NO: Sequence

HCDR2 647 FLVY

HCDR3 648 NFGILGY

LCDR1 649 YPNALDY

LCDR2 650 GLKSFYAMDH

LCDR3 651 QQGKTLPWT

DC-SIGN variant 3 HCDR1 652 QQGNTLPPT

HCDR2 653 QQHYITPLT

HCDR3 654 QQYGNLPYT

LCDR1 655 QQYYSTPRT

LCDR2 656 GQSYNYPPT

LCDR3 657 WQDTHFPHV

TABLE 6. APC Antibody V _H sequences and V _L sequences

Antibody Region SEQ Sequence

ID

NO:

CP-8709893 V _H 2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCAR DQPLGYCTNGVCSYFDYWGQGTLVTVSS

V _L 7 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTA

STLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKV EIK

SBT-040 V _H 2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCAR DQPLGYCTNGVCSYFDYWGQGTLVTVSS

V _L 7 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTA

STLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKV EIK

Dacetuzumab V _H 581 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYYIHWVRQAPGKGLEWVAR

VIPNAGGTSYNQKFKGRFTLSVDNSKNTAYLQMNSLRAEDTAVYYCAREG IYWWGQGTLVTVSS

V _L 586 DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGNTFLHWYQQKPGKAPKL

LIYTVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCSQTTHVPWTFG QGTKVEIK

Bleselumab V _H 591 QLQLQESGPGLLKPSETLSLTCTVSGGSISSPGYYGGWIRQPPGKGLEWIGSI

YKSGSTYHNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCTRPVVRY FGWFDPWGQGTLVTVSS

V _L 596 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDAS

NLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPTFGQGTKVEI

K

Lucatumuma V _H 601 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVA b VISYEESNRYHADSVKGRFTISRDNSKITLYLQMNSLRTEDTAVYYCARDG

GIAAPGPDYWGQGTLVTVSS

V _L 606 DIVMTQSPLSLTVTPGEPASISCRSSQSLLYSNGYNYLDWYLQKPGQSPQVL

ISLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQARQTPFTFG PGTKVDIR

ADC-1013 V _H 611 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWLSY

ISGGSSYIFYADSVRGRFTISRDNSENALYLQMNSLRAEDTAVYYCARILRG GSGMDLWGQGTLVTVSS

V _L 616 QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYNVYWYQQLPGTAPKLLIYG

NINRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDKSISGLVFGG GTKLTVL

APX005 V _H 621 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSTYVCWVRQAPGKGLEWIACI

YTGDGTNYSASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYFCARPDI

TYGFAINFWGPGTLVTVSS

V _L 626 DIQMTQSPSSLSASVGDRVTIKCQASQSISSRLAWYQQKPGKPPKLLIYRAS

TLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQCTGYGISWPIGGGTK Antibody Region SEQ Sequence

ID

NO:

VEIK

Chi Lob 7/4 V _H 631 EVQLQQSGPDLVKPGASVKISCKTSGYTFTEYIMHWVKQSHGKSLEWIGGI

IPNNGGTSYNQKFKDKATMTVDKSSSTGYMELRSLTSEDSAVYYCTRREV YGRNYYALDYWGQGTLVTVSS

V _L 636 DIQMTQTTSSLSASLGDRVTITCSASQGINNYLNWYQQKPDGTVKLLIYYTS

SLHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQQYSNLPYTFGGGTKLE IK

V _H 233 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

DEC-205 VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR variant 1 DLWGWYFDYWGQGTLVTVSS

V _L 238 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS

NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFGGGTKV EIK

V _H 246 EVQLVQSGAEVKKPGESLRISCKGSGDSFTTYWIGWVRQMPGKGLEWMGI

DEC-205 IYPGDSDTIYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRGDRG variant 2 VDYWGQGTLVTVSS

V _L 251 DIQMTQSPSSLSASVGDRVTITCRASQGISRWLAWYQQKPEKAPKSLIYAAS

SLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQYNSYPRTFGQGTKV EIK

V _H 658 DIQMTQSPSSLSASVGDRVTITCRASQGISRWLAWYQQKPEKAPKSLIYAAS

CD36 SLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQYNSYPRTFGQGTKV mannose EIK

Scavenger V _L 659 EVQLVQSGAEVKKPGESLRISCKGSGDSFTTYWIGWVRQMPGKGLEWMGI Receptor IYPGDSDTIYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRGDRG

VDYWGQGTLVTVSS

V _H 660 QIVESGGGLVQPKESLKISCTASGFTFSNAAIYWVRQTPGKGLEWVGRIRTR

CLEC9A PSKYATDYADSVRGRFTISRDDSKSMVYLQMDNLRTEDTAMYYCTPRATE

DVPFYWGQGVMVTVSS

V _L 661 DIVMTQTPSSQAVSAGEKVTMNCKSSQSVLYDENKKNYLAWYQQKSGQS

PKLLIYWASTGESGVPDRFIGSGSGTDFTLTISSVQAEDLAVYYCQQYYDFP PTFGGGTK

TABLE 7. APC Antibody Heavy Chain and Light Chain sequences

Antibody Region SEQ Sequence

ID

NO:

CP-8709893 Heavy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

Chain GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCAR

DQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

NFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQF

NSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQ

VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPML

DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 6 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTA Chain STLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC

SBT-040 Heavy 577 MDWTWRILFLVAAATGAHSQVQLVQSGAEVKKPGASVKVSCKASGYTFT

Chain GYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIST (IgGl) AYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSA

STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVEPKSCD

KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV

KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC Antibody Region SEQ Sequence

ID

NO:

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK

Heavy 578 MDWTWRILFLVAAATGAHSQVQLVQSGAEVKKPGASVKVSCKASGYTFT Chain GYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKFQGRVTMTRDTSIST (IgG2) AYMELNRLRSDDTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSA

STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV

ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNW

YVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNK

GLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHYTQKSLSLSPGK

Light 579 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTA Chain STLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC

Dacetuzumab Heavy 580 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYYIHWVRQAPGKGLEWVAR

Chain VIPNAGGTSYNQKFKGRFTLSVDNSKNTAYLQMNSLRAEDTAVYYCAREG

IYWWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT

VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM

TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 585 DIQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGNTFLHWYQQKPGKAPKL Chain LIYTVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCSQTTHVPWTFG

QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

Bleselumab Heavy 590 QLQLQESGPGLLKPSETLSLTCTVSGGSISSPGYYGGWIRQPPGKGLEWIGSI

Chain YKSGSTYHNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCTRPVVRY

FGWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV

DHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL

TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Light 595 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDAS Chain NLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPTFGQGTKVEI

KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG

NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS

FNRGEC

Lucatumuma Heavy 600 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVA b Chain VISYEESNRYHADSVKGRFTISRDNSKITLYLQMNSLRTEDTAVYYCARDG

GIAAPGPDYWGQGTLVTVSSASTKGPSVFPLAPASKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 605 DIVMTQSPLSLTVTPGEPASISCRSSQSLLYSNGYNYLDWYLQKPGQSPQVL Chain ISLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQARQTPFTFG

PGTKVDIRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV Antibody Region SEQ Sequence

ID

NO:

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

ADC-1013 Heavy 610 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWLSY

Chain ISGGSSYIFYADSVRGRFTISRDNSENALYLQMNSLRAEDTAVYYCARILRG

GSGMDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN

HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR

TPEVTCNAVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD

ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 615 QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYNVYWYQQLPGTAPKLLIYG Chain NINRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDKSISGLVFGG

GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKA DSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS

APX005 Heavy 620 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSTYVCWVRQAPGKGLEWIACI

Chain YTGDGTNYSASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYFCARPDI

TYGFAINFWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF

PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS

RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV

SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF

LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 625 DIQMTQSPSSLSASVGDRVTIKCQASQSISSRLAWYQQKPGKPPKLLIYRAS Chain TLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQCTGYGISWPIGGGTK

VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC

Chi Lob 7/4 Heavy 630 EVQLQQSGPDLVKPGASVKISCKTSGYTFTEYIMHWVKQSHGKSLEWIGGI

Chain IPNNGGTSYNQKFKDKATMTVDKSSSTGYMELRSLTSEDSAVYYCTRREV

YGRNYYALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY

ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 635 DIQMTQTTSSLSASLGDRVTITCSASQGINNYLNWYQQKPDGTVKLLIYYTS Chain SLHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQQYSNLPYTFGGGTKLE

IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS

GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK

SFNRGEC

DEC-205 Heavy 232 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA (variant 1) Chain VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 237 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS Chain NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT Antibody Region SEQ Sequence

ID

NO:

KSFNRGEC

DEC-205 Heavy 245 EVQLVQSGAEVKKPGESLRISCKGSGDSFTTYWIGWVRQMPGKGLEWMGI (variant 2) Chain IYPGDSDTIYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRGDRG

VDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT

VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM

TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 250 DIQMTQSPSSLSASVGDRVTITCRASQGISRWLAWYQQKPEKAPKSLIYAAS Chain SLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQYNSYPRTFGQGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

CLEC12A Heavy 662 QVQLQESGPGLVKPSETLSLTCVVSGGSISSSNWWSWVRQPPGKGLEWIGE

Chain IYHSGSPDYNPSLKSRVTISVDKSRNQFSLKLSSVTAADTAVYYCAKVSTG variant GFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 1 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Heavy 663 QVQLQESGPGLVKPSETLSLTCVVSGGSISSSNWWSWVRQPPGKGLEWIGE Chain IYHSGSPNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCARSSSGG variant FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP 2 VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Heavy 664 QVQLQESGPGLVKPSETLSLTCVVSGGSISSSNWWSWVRQPPGKGLEWIGE Chain IYHSGSPNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCARQTTA variant GSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 3 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT

PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 665 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAS Chain SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVE

IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS

GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK

SFNRGEC

BDCA-2 Heavy 666 QVQLVESGGGVVQPGRSLRLSCAASGFTLSSYGMHWVRQAPGKGLEWVA Variant 1 Chain VIWYDGNDKYYADSVKGRFTISRDNSKNTLYLQVNSLRAEDTAVYYCAR

GTGTPYWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY

ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 669 EIVLTQSPATLSLSPGERATLSCRASQSVNNYLAWYQQKPGQAPRLLIYDAS Chain NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSTWPPYTFGQGTK

LEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL Antibody Region SEQ Sequence

ID

NO:

QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC

BDCA-2 Heavy 667 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYLMNWVRQAPGKGLEWVA Variant 2 Chain NIEQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYFCARD

GDTAMITFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 670 DIQMTQSPSSVSASVGDRVTITCRASQGIRRWLAWYQQKPGKAPKLLIYAA Chain SSLQRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPWTFGQGTK

VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC

BDCA-2 Heavy 668 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWNWIRQHPGKGLEWIG Variant 3 Chain YIYYSGNTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADAAVYHCARGYG

DYGGGYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light 671 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKFLIYDVS Chain NLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPYTFGQGTKL

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ

SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT

KSFNRGEC

TABLE 8. Fusion Sequences - DEC-205 fusions via the heavy chain

Antibody Region SEQ Sequence

ID

NO:

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

LC tumor 846 DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKL mAb LIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIY containing PYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mab EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE scFv (LH) KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSDIQMTQSPS

SVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQ

SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTK

VEIKGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVS

CKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKF

QGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGV

CSYFDYWGQGTLVTVSS

Cetuximab HC DEC-205 507 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEW

LGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYY

CARALTYYDYEFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGG

SDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLI

KYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPT

TFGAGTKLELK

HC tumor 508 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLE mAb with WLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAI DEC-205 mAb YYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTS ScFv GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQV

QLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Panitumumab HC DEC-205 509 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP Antibody Region SEQ Sequence

ID

NO:

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGL

EWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIY

YCVRDRVTGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGS

DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKL

LIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLP

LAFGGGTKVEIK

HC tumor 510 QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKG mAb with LEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAI DEC-205 mAb YYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGG ScFv TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS

VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Nimotuzumab HC DEC-205 511 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLE

WIGGINPTSGGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAF

YFCARQGLWFDSDGRGFDFWGQGSTVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWY

QQTPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIAT

YYCFQYSHVPWTFGQGTKLEIK

HC tumor 512 QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGL mAb with EWIGGINPTSGGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAF DEC-205 mAb YFCARQGLWFDSDGRGFDFWGQGSTVTVSSASTKGPSVFPLAPSSK ScFv STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL

YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC

PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL

TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK Antibody Region SEQ Sequence

ID

NO:

Zalutumumab HC DEC-205 513 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLE

WVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSGGGGSGGGGS

GGGGSGGGGSAIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQ

QKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATY

YCQQFNSYPLTFGGGTKVEIK

HC tumor 514 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGL mAb with EWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAED DEC-205 mAb TAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFP ScFv LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGG

GGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWV

RQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQ

MNSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGG

GGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLA

WYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPED

FAVYYCQQRRNWPLTFGGGTKVEIK

Onartuzumab HC DEC-205 515 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLE

WVGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTA

VYYCATYRSYVTPLDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSDIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQ

KPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATY

YCQQYYAYPWTFGQGTKVEIK

HC tumor 516 EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGL mAb with EWVGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDT DEC-205 mAb AVYYCATYRSYVTPLDYWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE Antibody Region SEQ Sequence

ID

NO:

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Patritumab HC DEC-205 517 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLE

WIGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVY

YCARDKWTWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGS

DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNP

GQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY

CQQYYSTPRTFGQGTKVEIK

HC tumor 518 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGL mAb with EWIGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAV DEC-205 mAb YYCARDKWTWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSG ScFv GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Clivatuzumab HC DEC-205 519 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQQSGAEVKKPGASVKVSCEASGYTFPSYVLHWVKQAPGQGLE

WIGYINPYNDGTQYNEKFKGKATLTRDTSINTAYMELSRLRSDDTA

VYYCARGFGGSYGFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSDIQLTQSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGK

APKLWIYSTSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQ

WNRYPYTFGGGTRLEIK

HC tumor 520 QVQLQQSGAEVKKPGASVKVSCEASGYTFPSYVLHWVKQAPGQGL mAb with EWIGYINPYNDGTQYNEKFKGKATLTRDTSINTAYMELSRLRSDDT DEC-205 mAb AVYYCARGFGGSYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF Antibody Region SEQ Sequence

ID

NO:

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Sofituzumab HC DEC-205 521 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGGGLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGL

EWVGYISYSGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAV

YYCARWTSGLDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSD

IQMTQSPSSLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKLLI

YGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTTP

FTFGQGTKVEIK

HC tumor 522 EVQLVESGGGLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKG mAb with LEWVGYISYSGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTA DEC-205 mAb VYYCARWTSGLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT ScFv AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP

ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK

VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQL

VESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWV

AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV

YYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG

GSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR

LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Edrecolomab HC DEC-205 523 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLE

WIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSA

VYFCARDGPWFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGS

NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPK

LLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGY

SYPYTFGGGTKLEIK

HC tumor 524 QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGL Antibody Region SEQ Sequence

ID

NO:

mAb with EWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDS DEC-205 mAb AVYFCARDGPWFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGG ScFv TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS

VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Adecatumum HC DEC-205 525 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL ab mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLE

WVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSSGGGGSG

GGGSGGGGSGGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYL

NWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQP

EDSATYYCQQSYDIPYTFGQGTKLEIK

HC tumor 526 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGL mAb with EWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED DEC-205 mAb TAVYYCAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSSASTKGP ScFv SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP

KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

GGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMY

WVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTL

YLQMNSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGG

SGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSS

YLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSL

EPEDFAVYYCQQRRNWPLTFGGGTKVEIK

Anetumab HC DEC-205 527 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VELVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLE

WMGIIDPGDSRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAM Antibody Region SEQ Sequence

ID

NO:

YYCARGQLYGGTYMDGWGQGTLVTVSSGGGGSGGGGSGGGGSG GGGSDIALTQPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGK APKLMIYGVNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCS SYDIESATPVFGGGTKLTVL

HC tumor 528 QVELVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLE mAb with WMGIIDPGDSRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAM DEC-205 mAb YYCARGQLYGGTYMDGWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

huDS6 HC DEC-205 529 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

AQLVQSGAEVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGL

EWIGYIYPGNGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDSA

VYFCARGDSVPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLW

IYSTSSLASGVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFP

LTFGAGTKLELK

HC tumor 530 QAQLVQSGAEVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQG mAb with LEWIGYIYPGNGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDS DEC-205 mAb AVYFCARGDSVPFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSG ScFv GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Lifastuzumab HC DEC-205 531 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY Antibody Region SEQ Sequence

ID

NO:

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLE

WVATIGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARHRGFDVGHFDFWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQ

QKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFAT

YYCFQGSFNPLTFGQGTKVEIK

HC tumor 532 EVQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLE mAb with WVATIGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDT DEC-205 mAb AVYYCARHRGFDVGHFDFWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Sacituzumab HC DEC-205 533 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGL

KWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDT

AVYFCARGGFGSSYWYFDVWGQGSLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPG

KAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQ

QHYITPLTFGAGTKVEIK

HC tumor 534 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQG mAb with LKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADD DEC-205 mAb TAVYFCARGGFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG

LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV

KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS

LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT

VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS

QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL

EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED

TAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQ

APRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

RRNWPLTFGGGTKVEIK

PR1A3 HC DEC-205 535 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED Antibody Region SEQ Sequence

ID

NO:

tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VKLQQSGPELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGLK

WMGWINTKTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDTA

KYFCARWDFYDYVEAMDYWGQGTTVTVSSGGGGSGGGGSGGGG

SGGGGSDIVMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQ

KPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAE

YFCHQYYTYPLFTFGSGTKLEMK

HC tumor 536 QVKLQQSGPELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGL mAb with KWMGWINTKTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDT DEC-205 mAb AKYFCARWDFYDYVEAMDYWGQGTTVTVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG

LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV

KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS

LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT

VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS

QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL

EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED

TAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQ

APRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

RRNWPLTFGGGTKVEIK

Humanized HC DEC-205 818 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL PR1A3 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL

TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS

QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQG

LEWMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSD

DTAVYYCARWDFAYYVEAMDYWGQGTTVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWY

QQKPGKAPKLLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFA

TYYCHQYYTYPLFTFGQGTKLEIK

HC tumor 819 QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQG mAb with LEWMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSD DEC-205 mAb DTAVYYCARWDFAYYVEAMDYWGQGTTVTVSSASTKGPSVFPLA ScFv PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK

THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGS

GGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQ

APGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQM

NSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGG Antibody Region SEQ Sequence

ID

NO:

GSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAW YQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDF AVYYCQQRRNWPLTFGGGTKVEIK

Humanized HC DEC-205 836 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL Ab2-3 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL

TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEW

VAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAV

YYCAAHYFGSSGPFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSDIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSP

KLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHH

YGTPFTFGSGTKLEIK

HC tumor 837 EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLE mAb with WVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTA DEC-205 mAb VYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS

QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL

EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED

TAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQ

APRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

RRNWPLTFGGGTKVEIK

IMAB362, HC DEC-205 537 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL

CLAUDIXIM mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED

AB tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS

ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLE

WIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSA

VYYCTRSWRGNSFDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGG

GSDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQ

KPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAV

YYCQNDYSYPFTFGSGTKLEIK

HC tumor 538 QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGL mAb with EWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSA DEC-205 mAb VYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSG ScFv GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL Antibody Region SEQ Sequence

ID

NO:

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

AMG595 HC DEC-205 539 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLE

WVAVIWYDGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDGYDILTGNPRDFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTY

LSWLQQRPGQPPRLLIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEA

EDVGVYYCMQSTHVPRTFGQGTKVEIK

HC tumor 540 QVQLVESGGGVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKG mAb with LEWVAVIWYDGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAE DEC-205 mAb DTAVYYCARDGYDILTGNPRDFDYWGQGTLVTVSSASTKGPSVFPL ScFv APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL

QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD

KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGS

GGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQ

APGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMN

SLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGS

GGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQ

QKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAV

YYCQQRRNWPLTFGGGTKVEIK

ABT806 HC DEC-205 541 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLQESGPGLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLE

WMGYISYNGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATY

YCVTASRGFPYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

MTQSPSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYH

GTNLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWT

FGGGTKLEIK

HC tumor 542 EVQLQESGPGLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLE mAb with WMGYISYNGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATY DEC-205 mAb YCVTASRGFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL Antibody Region SEQ Sequence

ID

NO:

ScFv GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG

VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN

KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF

YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ

QGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVES

GGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVI

WYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC

ARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPL

TFGGGTKVEIK

Sibrotuzumab HC DEC-205 543 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLE

WIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAV

YYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGG

GSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYL

AWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQA

EDVAVYYCQQYFSYPLTFGQGTKVEIK

HC tumor 544 QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRL mAb with EWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTA DEC-205 mAb VYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAP ScFv SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS

SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT

HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN

GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ

VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGG

GSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGK

GLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRA

EDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGG

GSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKP

GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQRRNWPLTFGGGTKVEIK

DS-8895a HC DEC-205 545 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL variant 1 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLE

WMGWINTYTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDTA

VYYCATYYRYERDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSDIVMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKP Antibody Region SEQ Sequence

ID

NO:

GQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYY CFQGSHVPYTFGQGTKVEIK

HC tumor 546 QVQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQG mAb with LEWMGWINTYTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDT DEC-205 mAb AVYYCATYYRYERDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

DS-8895a HC DEC-205 547 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL variant 2 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

IQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLK

WMGWINTYTGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDTA

VYYCATYYRYERDFDYWGQGTLVTVSSGGGGSGGGGSGGGSGGG

GSDVLMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPG

QSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC

FQGSHVPYTFGQGTKVEIK

HC tumor 548 QIQLVQSGAEVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGL mAb with KWMGWINTYTGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDT DEC-205 mAb AVYYCATYYRYERDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGGSGGGGSGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

MEDI-547 HC DEC-205 549 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV Antibody Region SEQ Sequence

ID

NO:

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLE

WVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCAGYDSGYDYVAVAGPAEYFQHWGQGTLVTVSSGGGGSGGG

GSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISTWLAW

YQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDF

ATYYCQQYNSYSRTFGQGTKVEIK

HC tumor 550 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGL mAb with EWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT DEC-205 mAb AVYYCAGYDSGYDYVAVAGPAEYFQHWGQGTLVTVSSASTKGPS ScFv VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP

AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK

SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD

VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG

SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGG

GGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYW

VRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYL

QMNSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSG

GGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYL

AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPE

DFAVYYCQQRRNWPLTFGGGTKVEIK

Narnatumab HC DEC-205 551 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGGGLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLE

WVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDT

AVYYCTRDGYSSGRHYGMDVWGQGTTVIVSSGGGGSGGGGSGGG

GSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKP

GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQRSNWPRTFGQGTKVEIK

HC tumor 552 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLE mAb with WVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDT DEC-205 mAb AVYYCTRDGYSSGRHYGMDVWGQGTTVIVSSASTKGPSVFPLAPSS ScFv KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG

LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV

KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS

LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT

VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS

QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL

EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED

TAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQ

APRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

RRNWPLTFGGGTKVEIK

RG7841 HC DEC-205 553 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY Antibody Region SEQ Sequence

ID

NO:

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGPALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALEW

LGMIWGDGSTDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARDYYFNYASWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSDIQMTQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKT

VKLLIYYTSNLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQY

SELPWTFGQGTKVEIK

HC tumor 554 EVQLVESGPALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALE mAb with WLGMIWGDGSTDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTA DEC-205 mAb TYYCARDYYFNYASWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Farletuzumab HC DEC-205 555 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLE

WVAMISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTG

VYFCARHGDDPAWFAYWGQGTPVTVSSGGGGSGGGGSGGGGSGG

GGSDIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAP

KPWIYGTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQW

SSYPYMYTFGQGTKVEIK

HC tumor 556 EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLE mAb with WVAMISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTG DEC-205 mAb VYFCARHGDDPAWFAYWGQGTPVTVSSASTKGPSVFPLAPSSKSTS ScFv GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQV

QLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR Antibody Region SEQ Sequence

ID

NO:

RNWPLTFGGGTKVEIK

Mirvetuximab HC DEC-205 557 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLE

WIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFA

VYYCTRYDGSRAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGG

GSDIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPG

QQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYC

QQSREYPYTFGGGTKLEIK

HC tumor 558 QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSL mAb with EWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDF DEC-205 mAb AVYYCTRYDGSRAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTS ScFv GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQV

QLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

J591 variantl HC DEC-205 559 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLQQSGPELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWI

GNINPNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVY

YCAAGWNFDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSDIV

MTQSHKFMSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPKLLIY

WASTRHTGVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQYNSYP

LTFGAGTMLDLK

HC tumor 560 EVQLQQSGPELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLE mAb with WIGNINPNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSA DEC-205 mAb VYYCAAGWNFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTA ScFv ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV

TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE

LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQL Antibody Region SEQ Sequence

ID

NO:

VESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWV

AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV

YYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG

GSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR

LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

J591 variant 2 HC DEC-205 561 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLQQSGPELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWI

GNINPNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVY

YCAAGWNFDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSNIV

MTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLI

YGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSY

PYTFGGGTKLEIK

HC tumor 562 EVQLQQSGPELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLE mAb with WIGNINPNNGGTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSA DEC-205 mAb VYYCAAGWNFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTA ScFv ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV

TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE

LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQL

VESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWV

AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV

YYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG

GSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR

LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Rovalpituzum HC DEC-205 563 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL ab mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGL

EWMGWINTYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARIGDSSPSDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQA

PRLLIYYASNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQD

YTSPWTFGQGTKLEIK

HC tumor 564 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQG mAb with LEWMGWINTYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSD DEC-205 mAb DTAVYYCARIGDSSPSDYWGQGTLVTVSSASTKGPSVFPLAPSSKST ScFv SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP Antibody Region SEQ Sequence

ID

NO:

CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

PF-06647020 HC DEC-205 565 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLE

WIGVISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTA

VYYCARGNSYFYALDYWGQGTSVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKP

GQAPRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSNEDPWTFGGGTKLEIK

HC tumor 566 QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKR mAb with LEWIGVISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSED DEC-205 mAb TAVYYCARGNSYFYALDYWGQGTSVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Antibody to HC DEC-205 567 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL PTK7 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGLE

WVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARTYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIK

YASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPIT

FGQGTRLEIK Antibody Region SEQ Sequence

ID

NO:

HC tumor 568 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGL mAb with EWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT DEC-205 mAb AVYYCARTYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT ScFv AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP

ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK

VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQL

VESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWV

AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV

YYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG

GSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR

LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Ladiratuzuma HC DEC-205 569 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL b mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGL

EWMGWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDD

TAVYYCAVHNAHYGTWFAYWGQGTLVTVSSGGGGSGGGGSGGG

GSGGGGSDVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEY

FQQRPGQSPRPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDV

GVYYCFQGSHVPYTFGGGTKVEIK

HC tumor 570 QVQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQG mAb with LEWMGWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSD DEC-205 mAb DTAVYYCAVHNAHYGTWFAYWGQGTLVTVSSASTKGPSVFPLAPS ScFv SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT

HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN

GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ

VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGG

GSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGK

GLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRA

EDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGG

GSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKP

GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQRRNWPLTFGGGTKVEIK

Cirmtuzumab HC DEC-205 571 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLY tumor mAb LQMNSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGP ScFv SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP

KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

GGGGSGGGGSQVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHW Antibody Region SEQ Sequence

ID

NO:

VRQAPGQGLEWMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVL TMTNMDPVDTATYYCARGWYYFDYWGHGTLVTVSSGGGGSGGG GSGGGGSGGGGSDIVMTQTPLSLPVTPGEPASISCRASKSISKYLAW YQQKPGQAPRLLIYSGSTLQSGIPPRFSGSGYGTDFTLTINNIESEDA AYYFCQQHDESPY TFGEGTKVEIK

HC tumor 572 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLE mAb with WMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDT DEC-205 mAb ATYYCARGWYYFDYWGHGTLVTVSSASTKGPSVFPLAPSSKSTSG ScFv GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Antibody to HC DEC-205 573 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL MAGE-A3 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLY

tumor mAb LQMNSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGP ScFv SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP

KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

GGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCTASGFRFRSHGMH

WVRQAPGKGLEWVAVISYDGNNKLYADSVKGRITISRDNSKNTLFL

QMNNVRAEDTAVYYCASPYTSDWQYFQYWGQGTLVIVSSGGGGS

GGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERATFSCRASQNISTT

LAWYQQKPGQAPRLLIYDTSTRATGIPARFSGSGSGTEFTLTISSLQS

EDLAVYYCQQSNSWPLTFGGGTKVEIK

HC tumor 574 QVQLVESGGGVVQPGRSLRLSCTASGFRFRSHGMHWVRQAPGKGL mAb with EWVAVISYDGNNKLYADSVKGRITISRDNSKNTLFLQMNNVRAEDT DEC-205 mAb AVYYCASPYTSDWQYFQYWGQGTLVIVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Antibody to HC DEC-205 575 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL NY-ESO-1 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF Antibody Region SEQ Sequence

ID

NO:

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVQSGGGVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLE

WVAGMNWSGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVEDT

ALYFCARGEYSNRFDPRGRGTLVTVSSGGGGSGGGGSGGGGSGGG

GSDIVMTQTPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRP

GQSPRRLIYKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYC

MQGTHWPPIFGQGTKVEIK

HC tumor 576 QVQLVQSGGGVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGL mAb with EWVAGMNWSGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVED DEC-205 mAb TALYFCARGEYSNRFDPRGRGTLVTVSSASTKGPSVFPLAPSSKSTS ScFv GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQV

QLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Trastuzumab HC DEC-205 686 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSE

VQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE

WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDT

AVYYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKP

GKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC

QQHYTTPPTFGQGTKVEIK

HC tumor 687 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE mAb with WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDT DEC-205 mAb AVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSK ScFv STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL

YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC

PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL

TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

HC DEC205 797 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL Antibody Region SEQ Sequence

ID

NO:

mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED tumor mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS

ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY (LH,25mer) SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSD

IQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLL

IYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPP

TFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTN

GYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWG

GDGFYAMDYWGQGTLVTVSS

TABLE 9. Fusion Sequences - CD40 fusions via the light chain

Antibody Region SEQ Sequence

ID

NO:

Pertuzumab LC CD40 766 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNP

NSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCAR

NLGPSFYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM

TQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSA

SYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFG

QGTKVEIK

LC tumor 23 DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKL mAb LIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIY containing PYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP CD40 mAb REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQS

GAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGW

INPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

Cetuximab LC CD40 703 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLKQSGP

GLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGG

NTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTY

YDYEFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSDILLTQS

PVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS

GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTK

LELK

LC tumor 36 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK mAb YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT containing FGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA CD40 mAb KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH

ScFv KVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGAE Antibody Region SEQ Sequence

ID

NO:

VKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINP

DSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCAR

DQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGK

APNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ

ANIFPLTFGGGTKVEIK

Panitumumab LC CD40 760 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQESGP

GLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGfflYY

SGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVT

GAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPS

SLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLE

TGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTK

VEIK

LC tumor 49 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKL mAb LIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLP containing LAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQ ANIFPLTFGGGTKVEIK

Nimotuzumab LC CD40 751 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGA

EVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIGGINPTS

GGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAFYFCARQGL

WFDSDGRGFDFWGQGSTVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

MTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAP

KLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQYSH

VPWTFGQGTKLEIK

LC tumor 62 DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPG mAb KAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQ containing YSHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN CD40 mAb NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK

ScFv ADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQL

VQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEW

MGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTA

VYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGS

GGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWY

QQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA

TYYCQQ ANIFPLTFGGGTKVEIK

Zalutumumab LC CD40 802 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWD

DGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DGITMVRGVMKDYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSAIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAP Antibody Region SEQ Sequence

ID

NO:

KLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNS YPLTFGGGTKVEIK

LC tumor 75 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLI mAb YDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPL containing TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE CD40 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWIN

PDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCA

RDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPG

KAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ

QANIFPLTFGGGTKVEIK

Onartuzumab LC CD40 757 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPS

NSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYR

SYVTPLDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQ

SPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLL

IYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAY

PWTFGQGTKVEIK

LC tumor 88 DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKP mAb GKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC containing QQYYAYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC CD40 mAb LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

ScFv LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGL

EWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDD

TAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGG

GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLA

WYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPED

FATYYCQQANIFPLTFGGGTKVEIK

Patritumab LC CD40 763 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQWG

AGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHS

GSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKW

TWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIEMTQSP

DSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY

WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTP

RTFGQGTKVEIK

LC tumor 101 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNP mAb GQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY containing CQQYYSTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC CD40 mAb LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

ScFv LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGL

EWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDD

TAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGG

GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLA

WYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPED

FATYYCQQANIFPLTFGGGTKVEIK

Clivatuzumab LC CD40 709 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP Antibody Region SEQ Sequence

ID

NO:

containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGA

EVKKPGASVKVSCEASGYTFPSYVLHWVKQAPGQGLEWIGYINPY

NDGTQYNEKFKGKATLTRDTSINTAYMELSRLRSDDTAVYYCARG

FGGSYGFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLT

QSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGKAPKLWIYS

TSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQWNRYPYT

FGGGTRLEIK

LC tumor 114 DIQLTQSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGKAPK mAb LWIYSTSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQWN containing RYPYTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF CD40 mAb YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

ScFv YEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQ

SGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMG

WINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVY

YCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGG

GGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQ

KPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY

YCQQANIFPLTFGGGTKVEIK

Sofituzumab LC CD40 790 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGLEWVGYISY

SGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARWT

SGLDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPS

SLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKLLIYGATSLE

TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTTPFTFGQGT

KVEIK

LC tumor 127 DIQMTQSPSSLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKL mAb LIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTT containing PFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

Edrecolomab LC CD40 718 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGA

ELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGS

GGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARDG

PWFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSNIVMTQSP

KSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYGASN

RYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFG

GGTKLEIK

LC tumor 140 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPK mAb LLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQG containing YSYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF CD40 mAb YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

ScFv YEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQ

SGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMG Antibody Region SEQ Sequence

ID

NO:

WINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVY

YCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGG

GGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQ

KPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY

YCQQANIFPLTFGGGTKVEIK

Adecatumum LC CD40 694 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL ab mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLLESGG

GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYD

GSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD

MGWGSGWRPYYYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGS

GGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQ

PPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQ

SYDIPYTFGQGTKLEIK

LC tumor 153 ELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLI mAb YWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIP containing YTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE CD40 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWIN

PDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCA

RDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPG

KAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ

QANIFPLTFGGGTKVEIK

Anetumab LC CD40 700 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVELVQSGA

EVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLEWMGIIDPGD

SRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGQL

YGGTYMDGWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIALT

QPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKLMIYG

VNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDIESAT

PVFGGGTKLTVL

LC tumor 166 DIALTQPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKL mAb MIYGVNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDI containing ESATPVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLIS CD40 mAb DFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPE

ScFv QWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSGGGGSQVQLVQ

SGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMG

WINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVY

YCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGG

GGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQ

KPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY

YCQQANIFPLTFGGGTKVEIK

huDS6 LC CD40 724 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQAQLVQSGA

EVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGYIYPG

NGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDSAVYFCARGD

SVPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSEIVLTQSP

ATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLWIYSTSSLAS

GVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFPLTFGAGTK Antibody Region SEQ Sequence

ID

NO:

LELK

LC tumor 179 EIVLTQSPATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLWI mAb YSTSSLASGVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFP containing LTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

Lifastuzumab LC CD40 736 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLEWVATIGRV

AFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARH

RGFDVGHFDFWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

MTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGKAP

KLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGS

FNPLTFGQGTKVEIK

LC tumor 192 DIQMTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGK mAb APKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ containing GSFNPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN CD40 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

QSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQ

QKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT

YYCQQANIFPLTFGGGTKVEIK

Sacituzumab LC CD40 781 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGS

ELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWIN

TYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARG

GFGSSYWYFDVWGQGSLVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

LTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYS

ASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTF

GAGTKVEIK

LC tumor 205 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLL mAb IYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITP containing LTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE CD40 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWIN

PDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCA

RDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPG

KAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ

QANIFPLTFGGGTKVEIK

PR1A3 LC CD40 772 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE Antibody Region SEQ Sequence

ID

NO:

tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVKLQQSGP

ELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGLKWMGWINT

KTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDTAKYFCARW

DFYDYVEAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDI

VMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKA

LIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCHQYYT

YPLFTFGSGTKLEMK

LC tumor 218 DIVMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSP mAb KALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCHQY containing YTYPLFTFGSGTKLEMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN CD40 mAb NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK

ScFv ADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQL

VQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEW

MGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTA

VYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGS

GGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWY

QQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA

TYYCQQANIFPLTFGGGTKVEIK

Humanized LC CD40 820 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL PR1A3 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWINT

KTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCAR

WDFAYYVEAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGS

DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPK

LLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYT

YPLFTFGQGTKLEIK

LC tumor 817 DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPK mAb LLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYT containing YPLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY CD40 mAb PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQS

GAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGW

INPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

LC tumor 844 DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPK mAb LLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYT containing YPLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY CD40 mab PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY scFv (LH) EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSDIQMTQS

PSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTL

QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGT

KVEIKGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVK

VSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQ

KFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTN

GVCSYFDYWGQGTLVTVSS

Humanized LC CD40 838 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL Ab2-3 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQESGP

GLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGG

GITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHY Antibody Region SEQ Sequence

ID

NO:

FGSSGPFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMT QSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTR TLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGS GTKLEIK

LC tumor 835 DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLL mAb VYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGT containing PFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

LC tumor 842 DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLL mAb VYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGT containing PFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mab EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE scFv (LH) KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSDIQMTQSPS

SVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNLLIYTASTLQ

SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFPLTFGGGTK

VEIKGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVS

CKASGYTFTGYYMHWVRQAPGQGLEWMGWINPDSGGTNYAQKF

QGRVTMTRDTSISTAYMELNRLRSDDTAVYYCARDQPLGYCTNGV

CSYFDYWGQGTLVTVSS

IMAB362, LC CD40 727 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL

CLAUDIXIM mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP

AB containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQPGA

ELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSD

SYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSW

RGNSFDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQS

PSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLL

IYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS

YPFTFGSGTKLEIK

LC tumor 231 DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQK mAb PGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVY containing YCQNDYSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVC CD40 mAb LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

ScFv LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGL

EWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDD

TAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGG

GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLA

WYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPED

FATYYCQQANIFPLTFGGGTKVEIK

AMG595 LC CD40 697 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEWVAVIWY

DGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DGYDILTGNPRDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG

GSDTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRP

GQPPRLLIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEAEDVGVYYC

MQSTHVPRTFGQGTKVEIK Antibody Region SEQ Sequence

ID

NO:

LC tumor 270 DTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPG mAb QPPRLLIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEAEDVGVYYC containing MQSTHVPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL CD40 mAb LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL

ScFv SKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQV

QLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE

WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDT

AVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGG

SGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAW

YQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYYCQQANIFPLTFGGGTKVEIK

ABT806 LC CD40 691 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQESGP

GLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWMGYISYN

GNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTASRG

FPYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSM

SVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGTNLDDGV

PSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTKLE

IK

LC tumor 283 DIQMTQSPSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGL mAb IYHGTNLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQF containing PWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP CD40 mAb REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQS

GAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGW

INPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

Sibrotuzumab LC CD40 787 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNN

GIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIA

YGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI

VMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPG

QPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYC

QQYFSYPLTFGQGTKVEIK

LC tumor 296 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKP mAb GQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYY containing CQQYFSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC CD40 mAb LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

ScFv LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQ

VQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGL

EWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDD

TAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGG

GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLA

WYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPED

FATYYCQQANIFPLTFGGGTKVEIK

DS-8895a LC CD40 712 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL variant 1 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK Antibody Region SEQ Sequence

ID

NO:

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLEWMGWINT

YTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDTAVYYCATYY

RYERDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMT

QSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIY

KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVP

YTFGQGTKVEIK

LC tumor 309 DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSP mAb QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQG containing SHVPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN CD40 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

QSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQ

QKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT

YYCQQANIFPLTFGGGTKVEIK

DS-8895a LC CD40 715 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL variant 2 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQIQLVQSGA

EVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLKWMGWINT

YTGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDTAVYYCATYY

RYERDFDYWGQGTLVTVSSGGGGSGGGGSGGGSGGGGSDVLMTQ

SPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIYK

VSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYT

FGQGTKVEIK

LC tumor 322 DVLMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQS mAb PQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQ containing GSHVPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN CD40 mAb NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK

ScFv ADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQL

VQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEW

MGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTA

VYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGS

GGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWY

QQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA

TYYCQQANIFPLTFGGGTKVEIK

MEDI-547 LC CD40 742 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLLESGG

GLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPS

GGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGY

DSGYDYVAVAGPAEYFQHWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISTWLAWYQQKPG

KAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQ

QYNSYSRTFGQGTKVEIK

LC tumor 335 DIQMTQSPSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLL mAb IYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSY containing SRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG Antibody Region SEQ Sequence

ID

NO:

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQANIFPLTFGGGTKVEIK

Narnatumab LC CD40 748 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLEWVANIKQD

GSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDTAVYYCTRD

GYSSGRHYGMDVWGQGTTVIVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPR

TFGQGTKVEIK

LC tumor 348 EIVLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKPGQAPRLL mAb IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWP containing RTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

RG7841 LC CD40 775 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGP

ALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALEWLGMIWGD

GSTDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDY

YFNYASWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

MTQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKTVKLLIYY

TSNLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSELPWT

FGQGTKVEIK

LC tumor 361 DIQMTQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKTVKLL mAb IYYTSNLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSELP containing WTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

Farletuzumab LC CD40 721 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVAMISSG

GSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARH

GDDPAWFAYWGQGTPVTVSSGGGGSGGGGSGGGGSGGGGSDIQL

TQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYG

TSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSYPYM

YTFGQGTKVEIK

LC tumor 374 DIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKP Antibody Region SEQ Sequence

ID

NO:

mAb WIYGTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSS containing YPYMYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN CD40 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

QSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQ

QKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT

YYCQQANIFPLTFGGGTKVEIK

Mirvetuximab LC CD40 745 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYD

GDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYD

GSRAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQ

SPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIY

RASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPY

TFGGGTKLEIK

LC tumor 387 DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQ mAb PRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQ containing SREYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN CD40 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

QSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQ

QKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT

YYCQQANIFPLTFGGGTKVEIK

J591 variantl LC CD40 730 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQQSGP

ELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNINPNNG

GTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWN

FDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSHKF

MSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPKLLIYWASTRHT

GVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQYNSYPLTFGAGT

MLDLK

LC tumor 400 DIVMTQSHKFMSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPK mAb LLIYWASTRHTGVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQY containing NSYPLTFGAGTMLDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN CD40 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

QSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQ

QKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT

YYCQQANIFPLTFGGGTKVEIK

J591 variant 2 LC CD40 733 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQQSGP Antibody Region SEQ Sequence

ID

NO:

ELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNINPNNG

GTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWN

FDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSNIVMTQSPKSM

SMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYGASNRYT

GVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGGT

KLEIK

LC tumor 413 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPK mAb LLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQG containing YSYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF CD40 mAb YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

ScFv YEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQ

SGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMG

WINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVY

YCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGG

GGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQ

KPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY

YCQQANIFPLTFGGGTKVEIK

Rovalpituzum LC CD40 778 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL ab mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWIN

TYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCA

RIGDSSPSDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVM

TQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYY

ASNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTF

GQGTKLEIK

LC tumor 426 EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRL mAb LIYYASNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTS containing PWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP CD40 mAb REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQS

GAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGW

INPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

PF-06647020 LC CD40 769 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGP

EVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIGVISTY

NDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCAR

GNSYFYALDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQAPRL

LIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDP

WTFGGGTKLEIK

LC tumor 439 EIVLTQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQ mAb APRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQS containing NEDPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN CD40 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

QSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWM

GWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAV

YYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSG

GGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQ Antibody Region SEQ Sequence

ID

NO:

QKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQANIFPLTFGGGTKVEIK

Antibody to LC CD40 688 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL PTK7 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGLEWVAVISYD

GSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTY

YFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDF

QSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQSFSG

VPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPITFGQGTRLE

IK

LC tumor 452 EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLI mAb KYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPI containing TFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA CD40 mAb KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH

ScFv KVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGAE

VKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINP

DSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCAR

DQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGK

APNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ

ANIFPLTFGGGTKVEIK

Ladiratuzuma LC CD40 784 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL b mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWMGWIDP

ENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAV

HNAHYGTWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSD

VVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEYFQQRPGQSP

RPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGS

HVPYTFGGGTKVEIK

LC tumor 465 DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEYFQQRPGQ mAb SPRPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQ containing GSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN CD40 mAb NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK

ScFv ADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQL

VQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEW

MGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTA

VYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGS

GGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWY

QQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA

TYYCQQ ANIFPLTFGGGTKVEIK

Cirmtuzumab LC CD40 706 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQESGP

GLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPY

DGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARG

WYYFDYWGHGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQT

PLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQ

SGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPY

LC tumor 478 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLI mAb YSGSTLQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPY containing TFGEGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA Antibody Region SEQ Sequence

ID

NO:

CD40 mAb KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH ScFv KVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGAE

VKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINP

DSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCAR

DQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGK

APNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ

ANIFPLTFGGGTKVEIK

Antibody to LC CD40 739 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL MAGE-A3 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCTASGFRFRSHGMHWVRQAPGKGLEWVAVISYD

GNNKLYADSVKGRITISRDNSKNTLFLQMNNVRAEDTAVYYCASP

YTSDWQYFQYWGQGTLVIVSSGGGGSGGGGSGGGGSGGGGSEIV

MTQSPATLSVSPGERATFSCRASQNISTTLAWYQQKPGQAPRLLIYD

TSTRATGIPARFSGSGSGTEFTLTISSLQSEDLAVYYCQQSNSWPLTF

GGGTKVEIK

LC tumor 491 EIVMTQSPATLSVSPGERATFSCRASQNISTTLAWYQQKPGQAPRLL mAb IYDTSTRATGIPARFSGSGSGTEFTLTISSLQSEDLAVYYCQQSNSWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE CD40 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWIN

PDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYCA

RDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPG

KAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ

QANIFPLTFGGGTKVEIK

Antibody to LC CD40 754 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL NY-ESO-1 mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGG

GVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLEWVAGMNW

SGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVEDTALYFCARG

EYSNRFDPRGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQ

TPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPGQSPRRLI

YKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYCMQGTHW

PPIFGQGTKVEIK

LC tumor 504 DIVMTQTPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPG mAb QSPRRLIYKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYC containing MQGTHWPPIFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL CD40 mAb LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL

ScFv SKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQV

QLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE

WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDT

AVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGG

SGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAW

YQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYYCQQ ANIFPLTFGGGTKVEIK

Trastuzumab LC CD40 793 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQ ANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTN

GYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWG Antibody Region SEQ Sequence

ID

NO:

GDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF GQGTKVEIK

LC tumor 685 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKL mAb LIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTT containing PPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK

LC CD40 798 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK scFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSDIQMTQSPSS (LH,25mer) LSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYS

GVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTK

VEIKGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGG

SLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYAD

SVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAM

DYWGQGTLVTVSS

TABLE 10. Fusion Sequences - DEC-205 fusions via the light chain

Antibody Region SEQ Sequence

ID

NO:

Pertuzumab LC DEC-205 767 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNP

NSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCAR

NLGPSFYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM

TQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSA

SYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFG

QGTKVEIK

LC tumor 768 DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKL mAb LIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIY containing PYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR DEC-205 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Cetuximab LC DEC-205 704 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLKQSGP Antibody Region SEQ Sequence

ID

NO:

GLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGG

NTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTY

YDYEFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSDILLTQS

PVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS

GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTK

LELK

LC tumor 705 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK mAb YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTF containing GAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK DEC-205 mAb VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK ScFv VYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGGGV

VQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWYDG

SNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDL

WGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQ

SPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASN

RATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFGG

GTKVEIK

Panitumumab LC DEC-205 761 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQESGP

GLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGfflYYS

GNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTG

AFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSS

LSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLET

GVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKV

EIK

LC tumor 762 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKL mAb LIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLP containing LAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR DEC-205 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Nimotuzumab LC DEC-205 752 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGA

EVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIGGINPTS

GGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAFYFCARQGL

WFDSDGRGFDFWGQGSTVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

MTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAP

KLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQYSH

VPWTFGQGTKLEIK

LC tumor 753 DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGK mAb APKLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQY containing SHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL Antibody Region SEQ Sequence

ID

NO:

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN WPLTFGGGTKVEIK

Zalutumumab LC DEC-205 803 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWD

DGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DGITMVRGVMKDYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSAIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAP

KLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNS

YPLTFGGGTKVEIK

LC tumor 804 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLI mAb YDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPL containing TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

Onartuzumab LC DEC-205 758 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPS

NSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYR

SYVTPLDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQ

SPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLL

IYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAY

PWTFGQGTKVEIK

LC tumor 759 DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPG mAb KAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ containing QYYAYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL DEC-205 mAb NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS ScFv KADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Patritumab LC DEC-205 764 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQWG

AGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSG

STNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWT

WYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIEMTQSPD

SLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY

WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPR

TFGQGTKVEIK

LC tumor 765 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNP mAb GQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY Antibody Region SEQ Sequence

ID

NO:

containing CQQYYSTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC DEC-205 mAb LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT ScFv LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQ

VQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

Clivatuzumab LC DEC-205 710 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGA

EVKKPGASVKVSCEASGYTFPSYVLHWVKQAPGQGLEWIGYINPY

NDGTQYNEKFKGKATLTRDTSINTAYMELSRLRSDDTAVYYCARG

FGGSYGFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLT

QSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGKAPKLWIYS

TSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQWNRYPYT

FGGGTRLEIK

LC tumor 711 DIQLTQSPSSLSASVGDRVTMTCSASSSVSSSYLYWYQQKPGKAPKL mAb WIYSTSNLASGVPARFSGSGSGTDFTLTISSLQPEDSASYFCHQWNR containing YPYTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP DEC-205 mAb REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Sofituzumab LC DEC-205 791 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGLEWVGYISY

SGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARWT

SGLDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPS

SLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKLLIYGATSLE

TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTTPFTFGQGT

KVEIK

LC tumor 792 DIQMTQSPSSLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKL mAb LIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTT containing PFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR DEC-205 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Edrecolomab LC DEC-205 719 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGA

ELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGS Antibody Region SEQ Sequence

ID

NO:

GGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARDG PWFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSNIVMTQSP KSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYGASN RYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFG GGTKLEIK

LC tumor 720 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPK mAb LLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGY containing SYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY DEC-205 mAb PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVES

GGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVI

WYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC

ARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPL

TFGGGTKVEIK

Adecatumum LC DEC-205 695 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI ab mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLLESGG

GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYD

GSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD

MGWGSGWRPYYYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGS

GGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQ

PPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQ

SYDIPYTFGQGTKLEIK

LC tumor 696 ELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLI mAb YWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIP containing YTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

Anetumab LC DEC-205 701 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVELVQSGA

EVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLEWMGIIDPGD

SRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGQL

YGGTYMDGWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIALT

QPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKLMIYG

VNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDIESAT

PVFGGGTKLTVL

LC tumor 702 DIALTQPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKL mAb MIYGVNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDI containing ESATPVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLIS DEC-205 mAb DFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPE ScFv QWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSGGGGSQVQLVE

SGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVI

WYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC

ARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPL Antibody Region SEQ Sequence

ID

NO:

TFGGGTKVEIK

huDS6 LC DEC-205 725 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQAQLVQSGA

EVVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGYIYPG

NGATNYNQKFQGKATLTADPSSSTAYMQISSLTSEDSAVYFCARGD

SVPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSEIVLTQSP

ATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLWIYSTSSLAS

GVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFPLTFGAGTK

LELK

LC tumor 726 EIVLTQSPATMSASPGERVTITCSAHSSVSFMHWFQQKPGTSPKLWI mAb YSTSSLASGVPARFGGSGSGTSYSLTISSMEAEDAATYYCQQRSSFP containing LTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR DEC-205 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Lifastuzumab LC DEC-205 737 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLEWVATIGRV

AFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARH

RGFDVGHFDFWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

MTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGKAP

KLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSF

NPLTFGQGTKVEIK

LC tumor 738 DIQMTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGK mAb APKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ containing GSFNPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Sacituzumab LC DEC-205 782 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQSGS

ELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWIN

TYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARG

GFGSSYWYFDVWGQGSLVTVSSGGGGSGGGGSGGGGSGGGGSDIQ

LTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYS

ASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTF

GAGTKVEIK

LC tumor 783 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLL mAb IYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITP containing LTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE Antibody Region SEQ Sequence

ID

NO:

DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

PR1A3 LC DEC-205 773 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVKLQQSGP

ELKKPGETVKISCKASGYTFTEFGMNWVKQAPGKGLKWMGWINT

KTGEATYVEEFKGRFAFSLETSATTAYLQINNLKNEDTAKYFCARW

DFYDYVEAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDI

VMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKA

LIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCHQYYT

YPLFTFGSGTKLEMK

LC tumor 774 DIVMTQSQRFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPK mAb ALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCHQYY containing TYPLFTFGSGTKLEMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Humanized LC DEC-205 821 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLL PR1A3 mAb IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNW containing PLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR tumor mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWIN

TKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCAR

WDFAYYVEAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGS

DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPK

LLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYT

YPLFTFGQGTKLEIK

LC tumor 822 DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPK mAb LLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYT containing YPLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY DEC-205 mAb PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVES

GGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVI

WYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC

ARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPL

TFGGGTKVEIK

Humanized LC DEC-205 839 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLL Ab2-3 mAb IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNW containing PLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR tumor mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQESG

PGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSG

GGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAH Antibody Region SEQ Sequence

ID

NO:

YFGSSGPFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM TQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNT RTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFG SGTKLEIK

LC tumor 840 DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLL mAb VYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGT containing PFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR DEC-205 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLT

FGGGTKVEIK

IMAB362, LC DEC-205 728 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI

CLAUDIXIM mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP

AB containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQQPGA

ELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSD

SYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSW

RGNSFDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQS

PSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLL

IYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSY

PFTFGSGTKLEIK

LC tumor 729 DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKP mAb GQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYY containing CQNDYSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL DEC-205 mAb LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL ScFv SKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQV

QLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

AMG595 LC DEC-205 698 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQSGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEWVAVIWY

DGSDKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DGYDILTGNPRDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SDTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPG

QPPRLLIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEAEDVGVYYCM

QSTHVPRTFGQGTKVEIK

LC tumor 699 DTVMTQTPLSSHVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPG mAb QPPRLLIYRISRRFSGVPDRFSGSGAGTDFTLEISRVEAEDVGVYYCM containing QSTHVPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL DEC-205 mAb NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS ScFv KADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK Antibody Region SEQ Sequence

ID

NO:

ABT806 LC DEC-205 692 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQESGP

GLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWMGYISYN

GNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTASRG

FPYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSM

SVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGTNLDDGV

PSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTKLE

IK

LC tumor 693 DIQMTQSPSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGL mAb IYHGTNLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQF containing PWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP DEC-205 mAb REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Sibrotuzumab LC DEC-205 788 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNN

GIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIA

YGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI

VMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPG

QPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYC

QQYFSYPLTFGQGTKVEIK

LC tumor 789 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKP mAb GQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYY containing CQQYFSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL DEC-205 mAb LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL ScFv SKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQV

QLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLE

WVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT

AVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSG

GGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA

PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQR

RNWPLTFGGGTKVEIK

DS-8895a LC DEC-205 713 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI variant 1 mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLEWMGWINT

YTGEPTYSDDFKGRVTITADTSTSTAYLELSSLRSEDTAVYYCATYY

RYERDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMT

QSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIY

KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVP

YTFGQGTKVEIK

LC tumor 714 DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSP mAb QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQG containing SHVPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA Antibody Region SEQ Sequence

ID

NO:

ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

DS-8895a LC DEC-205 716 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI variant 2 mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQIQLVQSGAE

VKKPGASVKVSCKASGYTFIDYSMHWVRQAPGQGLKWMGWINTY

TGEPTYSDDFKGRFAFSLDTSTSTAYLELSSLRSEDTAVYYCATYYR

YERDFDYWGQGTLVTVSSGGGGSGGGGSGGGSGGGGSDVLMTQS

PLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQSPQLLIYKV

SNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTF

GQGTKVEIK

LC tumor 717 DVLMTQSPLSLPVTPGEPASISCRSSQSIVHSSGITYLEWYLQKPGQS mAb PQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQ containing GSHVPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN DEC-205 mAb NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ScFv ADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQL

VESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWV

AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV

YYCARDLWGWYFDYWGQGTLVTVSSGGGGGSGGGGSGGGSGGG

GSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR

LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

MEDI-547 LC DEC-205 743 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLLESGG

GLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPS

GGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGY

DSGYDYVAVAGPAEYFQHWGQGTLVTVSSGGGGSGGGGSGGGGS

GGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISTWLAWYQQKPG

KAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQ

QYNSYSRTFGQGTKVEIK

LC tumor 744 DIQMTQSPSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLL mAb IYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYS containing RTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

Narnatumab LC DEC-205 749 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFTFSSYLMTWVRQAPGKGLEWVANIKQD

GSEKYYVDSVKGRFTISRDNAKNSLNLQMNSLRAEDTAVYYCTRD

GYSSGRHYGMDVWGQGTTVIVSSGGGGSGGGGSGGGGSGGGGSEI Antibody Region SEQ Sequence

ID

NO:

VLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPR

TFGQGTKVEIK

LC tumor 750 EIVLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKPGQAPRLL mAb IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWP containing RTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

RG7841 LC DEC-205 776 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGP

ALVKPTQTLTLTCTVSGFSLTGYSVNWIRQPPGKALEWLGMIWGDG

STDYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYY

FNYASWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM

TQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKTVKLLIYYT

SNLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSELPWTF

GQGTKVEIK

LC tumor 777 DIQMTQSPSSLSASVGDRVTITCSASQGISNYLNWYQQKPGKTVKLL mAb IYYTSNLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSELP containing WTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR DEC-205 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

Farletuzumab LC DEC-205 722 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVAMISSGG

SYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARHG

DDPAWFAYWGQGTPVTVSSGGGGSGGGGSGGGGSGGGGSDIQLT

QSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYGT

SNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSYPYMY

TFGQGTKVEIK

LC tumor 723 DIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKP mAb WIYGTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSS containing YPYMYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Mirvetuximab LC DEC-205 746 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI Antibody Region SEQ Sequence

ID

NO:

mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYD

GDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYD

GSRAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQS

PLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYR

ASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYT

FGGGTKLEIK

LC tumor 747 DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQ mAb PRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQ containing SREYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

J591 variantl LC DEC-205 731 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQQSGP

ELKKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNINPNNG

GTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWN

FDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSHKF

MSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPKLLIYWASTRHT

GVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQYNSYPLTFGAGT

MLDLK

LC tumor 732 DIVMTQSHKFMSTSVGDRVSIICKASQDVGTAVDWYQQKPGQSPKL mAb LIYWASTRHTGVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQQYNS containing YPLTFGAGTMLDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY DEC-205 mAb PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVES

GGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVI

WYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC

ARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPL

TFGGGTKVEIK

J591 variant 2 LC DEC-205 734 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLQQSGP

ELVKPGTSVRISCKTSGYTFTEYTIHWVKQSHGKSLEWIGNINPNNG

GTTYNQKFEDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAAGWN

FDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGGGSNIVMTQSPKSM

SMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYGASNRYT

GVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGGT

KLEIK

LC tumor 735 NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPK mAb LLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQGY containing SYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY DEC-205 mAb PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY ScFv EKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVES Antibody Region SEQ Sequence

ID

NO:

GGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVI

WYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC

ARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEI

VLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPL

TFGGGTKVEIK

Rovalpituzum LC DEC-205 779 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI ab mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWIN

TYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCA

RIGDSSPSDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMT

QSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYYA

SNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFG

QGTKLEIK

LC tumor 780 EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRL mAb LIYYASNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTS containing PWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP DEC-205 mAb REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE ScFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESG

GGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIW

YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA

RDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIV

LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

PF-06647020 LC DEC-205 770 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGP

EVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIGVISTY

NDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCARG

NSYFYALDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSEIVLT

QSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQAPRLLI

YRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDPW

TFGGGTKLEIK

LC tumor 771 EIVLTQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQ mAb APRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQS containing NEDPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN DEC-205 mAb FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ScFv DYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLV

ESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVA

VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY

YCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG

SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL

LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Antibody to LC DEC-205 689 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI PTK7 mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSSYAFHWVRQAPGKGLEWVAVISYD

GSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTY

YFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDF

QSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQSFSG Antibody Region SEQ Sequence

ID

NO:

VPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPITFGQGTRLEI K

LC tumor 690 EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLI mAb KYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPI containing TFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA DEC-205 mAb KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH ScFv KVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGGG

VVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWYD

GSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD

LWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLT

QSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS

NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

Ladiratuzuma LC DEC-205 785 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI b mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGA

EVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWMGWIDP

ENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAV

HNAHYGTWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSD

VVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEYFQQRPGQSP

RPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGS

HVPYTFGGGTKVEIK

LC tumor 786 DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEYFQQRPGQ mAb SPRPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQ containing GSHVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN DEC-205 mAb NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ScFv ADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQL

VESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWV

AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV

YYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG

GSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR

LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRN

WPLTFGGGTKVEIK

Cirmtuzumab LC DEC-205 707 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLQESGP

GLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPY

DGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARG

WYYFDYWGHGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQT

PLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQ

SGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPY

LC tumor 708 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLI mAb YSGSTLQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPY containing TFGEGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA DEC-205 mAb KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH ScFv KVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGGG

VVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWYD

GSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD

LWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLT

QSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS

NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

Antibody to LC DEC-205 740 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI MAGE-A3 mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE Antibody Region SEQ Sequence

ID

NO:

tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCTASGFRFRSHGMHWVRQAPGKGLEWVAVISYD

GNNKLYADSVKGRITISRDNSKNTLFLQMNNVRAEDTAVYYCASP

YTSDWQYFQYWGQGTLVIVSSGGGGSGGGGSGGGGSGGGGSEIVM

TQSPATLSVSPGERATFSCRASQNISTTLAWYQQKPGQAPRLLIYDT

STRATGIPARFSGSGSGTEFTLTISSLQSEDLAVYYCQQSNSWPLTFG

GGTKVEIK

LC tumor 741 EIVMTQSPATLSVSPGERATFSCRASQNISTTLAWYQQKPGQAPRLL mAb IYDTSTRATGIPARFSGSGSGTEFTLTISSLQSEDLAVYYCQQSNSWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG

GGTKVEIK

Antibody to LC DEC-205 755 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI NY-ESO-1 mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSGG

GVVRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLEWVAGMNW

SGDKKGHAESVKGRFIISRDNAKNTLYLEMSSLRVEDTALYFCARG

EYSNRFDPRGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQ

TPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPGQSPRRLI

YKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYCMQGTHW

PPIFGQGTKVEIK

LC tumor 756 DIVMTQTPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPGQ mAb SPRRLIYKVSSRDPGVPDRFSGTGSGTDFTLEISRVEAEDIGVYYCM containing QGTHWPPIFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL DEC-205 mAb NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS ScFv KADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQ

LVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEW

VAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA

VYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGG

GGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP

RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRR

NWPLTFGGGTKVEIK

Trastuzumab LC DEC-205 794 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVESGG

GLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTN

GYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWG

GDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM

TQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS

ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF

GQGTKVEIK

LC tumor 795 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKL mAb LIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTP containing PTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC-205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK ScFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR Antibody Region SEQ Sequence

ID

NO:

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTFG GGTKVEIK

LC DEC205 799 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI mAb YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE tumor mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK scFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSDIQMTQSPSS (LH,25mer) LSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYS

GVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKV

EIKGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGS

LRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADS

VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAM

DYWGQGTLVTVSS

TABLE 11. Fusion Sequences - CD40 fusion with DEC205

Antibody Region SEQ Sequence

ID

NO:

DEC205 HC DEC205 243 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGL variant 1 mAb with EWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED

CD40 mAb TAVYYCARDLWGWYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS ScFv TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP

PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL

TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS

QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQG

LEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSD

DTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGG

GGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWL

AWYQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPE

DFATYYCQQANIFPLTFGGGTKVEIK

HC CD40 242 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQG mAb with LEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSD DEC205 mAb DTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSV ScFv FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS

CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGG

GGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWV

RQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQ

MNSLRAEDTAVYYCARDLWGWYFDYWGQGTLVTVSSGGGGSGG

GGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLA

WYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPED

FAVYYCQQRRNWPLTFGGGTKVEIK

LC DEC205 244 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLL mAb IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNW containing PLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE scFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI Antibody Region SEQ Sequence

ID

NO:

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQANIFPLTFGGGTKVEIK

LC CD40 800 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK scFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVESGG

GVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVAVIWY

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

DLWGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVL

TQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA

SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRRNWPLTF

GGGTKVEIK

DEC205 HC DEC205 256 EVQLVQSGAEVKKPGESLRISCKGSGDSFTTYWIGWVRQMPGKGL variant 2 mAb with EWMGIIYPGDSDTIYSPSFQGQVTISADKSISTAYLQWSSLKASDTA

CD40 mAb MYYCTRGDRGVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG ScFv TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS

VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQV

QLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLE

WMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDT

AVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGG

SGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAW

YQQKPGKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYYCQQANIFPLTFGGGTKVEIK

HC CD40 255 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQG mAb with LEWMGWINPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSD DEC205 mAb DTAVYYCARDQPLGYCTNGVCSYFDYWGQGTLVTVSSASTKGPSV ScFv FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS

CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGG

GGSGGGGSEVQLVQSGAEVKKPGESLRISCKGSGDSFTTYWIGWVR

QMPGKGLEWMGIIYPGDSDTIYSPSFQGQVTISADKSISTAYLQWSS

LKASDTAMYYCTRGDRGVDYWGQGTLVTVSSGGGGSGGGGSGGG

GSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISRWLAWYQQK

PEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYY

CQQYNSYPRTFGQGTKVEIK

LC DEC205 257 DIQMTQSPSSLSASVGDRVTITCRASQGISRWLAWYQQKPEKAPKS mAb LIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQYNSY containing PRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR CD40 mAb EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE scFv KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQVQLVQSG

AEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWI

NPDSGGTNYAQKFQGRVTMTRDTSISTAYMELNRLRSDDTAVYYC

ARDQPLGYCTNGVCSYFDYWGQGTLVTVSSGGGGSGGGGSGGGG

SGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKP

GKAPNLLIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

QQANIFPLTFGGGTKVEIK Antibody Region SEQ Sequence

ID

NO:

LC CD40 801 DIQMTQSPSSVSASVGDRVTITCRASQGIYSWLAWYQQKPGKAPNL mAb LIYTASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANIFP containing LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE DEC205 mAb AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK scFv HKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSEVQLVQSGA

EVKKPGESLRISCKGSGDSFTTYWIGWVRQMPGKGLEWMGIIYPGD

SDTIYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRGDRG

VDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSL

SASVGDRVTITCRASQGISRWLAWYQQKPEKAPKSLIYAASSLQSG

VPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQYNSYPRTFGQGTKV

EIK

Immune-Stimulatory Compounds

[0304] In some embodiments, the immune- stimulatory conjugates described herein further comprise an immune- stimulatory compound. An immune- stimulatory compound can be a small molecule, a compound or molecule that binds to a protein target and can activate the target protein' s function, or a compound that binds to a protein target and can inhibit the protein target's function, resulting in immune stimulation or modulation. In certain embodiments, an immune- stimulatory compound of a conjugate (i.e., attached to an antibody construct either directly or via a linker) can stimulate or activate its protein target with no or minimal processing of the conjugate. In certain embodiments, an immune- stimulatory compound of a conjugate (i.e., attached to an antibody construct either directly or via a linker) can inhibit its protein target with no or minimal processing of the conjugate. In this context, processing refers to degradation of the antibody construct or cleavage of the linker to liberate the immune- stimulatory compound or degredation product of the conjugate containing the immune- stimulatory compound. In certain embodiments, the protein target of the immune- stimulatory compound is an extracellular protein target and is located on the cell surface membrane or cellular compartments in communication with the cell surface, such as in the endoplasmic reticulum (ER). In certain embodiments, the protein target is intracellular, such as in the cytoplasm.

[0305] In some embodiments, an immune- stimulatory compound can activate immune cells. In some embodiments, an immune- stimulatory compound can reduce inhibition of immune cells. In some embodiments, an immune- stimulatory compound can stimulate immune activation by triggering degradation of a protein target.

[0306] In some embodiments, an immune- stimulatory compound can be a molecule or

compound whose action on its target can lead to immune stimulation by direct immune cell activation. In some embodiments, the immune activation can be indirect by alteration of the immune suppressive microenvironment of a tumor (e.g., removing an immunosuppressive signal or altering an immunosuppressive state). In some embodiments, the immune- stimulatory compound's activity can be both direct and indirect. In certain embodiments, an immune- stimulatory conjugate can alter the activity of its protein target in cells having an antigen bound by the conjugate as compared to activity of the protein target in non- antigen bearing cells (i.e., the immune- stimulatory activity is antigen-specific).

[0307] In certain embodiments, the immune- stimulatory compound can be coupled to an Fc domain or other portion of an antibody construct via a linker. In each of the embodiments described herein, the immune- stimulatory compound can be coupled to the antibody construct via a linker.

[0308] An immune- stimulatory compound can be a Pattern recognition receptor (PRR) agonist. Pattern recognition receptors (PRRs) can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). A PRR can be membrane bound. A PRR can be cytosolic. A PAMP molecule can be a toll-like receptor agonist. A PRR can be a to 11- like receptor (TLR). A PRR can be RIG-I-like receptor. A PRR can be a receptor kinase. A PRR can be a C-type lectin receptor. A PRR can be a NOD-like receptor. A PRR can be TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR 10, TLR11, TLR 12, or TLR13.

[0309] A PRR agonist can be a damage-associated molecular pattern (DAMP) molecule. A DAMP molecule can be an intracellular protein. A DAMP molecule can be a heat-shock protein. A DAMP molecule can be an HMGB 1 protein. A DAMP molecule can be a protein derived from the extracellular matrix that is generated after tissue injury. A DAMP molecule can be a hyaluronan fragment. A DAMP molecule can be DNA. A DAMP molecule can be RNA. A DAMP molecule can be an S 100 molecule. A DAMP molecule can be a nucleotide(s). A DAMP molecule can be ATP. A DAMP molecule can be a nucleoside(s). A DAMP molecule can be an adenosine. A DAMP molecule can be uric acid.

[0310] In some embodiments, the immune- stimulatory compound can be a Toll-like receptor agonist, a RIG-I agonist, a STING agonist, a GPCR agonist, an ion channel agonist, a membrane transporter agonist, an ER protein agonist, a beta-catenin pathway inhibitor, a kinase inhibitor, a TNIK inhibitor, a Tankyrase inhibitor, a GPCR antagonist, an HSP90 inhibitor, or an AAA- ATPase p97 inhibitor. In some embodiments, the immune- stimulatory compound can be a Tolllike receptor agonist, a RIG-I agonist or a STING agonist. In some embodiments, the immune- stimulatory compound can be a beta-catenin pathway inhibitor, such as a TNIK inhibitor or a Tankyrase inhibitor.

[0311] In some embodiments, the immune- stimulatory compound is a Toll-like receptor agonist.

A toll- like receptor agonist can be any molecule that acts as an agonist to at least one toll- like receptor. In some embodiments, the Toll- like receptor agonist can be a molecule selected from a

CpG oligonucleotide, Poly G10, Poly G3, Poly I:C, a lipopolysaccharide, a zymosan, a bacterial flagella protein (e.g., flagellin), PamjCSIQ, PamCysPamSK ₄ , dsRNA, ssRNA, a diacylated lipopeptide, a bacterial lipoprotein, a triacylated lipoprotein, lipoteichoic acid, or a peptidoglycan (such as a bacterial peptidoglycan).

[0312] In some embodiments, an immune- stimulatory compound is not a toll-like receptor agonist. In some embodiments, a toll- like receptor agonist is not a naturally occurring molecule, such as CpG oligonucleotide, a lipopolysaccharide, a zymosan, a bacterial flagella protein (e.g., flagellin), PamjCSIQ, PamCysPamSIQ, dsRNA, ssRNA, a diacylated lipopeptide, a bacterial lipoprotein, a triacylated lipoprotein, lipoteichoic acid, or a peptidoglycan (such as a bacterial peptidoglycan). In some further embodiments, a toll- like receptor agonist is not a synthetic nucleic acid, such as Poly G10, Poly G3 or Poly I:C.

[0313] In some embodiments, a toll- like receptor agonist can be a synthetic small molecule. A to 11- like receptor agonist can be imiquimod. A to 11- like receptor agonist can be CL307. A to 11- like receptor agonist can be S-27609. A toll-like receptor agonist can be resiquimod. A toll-like receptor agonist can be UC-IV150. A to 11- like receptor agonist can be gardiquimod. A to 11- like receptor agonist can be motolimod. A toll-like receptor agonist can be a motolimod analog. A to 11- like receptor agonist can be VTX-1463. A to 11- like receptor agonist can be GS-9620. A tolllike receptor agonist can be GSK2245035. A toll- like receptor agonist can be TMX-101. A tolllike receptor agonist can be TMX-201. A toll- like receptor agonist can be TMX-202. A toll- like receptor agonist can be isatoribine. A toll-like receptor agonist can be AZD8848. A toll-like receptor agonist can be MEDI9197. A to 11- like receptor agonist can be 3M-051. A to 11- like receptor agonist can be 3M-852. A toll-like receptor agonist can be 3M-052. A toll-like receptor agonist can be 3M-854A. A toll-like receptor agonist can be S-34240. A toll-like receptor agonist can be CL663. A to 11- like receptor agonist can be KU34B.

[0314] A RIG-I agonist can be KIN1148. A RIG-I agonist can be SB-9200. A RIG-I agonist comprises a 5'ppp-dsRNA.

[0315] In some embodiments, the immune- stimulatory compound can comprise a non-naturally occurring chemotype, such as a substituted pyrimidine, a substituted purine, a substituted guanine nucleoside, a substituted 8-oxoadenine, a substituted imidazoquinoline, a substituted

thiazoquinoline, a substituted 2- amino imidazole, a substituted furo[2,3-c]pyridine, a substituted pyrazine, a substituted furo[2,3-c]quinoline, a substituted 2-aminobenzimidazole, a substituted 2- aminoquinoline, or a substituted 2-aminobenzazepine.

[0316] In certain embodiments, the immune- stimulatory compound can comprise S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463, GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, SB9200, SB 11285, 8-substituted imidazo[l,5- a]pyridine, or CL663.

[0317] An immune- stimulatory compound can comprise an inhibitor of TGFbeta, Beta-Catenin, PI3K-beta, STAT3, IL-10, IDO or TDO. The immune- stimulatory compound can comprise LY2109761, GSK263771, iCRT3, iCRT5, iCRT14, LY2090314, CGX-1321, PRI-724, BC21, ZINCO2092166, LGK974, IWP2, LY3022859, LY364947, SB431542, AZD8186, SD-208, indoximod (NLG8189), F001287, GDC-0919, epacadostat (INCB024360), RG70099, 1-methyl- L-tryptophan, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, PIM, LM10, 8-substituted 2-amino-3H-benzo[b]azepine-4-carboxamide, or INCB023843.

[0318] Additionally, stimulator of interferon genes (STING) can act as a cytosolic DNA sensor wherein cytosolic DNA and unique bacterial nucleic acids called cyclic dinucleo tides are recognized by STING, and therefore STING agonists. In certain embodiments, the STING agonist can comprise a cyclic dinucleotide. Other non- limiting examples of STING agonists include:

[0319] , wherein in some embodiments, Xi=X ₂ =0; X ₃ =G; X ₄ =G; X ₆ =2 TEAH; in some embodiments, X ₁₌ X ₂ =S [R _p ,R _p ]; X ₃ =G; X ₄ =A; X ₅ =H; X ₆ =2 TEAH; in some embodiments, Xi=X ₂ =S [R _P ,R _P ] ; X ₃ =A; X ₄ =A; X ₅ =H; X ₆ =2 Na; in some embodiments, X ₁₌ X ₂ =S [R _P ,R _P ] ; X ₃ =A; X ₄ =A; X ₅ =H; X ₆ =2 NH ₄ ; and in some embodiments, X ₁₌ X ₂ =0 ; X ₃ =G; X ₄ =A; X ₅ =H; X ₆ =2 TEAH;

, wherein Ri=R ₂ =H; R ₂ =H; Ri=H, R ₂ =propargyl; Ri=allyl, R ₂ =H; Ri=H, R ₂ =allyl; Ri=methyl, R ₂ =H; Ri=H, R ₂ =methyl; Ri=ethyl, R ₂ =H; Ri=H, R ₂ =ethyl; Ri=propyl, R ₂ =H; Ri=H, R ₂ =propyl; Ri=benzyl, R ₂ =H; Ri=H, R ₂ =benzyl; Ri=myristoyl, R ₂ =H; Ri=H, R ₂ =myristoyl; Ri=R ₂ =heptanoyl; Ri=R ₂ =hexanoyl; or Ri=R ₂ =pentanoyl;

[0320] wherein Ri=R ₂ =H; Ri=propargyl, R ₂ =H; Ri=H, R ₂ =propargyl; Ri=allyl, R ₂ =H; Ri=H, R ₂ =allyl; Ri=methyl, R ₂ =H; Ri=H, R ₂ =methyl; Ri=ethyl, R ₂ =H; Ri=H, R ₂ =ethyl; Ri=propyl, R ₂ =H; Ri=H, R ₂ =propyl; Ri=benzyl, R ₂ =H; Ri=H, R ₂ =benzyl; Ri=myristoyl, R ₂ =H; Ri=H, R ₂ =myristoyl; Ri=R ₂ =heptanoyl; Ri=R ₂ =hexanoyl; or Ri=R ₂ =pentanoyl;

[0321] wherein Ri=R ₂ =H; Ri=propargyl, R ₂ =H; Ri=H, R ₂ =propargyl; Ri=allyl, R ₂ =H; Ri=H, R ₂ =allyl; Ri=methyl, R ₂ =H; Ri=H, R ₂ =methyl; Ri=ethyl, R ₂ =H; Ri=H, R ₂ =ethyl; Ri=propyl, R ₂ =H; Ri=H, R ₂ =propyl; Ri=benzyl, R ₂ =H; Ri=H, R ₂ =benzyl; Ri=myristoyl, R ₂ =H; Ri=H, R ₂ =myristoyl; Ri=R ₂ =heptanoyl; Ri=R ₂ =hexanoyl; or Ri=R ₂ =pentanoyl;

, wherein each X is independently O or S, and R3 and R4 are each independently H or an optionally substituted straight chain alkyl of from 1 to 18 carbons and from 0 to 3 heteroatoms, an optionally substituted alkenyl of from 1-9 carbons, an optionally substituted alkynyl of from 1-9 carbons, or an optionally substituted aryl, wherein substitution(s), when present, may be independently selected from the group consisting of Ci-6 alkyl straight or branched chain, benzyl, halogen, trihalo methyl, Ci-6 alkoxy,— N0 ₂ ,— NH ₂ ,— OH, =0,— COOR ^' where R ^' is H or lower alkyl,— CH ₂ OH, and— CONH ₂ , wherein R3 and R4 are not both H;

0; X ₁₌ X ₂ =S; or Xi=0 and X ₂ =S,

-198- [0322] In some embodiments, an immune- stimulatory compound can be a kinase inhibitor. An immune- stimulatory compound can inhibit one or more kinases.

[0323] An immune- stimulatory compound can be an inhibitor of ALK, Bcr-Abl, BRAF, BTK, c- KIT, EGFR, ErbB2, JAK, MEK, MET, PDGFRB, RET, ROS 1, Syk, SRC, TGFpR2, TNIK, TNKS, TNKS2, TrkA, TrkB, TrkC, VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, FGFR4, CSFIR, RON/MSTIR, TYR03, MERTK, AXL, ΡΙ3Κδ, ΡΙ3Κγ, MAP4K1, PERK, KIT, or any combination thereof. An immune- stimulatory compound can be an inhibitor of TGFpRl, TGFpR2, TNIK, TNKS, ΡΙ3Κ-β, STAT3, IL-10, IDO, or TDO.

[0324] In various embodiments, the immune- stimulatory compound comprises LY2109761, GSK263771, iCRT3, iCRT5, iCRT14, LY2090314, CGX-1321, PRI-724, BC21,

ZINCO2092166, LGK974, IWP2, LY3022859, LY364947, SB431542, AZD8186, SD-208, indoximod (NLG8189), F001287, GDC-0919, epacadostat (INCB024360), RG70099, 1-methyl- L-tryptophan, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, PIM, LM10, INCB023843, or 8-substituted imidazo[ 1,5 -a] pyridine.

[0325] An immune- stimulatory compound can be an agonist of a GPCR, an ion channel, a membrane transporter, or an ER protein.

[0326] An immune- stimulatory compound can be an antagonist of the GPCR A2aR, the sphingosine 1 -phosphate receptor 1, prostaglandin receptor EP3, prostanglandin receptor E2, Frizzled, CXCR4, or an LPA receptor.

[0327] An immune- stimulatory compound can be an ion channel agonist for CRAC, Kvl.3, or KCa3.1.

[0328] An immune- stimulatory compound can be an inhibitor of HSP90 or AAA-ATPase p97. Immune-Stimulatory Conjugate Properties

[0329] In certain embodiments, an immune- stimulatory compound of a conjugate (i.e, attached to an antibody construct either directly or via a linker) has a biological potency no less than at least about 0.33%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% of the potency of the control (free) immune- stimulatory compound (i.e., not attached to an antibody construct).

[0330] The specificity of the antigen-binding domain (of a conjugate) for an antigen can be influenced by the attachment of an immune- stimulatory compound to an antibody construct. In various embodiments, an antigen-binding domain of the conjugate can bind to its antigen with at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% of the specificity of the antigen-binding domain for the antigen in the absence of attachment of the immune- stimulatory compound.

[0331] The specificity of the Fc domain (of a conjugate) for an Fc receptor can be influenced by the attachment site of an immune- stimulatory compound (directly or via a linker). In some embodiments, the Fc domain of a conjugate retains the specificity of the unconjugated Fc domain to bind to an Fc receptor. In specific embodiments, the Fc domain of the conjugate can bind to an Fc receptor with at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% of the specificity of the Fc domain to the Fc receptor in the absence of attachment of the immune- stimulatory compound.

[0332] In some embodiments, the Fc domain of a conjugate has an altered specificity for an Fc receptor relative to the corresponding unconjugated Fc domain. In specific embodiments, the Fc domain of the conjugate can bind to an Fc receptor with at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% loss of specificity of the Fc domain to the Fc receptor as compared to an Fc domain of a conjugate not attached to an immune- stimulatory compound (in the absence of the immune- stimulatory compound). In some embodiments, the Fc domain is an Fc null.

[0333] The affinity of the antigen-binding domain of a conjugate to an antigen can be influenced by the attachment of an immune- stimulatory compound attached to the antibody construct. In some embodiments, the affinity of the antigen-binding domain of the conjugate for binding to an antigen is at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% of the affinity of the antigen-binding domain to the antigen in the absence of the immune- stimulatory compound (not attached to the antibody construct).

[0334] The affinity of the Fc domain to an Fc receptor of a conjugate can be influenced by attachment of an immune- stimulatory compound to the antibody construct (either directly or indirectly). In some embodiments, the Fc domain of the conjugate can bind to an Fc receptor with at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% of the affinity of the Fc domain to the Fc receptor in the absence of the immune- stimulatory compound attached to the antibody construct. In some embodiments, the Fc domain of the conjugate can bind to an Fc receptor with a reduced affinity of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100% of the affinity of the Fc domain to the Fc receptor in the absence of attachment the immune- stimulatory compound (directly or via a linker). In some embodiments, the Fc domain is an Fc null.

[0335] The K _d for binding of an antigen-binding domain to an antigen when an immune- stimulatory compound is attached to the antibody construct can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times greater than the K _d for binding of the antigen binding domain to the antigen in the absence of the immune- stimulatory compound attached to the antibody construct.

[0336] In some embodiments, the K _d for binding of an Fc domain to an Fc receptor when an immune- stimulatory compound is attached to an antibody construct can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times greater than the K _d for binding of the Fc domain to the Fc receptor without the immune- stimulatory compound attached to the antibody construct.

[0337] In some embodiments, the K _d for binding of an Fc domain to a Fc receptor when the immune- stimulatory compound is attached to the antibody construct can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times less than the K _d for binding of the Fc domain to the Fc receptor when the immune- stimulatory compound is not attached to the antibody construct.

[0338] Affinity is the strength of the sum total of noncovalent interactions between a single binding site of a molecule, for example, an antibody, and the binding partner of the molecule, for example, an antigen. The affinity can also measure the strength of an interaction between an Fc domain of an antibody and an Fc receptor. Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1: 1 interaction between members of a binding pair (e.g., antibody and antigen or Fc domain and Fc receptor). The affinity of a molecule

X for its partner Y can generally be represented by the dissociation constant (K _d ). Affinity can be measured by common methods known in the art. Specific illustrative and exemplary

embodiments for measuring binding affinity are described in the following. [0339] In some embodiments, an antibody construct (e.g., an antibody or antigen-binding fragment thereof) can have a dissociation constant (K _d ) for an antigen or Fc receptor of about 1 μΜ, about 100 nM, about 10 nM, about 5 nM, about 2 nM, about 1 nM, about 0.5 nM, about 0.1 nM, about 0.05 nM, about 0.01 nM, or about 0.001 nM or less (e.g., 10 ^"6 or less, 10 ^"8 M or less, from 10 ^"8 M to 10 ^"13 M, or from 10 ^"9 M to 10 ^"13 M). An affinity matured antibody can be an antibody with one or more alterations in one or more complementarity determining regions (CDRs), compared to a parent antibody, which may not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen. These antibodies can bind to their antigen with a K _d of about 5xl0 ^"9 M, about 2xl0 ^"9 M, about lxlO ^"9 M, about 5xl0 ^"10 M, about lxlO ^"10 M, about 5xl0 ^"u M, about lxlO ^"11 M, about 5xl0 ^"12 M, about lxlO ^"12 M, or less. In some embodiments, the antibody construct (e.g., affinity matured antibody) can have an increased affinity of at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or greater as compared to an antibody construct without alterations in one or more CDRs.

[0340] K _d can be measured by any suitable assay. For example, K _d can be measured by a radiolabeled antigen binding assay (RIA). For example, K _d can be measured using surface plasmon resonance assays (e.g., using a BIACORE®-2000 or a BIACORE®-3000).

[0341] The molar ratio or drug-antibody ratio of a conjugate refers to the number of immune- stimulatory compounds attached to an antibody construct in a conjugate or preparation of immune- stimulatory conjugates. The molar ratio can refer to the number of immune- stimulatory compounds attached (e.g., conjugated) to an antibody construct of a particular conjugate and is an integer, such as from 0-8 or 0 to 20. The molar ratio can also refer to the average number of immune- stimulatory compounds attached to antibody constructs in a mixture of conjugates, such as in a pharmaceutical composition.

[0342] The molar ratio can be determined, for example, by Liquid Chromatography/Mas s Spectrometry (LC/MS), in which the number of immune- stimulatory compounds attached to the antibody construct can be directly determined. Additionally, as non- limiting examples, the molar ratio can be determined based on hydrophobic interaction chromatography (HIC) peak area, by liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI-MS), by UV/Vis spectroscopy, by reversed-phase-HPLC (RP-HPLC), or by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS).

[0343] In some embodiments, the molar ratio of immune- stimulatory compound to antibody construct can be less than 8 or less than 20. In other embodiments, the molar ratio of immune- stimulatory compound to an antibody construct can be 8, 7, 6, 5, 4, 3, 2, or 1. In some embodiments, the average molar ratio of immune- stimulatory compounds to antibody constructs in a composition can be less than 8, such as about 3 to 5 or about 2. In other embodiments, the average molar ratio of immune- stimulatory compounds to antibody constructs in a composition can be 8, 7, 6, 5, 4, 3, 2, or 1 or fractions hereof, or such as about 3.5 or about 1.8.

[0344] In a conjugate, an antibody construct (e.g., an antibody) can be linked to an immune- stimulatory compound in such a way that the antibody construct can still bind to an antigen and the Fc domain of the antibody construct can still bind to an FcR. In a conjugate, an antibody construct can be linked to an immune- stimulatory compound in such a way that the linking does not interfere with the ability of the antigen binding domain of the antibody construct to bind to its antigen, the ability of the Fc domain of the antibody construct to bind to an FcR, or FcR- mediated signaling resulting from the Fc domain of the antibody construct binding to an FcR. In a conjugate, an immune- stimulatory compound can be linked to an antibody construct in such a way that the linking does not interfere with the ability of the immune- stimulatory compound to bind to its receptor or otherwise can induce a biological effect. In some embodiments, a conjugate can produce stronger immune stimulation and a greater therapeutic window than components of the conjugate alone. For example, in an anti-tumor or anti-CD40 antibody linked to a TLR agonist, the combination of CD40 agonism, TLR agonism and an accessible Fc domain of the anti-CD40 antibody resulting in FcR-mediated signaling can produce stronger immune stimulation and a greater therapeutic window than the CD40 agonism, TLR agonism, or the FcR- mediated signaling alone.

[0345] In some embodiments, a conjugate can comprise a first binding domain, wherein the first binding domain contributes to immune- stimulatory activity; a first and second binding domain, wherein the second binding domain contributes to immune stimulatory activity; or a first binding domain and second binding domain, wherein the first binding domain and the second binding domain contribute to immune- stimulatory activity. The first binding domain and the second binding domain can contribute to the same immune- stimulatory activity. The first binding domain and the second binding domain can contribute to different immune- stimulatory activities.

[0346] In some embodiments, a conjugate in which the first binding domain contributes to immune- stimulatory activity can increase the immune- stimulation of the conjugate.

Immune-Stimulatory Compound Potency and Binding Activity

[0347] In certain embodiments, an immune- stimulatory compound has similar activity when bound to the antibody construct as when not bound to the antibody construct. In certain embodiments, the immune- stimulatory compound maintains the same level of potency and/or binding affinity when bound to an antibody construct as compared to the unbound immune- stimulatory compound. [0348] For many known antibody-drug conjugates, the payload/drug of the conjugate is a cytotoxic agent that acts on an intracellular target. The antibody generally targets a certain tumor marker on the surface of a cancer cell and upon binding of the antibody to the tumor cell, the cancer cell then internalizes the antibody-cytotoxic agent conjugate. The cytotoxic agent is released within the cell through enzymatic cleavage or other cleavage of the agent's linkage to the antibody or through enzymatic degradation of the antibody. The released cytotoxic agent or degredation product acts on the intracellular target of the cytotoxic agent to kill the cancer cell. Important to the mechanism of action of many antibody-cytotoxic agent conjugates is: (1) that the cytotoxic agent is bound to the antibody with a linker, wherein the linker is not cleaved until exposed to enzymes or conditions inside a target cell, e.g., a cancer cell; (2) that the cytotoxic agent is released from the antibody inside of the cell to perform its cytotoxic function; and (3) that the cytotoxic agent is not active or minimally active (i.e., in a prodrug form) when bound to the antibody such that the cytotoxic agent does not indiscriminately kill cells and harm organ systems distributed thorught the body on the path to the cancer cell.

[0349] In certain aspects, the immune- stimulatory conjugates of the disclosure operate under a different paradigm from such antibody-cytotoxic agent conjugates. The immune- stimulatory conjugates of the disclosure can be designed in a way that the payload immune- stimulatory compound has the same potency, similar potency, or increased potency when bound to the antibody construct as compared to the unbound immune- stimulatory compound and in contrast to antibody-cytotoxic agent conjugates. The immune- stimulatory conjugates of the disclosure may perform, and in some cases preferably perform, the intended function of the compound, i.e., stimulate or modulate the function of immune cells or other target cells, without prior release of the compound from the conjugate (i.e., while attached to the antibody construct). The features of the immune- stimulatory compound-conjugates and assays that enable these functions and others are described further herein.

[0350] The potency of the immune- stimulatory compound of the conjugate may not be significantly reduced relative to the potency of the un-attached (free) immune- stimulatory compound. In particular, the potency of the immune- stimulatory compound of the conjugate (i.e., as part of the conjugate or covalently bound to the antibody construct) is preferably no greater than 500-fold less, no greater than 400-fold less, no greater than 300-fold less, no greater than 200-fold less, no greater than 100-fold less, no greater than 50-fold less, or no greater than 10- fold less than the potency of a control compound, wherein the control compound is the unbound immune- stimulatory compound. For example, for an immune- stimulatory conjugate represented by the structure: Ab - L - C, wherein A is an antibody construct, L is a linker, and C is an immune- stimulatory compound, the immune- stimulatory activity of C of the conjugate A - L - C is preferably no greater than 500-fold less, no greater than 400-fold less, no greater than 300-fold less, no greater than 200-fold less, no greater than 100-fold less, no greater than 50-fold less, or no greater than 10-fold less than the potency of the immune- stimulatory compound, C, unbound from the immune- stimulatory conjugate, A - L - C, in the absence of processing of the immune- stimulatory conjugate in a cell.

[0351] In particular embodiments, the potency of an immune- stimulatory compound of the conjugate (i.e., covalently bound to the antibody construct) is near or equivalent to the potency of the unbound immune- stimulatory compound, such as within about 10-fold, within about 8-fold, within about 5-fold, or within about 2-fold of the potency of the unbound immune- stimulatory compound. The potency of the immune- stimulatory compound of the conjugate may be greater than the potency of the unbound immune- stimulatory compound, such as about 2-fold or greater, 5-fold or greater, 10-fold or greater, 100-fold or greater, 200-fold or greater, 300-fold or greater, 400-fold or greater, or even 500-fold or greater than the potency of the unbound immune- stimulatory compound. In certain embodiments, the tolerability of an immune- stimulatory compound when part of a construct is greater than the tolerability of the unbound immune- stimulatory compound in a subject.

[0352] In certain embodiments, the potency of the immune- stimulatory compound when bound to a 5-500 atom linker is the same, similar, or increased as compared to the potency of the immune- stimulatory compound not bound to the 5-500 atom linker. In certain embodiments, the tolerability of the immune- stimulatory compound in a subject when bound to a 5-500 atom linker is the same, similar, or increased as compared to the tolerability of the immune- stimulatory compound not bound to the 5-500 atom linker.

[0353] The "5-500 atom linker" referred to herein has 5 to 500 consecutive atoms from end to end. When attached to an immune- stimulatory compound and to an antibody construct, a 5-500 atom linker has 5-500 consecutive atoms between the point of attachment to the immune- stimulatory compound and the point of attachment to the antibody construct. A 5-500 atom linker can have, for example, from about 50 to about 500 atoms, such as about 50 to about 300 atoms or such as about 50 to about 200 atoms. A 5-500 atom linker can have, for example, from about 25 to about 500 atoms, such as about 25 to about 300 atoms or such as about 25 to about 200 atoms. In certain embodiments, the linker includes one or more peptide bonds. In certain embodiments, the linker includes one or more ethylene glycol groups. In certain embodiments, the linker includes a peptide backbone and one or more side chains. In certain embodiments, the linker is not cleaved from the immune- stimulatory compound in the assay evaluating potency.

[0354] Exemplary 5-500 atom linkers include Fleximer linkers, linkers with one or more carbamate or amide linkages and linkers represented by the formula:

antibody construct, R is hydrogen, Ci-ioalkyl, sulfonate and methyl sulfonate and the wavy line indicates an attachment to the rest of the linker or to the immune- stimulatory compound.

[0355] In some embodiments, the linker is a non-cleavable linker. Examples of non-cleavable linkers include the following:

wherein R ^x is a reactive moiety for attachment to the antibody construct, R is hydrogen, Q. _l oalkyl, sulfonate and methyl sulfonate and the wavy line indicates an attachment to the rest of the linker or to the immune- stimulatory compound.

[0356] Further examples of non-cleavable linkers include:

wherein the wavy line indicates an attachment to the rest of the linker or to the immune- stimulatory compound.

[0357] In some embodiments, the potency of an immune- stimulatory compound when bound to a 5-500 atom linker can be no greater than 500-fold less, no greater than 400-fold less, no greater than 300-fold less, no greater than 200-fold less, no greater than 100-fold less, no greater than 50-fold less, or no greater than 10-fold less than the potency of a control compound, wherein the control compound is the unbound immune- stimulatory compound. For example, for compounds suitable for use in the conjugates of the disclosure, the immune- stimulatory activity of the immune- stimulatory compound bound to a 5-500 atom linker, represented by the formula: C - L* , wherein L* is a 5-500 atom linker, is preferably no greater than 500-fold less, no greater than 400-fold less, no greater than 300-fold less, no greater than 200-fold less, no greater than 100- fold less, no greater than 50-fold less, or no greater than 10-fold less than the potency of the immune- stimulatory compound, C, unbound from linker L*.

[0358] In particular embodiments, the potency of the immune- stimulatory compound bound to a 5-500 atom linker is equivalent to the potency of the unbound immune- stimulatory compound, such as within about 10-fold, within about 8-fold, within about 5-fold, or within about 2-fold of the potency of the unbound immune- stimulatory compound. One exemplary embodiment is depicted in FIGURE 16, wherein the designed inhibitor bound to a linker surrogate, L* as discussed herein, displays a similar EC ₅₀ value relative to the compound unbound from the linker. In certain embodiments, the potency of the immune- stimulatory compound bound to a 5- 500 atom linker may be greater than the potency of the unbound immune- stimulatory compound, such as about 2-fold or greater, 5-fold or greater, 10-fold or greater, 100-fold or greater, 200-fold or greater, 300-fold or greater, 400-fold or greater than 500-fold than the potency of the unbound immune- stimulatory compound. In certain embodiments, the tolerability of the immune- stimulatory compound bound to an antibody construct by a 5-500 atom linker may be greater than the potency of the unbound immune- stimulatory compound, such as about 2-fold or greater, 5-fold or greater, 10-fold or greater, 100-fold or greater, 200-fold or greater, 300-fold or greater, 400-fold or greater than 500-fold than the potency of the unbound immune- stimulatory compound.

[0359] "Unbound immune- stimulatory compound" or reference to an immune- stimulatory compound without specifying its connection to a linker or antibody, as used herein, refers to a compound with immune- stimulatory activity that is not bound to a linker (such as the linkers described herein) and not part of an immune- stimulatory conjugate, as described herein. In certain embodiments, the "control compound" as compared to a conjugate or linker-bound immune- stimulatory compound is the unbound immune- stimulatory compound. Unbound immune- stimulatory compounds are generally not suitable for direct attachment to an antibody construct (such as an antibody) without a linker, such as those described herein. An unbound immune- stimulatory compound may be a synthetic precursor to an immune- stimulatory conjugate, wherein the immune- stimulatory compound may be modified by attaching a linker such as the linkers described herein and optionally further bound to an antibody to form an immune- stimulatory conjugate.

[0360] In certain aspects, the potency of the immune- stimulatory compound of the conjugate, the potency of the immune- stimulatory compound bound to a 5-500 atom linker, and the potency of the unbound immune- stimulatory compound may be determined using a PBMC assay as described in Example 7.

[0361] The immune- stimulatory conjugates of the disclosure can be engineered to maintain, not significantly reduce, or increase the potency of the immune- stimulatory compound in the conjugate relative to the unbound immune- stimulatory compound. In certain embodiments, a highly potent immune- stimulatory compound, e.g., the unbound immune- stimulatory agent has an EC ₅₀ of less than 500 nM, such as less than 400 nM, such as less than 300 nM, such as less than 200 nM, such as less than 100 nM, such as less than 50 nM, or such as less than 10 nM, is used as an immune- stimulatory compound of the conjugates herein.

[0362] In designing an immune- stimulatory conjugate of the disclosure, an unbound immune- stimulatory compound can be bound to a linker at a position on the immune- stimulatory compound that does not interfere with the ability of the immune- stimulatory compound to interact with its protein binding site. For example, a linker can be attached to an immune- stimulatory compound at a solvent accessible site on the compound when the compound would be bound to its protein target. For example, as depicted in FIGURE 20A, an antibody 3405 bound to a linker 3410 is bound to an immune- stimulatory compound 3415. The linker 3410 is bound to a position of the immune- stimulatory compound 3415 such that the linker 3410 and/or antibody 3405 does not interfere with the interaction between the immune- stimulatory compound 3415 and the active site 3425 of a target protein 3420 (FIGURE 20B). The linker 3410 may extend out from the active site 3425 of the target protein 3420 at the solvent/active site interface 3430.

[0363] The potency of the unbound immune- stimulatory compound may also be evaluated relative to the potency of the immune- stimulatory compound bound to a 5-500 atom linker as a surrogate for the immune- stimulatory conjugate. Evaluating the potency of the immune- stimulatory compound bound to a 5-500 atom linker, as described herein, can be predictive of the activity of the immune- stimulatory compound in the conjugate. For example, as depicted in

FIGURE 20C, a linker 3410 is bound to an immune- stimulatory compound 3415. The linker 3410 is bound to a portion of the immune- stimulatory compound 3415 such that the linker 3410 does not interfere with the interaction between the immune- stimulatory compound 3415 and the active site 3425 of a target protein 3420. FIGURE 20D depicts the unbound immune- stimulatory compound 3415 in the active site 3425 of a target protein 3420.

[0364] In certain embodiments, the binding position of the linker 3410 on the immune- stimulatory compound 3415 may be determined using target protein crystal structures and active site protein modeling. As depicted in FIGURE 15B and FIGURE 15C an immune- stimulatory compound, such as the left-hand compound of FIGURE 15A, may be modeled in an active site of a target protein and the positioning of the linker attachment to the immune- stimulatory compound may be selected based on this modeling. For example, the modeling may indicate that positioning of a linker on the 4-position of the benzimidazole of the left-hand compound of

FIGURE 15A would extend from the active site and not interfere with the active site interactions of the compound as depicted in FIGURE 15B and FIGURE 15C.

[0365] The linker can be covalently bound to the immune- stimulatory compound at a position on the immune- stimulatory compound that is at or near the solvent interface of the protein active site, as determined by modeling of the immune- stimulatory compound in the protein active site. In certain embodiments, the linker is covalently bound to the immune- stimulatory compound at a position on the immune- stimulatory compound such that when the immune- stimulatory compound is positioned in the protein active site, the linker extends out from the protein active site into the solvent, as determined by modeling of the immune- stimulatory compound in the protein active site. FIGURE 17B and FIGURE 17C depict binding of the left-hand compound of FIGURE 17A. A linker may be positioned on the phenyl ring to extend out of the protein active site, e.g., see left portion of right-hand compound of FIGURE 17A. FIGURE 18B and FIGURE 18C depict binding of the left-hand compound of FIGURE 18A. The trifluoromethyl substituent on the phenyl group may be replaced with a linker at this position to extend out of the protein active site, e.g., see left portion of right-hand compound of FIGURE 18A. FIGURE 19B and FIGURE 19C depict binding of the left-hand compound of FIGURE 19A with the linker (left side of right hand molecule) positioned to extend out of the protein active site.

[0366] In certain embodiments, the immune- stimulatory compounds have similar binding affinity to a protein active site when bound to the antibody construct as when not bound to the antibody construct. In certain embodiments, the immune- stimulatory compounds maintain the binding affinity to a protein active site when bound to an antibody construct as compared to the binding affinity of the unbound immune- stimulatory compound.

[0367] In certain embodiments, the K _d for binding of the immune- stimulatory compound of the conjugate to a protein active site is no greater than 50 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. (As used herein, the phrase "of the conjugate" refers to the immune- stimulatory compounds while attached to the antibody construct, usually via a linker(s).) For example, the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site may be no greater than 40 times, no greater than 30 times, no greater than 20 times, or no greater than 10 times the K _d for binding of the unbound immune- stimulatory compound to the protein active site. In certain embodiments, the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site is no greater than 10 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. The K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site may be no greater than 9 times, no greater than 8 times, no greater than 7 times, no greater than 6 times, no greater than 5 times, no greater than 4 times, no greater than 3 times, or no greater than 2 times the K _d for binding of the unbound immune- stimulatory compound to the protein active site.

[0368] In certain embodiments, the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site is close to or equivalent to the K _d for binding of a control compound, such as within about 10 times, within about 8 times, within about 6 times, within about 5 times, within about 4 times, within about 3 times or within about 2 times the binding affinity of the unbound immune- stimulatory compound. In certain embodiments, the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site is less than the K _d for binding of the unbound immune- stimulatory compound.

[0369] In certain embodiments, the binding affinity to a protein active site of an immune- stimulatory compound bound to a 5-500 atom linker, as described herein, is the same, similar, or increased as compared to the binding affinity of the immune- stimulatory compound not bound to the 5-500 atom linker. In particular embodiments, the binding affinity of the immune- stimulatory compound when bound to a 5-500 atom linker is no greater than 40 times, no greater than 30 times, no greater than 20 times, or no greater than 10 times the K _d for binding of the unbound immune- stimulatory compound to the protein active site.

[0370] In certain embodiments, the binding affinity to a protein active site of the immune- stimulatory compound bound to a 5-500 atom linker is no greater than 10 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. The binding affinity to a protein active site of the immune- stimulatory compound bound to a 5-500 atom linker may be no greater than 9 times, no greater than 8 times, no greater than 7 times, no greater than 6 times, no greater than 5 times, no greater than 4 times, no greater than 3 times, or no greater than 2 times the K _d for binding of the unbound immune- stimulatory compound to the protein active site.

[0371] In certain embodiments, the binding affinity to a protein active site of the immune- stimulatory compound bound to a 5-500 atom linker is close to or equivalent to the K _d for binding of a control compound, such as within about 10 times, within about 8 times, within about 6 times, within about 5 times, within about 4 times, within about 3 times or within about 2 times the binding affinity of the unbound immune- stimulatory compound. In certain embodiments, the binding affinity to a protein active site of the immune- stimulatory compound bound to a 5-500 atom linker is less than the K _d for binding of the unbound immune- stimulatory compound.

[0372] In certain aspects, the binding affinity of the immune- stimulatory compound of the conjugate, the binding affinity of the immune- stimulatory compound bound to a 5-500 atom linker, and the binding affinity of the unbound immune- stimulatory compound may be determined using an assay such as a Bio-layer Interferometry (BLI) as described in Example 8.

[0373] In certain embodiments, the immune- stimulatory compound binds to a cell membrane or ER protein target. In certain embodiments, the immune- stimulatory compound binds to a cell membrane or ER protein target and is other than a TLR agonist. In some embodiments, the immune- stimulatory compound is a kinase inhibitor and the protein active site is a kinase active site. Kinase inhibitors are a type of enzyme inhibitor that block the action of at least one protein kinase, which are enzymes that can add at least one phosphate group to a protein and thereby modulate its function or activity. In certain embodiments, the immune- stimulatory compound is a kinase inhibitor. In some embodiments, the kinase inhibitor targets a protein kinase that acts on both serine and threonine residues. In certain embodiments, the kinase inhibitor targets protein kinases that act on tyrosine residues. In certain embodiments, the kinase inhibitor targets protein kinases that act on serine, threonine and tyrosine residues. In other embodiments, the kinase inhibitor targets protein kinases that act on amino acids other than serine, threonine and tyrosine, such as histine kinases. The kinase inhibitors may target ALK, Bcr-Abl, BRAF, BTK, c-KIT, EGFR, ErbB2, JAK, MEK, MET, PDGFRB, RET, ROS 1, Syk, SRC, TGFpR2, TNIK, TNKS, TNKS2, TrkA, TrkB, TrkC, VEGFR1, VEGFR2, VEGFR3, PI3K, AKT, mTOR, and

combinations thereof.

[0374] In various embodiments, when the immune- stimulatory compound is a kinase inhibitor, the linker is covalently bound to the kinase inhibitor at a position on the kinase inhibitor that is at or near the solvent interface of the kinase active site when the inhibitor is bound to the protein target, as determined by modeling of the kinase inhibitor in the kinase active site. In certain embodiments, the linker is covalently bound to the kinase inhibitor at a position on the kinase inhibitor such that when the kinase inhibitor is bound to the active site, the linker extends out from the kinase active site into the solvent, as determined by modeling of the kinase inhibitor in the kinase active site.

[0375] In some aspects, the present disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site and stimulates an immune response; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound; wherein the K _d for binding of the immune- stimulatory compound of the conjugate (attached to the antibody construct via the linker) to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the EC50 or IC50 of the immune- stimulatory compound of the conjugate is no greater than 300-fold higher the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound and optionally wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody to the Fc receptor, wherein the control antibody is the antibody construct itself.

[0376] In various embodiments, the K _d for binding of the immune- stimulatory compound of the conjugate (attached to the antibody construct via the linker) to the protein active site is no greater than 50 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. In certain embodiments, the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site is no greater than 10 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. In an exemplary embodiment, the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site is equivalent to or less than the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound.

[0377] In some embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 100-fold higher than the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In certain embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound of the conjugate is no greater than 10-fold higher than the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In an exemplary embodiment, the potency of the immune- stimulatory compound of the conjugate is equivalent to or greater than the potency of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

[0378] In some embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound-linker construct is no greater than 100-fold higher than the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In certain embodiments, the EC ₅₀ or IC ₅₀ of the immune- stimulatory compound-linker construct is no greater than 10-fold higher than the EC ₅₀ or IC ₅₀ of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In an exemplary embodiment, the potency of the immune- stimulatory compound-linker construct is equivalent to or greater than the potency of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

[0379] In some aspects, the present disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site and stimulates an immune response through target inhibition (e.g., inhibition of a protein); (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound; wherein the K _d for binding of the immune- stimulatory compound of the conjugate to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC50 of the immune- stimulatory compound of the conjugate is no greater than 300-fold the IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound, and optionally wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody to the Fc receptor, wherein the control antibody is the antibody construct itself.

[0380] A first antigen, second antigen, or first and second antigens of the antibody construct binding domains are chosen to deliver the immune- stimulatory compound into tumor cells, immune cells, or both, but not into non-antigen bearing cell types, thereby selectively increasing immune activation and lowering systemic toxicity.

[0381] In some embodiments, the immune- stimulatory conjugate targets the activity of the immune- stimulatory compound to within an immune cell, such as an immune cell like an APC, to within tumor cells, or within both.

[0382] In some embodiments, the immune stimulatory conjugate targets the activity of the immune- stimulatory compound to cells within a tissue or within the tumor microenvironment.

[0383] In some embodiments, the immune- stimulatory conjugate systemically increases antitumor immunity with lower toxicity than an effective systemic dose of the immune- stimulatory compound itself.

[0384] In some aspects, the present disclosure provides an immune- stimulatory conjugate comprising: (a) an immune- stimulatory compound that binds to a protein active site and stimulates or otherwise modulates an immune response; (b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain binds to a first antigen and wherein the Fc domain binds to an Fc receptor; and (c) a linker, wherein the linker is covalently bound to the antibody construct and the linker is covalently bound to the immune- stimulatory compound; wherein the K _d for binding of the immune- stimulatory compound, when bound to a 5-100 atom linker, to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the EC50 or IC50 of the immune- stimulatory compound when bound to a 5-100 atom linker is no greater than 300-fold EC50 or IC50 of a control compound, wherein the control compound is the immune- stimulatory compound, and optionally wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody to the Fc receptor, wherein the control antibody is the antibody construct.

[0385] In various embodiments, the potency of the immune- stimulatory compound when bound to a 5-100 atom linker is no greater than 100-fold less than the potency of a control compound, wherein the control compound is the unbound immune- stimulatory compound. In certain embodiments, the potency of the immune- stimulatory compound when bound to a 5-100 atom linker is no greater than 10-fold less than the potency of a control compound, wherein the control compound is the immune- stimulatory compound. In an exemplary embodiment, the potency of the immune- stimulatory compound when bound to a 5-100 atom linker is equivalent to or greater than the potency of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

[0386] In some embodiments, the K _d for binding of the immune- stimulatory compound when bound to a 5-100 atom linker to the protein active site is no greater than 50 times the K _d for binding of a control compound to the protein active site, wherein the control compound is the unbound immune- stimulatory compound. In certain embodiments, the K _d for binding of the of the immune- stimulatory compound when bound to a 5-100 atom linker to the protein active site is no greater than 10 times the K _d for binding of a control compound to the protein active site. In an exemplary embodiment, the K _d for binding of the immune- stimulatory compound when bound to a 5-100 atom linker to the protein active site is equivalent to or less than the K _d for binding of a control compound to the protein active site.

Linkers

[0387] The immune- stimulatory compounds and salts thereof described herein may be attached, i.e., covalently attached, to a linker, e.g., a cleavable linker or a non-cleavable linker, and to an antibody construct and referred to as an immune- stimulatory compound conjugate, an immune- stimulatory conjugate or a conjugate. Linkers of the conjugates described herein may not affect the binding of active portions of a conjugate, e.g., the first binding domains, Fc domains, second antigen binding domains, antibodies, immune- stimulatory compounds or the like, to a target molecule, which can be a cognate binding partner such as an antigen. A conjugate can comprise multiple linkers. These linkers can be the same linkers or different linkers. A linker described herein can be a multi-functional linker linking two small molecule binding moieties and linking the linked small molecules to an antibody. A linker also may be referred to as a linker of a linker moiety.

[0388] A linker can be short, flexible, rigid, cleavable, non-cleavable, hydrophilic, or hydrophobic. A linker can contain segments that have different characteristics, such as segments of flexibility or segments of rigidity. The linker can be chemically stable to extracellular environments, for example, chemically stable in the blood stream, or may include linkages that are not stable. The linker can include linkages that are designed to cleave and/or immolate or otherwise breakdown specifically or non- specifically inside cells. A cleavable linker can be sensitive to enzymes. A cleavable linker can be cleaved by enzymes such as proteases. A cleavable linker can have a valine-citrulline or a valine- alanine dipeptide. A valine-citrulline- or valine-alanine-containing linker also can contain a pentafluorophenyl group. A valine-citrulline- or valine-alanine-containing linker also can contain a succinimide group or a maleimide group. A valine-citrulline- or valine-alanine-containing linker can also contain a para aminobenzoic acid (PABA) group. A valine-citrulline or valine- alanine (VA)-containing linker or a glycine-glycine- phenylalanine-glycine (GGFG) tetrapeptide-containing linker also can contain a PABA group and a pentafluorophenyl group. A peptide-based valine-citrulline or valine- alanine linker can contain a PABA group and a succinimide group. [0389] A non-cleavable linker is protease insensitive and insensitive to cleavage by other intracellular processes. A non-cleavable linker can be maleimidocaproyl linker. A

maleimidocaproyl linker can comprise N-maleimidomethylcyclohexane-l-carboxylate. A maleimidocaproyl linker can contain a succinimide group. A linker can be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules. A linker can be a maleimide-PEGx linker, where x = 2-12. A linker can be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules. A linker can contain a maleimide(s) linked to polyethylene glycol molecules in which the polyethylene glycol can allow for more linker flexibility or can be used.

[0390] A linker can also include an alkylene, alkenylene, alkynylene, polyether, polyester, polyamide, polyamino acids, polypeptides, cleavable peptides, or amino benzylcarbamates. A linker can contain a maleimide at one end and an N-hydroxysuccinimidyl ester at the other end. A linker can contain a lysine with an N-terminal amine acetylated, and a valine-citrulline peptide cleavage site. A linker can be a link created by a microbial transglutaminase, wherein the link can be created between an amine-containing moiety and a moiety engineered to contain glutamine as a result of the enzyme catalyzing a bond formation between the acyl group of a glutamine side chain and the primary amine of a lysine chain. A linker can contain a reactive primary amine. A linker can be a Sortase A linker. A Sortase A linker can be created by a Sortase A enzyme fusing an LPXTG recognition motif (SEQ ID NO: 672) to an N-terminal GGG motif to regenerate a native amide bond. A linker created can therefore link a moiety attached to the LPXTG recognition motif (SEQ ID NO: 672) with a moiety attached to the N-terminal GGG motif.

[0391] In the conjugates described herein, an immune- stimulatory compound is linked to the antibody construct by way of a linker. The linker attaching the compound or a salt thereof to the antibody construct may be short, long, hydrophobic, hydrophilic, flexible or rigid, or may be composed of segments that each independently have one or more of the above-mentioned properties such that the linker may include segments having different properties. A linker may be polyvalent such that it covalently links more than one compound or salt to a single site on the antibody construct, or monovalent such that covalently it links a single compound or salt to a single site on the antibody construct.

[0392] As will be appreciated by skilled artisans, the linkers attach the immune- stimulatory compounds to the antibody construct by covalent linkages between the linker(s) and the antibody construct and compound. As used herein, the expression "linker" is intended to include (i) unconjugated forms of the linker that include a functional group capable of covalently linking the linker to an immune- stimulatory compound and a functional group capable of covalently linking the linker to an antibody; (ii) partially conjugated forms of the linker that include a functional group capable of covalently linking the linker to an antibody and that is covalently linked to an immune- stimulatory compound, or vice versa; and (iii) fully conjugated forms of the linker that is covalently linked to both an immune- stimulatory compound and an antibody.

[0393] Exemplary polyvalent linkers that may be used to link many immune- stimulatory compounds to an antibody construct are described. In some embodiments, the conjugate uses any linker as disclosed in U.S. Patent No. 9,254,339, U.S. Patent No. 9,144,615, U.S. Patent No. 8,821,850, U.S. Patent No. 8,808,679, U.S. Patent No. 8,685,383, U.S. Patent No. 8,524,214, or Published U.S. Publication No. 2011/0243892, in which each of these references are herein incorporated by reference in their entirety. For example, Fleximer® linker technology has the potential to enable high-DAR conjugates with good physicochemical properties. As shown below, the Fleximer® linker technology is based on incorporating drug molecules into a solubilizing poly-acetal backbone via a sequence of ester bonds. The methodology renders highly-loaded conjugates (DAR up to 20) whilst maintaining good physicochemical properties.

add Fleximer linker

[0394] To utilize the Fleximer® linker technology depicted in the scheme above, an aliphatic alcohol can be present or introduced into the immune- stimulatory compound. The alcohol moiety is then attached to an alanine moiety, which is then synthetically incorporated into the Fleximer® linker. Liposomal processing of the conjugate in vitro releases the parent alcohol-containing drug.

[0395] Cleavable linkers can be cleavable in vitro and in vivo. Cleavable linkers can include chemically or enzymatically unstable or degradable linkages. Cleavable linkers can rely on processes inside the cell to liberate an immune- stimulatory compound, such as reduction in the cytoplasm, exposure to acidic conditions in the lysosome, or cleavage by specific proteases or other enzymes within the cell. Cleavable linkers can incorporate one or more chemical bonds that are either chemically or enzymatically cleavable while the remainder of the linker can be non- cleavable. [0396] A linker can contain a chemically labile group such as a hydrazone and/or disulfide group. Linkers comprising chemically labile groups can exploit differential properties between the plasma and some cytoplasmic compartments. The intracellular conditions that can facilitate immune- stimulatory compound release for hydrazone-containing linkers can be the acidic environment of endosomes and lysosomes, while the disulfide containing linkers can be reduced in the cytosol, which can contain high thiol concentrations, e.g., glutathione. The plasma stability of a linker containing a chemically labile group can be increased by introducing steric hindrance using substituents near the chemically labile group.

[0397] Acid-labile groups, such as hydrazone, can remain intact during systemic circulation in the blood's neutral pH environment (pH 7.3-7.5) and can undergo hydrolysis and can release the immune- stimulatory compound once the immune- stimulatory conjugate is internalized into mildly acidic endosomal (pH 5.0-6.5) and lysosomal (pH 4.5-5.0) compartments of the cell. This pH dependent release mechanism can be associated with nonspecific release of the compound. To increase the stability of the hydrazone group of the linker, the linker can be varied by chemical modification, e.g., substitution, allowing tuning to achieve more efficient release in the lysosome with a minimized loss in circulation.

[0398] Hydrazone-containing linkers can contain additional cleavage sites, such as additional acid-labile cleavage sites and/or enzymatically labile cleavage sites. Immune- stimulatory conjugates can include exemplary hydrazone-containing linkers can include, for example, the following structures:

wherein D is an immune- stimulatory compound, Ab is an antibody construct, -NH- or -S-

(connected to Ab) are part of the antibody construct, and n represents the number of compounds bound to linkers bound to the antibody construct. In certain linkers, such as linker (la), the linker can comprise two cleavable groups- a disulfide and a hydrazone moiety. For such linkers, effective release of the unmodified free immune- stimulatory compound can require acidic pH or disulfide reduction and acidic pH. Linkers such as (lb) and (Ic) can be effective with a single hydrazone cleavage site.

[0399] Other acid-labile groups that can be included in linkers include czs-aconityl-containing linkers, cis- Aconityl chemistry can use a carboxylic acid juxtaposed to an amide bond to accelerate amide hydrolysis under acidic conditions.

[0400] Cleavable linkers can also include a disulfide group. Disulfides can be

thermodynamically stable at physiological pH and can be designed to release the immune- stimulatory compound upon internalization inside cells, wherein the cytosol can provide a significantly more reducing environment compared to the extracellular environment. Scission of disulfide bonds can require the presence of a cytoplasmic thiol cofactor, such as (reduced) glutathione (GSH), such that disulfide-containing linkers can be reasonably stable in circulation, selectively releasing the immune- stimulatory compound in the cytosol. The intracellular enzyme protein disulfide isomerase, or similar enzymes capable of cleaving disulfide bonds, can also contribute to the preferential cleavage of disulfide bonds inside cells. GSH can be present in cells in the concentration range of 0.5-10 mM compared with a significantly lower concentration of GSH or cysteine, the most abundant low-molecular weight thiol, in circulation at approximately 5 μΜ. Tumor cells, where irregular blood flow can lead to a hypoxic state, can result in enhanced activity of reductive enzymes and therefore even higher glutathione concentrations. The in vivo stability of a disulfide-containing linker can be enhanced by chemical modification of the linker, e.g., use of steric hindrance adjacent to the disulfide bond.

[0401] Immune- stimulatory conjugates can include exemplary disulfide-containing linkers having the following structures:

wherein D is an immune- stimulatory compound, Ab is an antibody construct, -NH- or -S- (connected to Ab) are part of the antibody construct, n represents the number of compounds bound to linkers bound to the antibody construct and R is independently selected at each occurrence from hydrogen or Ci-ioalkyl, for example. Increasing steric hindrance adjacent to the disulfide bond can increase the stability of the linker. Structures such as (Ila) and (lie) can show increased in vivo stability when one or more R groups is selected from a lower alkyl such as methyl.

[0402] Another type of linker that can be used is a linker that is specifically cleaved by an enzyme. For example, the linker can be cleaved by a lysosomal enzyme. Such linkers can be peptide-based or can include peptidic regions that can act as substrates for enzymes. Peptide based linkers can be more stable in plasma and extracellular milieu than chemically labile linkers.

[0403] Peptide bonds can have good serum stability, as lysosomal proteolytic enzymes can have very low activity in blood due to endogenous inhibitors and the unfavorably high pH value of blood compared to lysosomes. Release of an immune- stimulatory compound from an antibody construct can occur due to the action of lysosomal proteases, e.g., cathepsin and plasmin. These proteases can be present at elevated levels in certain tumor tissues. The linker can be cleavable by a lysosomal enzyme. The lysosomal enzyme can be, for example, cathepsin B, β- glucuronidase, or β-galactosidase.

[0404] The peptide can be selected from tetrapeptides such as Gly-Phe-Leu-Gly, Ala- Leu- Ala- Leu, Gly-Gly-Phe-Gly or dipeptides such as Val-Cit, Val-Ala, and Phe-Lys. Dipeptides can have lower hydrophobicity compared to longer peptides, depending on amino acid composition. A peptide can also include non-natural amino acids or a mix of natural and non-natural amino acids.

[0405] A variety of dipeptide-based cleavable linkers can be used in the immune- stimulatory conjugates described herein.

[0406] Enzymatically cleavable linkers can include a self-immolative spacer to spatially separate the immune- stimulatory compound from the site of enzymatic cleavage. The direct attachment of an immune- stimulatory compound to a peptide linker can result in proteolytic release of an amino acid adduct of the immune- stimulatory compound, thereby impairing its activity. The use of a self-immolative spacer can allow for the elimination of the fully active, chemically unmodified immune- stimulatory compound upon amide bond hydrolysis.

[0407] One self-immolative spacer can be a bifunctional /?ara-aminobenzyl alcohol group, which can link to the peptide through an amino group of the immune- stimulatory compound, forming an amide bond, while amine containing immune- stimulatory compounds can be attached through carbamate functionalities to the benzylic hydroxyl group of the linker (to give a p- amidobenzylcarbamate, PABC). The resulting pro-immune-stimulatory compound can be activated upon protease-mediated cleavage, leading to a 1,6-elimination reaction releasing the unmodified immune- stimulatory compound, carbon dioxide, and remnants of the linker. The following scheme depicts the fragmentation of p- amidobenzyl carbamate and release of the immune- stimulator compound:

X-D

wherein X-D represents the unmodified immune- stimulatory compound. Heterocyclic variants of this self-immolative group have also been described.

[0408] The enzymatically cleavable linker can be a B-glucuronic acid-based linker. Facile release of the immune- stimulatory compound can be realized through cleavage of the B-glucuronide glycosidic bond by the lysosomal enzyme B-glucuronidase. This enzyme can be abundantly present within lysosomes and can be overexpressed in some tumor types, while the enzyme activity outside cells can be low. B-Glucuronic acid-based linkers can be used to circumvent the tendency of an immune- stimulatory conjugate to undergo aggregation due to the hydrophilic nature of B-glucuronides. In certain embodiments, B-glucuronic acid-based linkers can link an antibody construct to a hydrophobic immune- stimulatory compound. The following scheme depicts the release of an immune- stimulatory compound (D) from an immune- stimulatory con ugate containing a B-glucuronic acid-based linker and an antibody construct (Ab):

[0409] A variety of cleavable β-glucuronic acid-based linkers useful for linking drugs such as auristatins, camptothecin and doxorubicin analogues, CBI minor-groove binders, and psymberin to antibodies have been described. These β-glucuronic acid-based linkers may be used in the conjugates described herein. In certain embodiments, the enzymatically cleavable linker is a β- galacto side-based linker. β-Galactoside is present abundantly within lysosomes, while the enzyme activity outside cells is low.

[0410] Additionally, immune- stimulatory compounds containing a phenol group can be covalently bonded to a linker through the phenolic oxygen. One such linker relies on a methodology in which a diamino-ethane "Space Link" is used in conjunction with traditional "PABO" -based self-immolative groups to deliver phenols. Methylene carbamate linkers have also been described that allow linkages to hydroxyl groups on compounds.

[0411] Immune- stimulatory compounds containing a tertiary amine can be covalently bond to a linker to the tertiary amine by creating a quaternary amine linkage.

[0412] Cleavable linkers can include non-cleavable portions or segments, and/or cleavable segments or portions can be included in an otherwise non-cleavable linker to render it cleavable. By way of example only, polyethylene glycol (PEG) and related polymers can include cleavable groups in the polymer backbone. For example, a polyethylene glycol or polymer linker can include one or more cleavable groups such as a disulfide, a hydrazone or a dipeptide.

[0413] Other degradable linkages that can be included in linkers can include ester linkages formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on an immune- stimulatory compound, wherein such ester groups can hydrolyze under physiological conditions to release the immune- stimulatory compound. Hydrolytically degradable linkages can include, but are not limited to, carbonate linkages; imine linkages resulting from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide.

[0414] A linker can contain an enzymatically cleavable peptide moiety, for example, a linker comprising structural formula (Ilia), (Mb), (IIIc), or (Hid):

or a salt thereof, wherein: peptide represents a peptide (illustrated N→C, wherein peptide includes the amino and carboxy "termini") cleavable by a lysosomal enzyme; T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or combinations thereof; R is selected from hydrogen, alkyl, sulfonate and methyl sulfonate; R ^y is hydrogen or Ci.4 alkyl-(0) _r -(Ci _-4 alkylene) _s -G ¹ or Ci _-4 alkyl-(N)-[(Ci _-4 alkylene)^ ¹ ] ₂ ; R ^z is C ₁₄ alkyl-(0) _r - (Ci _-4 alkylene) _s -G ² ; G ¹ is S0 ₃ H, C0 ₂ H, PEG 4-32, or sugar moiety; G ² is S0 ₃ H, C0 ₂ H, or PEG 4-32 moiety; r is 0 or 1; s is 0 or 1; p is an integer ranging from 0 to 5; q is 0 or 1; x is 0 or 1; y is

i

0 or 1; represents the point of attachment of the linker to an immune- stimulatory compound; and * represents the point of attachment to the remainder of the linker, such as to a reactive group (R ^x ).

[0415] In certain embodiments, the peptide can be selected from a tripeptide or a dipeptide. In particular embodiments, the dipeptide can be selected from: Val-Cit; Cit-Val; Ala- Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ala-Val; Val-Ala; Phe-Lys; Lys-Phe; Val-Lys; Lys-Val; Ala-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu- Cit; Cit-Leu; Ile-Cit; Cit-Ile; Phe-Arg; Arg-Phe; Cit-Trp; and Trp-Cit, or salts thereof.

[0416] In certain embodiments, the peptide can be selected from a di-peptide or tri-peptide of non-natural amino acids, a mixture of natural and non-natural amino acids, amino acid analogs or a mixture of amino acids and amino acid analogs.

[0417] Exemplary embodiments of linkers according to structural formula (Ilia) that can be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct): wherein the wavy line indicates point to the immune- stimulatory compound.

[0418] Exemplary embodiments of linkers according to structural formula (Illb), (IIIc), or (Hid) that can be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers can include a group suitable for covalently linking the linker to an antibody construct):

-227-

-229-

wherein the wavy line indicates point to the immune- stimulatory compound.

[0419] The linker can contain an enzymatically cleavable sugar moiety, for example, a linker comprising structural formula (IVa), (IVb), (IVc), (IVd), or (IVe):

or a salt thereof, wherein: q is 0 or 1; r is 0 or 1; X l is C¾, O, or NH; * * represents the point of attachment of the linker to an immune- stimulatory compound; and * represents the point of attachment to the remainder of the linker.

[0420] Exemplary embodiments of linkers according to structural formula (IVa) that may be included in the immune- stimulatory conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct):

-234-

wherein the wavy line indicates a point of attachment to the immune- stimulatory compound.

[0421] Exemplary embodiments of linkers according to structural formula (IVb) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct):

-236-

-237-

wherein the wavy line indicates a point of attachment to the immune- stimulatory compound.

[0422] Exemplary embodiments of linkers according to structural formula (IVc) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct):

-239-

wherein the wavy line indicates a point of attachment to the immune- stimulatory compound.

[0423] Exemplary embodiments of linkers according to structural formula (IVd) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct):

wherein the wavy line indicates a point of attachment to the immune- stimulatory compound. [0424] Exemplary embodiments of linkers according to structural formula (IVe) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct):

wherein the wavy line indicates a point of attachment to the immune- stimulatory compound.

[0425] Although cleavable linkers can provide certain advantages, the linkers comprising the conjugate described herein need not be cleavable. For non-cleavable linkers, the immune- stimulatory compound release may not depend on the differential properties between the plasma and some cytoplasmic compartments. The release of an active form of the immune- stimulatory compound can occur after internalization of the immune- stimulatory conjugate via antigen- mediated endocytosis and delivery to lysosomal compartment, where the antibody construct can be degraded to the level of amino acids through intracellular proteolytic degradation. This process can release an immune- stimulatory compound derivative, which is formed by the immune- stimulatory compound, the linker, and the amino acid residue to which the linker was covalently attached (e.g., a cysteine residue). The immune- stimulatory compound derivative from immune- stimulatory conjugates with non-cleavable linkers can be more hydrophilic and less membrane permeable, which can lead to less bystander effects and less nonspecific toxicities compared to immune- stimulatory conjugates with a cleavable linker. Immune- stimulatory conjugates with non-cleavable linkers can have greater stability in circulation than immune- stimulatory conjugates with cleavable linkers. Non-cleavable linkers can be alkylene chains, or can be polymeric, such as, for example, based upon polyalkylene glycol polymers, amide polymers, or can include segments of alkylene chains, polyalkylene glycols and/or amide polymers. The linker can contain a polyethylene glycol segment having from 1 to 6 ethylene glycol units.

[0426] The linker can be non-cleavable in vivo, for example, a linker according to the

formulations below:

thereof, wherein: R is selected from hydrogen, Ci-ioalkyl, sulfonate and methyl sulfonate; R ^x is a moiety including a functional group capable of covalently linking the linker to an antibody construct; and ^ represents the point of attachment of the linker to an immune- stimulatory compound.

[0427] Exemplary embodiments of linkers according to structural formula (Va)-(Ve) that may be included in the conjugates described herein include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct, and represents the point of attachment to an immune- stimulatory compound):

0428]

[0429] Attachment groups (also referred to as reactive groups herein) that are used to attach the linkers to an antibody construct can be electrophilic in nature and include, for example, maleimide groups, activated disulfides, active esters such as NHS esters and HOBt esters, haloformates, acid halides, alkyl, and benzyl halides such as haloacetamides. There are also emerging technologies related to "self- stabilizing" maleimides and "bridging disulfides" that can be used in accordance with the disclosure.

[0430] One example of a "self- stabilizing" maleimide group that hydrolyzes spontaneously under conjugation conditions to give a conjugate species with improved stability is depicted in the schematic below. Thus, the maleimide attachment group is reacted with a sulfhydryl of an antibody to give an intermediate succinimide ring, after which the succinmide ring hydrolizes opens to form a ring opened form. The hydro lyzed form of the attachment group is resistant to deconjugation in the presence of plasma proteins.

Leads to "DAR loss" over time

Self-stabilizing attachment:

contains maleimide contains succinumide hydrolized forms of succinumide ring r ⁱⁿ 9 ^r ' ⁿ 9 hydrolized forms are stable in plasma

[0431] A method for bridging a pair of sulfhydryl groups derived from reduction of a native hinge disulfide bond has been disclosed and is depicted in the schematic below. An advantage of this methodology is the ability to synthesize homogenous DAR4 conjugates by full reduction of

IgGls (to give 4 pairs of reactive sulfhydryls) followed by reaction with 4 equivalents of the alkylating agent. Conjugates containing "bridged disulfides" are also claimed to have increased stability.

"bridged disulfide"

[0432] Similarly, as depicted below, a maleimide derivative that is capable of bridging a pair of sulfhydryl groups has been developed.

[0433] The attachment moiety can contain the following structural formulas (Via), (VIb), or (Vic):

or salts thereof, wherein: R ^q is H or-0-(CH ₂ CH ₂ 0)n-CH ₃ ; x is 0 or 1; y is 0 or 1; G ² is- CH ₂ CH ₂ CH ₂ S0 ₃ H or-CH ₂ CH ₂ 0-(CH ₂ CH ₂ 0)n-CH ₃ ; R ^w is-0-CH ₂ CH ₂ S0 ₃ H or-NH(CO)- CH ₂ CH ₂ 0-(CH ₂ CH ₂ 0)i ₂ -CH ₃ ; and * represents the point of attachment to the remainder of the linker.

[0434] Exemplary embodiments of linkers according to structural formulae (Via) and (VIb) that can be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers can include a group suitable for covalently linking the linker to an antibody construct):

-247-

-248-

-249- wherein the wavy line indicates a point of attachment to the immune- stimulatory compound.

[0435] Exemplary embodiments of linkers according to structural formula (Vic) that can be included in the immune- stimulatory conjugates described herein can include the linkers illustrated below (as illustrated, the linkers can include a group suitable for covalently linking the linker to an antibod construct):

wherein the wavy line indicates a point of attachment to the immune- stimulatory compound.

[0436] As is known by skilled artisans, the linker selected for a particular immune- stimulatory conjugate may be influenced by a variety of factors, including but not limited to, the site of attachment to the antibody construct (e.g., lysine, cysteine, glutamine, glutamate or other amino acid residue(s)), structural constraints of the drug pharmacophore and the lipophilicity of the drug. The specific linker selected for a conjugate should seek to balance these different factors for the specific antibody construct/immune stimulatory compound combination.

[0437] For example, ADCs with cytotoxic agents have been observed to effect killing of bystander antigen-negative cells present in the vicinity of the antigen-positive tumor cells. The mechanism of bystander cell killing by ADCs has indicated that metabolic products formed during intracellular processing of the ADCs may play a role. Neutral and/or hydrophobic cytotoxic metabolites generated by metabolism of the ADCs in antigen-positive cells appear to play a role in bystander cell killing while charged or hydrophilic metabolites may be prevented from diffusing across the membrane into the medium and therefore cannot affect bystander killing. In certain embodiments as described herein, the linker for an immune- stimulatory conjugate is selected to attenuate the bystander effect caused by cellular metabolites of the conjugate. In certain embodiments, the linker is selected to increase the bystander effect.

[0438] The properties of the linker may also affect aggregation of the conjugate under conditions of use and/or storage. Typically, ADCs reported in the literature contain no more than 3-4 drug molecules per antibody molecule. Attempts to obtain higher drug-to-antibody ratios ("DAR") often failed, particularly if both the drug and the linker were hydrophobic, due to aggregation of the ADC. In many instances, DARs higher than 3-4 could be beneficial as a means of increasing potency. In instances where the drug is hydrophobic in nature, it may be desirable to select linkers that are relatively hydrophilic as a means of reducing aggregation, especially in instances where DARs greater than 3-4 are desired. Thus, in certain embodiments, the linker of an immune- stimulatory conjugate incorporates chemical moieties that reduce aggregation of the conjugate during storage and/or use. A linker may incorporate polar or hydrophilic groups such as charged groups or groups that become charged under physiological pH to reduce the aggregation of the conjugate. For example, a linker may incorporate charged groups such as salts or groups that deprotonate, e.g., carboxylates, or protonate, e.g., amines, at physiological pH.

[0439] In particular embodiments, the aggregation of the conjugates during storage or use is less than about 40% as determined by size-exclusion chromatography (SEC). In particular

embodiments, the aggregation of the conjugates during storage or use is less than 35%, such as less than about 30%, such as less than about 25%, such as less than about 20%, such as less than about 15%, such as less than about 10%, such as less than about 5%, such as less than about 4%, or even less, as determined by size-exclusion chromatography (SEC).

General method for interchain cysteine-based bioconjugations

[0440] An antibody construct can be conjugated to a linker via cysteine-based bioconjugation.

An antibody construct can be exchanged into an appropriate buffer, for example, phosphate, borate, PBS, histidine, Tris-Acetate at a concentration of about 2 mg/mL to about 10 mg/mL with an appropriate number of equivalents of a reducing agent, for example, dithiothreitol or tris(2- carboxyethyl)phosphine. The resultant solution can be stirred for an appropriate amount of time and temperature to effect the desired reduction. A construct of an amino-pyrazinecarboxamide compound and a linker can be added as a solution with stirring. Dependent on the physical properties of the linker-pay load, a co-solvent can be introduced prior to the addition of the linker- payload to facilitate solubility. The reaction can be stirred at room temperature for about 1 hour to about 12 hours depending on the observed reactivity. The progression of the reaction can be monitored by liquid chromatography-mass spectrometry (LC-MS). Once the reaction is deemed complete, the remaining free linker-pay load can be removed by applicable methods and the antibody conjugate can be exchanged into the desired formulation buffer. Such cysteine-based conjugates can be synthesized starting with an antibody (rnAb) and linker-payload, e.g., 7 equivalents, using the conditions described in Scheme A below (Conjugate = antibody conjugate). Monomer content and drug-antibody ratios can be determined by methods described herein.

Scheme A.

1 . reducing agent

rnAb Conjugate

7 eq of compound-linker construct

sodium phosphate

pH = 8

20% v/v DMSO

General method for lysine-based bioconjugations

[0441] An antibody construct can be conjugated to a linker via lysine-based bioconjugation. An antibody construct can be exchanged into an appropriate buffer, for example, phosphate, borate, PBS, histidine, Tris-Acetate at a concentration of about 2 mg/mL to about 10 mg/mL. An appropriate number of equivalents of a construct of an amino-pyrazinecarboxamide compound, and a linker, linker-payload, as described herein, can be added as a solution with stirring.

Dependent on the physical properties of the linker-payload, a co-solvent can be introduced prior to the addition of the linker-payload to facilitate solubility. The reaction can be stirred at room temperature for 2 hours to about 12 hours depending on the observed reactivity. The progression of the reaction can be monitored by LC-MS. Once the reaction is deemed complete, the remaining linker-payloads can be removed by applicable methods and the antibody conjugate can be exchanged into the desired formulation buffer. Lysine-linked conjugates can be synthesized starting with ab antibody (rnAb) and linker-payload, e.g., 10 equivalents, following Scheme B below (Conjugate = antibody conjugate). Monomer content and drug-antibody construct ratios (molar ratios) can be determined by methods described herein.

Scheme B.

10 eq of compound-linker construct

sodium phosphate

rnAb Conjugate

pH = 8

20% v/v DMSO Conjugates of PROTACS

[0442] The conjugates described herein may also comprise antibody constructs and constructs having immune-modulatory activity through targeted degradation of proteins. As used herein, such conjugates are termed immune-modulatory conjugates and have a direct or indirect effect on the immune system. In some embodiments, the conjugates can target proteins involved in immune activation, inhibition or regulation. In some embodiments, the conjugates can target proteins in tumor cells and cause cell death or apoptois and indirectly stimulate the immune system. In various embodiments, proteolysis targeting modules (PTM) are attached (e.g., conjugated) through a linker to an antibody construct to form immune-modulatory conjugates.

[0443] In certain embodiments, an immune-modulatory conjugate comprises an antibody construct, a linker, and two binding moieties. The linker can be a multifunctional linker (W) that can covalently attach two binding moieties (X and Y) to form a proteolysis targeting module (X- W-Y) designed to induce degradation of a protein target. A PTM can comprise a first binding moiety (X) that can bind to a protein target (the moiety also referred to as a target protein binding moiety or protein targeting moiety) and a second binding moiety (Y) that can bind to an E3 ubiquitin ligase. The multi-functional linker also can covalently attach the PTM to a residue(s) (e.g., lysine, cysteine or engineered residue) on an antibody construct (Z) (e.g., an antibody) to form an immune-modulatory conjugate, as shown below:

W = multifunctional linker; X = Binding moeity 1 ; Y = Binding moiety 2; Z = antibody

[0444] In some aspects, an immune-modulatory conjugate comprises a proteolysis targeting module that can bind to a protein active site and can stimulate an immune response through protein target degradation; an antibody construct comprising an antigen binding domain and an Fc domain, wherein the antigen binding domain can bind to a first antigen; and a multifunctional linker, wherein the linker is covalently bound to the antibody construct and to protein targeting moiety (a first binding moiety) and an E3 ubiquitin ligase binding moiety (second binding moiety). In some embodiments, the Fc domain is an Fc null. In some embodiments, the Fc domain is a wild-type IgG that can bind to Fey receptors. In some embodiments, the Fc domain can bind to an Fc receptor, wherein the IQ for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct. In some embodiments, the K _d for binding of the first binding moiety of the conjugate to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC50 of the first binding moiety of the conjugate is no greater than 300-fold the IC50 of a control compound, wherein the control compound is the free first binding moiety. In some embodiments, the proteolysis targeting module can be comprised of: a) a small molecule that can bind a protein target, degredation or inhibition of which is immune stimulatory, b) a multi-functional linker that can be covalently bonded to elements a) and c); and c) a small molecule that can bind to an E3 ubiquitin ligase.

[0445] In some embodiments, the proteolysis targeting module can be comprised of a) a small molecule that can bind to a protein target, inhibition or degredation of which is immune stimulatory, b) a multi-functional linker that can be covalently bonded to elements a) and c); and c) a small molecule that can bind an E3 ubiquitin ligase, wherein the proteolysis targeting module can increase degradation of the protein target within a cell.

[0446] In some embodiments, the proteolysis targeting module can be comprised of a) a first binding moiety that can bind an immune inhibitory target, b) a linker that can attach the first binding moiety to element c), and c) a compound that can bind an E3 ubiquitin ligase, wherein the PTM can increase degradation of the immune-inhibitory target in cells expressing antigen of the first binding domain or second binding domain of the conjugate (containing the PTM) compared to degradation of the immune-inhibitory target in cells not expressing, or expressing lower levels of, antigen of the first binding domain or second binding domain of the conjugate. The PTM is attached to the antibody construct via another linker, as further described below.

[0447] In other embodiments, the proteolysis targeting module can be comprised of a) a first binding moiety that can bind to an immune stimulatory target, b) a second linker that can attach the first binding moiety to element c), and c) a compound that can bind to an E3 ubiquitin ligase, wherein the PTM can increase degradation of the immune- stimulatory target in cells expressing antigen of the first binding domain or second binding domain of the conjugate (containing the PTM) compared to degradation of the immune- stimulatory target in cells not expressing, or expressing lower levels of, antigen of the first binding domain or second binding domain of the conjugate.

[0448] These conjugates can be made by various methods. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described herein by using the appropriate starting materials and modifying the synthetic route as needed. Starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0449] In other embodiments, immune-modulatory conjugates have the following general formula:

wherein Ab is an antibody construct, L is a linker, D is an immune-modulatory compound, x may be from 1 to 20 (wherein each x denotes a distinct compound), n may be from 1 to 20, and z may be from 1 to 20.

[0450] In some embodiments, x is 1, n is 1 and z may be from 1 to 10, such as from 1 to 9, such as from 1 to 8, such as from 2 to 8, such as from 1 to 6, such as from 3 to 5 or such as about 2.

[0451] In some embodiments x is 1, n is 2, and z may be from 1 to 10, such as from 1 to 9, such as from 1 to 8, such as from 2 to 8, such as from 1 to 6 or such as from 3 to 5. In certain embodiments, z is 4.

[0452] In certain embodiments, con ugates are represented by the following formula: wherein Ab is an antibody construct, L is a linker having the structure -A _a -W _w -Y _y -, where A is a spacer, a is 0 or 1, W is a cleavable unit, w may be from 0 to 10, Y is a stretcher, y may be from

0 to 3, D is an immune-modulatory compound, x may be from 1 to 20 (wherein each x denotes a distinct compound), n may be from 1 to 20, and z may be from 1 to 20.

[0453] In some embodiments, a is 1, w is 0, y is 0, x is 1, n is 1, and z may be from 1 to 20, 1 to 10, 1 to 9, 1 to 8, such as from 2 to 8, 1 to 6 or 3 to 5. In certain embodiments, z is 4 or 2.

[0454] In some embodiments, a isl, w is 1, y is 1, x is 1, n is 1 and z may be from 1 to 10, 1 to 9,

1 to 8, 2 to 8, 1 to 6, 3 to 5, or 4.

[0455] In some embodiments, a isl, w is 1, y is from 0, x is 1, n is 1 and z may be from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 1 to 6, 3 to 5, or 4.

[0456] In some embodiments, a is 0 or 1, w is from 0 to 10, y is from 0-3, where at least one of A, W or Y is present, x may be from 1 to 20, n may be from 1-20, and z may be from 1 to 20.

[0457] In certain embodiments, an immune-modulatory conjugate can be designed to increase ubiquitin-mediated target protein destruction via the ubiquitin pathway. The process of attaching ubiquitin molecules to a protein target typically involves 3 enzymates and steps: 1) an El enzyme that can activate ubiquitin, 2) an E2 enzyme that can transfer activated ubiquitin, and 3) a multi- subunit E3 enzyme ligase that can receive the activated ubiquitin and catalyze a ubiquitin attachment to the target protein.

[0458] In some embodiments, an immune-modulatory conjugate is provided that includes a proteolysis targeting module (PTM; also referred to as a proteolysis-targetting chimera or

PROTAC). PTMs can comprise a small molecule, a target binding moiety that binds a protein target and can be covalently attached, directly or by a spacer, to the small molecule that can bind an E3 ubiquitin ligase subunit. In some embodiments, a PTM includes a protein targeting moiety, such as an immune-modulatory compound (IMC), that is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and a linker (L) that is covalently attached to the PTM and to the antibody construct (Ab), as represented by the formula Ab-(L-PTM _n ) _z , where n is from 1-20 and z is from 1 to 20. In some embodiments, L is a cleavable linker. The cleavable linker can be a peptide linker or other cleavable linker described above in the Section on Linkers. In some embodiments, L is a non-cleavable linker. In some embodiments, the Fc domain of the conjugate is an Fc null. In some embodiments, the Fc domain is a wild-type IgG that can bind to Fey receptors. In some embodiments, the Fc domain can bind to an Fc receptor, wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct. In some embodiments, the K _d for binding of the IMC of the conjugate to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC50 of the IMC of the conjugate is no greater than 300-fold the IC50 of a control compound, wherein the control compound is the free IMC.

[0459] In some embodiments, a protein targeting moiety, such as an immune-modulatory compound (IMC), is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and a linker (L) is covalently attached to the spacer (s), n is from 1-20 and z is from 1 to 20 as represented by the formula:

VII [0460] In some embodiments, L is a cleavable linker. The cleavable linker can be a peptide linker or other cleavable linker described above in the Section on Linkers. In some embodiments, L is a non-cleavable linker. In some embodiments, the Fc domain of the conjugate is an Fc null. In some embodiments, the Fc domain is a wild-type IgG that can bind to Fey receptors. In some embodiments, the Fc domain can bind to an Fc receptor, wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct. In some embodiments, the K _d for binding of the IMC of the conjugate to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC50 of the IMC of the conjugate is no greater than 300-fold the IC50 of a control compound, wherein the control compound is the free IMC.

[0461] In some embodiments, a protein targeting moiety, such as an immune-modulatory compound (IMC), is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and a linker (L) is covalently attached to the protein targeting moiety, n is from 1-20 and z is from 1 to 20 as represented by the formula:

[0462] In some embodiments, L is a cleavable linker. The cleavable linker can be a peptide linker or other cleavable linker described above in the Section on Linkers. In some embodiments, L is a non-cleavable linker. In some embodiments, the Fc domain of the conjugate is an Fc null. In some embodiments, the Fc domain is a wild-type IgG that can bind to Fey receptors. In some embodiments, the Fc domain can bind to an Fc receptor, wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct. In some embodiments, the K _d for binding of the IMC of the conjugate to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC50 of the IMC of the conjugate is no greater than 300-fold the IC50 of a control compound, wherein the control compound is the free IMC.

[0463] In some embodiments, a protein targeting moiety, such as an immune-modulatory compound (IMC), is covalently attached to an E3 ubiquitin ligase binding moiety (ULM) through a spacer (S) and linker L is covalently attached to the ubiquitin E3 ligase moiety (ULM), n is from 1-20 and z is from 1 to 20 as represented by the formula:

(IX)

[0464] In some embodiments, L is a cleavable linker. The cleavable linker can be a peptide linker or other cleavable linker described above in the Section on Linkers. In some embodiments, L is a non-cleavable linker. In some embodiments, the Fc domain of the conjugate is an Fc null. In some embodiments, the Fc domain is a wild-type IgG that can bind to Fey receptors. In some embodiments, the Fc domain can bind to an Fc receptor, wherein the K _d for binding of the Fc domain of the conjugate to an Fc receptor is no greater than about 100 times the K _d for binding of a control antibody construct to the Fc receptor, wherein the control antibody construct is the unconjugated antibody construct. In some embodiments, the K _d for binding of the IMC of the conjugate to the protein active site is no greater than 100 times the K _d for binding of a control compound to the protein active site or wherein the IC50 of the IMC of the conjugate is no greater than 300-fold the IC50 of a control compound, wherein the control compound is the free IMC.

[0465] In certain embodiments, the E3 ubiquitin ligase binding moiety is linked to a protein targeting moiety, such as an immune-modulatory compound, in the conjugate as described herein, via a spacer. In certain embodiments, the E3 ubiquitin ligase binding moiety can be linked to the protein targeting moiety via a spacer having a linear non-hydrogen atom number in the range of 1 to 25 or 1 to 20. In certain embodiments, the spacer has 5 to 20 or 5 to 15 linear non- hydrogen atoms. The spacer is typically non-cleavable.

[0466] The E3 ubiquitin ligase binding moiety can be linked to the spacer of the protein targeting moiety with a functional group such as an ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The E3 ubiquitin ligase binding moiety can be linked to the spacer of the protein targeting moiety via a spacer comprising an aromatic, heteroaromatic, cyclic, bicyclic, and/or tricyclic moiety.

[0467] Spacer length can be varied to optimize the activity of the protein targeting moiety for its target protein. In some embodiments, the spacer is non-cleavable and comprises segments of alkylene, alkenylene, alkynylene, -(CH ₂ 0)-, -CH ₂ CH ₂ 0)-, -(CH ₂ OCH ₂ )-, -C(O)-, -NH-, and -0-, having a length of from 1-25, 1-20, 1-15, 5-25, 5-20, or 5-15 linear non-hydrogen atoms. A spacer may be optionally substituted with Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, -(CH ₂ 0) _n iH, - (CH ₂ CH ₂ 0) _n iH, -(CH ₂ 0) _n iCH ₃ , -C(0)OH or -NH ₂ , wherein nl is from 1 to 8, and may further optionally comprise a reactive group, R ^x , to form a functional group, such as an ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone, forming an attachment to a linker (L). In some embodiments, the spacer is not unsubstituted. In some embodiments, the spacer is substituted with R ^x .

[0468] A spacer may be a Ci- ₂₅ alkylene or optionally substituted Q-25 heteroalkylene, wherein the heteroalkylene is a Q-2 ₄ alkylene chain interspersed with one or more groups independently selected from: -0-, -S-, -NH2-, and -C(0)NH-. The spacer may also be optionally substituted with a reactive group, R , that can form a functional group, such as an amide bond, an ester bond, an ether bond, a carbonate bond, a carbamate bond, or a thioether bond; such reactive groups can be, for example, amino groups; carboxyl groups; aldehyde groups; azide groups; alkyne and alkene groups; ketones; carbonates; carbonyl functionalities bonded to leaving groups such as cyano and succinimidyl and hydroxyl groups. In some embodiments, R ^x can be -NH ₂ , -S or a maleimide. In some embodiments, R ^x is -NH ₂ . The spacer may also be optionally substituted with Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, -(CH ₂ 0) _n iH, -(CH ₂ CH ₂ 0) _n iH, - (CH ₂ 0) _n iCH ₃ , -C(0)OH or -NH ₂ , wherein nl is from 1 to 8. In some embodiments, the spacer is not unsubstituted. In some embodiments, the spacer is substituted with R ^x .

[0469] In certain embodiments, the spacer (S) has the formula -C(O)N(R ¹⁰⁰ )R ¹⁰¹ C(O)N(R ¹⁰⁰ )-, - C(O)R ¹⁰¹ C(O)-, -C(0)R ¹⁰¹ N(RiooK -N(Ri ₀₀ )R ¹⁰¹ C(O)-, -N(R ¹⁰⁰ )C(O)R ¹⁰¹ C(O)-, - N(R ¹⁰⁰ )C(0)R ¹⁰¹ N(RiooK -N(Ri ₀₀ )R ¹⁰¹ C(O)N(R100)-, -N(R ¹⁰⁰ )C(O)R ¹⁰¹ C(O)N(R ¹⁰⁰ )-, - N(R ¹⁰⁰ )C(0)R ¹⁰¹ N(Rioo)C(0)-, and -C(O)N(Ri ₀₀ )R ¹⁰¹ C(O)N(R100)-; wherein each R ¹⁰⁰ is independently selected from H or C ₁ -C3 alkyl and R ¹⁰¹ is -Ci-C ₂₅ alkylene-, -Ci-C ₂₅ alkenylene-, - Ci-C ₂₅ alkynlene-, -Ci-Ci ₂ alkylene(CH ₂ 0) _n Ci-Ci ₅ alkylene-, -Ci-Ci ₂ alkylene((CH ₂ OCH ₂ ) _n Ci- Ci ₂ alkylene-, -Ci-Ci ₂ alkylene(CH ₂ CH ₂ 0) _n Ci-Ci ₂ alkylene-, -Ci-Ci ₂ alkenylene-((CH ₂ 0) _n Ci- C i ₂ alkylene- , -C ₁ -C i ₂ alkenylene-(CH ₂ CH ₂ 0) _n C ₁ -C i ₂ alkylene- , -C ₁ -C i ₂ alkenylene- ((CH ₂ OCH ₂ ) _n Ci-Ci ₂ alkylene-, -Ci-Ci ₂ alkylene-(CH ₂ 0) _n Ci-Ci ₂ alkenylene-, -Ci-Ci ₂ alkylene- (CH ₂ CH ₂ 0) _n Ci-Ci ₂ alkenylene-, -Ci-Ci ₂ alkylene-(CH ₂ OCH ₂ ) _n Ci-Ci ₂ alkenylene-, -Q- Ci ₂ alkynylene-(CH ₂ 0) _n Ci-Ci ₂ alkylene-, -Ci-Ci ₂ alkynylene-(CH ₂ CH ₂ 0) _n Ci-Ci ₂ alkylene-, -Q- Ci ₂ alkynylene-(CH ₂ OCH ₂ ) _n Ci-Ci ₂ alkylene-, -Ci-Ci ₂ alkynylene-(CH ₂ 0) _n Ci-Ci ₂ alkenylene-, -Q- Ci ₂ alkynylene-(CH ₂ CH ₂ 0) _n Ci-Ci ₂ alkenylene-, -Ci-Ci ₂ alkynylene-(CH ₂ OCH ₂ ) _n Ci- Ci ₂ alkenylene-,-Ci-Ci ₂ alkynylene-(CH ₂ 0) _n Ci-Ci ₂ alkynylene-, -Ci-Ci ₂ alkynylene- (CH ₂ CH ₂ 0) _n Ci-Ci ₂ alkynylene-, -Ci-Ci ₂ alkynylene-(CH ₂ OCH ₂ ) _n Ci-Ci ₂ alkynylene-, in each case optionally substituted with a reactive moiety R ^x for attachment to the linker (L), and n is 0 to 8. R can be a reactive group that can form an amide bond, an ester bond, an ether bond, a carbonate bond, a carbamate bond, or a thioether bond; such reactive groups can be, for example, amino groups; carboxyl groups; aldehyde groups; azide groups; alkyne and alkene groups;

ketones; carbonates; carbonyl functionalities bonded to leaving groups such as cyano and succinimidyl and hydroxyl groups. In some embodiments, R ^x can be -N¾, -S or a maleimide. In some embodiments, R ^x is -N¾.

[0470] In certain embodiments, the spacer (S) comprises glutamate, a glycine-glutamate dipeptide, glycine-PEGl -glutamate, glycine-PEG2-glutamate, glycine-PEG3 -glutamate, glycine-PEG4-glutamate or glycine-PEG5-glutamate, wherein the E3 ubquitin ligase binding moiety and the protein targeting moiety are attached to the spacer via amide bonds.

[0471] An E3 ubiquitin ligase binding moiety can bind to an E3 ubiquitin ligase, such as Von Hippel-Lindaue E3 ubiquitin ligase (VHL), cereblon, mouse double minute 2 homolog (MDM2), AMFR, APC/Cdc20, APC/Cdhl, C6orfl57, Cbl, CBLL1, CHFR, CHIP, DTL (Cdt2), E6-AP, HACEl, HECTDl, HECTD2, HECTD3, HECWl, HECW2, HERC2, HERC3, HERC4, HERC5, HUWE1, HYD, ITCH, LNX1, mahogunin, MARCH-I, MARCH-II, MARCH-III, MARCH-IV, MARCH- VI, MARCH- VII, MARCH- VIII, MARCH-X, MEKK1, MIB1, MIB2, MycBP2, NEDD4, NEDD4L, Parkin, PELI1, Pirh2, PJA1, PJA2, RFFL, RFWD2, Rictor, RNF5, RNF8, RNF19, RNF190, RNF20, RNF34, RNF40, RNF125, RNF128, RNF138, RNF168, SCF/p-TrCP, SCF/FBW7, SCF/Skp2, SHPRH, SIAH1, SIAH2, SMURF1, SMURF2, TOPORS, TRAF6, TRAF7, TRIM63, UBE3B, UBE3C, UBR1, UBR2, UHRF2, WWP1, WWP2, or ZNRF1.

[0472] In other embodiments, an E3 ubiquitin ligase binding moiety can be selected from an E3 ubiquitin ligase selected from von Rippel-Lindau (VHL), cereblon, XIAP, E3A, MDM2, Anaphase-promoting complex (APC), UBR5 (EDDI), SOCS/ BC-box/ eloBC/ CUL5/ RING, LNXp80, CBX4, CBLLI, HACEl, HECTDl, HECTD2, HECTD3, HECWl, HECW2, HERCI, HERC2, HERC3, HERC4, HUWEI, ITCH, NEDD4, NEDD4L, PPIL2, PRPFI9, PIASI, PIAS2, PI AS 3, PI AS 4, RANBP2, RNF4, RBXI, SMURFI, SMURF2, STUB I, TOPORS, TRIPI2, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWPI, WWP2, Parkin,

A20/TNFAIP3, AMFR/gp78, ARA54, beta-TrCPI/BTRC, BRCAI, CBL, CHIP/STUB I, E6, E6AP/UBE3A, F-box protein I5/FBXOI5, FBXW7/Cdc4, GRAIL/RNFI28, HOIP/RNF3 I, cIAP-I/HIAP-2, cIAP-2/HIAP-I, cIAP (pan), ITCH/AIP4, KAPI, MARCH8, Mind Bomb I/MIBI, Mind Bomb 2/MIB2, MuRFI/TRIM63, NDFIPI, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNFI68, RNF43, SARTI, Skp2, SMURF2, TRAF-I, TRAF-2, TRAF-3, TRAF-4, TRAF- 5, TRAF-6, TRIMS, TRIM2I, TRIM32, UBR5, and ZNRF3.

[0473] In further embodiments, an E3 ubiquitin ligase can be selected from the following types: HECT type, RING-type, PARKIN-finger type, RING-variant type, U-box type, A20-finger type, PIAS-finger type, PHD-finger type, Skpl-like type, Cullin-type, F-box type, SOCS-box type, BTB-type, DDBl-like type and APC/cyclosome type.

[0474] An E3 ubiquitin ligase binding moiety can be a VHL binding moiety such as (S)-2- amino-Nl-(4-(5-amino-6-((4-morpholinopyridin-3-yl)carbamoyl) pyrazin-2-yl)benzyl)-N5-(2-(3- (((S)-l-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzy l)carbamoyl)pyrrolidin-l-yl)-^ dimethyl- l-oxobutan-2-yl)amino)-3-oxopropoxy)ethyl)pentanediamide (Example 1) or a cereblon binding moiety such as 3-amino-6-(4-(2-((2S)-2-amino-6-(2-((2-(2,6-dioxopiperidin-3 - yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)hexanamido)ethyl) phenyl)-N-(4-morpholinopyridin- 3-yl)pyrazine-2-carboxamide (Example 2). Other compounds that bind VHL may be

hydroxyproline compounds such as those disclosed in WO 2013/106643, and other compounds described in US 2016/0045607, WO 2014187777, US 2014/0356322, and U.S. 9,249,153. Other compounds that bind to cereblon include thalidomide, lenalidomide, pomalidomide and analogs thereof. Other small molecule compounds that bind to cereblon are also known, e.g., the compounds disclosed as an in US 2016/0058872 and US 2015/0291562.

[0475] In certain embodiments, the linker (L) is attached to the PTM at a reactive site R ^x in the spacer. In certain embodiments, the linker (L) is attached to the PTM via an attachment site in the E3 ubiquitin ligase binding moiety. In certain embodiments, the linker (L) is attached to the PTM via an attachment site in the protein targeting moiety.

[0476] The linker (L) and/or covalent attachment site(s) of the linker (L) to the proteolysis targeting module can be cleavable or non-cleavable. In certain embodiments, the linker is cleavable. In certain embodiments, the linker is non-cleavable linker. In some embodiments, the linker is non-cleavable and is attached to the proteolysis targeting module at site wherein the protein targeting moiety can bind to its protein target, and, if active, does not lose immune- modulatory activity, as determined by Kd measurement, by altered target protein function in a cell-based assay, or both. Linker length can be varied to optimize the activity of the protein targeting moiety for its target protein. Such linkers can be short, flexible, rigid, hydrophilic, or hydrophobic. The linker can contain segments that have different characteristics, such as segments of flexibility or segments of rigidity. The linker can be chemically stable to

extracellular environments. Non-limiting examples can be maleimidocaproyl linkers. A maleimidocaproyl linker can comprise N-maleimidomethylcyclohexane-l-carboxylate.

[0477] In some embodiments, the linker (L) is a cleavable linker and can be selected from the linkers of formulae Ila, lib, lie, Ilia, Mb, IIIc, Hid, IVa, IVb, IVc, IVd, and IVe and specific structures therein, as shown above.

[0478] A linker (L) can be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules.

[0479] A linker (L) may comprise from 5 to 100 linear non-hydrogen atoms that may be covalently attached to an antibody construct.

[0480] In some embodiments, the protein targeting moiety of the proteolysis targeting module is an immune-modulatory compound, such as those disclosed herein. In some embodiments, For example, a protein targeting moiety can be an antagonist of an immune-modulatory or immune- inhibitory protein, such as a beta-catenin pathway inhibitor, a kinase inhibitor, a TNIK inhibitor, a Tankyrase (TNKS) inhibitor, TGFpRl, TGFpR2, ΡΙ3Κ-β, STAT3, IL-10, IDO, or TDO. In some embodiments, the protein targeting moiety is a kinase inhibitor that binds to ALK, Bcr-Abl, BRAF, BTK, c-KIT, EGFR, ErbB2, JAK, MEK, MET, PDGFRB, RET, ROS 1, Syk, SRC, TGFpR2, TNIK, TNKS, TNKS 2, TrkA, TrkB, TrkC, VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, FGFR4, CSF1R, RON/MS T1R, TYR03, MERTK, AXL, ΡΙ3Κδ, ΡΙ3Κγ, MAP4K1, PERK, KIT, or any combination thereof.

[0481] In some embodiments, the protein targeting moiety binds to aryl hydrocarbon receptor, androgen receptor, estrogen receptor, FK506-binding protein 12, fibroblast growth factor receptor substrate 2, phosphatidylinositol -4,5-biphosphate 3-kinase, SMAD family member 3, bromodomain and extra-territorial family of proteins (BET), bromodomain-containing protein 4 member of the BET family, Abelson tyrosine kinase, receptor- interacting serine/threo nine- protein kinase 1, estrogen-related receptor, TRAF2 and NCK- interacting protein kinases (TNIK), and transforming growth factor beta. The protein targeting moiety can be an antagonist or inhibitor of any of these protein targeting moieties.

[0482] In some embodiment, the protein targeting moiety binds to TGFPR2, TGFpRl, SMAD2, SMAD3, SMAD4, beta-catenin, TNIK, CREBB2, Beta catenin/TCF4, beta catenin/LEF, beta catenin/CREBBP, YAP, TAZ, YAP/TAZ, TNKS 1 , TNKS 2, MST1, MST2, NRAS, HRAS, KRAS, RASmutl2, RASmutl3, PERK (EIF2AK3), RON/MS T1R, PARP1,2, MTOR, STAT3, MCTl, MCT2, or MCT4. The protein targeting moiety can be an antagonist or inhibitor of any of these protein targeting moieties.

[0483] In some embodiments, the protein targeting moiety is CSFR1, RON/MST1, PI3Kd, PI3Kg, PARP1, PD-L1, PP2A, A2ar, TYR03, AXL, or MER. The protein targeting moiety can be an antagonist or inhibitor of any of these protein targeting moieties.

[0484] In other embodiments, the protein targeting moiety can be a Pattern recognition receptor (PRR) agonist, such a PAMP molecule or a DAMP molecule. In some embodiments, the protein targeting moiety can be a Toll- like receptor agonist, a RIG-I agonist, a STING agonist, a GPCR agonist, an ion channel agonist, a membrane transporter agonist, or an ER protein agonist.

Conjugates

[0485] In some embodiments, the conjugates described herein comprise an antibody construct, at least one an immune- stimulatory compound, and at least one linker. A conjugate can comprise an antibody construct, at least one pattern recognition receptor (PRR) agonist, and at least one linker. A conjugate can comprise an antibody construct, at least one pattern-associated molecular pattern (PAMP) molecule, and at least one linker. A conjugate can comprise an antibody construct, at least one damage-associated molecular pattern (DAMP) molecule, and at least one linker. A conjugate can comprise an antibody construct, at least one STING agonist, and at least one linker. A conjugate can comprise an antibody construct, at least one toll-like receptor agonist, and at least one linker. A conjugate can comprise an antibody construct, at least one kinase inhibitor and at least one linker. An antibody construct of any of the conjugates described herein can have a modified Fc domain.

[0486] In some embodiments, an Fc domain or region can exhibit reduced binding affinity to one or more Fc receptors. In some embodiments, an Fc domain or region can exhibit reduced binding affinity to one or more Fcgamma receptors. In some embodiments, an Fc domain or region can exhibit reduced binding affinity to FcRn receptors. In some embodiments, an Fc domain or region can exhibit reduced binding affinity to Fcgamma and FcRn receptors. In some embodiments, an Fc domain is an Fc null domain or region. As used herein, an "Fc null" refers to a domain that exhibits weak to no binding to any of the Fcgamma receptors. In some embodiments, an Fc null domain or region exhibits a reduction in binding affinity (e.g., increase in Kd) to Fc gamma receptors of at least 1000-fold.

[0487] The Fc domain may have one or more, two or more, three or more, or four or more amino acid substitutions that decrease binding of the Fc domain to an Fc receptor. In certain

embodiments, an Fc domain exhibits decreased binding to FcyRI (CD64), FcyRIIA (CD32), FcyRIIIA (CD 16a), FcyRIIIB (CD 16b), or any combination thereof. In order to decrease binding affinity of an Fc domain or region to an Fc receptor, the Fc domain or region may comprise one or more substitutions that has the effect of reducing the affinity of the Fc domain or region to an Fc receptor. In certain embodiments, the one or more substitutions comprise any one or more of IgGl heavy chain mutations corresponding to E233P, L234V, L234A, L235A, L235E, AG236, G237A, E318A, K320A, K322A, A327G, A330S, or P331S according to the EU index of Kabat numbering.

[0488] In some embodiments, the Fc domain or region can comprise a sequence of the IgGl isoform that has been modified from the wild-type IgGl sequence. A modification can comprise a substitution at more than one amino acid residue, such as at 5 different amino acid residues including L235V/F243L/R292P/Y300L/P396L (IgGlVLPLL) according to the EU index of

Kabat numbering. A modification can comprise a substitution at more than one amino acid residue such as at 2 different amino acid residues including S239D/I332E (IgGlDE) according to the EU index of Kabat numbering. A modification can comprise a substitution at more than one amino acid residue such as at 3 different amino acid residues including S298A/E333A/K334A

(IgGl AAA) according to the EU index of Kabat numbering. [0489] In some embodiments, the Fc domain or region can comprise a sequence of an IgG isoform that has been modified from the wild-type IgG sequence. In some embodiments, the Fc domain or region can comprise a sequence of the IgGl isoform that has been modified from the wild-type IgGl sequence. In some embodiments, the modification comprises substitution of one or more amino acids that reduce binding affinity of an IgG Fc domain or region to all Fey receptors. A modification can be substitution of E233, L234, and L235, such as

E233P/L234V/L235A or E233P/L234V/L235A/AG236, according to the EU index of Kabat. A modification can be substitution of L235, F243, R292, Y300 and P396, such as

L235V/F243L/R292P/Y300L/P396L (IgGlVLPLL) according to the EU index of Kabat. A modification can be a substitution of P238, such as P238A, according to the EU index of Kabat. A modification can be a substitution of D265, such as D265A, according to the EU index of Kabat. A modification can be a substitution of N297, such as N297A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A327Q, according to the EU index of Kabat. A modification can be a substitution of P329, such as P239A, according to the EU index of Kabat.

[0490] In some embodiments, an IgG Fc domain or region comprises at least one amino acid substitution that reduces its binding affinity to FcyRl, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at F241, such as F241A, according to the EU index of Kabat. A modification can comprise a substitution at F243, such as F243A, according to the EU index of Kabat. A modification can comprise a substitution at V264, such as V264A, according to the EU index of Kabat. A modification can comprise a substitution at D265, such as D265A according to the EU index of Kabat.

[0491] In some embodiments, an IgG Fc domain or region comprises at least one amino acid substitution that increases its binding affinity to FcyRl, as compared to a wild-type or reference IgG Fc domain. A modification can comprise a substitution at A327 and P329, such as

A327Q/P329A, according to the EU index of Kabat.

[0492] In some embodiments, the modification comprises substitution of one or more amino acids that reduce binding affinity of an IgG Fc domain or region to FcyRII and FcyRIIIA receptors. A modification can be a substitution of D270, such as D270A, according to the EU index of Kabat. A modification can be a substitution of Q295, such as Q295A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A237S, according to the EU index of Kabat.

[0493] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRII and FcyRIIIA receptors. A modification can be a substitution of T256, such as T256A, according to the EU index of Kabat. A modification can be a substitution of K290, such as K290A, according to the EU index of Kabat.

[0494] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRII receptor. A modification can be a substitution of R255, such as R255A, according to the EU index of Kabat. A modification can be a substitution of E258, such as E258A, according to the EU index of Kabat. A modification can be a substitution of S267, such as S267A, according to the EU index of Kabat. A modification can be a substitution of E272, such as E272A, according to the EU index of Kabat. A modification can be a substitution of N276, such as N276A, according to the EU index of Kabat. A modification can be a substitution of D280, such as D280A, according to the EU index of Kabat. A modification can be a substitution of H285, such as H285A, according to the EU index of Kabat. A modification can be a substitution of N286, such as N286A, according to the EU index of Kabat. A modification can be a substitution of T307, such as T307A, according to the EU index of Kabat. A modification can be a substitution of L309, such as L309A, according to the EU index of Kabat. A modification can be a substitution of N315, such as N315A, according to the EU index of Kabat. A modification can be a substitution of K326, such as K326A, according to the EU index of Kabat. A modification can be a substitution of P331, such as P331A, according to the EU index of Kabat. A modification can be a substitution of S337, such as S337A, according to the EU index of Kabat. A modification can be a substitution of A378, such as A378A, according to the EU index of Kabat. A modification can be a substitution of E430, such as E430, according to the EU index of Kabat.

[0495] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRII receptor and reduces the binding affinity to FcyRIIIA receptor. A modification can be a substitution of H268, such as H268A, according to the EU index of Kabat. A modification can be a substitution of R301, such as R301A, according to the EU index of Kabat. A modification can be a substitution of K322, such as K322A, according to the EU index of Kabat.

[0496] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain or region to FcyRII receptor but does not affect the binding affinity to FcyRIIIA receptor. A modification can be a substitution of R292, such as R292A, according to the EU index of Kabat. A modification can be a substitution of K414, such as K414A, according to the EU index of Kabat.

[0497] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain or region to FcyRII receptor and increases the binding affinity to FcyRIIIA receptor. A modification can be a substitution of S298, such as S298A, according to the EU index of Kabat. A modification can be substitution of S239, 1332 and A330, such as S239D/I332E/A330L. A modification can be substitution of S239 and 1332, such as S239D/I332E.

[0498] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc domain or region to FcyRIIIA receptor and does not affect the binding affinity to FcyRII receptor. A modification can be a substitution of S239, such as S239A, according to the EU index of Kabat. A modification can be a substitution of E269, such as E269A, according to the EU index of Kabat. A modification can be a substitution of E293, such as E293A, according to the EU index of Kabat. A modification can be a substitution of Y296, such as Y296F, according to the EU index of Kabat. A modification can be a substitution of V303, such as V303A, according to the EU index of Kabat. A modification can be a substitution of A327, such as A327G, according to the EU index of Kabat. A

modification can be a substitution of K338, such as K338A, according to the EU index of Kabat. A modification can be a substitution of D376, such as D376A, according to the EU index of Kabat.

[0499] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc domain or region to FcyRIIIA receptor and does not affect the binding affinity to FcyRII receptor. A modification can be a substitution of E333, such as E333A, according to the EU index of Kabat. A modification can be a substitution of K334, such as K334A, according to the EU index of Kabat. A modification can be a substitution of A339, such as A339T, according to the EU index of Kabat. A modification can be substitution of S239 and 1332, such as S239D/I332E.

[0500] In some embodiments, an IgG Fc domain or region comprises at least one amino acid substitution that reduces the binding affinity to FcRn, as compared to a wild-type or reference

IgG Fc domain. A modification can comprise a substitution at H435, such as H435A according to the EU index of Kabat. A modification can comprise a substitution at 1253, such as 1253 A according to the EU index of Kabat. A modification can comprise a substitution at H310, such as

H310A according to the EU index of Kabat. A modification can comprise substitutions at 1253,

H310 and H435, such as I253A/H310A/H435A according to the EU index of Kabat.

[0501] A modification can comprise a substitution of one amino acid residue that increases the binding affinity of an IgG Fc domain for FcRn, relative to a wildtype or reference IgG Fc domain. A modification can comprise a substitution at V308, such as V308P according to the

EU index of Kabat. A modification can comprise a substitution at M428, such as M428L according to the EU index of Kabat. A modification can comprise a substitution at N434, such as

N434A according to the EU index of Kabat or N434H according to the EU index of Kabat. A modification can comprise substitutions at T250 and M428, such as T250Q and M428L according to the EU index of Kabat. A modification can comprise substitutions at M428 and N434, such as M428L and N434S, N434A or N434H according to the EU index of Kabat. A modification can comprise substitutions at M252, S254 and T256, such as M252Y/S254T/T256E according to the EU index of Kabat. A modification can be a substitution of one or more amino acids selected from P257L, P257N, P257I, V279E, V279Q, V279Y, A281S, E283F, V284E, L306Y, T307V, V308F, Q311V, D376V, and N434H. Other substitutions in an IgG Fc domain that affect its interaction with FcRn are disclosed in U.S. Patent No. 9,803,023 (the disclosure of which is incorporated by reference herein).

[0502] The antibody construct of a conjugate can be an anti-tumor antigen construct. The antibody construct can be an anti-tumor antigen antibody. An antigen recognized by the antibody construct can be CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin Bl, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYPIBI, PLAVl, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16),

CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD- Ll, VTCN1 (B7-H4), VISTA, or any fragment thereof.

[0503] The antibody construct can recognize an antigen that can be expressed on a cell. The antibody construct can recognize an antigen that can be expressed by a cell. The antibody construct can recognize an antigen that can be expressed in the context of a Major

Histocompatibility Complex. The antibody construct can recognize an antigen that can stimulate activity of a cell, such as an immune cell. The antibody construct can recognize an antigen that can stimulate an immune response. The antibody construct can recognize an antigen that can reduce an immune response. The antibody construct can recognize an antigen that can reduce activity of a cell. The antibody construct can recognize an antigen that can be expressed on an immune cell. The antibody construct can recognize an antigen that can be expressed by an immune cell. The antibody construct can recognize an antigen that can be in the context of a Major Histocompatibility Complex. The antibody construct can recognize an antigen on a cell wherein the antigen can be involved in stimulating activity of a cell. The antibody construct can recognize an antigen on an immune cell that can be involved in the costimulation of an immune cell. The antibody construct can recognize an antigen on an immune cell that can be involved in the costimulation of an immune cell during an immune response. The antibody construct can recognize a receptor. The antibody construct can recognize a receptor on a cell. The antibody construct can recognize a receptor ligand. The antibody construct can recognize a receptor on a cell wherein the receptor can be involved in stimulating activity of a cell. The antibody construct can recognize a receptor on an immune cell. The antibody construct can recognize a receptor on an immune cell that can be involved in stimulating activity of an immune cell. The antibody construct can recognize a receptor on an immune cell that can be involved in the costimulation of an immune cell. The antibody construct can recognize a receptor on an immune cell that can be involved in the costimulation of an immune cell during an immune response. The antibody construct can recognize an antigen that can be expressed on an immune cell and that can stimulate activity of an immune cell. The antibody construct can recognize an antigen that can be expressed on an immune that can reduce activity of an immune cell.

[0504] The antibody construct can be an antibody that specifically binds to CEA, HER2, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, or gpNMB.

[0505] The antibody construct can be capable of recognizing a single antigen. The antibody construct can be capable of recognizing two or more antigens. The antibody construct can be capable of recognizing three or more antigens. The IQ for binding of a second binding domain of an immune- stimulatory conjugate to an antigen in the presence of an immune- stimulatory compound can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times greater than the IQ for binding of the second binding domain to the antigen of an antibody construct in the absence of the immune- stimulatory compound. The K _d for binding of a second binding domain of an immune- stimulatory conjugate to an antigen in the presence of the immune- stimulatory compound can be less than 10 nM. The K _d for binding of a second binding domain of an immune- stimulatory conjugate to an antigen in the presence of the immune- stimulatory compound can be less than 100 nM, less than 50 nM, less than 20 nM, less than 5 nM, less than 1 nM, or less than 0.1 nM. In contrast, the K _d for binding of a second binding domain of an immune- stimulatory conjugate to an antigen in the presence of the immune- stimulatory compound when the first binding domain is bound to the first binding domain's antigen can be greater than 100 nM. The K _d for binding of a second binding domain of an immune- stimulatory conjugate to an antigen in the presence of the immune- stimulatory compound when the first binding domain is bound to the first binding domain's antigen can be greater than 100 nM, greater than 200 nM, greater than 300 nM, greater than 400 nM, greater than 500 nM, or greater than 1000 nM. The K _d for binding of a first binding domain of an immune- stimulatory conjugate to an antigen in the presence of an immune- stimulatory compound can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times greater than the K _d for binding of the first binding domain to the antigen of an antibody construct in the absence of the immune- stimulatory compound. The K _d for binding of a first binding domain of an immune- stimulatory conjugate to an antigen in the presence of the immune- stimulatory compound can be less than 10 nM. The K _d for binding of a first binding domain of an immune- stimulatory conjugate to an antigen in the presence of the immune- stimulatory compound can be less than 100 nM, less than 50 nM, less than 20 nM, less than 5 nM, less than 1 nM, or less than 0.1 nM.

[0506] In some embodiments, an engineered cysteine is introduced in an antibody construct so that a linker can be attached at such engineered cysteine. For example an engineered cysteine can be introduced into an IgG (typically an IgGl) at Tl 14 (heavy chain), A 140 (heavy chain), L174 (heavy chain), L179 (heavy chain), T187 (heavy chain), T209 (heavy chain), S239 (heavy chain), V262 (heavy chain), G371 (heavy chain), Y373 (heavy chain), E382 (heavy chain), S400 (heavy chain), S424 (heavy chain), N434 (heavy chain), Q438 (heavy chain), 1106 (light chain), R108 (light chain), A118 (heavy chain), R142 (light chain), K149 (light chain) and/or V205 (light chain), according to the EU numbering of Kabat.

[0507] In certain embodiments, a linker or linker bound to an immune-modulatory compound disclosed herein may not be attached to an amino acid residue of an IgG Fc domain disclosed herein selected from: 221, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240,

241, 243, 244, 245, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 275, 276, 278, 280, 281, 283, 285, 286, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 318, 323, 324, 325, 327, 328, 329, 330, 331, 332, 333, 335, 336, 396, or 428, wherein numbering of amino acid residues in the Fc domain is according to the EU index as in Kabat.

[0508] In certain embodiments, a linker or linker bound to an immune-modulatory compound disclosed herein may be attached to an amino acid residue of an IgG Fc domain disclosed herein selected from: 221, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 275, 276, 278, 280, 281, 283, 285, 286, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 318, 323, 324, 325, 327, 328, 329, 330, 331, 332, 333, 335, 336, 396, or 428, wherein numbering of amino acid residues in the Fc domain is according to the EU index as in Kabat.

[0509] The conjugates can have an Fc domain that can bind to an FcR when linked to an immune- stimulatory compound. The conjugate can have an Fc domain that can bind to an FcR to initiate FcR-mediated signaling when linked to an immune stimulatory compound. The conjugate can bind to its antigen when linked to an immune- stimulatory compound. The conjugate can bind to its antigen when linked to an immune- stimulatory compound and the Fc domain of the conjugate can bind to an FcR when linked to an immune- stimulatory compound. The conjugate can bind to its antigen when linked to an immune- stimulatory compound and the Fc domain of the antibody construct can bind to an FcR to initiate FcR-mediated signaling when linked to an immune stimulatory compound. The Fc domain linked to an immune- stimulatory compound can be a modified Fc domain as described above.

[0510] The K _d for binding of an Fc domain to a Fc receptor when the Fc domain is linked to an immune- stimulatory compound can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about

20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about

50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about

110 times, or about 120 times greater than the K _d for binding of the Fc domain to the Fc receptor in the absence of linking to the immune- stimulatory compound. The K _d for binding of an Fc domain to an Fc receptor when linked to an immune- stimulatory compound can be less than 10 nM. The K _d for binding of an Fc domain to an Fc receptor when linked to an immune- stimulatory compound can be less than 100 nM, less than 50 nM, less than 20 nM, less than 5 nM, less than 1 nM, or less than 0.1 nM. In contrast, the K _d for binding of an Fc domain to an Fc receptor when linked to an immune- stimulatory compound and when the first binding domain is bound to its antigen can be greater than 100 nM. The K _d for binding of an Fc domain to an Fc receptor when linked to an immune- stimulatory compound and when the first binding domain is bound to its antigen can be greater than 100 nM, greater than 200 nM, greater than 300 nM, greater than 400 nM, greater than 500 nM, or greater than 1000 nM.

[0511] The binding domain can be selected in order to recognize an antigen. For example, an antigen can be expressed on an immune cell. An antigen can be a peptide or fragment thereof. An antigen can be expressed on an antigen-presenting cell. An antigen can be expressed on a dendritic cell, a macrophage, or a B cell. An antigen can be CD40 and a binding domain can recognize a CD40 antigen. A binding domain can be a CD40 agonist. A binding domain can be CD40.

[0512] A conjugate can be formed by a linker that can connect an antibody construct to a molecule that binds a PRR. A conjugate can be formed by a linker that can connect an antibody construct to a PAMP molecule. A conjugate can be formed by a linker that can connect an antibody construct and a DAMP molecule. A conjugate can be formed by a linker that can connect an antibody construct to a molecule that binds a PRR, and a linker that can connect an antibody construct and a binding domain. A conjugate can be formed by a linker that can connect an antibody construct to a PAMP molecule, and a linker that can connect an antibody construct and a binding domain. A conjugate can be formed by a linker that can connect an antibody construct and a DAMP molecule, and a linker that can connect an antibody construct and a binding domain.

[0513] A conjugate can be formed by a linker that can attach an antibody construct to a kinase inhibitor, an antibody construct attached to a GPCR antagonist, an antibody construct attached to an ion channel antagonist, an antibody construct attached to a membrane transport inhibitor, an antibody construct to a phosphatase inhibitor, or an antibody construct attached to a kinase inhibitor.

[0514] A linker can be connected to an antibody construct by a direct linkage between the antibody construct and the linker. A linker can be connected to an anti-tumor antigen antibody construct by a direct linkage between the anti-tumor antigen antibody construct and the linker. A linker can be connected to an anti-tumor antigen antibody by a direct linkage between the antitumor antigen antibody and the linker. A direct linkage is a covalent bond. For example, a linker can be attached to a terminus of an amino acid sequence of an antibody construct, or could be attached to a side chain modification of the antibody construct, such as the side chain of a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, a non-natural amino acid residue, glutamine, or glutamic acid residue. An attachment can be via any of a number of bonds, for example but not limited to, an amide bond, an ester bond, an ether bond, a carbon-nitrogen bond, a carbon- carbon single double or triple bond, a disulfide bond, or a thioether bond. A linker can have at least one functional group, which can be linked to the antibody construct. Non- limiting examples of the functional groups can include those which form an amide bond, an ester bond, an ether bond, a carbonate bond, a carbamate bond, or a thioether bond; such functional groups can be, for example, amino groups; carboxyl groups; aldehyde groups; azide groups; alkyne and alkene groups; ketones; carbonates; carbonyl functionalities bonded to leaving groups such as cyano and succinimidyl and hydroxyl groups. A linker can be attached to an antibody construct at an interchain disulfide. A linker can be connected to an antibody construct at a hinge cysteine. A linker can be connected to an antibody construct at an engineered cysteine. A linker can be connected to an antibody construct at a light chain constant domain lysine. A linker can be connected to an antibody construct at an engineered cysteine in the light chain. A linker can be connected to an antibody construct at an engineered light chain glutamine. A linker can be connected to an antibody construct at an unnatural amino acid engineered into the light chain. A linker can be connected to an antibody construct at a heavy chain constant domain lysine. A linker can be connected to an antibody construct at an engineered cysteine in the heavy chain. A linker can be connected to an antibody construct at an engineered heavy chain glutamine. A linker can be connected to an antibody construct at an unnatural amino acid engineered into the heavy chain. Amino acids can be engineered into an amino acid sequence of an antibody construct as described herein. Engineered amino acids can be added to a sequence of existing amino acids. Engineered amino acids can be substituted for one or more existing amino acids of a sequence of amino acids. A linker can be conjugated to an antibody construt via a sulfhydryl group. A linker can be conjugated to an antibody construct via a primary amine. A linker can be a link created between an unnatural amino acid on an antibody construct by reacting with oxime bond that was formed by modifying a ketone group with an alkoxyamine on an immune- stimulatory compound. When a linker is connected to an antibody construct at the sites described herein, an Fc domain of the construct can bind to Fc receptors. When a linker is connected to an antibody construct at the sites described herein, the antigen binding domain of the construct can bind its antigen. When a linker is connected to an antibody construct at the sites described herein, a binding domain of the construct can bind its antigen.

[0515] An antibody with engineered reactive cysteine residues (THIOMAB) can be used to link a binding domain to an antibody or to an antibody construct. A linker can connect an antibody construct to a binding domain via Sortase A linker. A Sortase A linker can be created by a Sortase A enzyme fusing an LPXTG recognition motif (SEQ ID NO: 672) to an N-terminal GGG motif to regenerate a native amide bond. The linker created can therefore link an antibody construct attached to the LPXTG recognition motif (SEQ ID NO: 672) with a binding domain attached to the N-terminal GGG motif. A binding domain can be connected to a linker by a direct linkage. A direct linkage can be a covalent bond. For example, a linker can be attached to a terminus of an amino acid sequence of a binding domain, or could be attached to a side chain modification to the binding domain, such as the side chain of a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, a non-natural amino acid residue, glutamine, or glutamic acid residue. An attachment can be via any of a number of bonds, for example but not limited to, an amide bond, an ester bond, an ether bond, a carbon-nitrogen bond, a carbon-carbon single double or triple bond, a disulfide bond, or a thioether bond. A linker can have at least one functional group, which can be linked to the binding domain. Non- limiting examples of the functional groups can include those which form an amide bond, an ester bond, an ether bond, a carbonate bond, a carbamate bond, or a thioether bond; such functional groups can be, for example, amino groups; carboxyl groups; aldehyde groups; azide groups; alkyne and alkene groups; ketones; carbonates; and carbonyl functionalities bonded to leaving groups such as cyano and succinimidyl and hydroxyl groups. Amino acids can be engineered into an amino acid sequence of the binding domain. Engineered amino acids can be added to a sequence of existing amino acids. Engineered amino acids can be substituted for one or more existing amino acids of a sequence of amino acids. A linker can be conjugated to a binding domain via a sulfhydryl group. A linker can be conjugated to a binding domain via a primary amine. A binding domain can be conjugated to the C-terminal of an Fc domain of an antibody construct.

[0516] An antibody with engineered reactive cysteine residues (THIOMAB) can be used to link an immune- stimulatory compound to an antibody or antibody construct. A linker can connect an antibody construct to an immune- stimulatory compound via an mc-vc-PABC linker. A linker can connect an antibody construct to an immune- stimulatory compound via Sortase A linker. A

Sortase A linker can be created by a Sortase A enzyme fusing an LPXTG recognition motif (SEQ

ID NO: 672) to an N-terminal GGG motif to regenerate a native amide bond. The linker created can therefore link an antibody construct attached the LPXTG recognition motif (SEQ ID NO:

672) with an immune- stimulatory compound attached to the N-terminal GGG motif. A linker can be a link created between an unnatural amino acid on a construct by reacting with oxime bond that was formed by modifying a ketone group with an alkoxyamine on an immune- stimulatory compound. The immune- stimulatory compound can comprise one or more rings selected from carbocyclic and heterocyclic rings. The immune- stimulatory compound can be covalently bound to a linker by a bond to an exocyclic carbon or nitrogen atom on the immune- stimulatory compound. A linker can be attached to an immune- stimulatory compound via an exocyclic nitrogen or carbon atom of an immune- stimulatory compound. The K _d for binding of a binding domain of any of these conjugates to its antigen can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times greater than the K _d for binding of the binding domain to its antigen in the absence of the immune- stimulatory compound. The K _d for binding of the binding domain of any of these conjugates to its antigen can be less than 10 nM. The K _d for binding of the binding domain of any of the conjugates to its antigen can be less than 100 nM, less than 50 nM, less than 20 nM, less than 5 nM, less than 1 nM, or less than 0.1 nM. The K _d for binding of the Fc domain of any of the conjugates to an Fc receptor can be about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, or about 120 times greater than the K _d for binding of the Fc domain to the Fc receptor in the absence of the immune- stimulatory compound. The K _d for binding of the Fc domain of any of the conjugates to an Fc receptor can be less than 10 nM. The K _d for binding of the Fc domain of any of the conjugates to an Fc receptor can be less than 100 nM, less than 50 nM, less than 20 nM, less than 5 nM, less than 1 nM, or less than 0.1 nM.

[0517] In some embodiments, in a conjugate, an antibody can be linked to an immune- stimulatory compound in such a way that the antibody construct, such as an antibody, can still bind to an antigen and the Fc domain of the antibody construct, can still bind to an FcR. In a conjugate, an antibody construct is linked to an immune- stimulatory compound in such a way that the linking does not interfere with ability of the antigen binding domain of the antibody construct to bind to antigen, the ability of the Fc domain of the antibody construct to bind to an FcR, or FcR-mediated signaling resulting from the Fc domain of the antibody construct from binding to an FcR. In a conjugate, an immune- stimulatory compound can be linked to an antibody construct in such a way the linking does not interfere with the ability of the immune- stimulatory compound to bind to its receptor. A conjugate can produce stronger immune stimulation and a greater therapeutic window than components of the conjugate alone.

Pharmaceutical Formulations

[0518] The conjugates and methods described herein can be useful as pharmaceutical compositions for administration to a subject in need thereof. Pharmaceutical compositions can comprise at least the conjugates described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition can comprise a conjugate having an antibody construct and an immune stimulatory compound, scuh as an agonist. A pharmaceutical composition can comprise a conjugate having an antibody construct having a binding domain, and an immune- stimulatory compound. A pharmaceutical composition can comprise any conjugate described herein. In some embodiments, a pharmaceutical composition can comprise an antibody to a tumor antigen and an immune stimulatory compound selected from a toll- like receptor agonist, a STING agonist, RIG-I agonist, PAMP agonist, DAMP agonist and a kinase inhibitor. In some embodiments, a pharmaceutical composition can comprise an antibody to a tumor antigen and an immune stimulatory compound selected from a tankyrase inhibitor and a TNIK inhibitor.

[0519] In some embodiments, the antibody construct is an anti-HER2 antibody, an anti-TROP2 antibody, an anti-CEA antibody, an anti-claudin-6 (CLDN6) antibody, an anti-Claudin-16 (CLD 16) antibody, an anti-CLD 18.2 antibody, an anti-RON antibody, an anti-LY6E antibody, an anti-FRA antibody, an anti-DLL3 antibody, an anti-TK7 antibody, an anti- Uroplakin-IB (UPK1B) antibody, an anti-LIVl antibody, an anti-RORl antibody, an anti- STRA6 antibody, an anti-TMPRSS3 antibody, an anti-TMPRSS4 antibody, an anti-TMEM238 antibody, an anti-Cl or fl86 antibody, an anti-Fos-related antigen 1 antibody, an anti-VEGFRl antibody, an anti-endoglin antibody, an anti-VTCNl (B7-H4) antibody, an anti- VISTA antibody or an anti-gpNMB antibody. A conjugate can comprise an antibody and a PAMP molecule. A conjugate can comprise an antibody and a DAMP molecule. A pharmaceutical composition can further comprise buffers, antibiotics, steroids, carbohydrates, drugs (e.g., chemotherapy drugs), radiation, polypeptides, chelators, adjuvants, and/or preservatives.

[0520] In some embodiments, a pharmaceutical composition comprises an immune-modulatory conjugate comprising an antibody construct, a proteolysis targeting module and a linker covalently linking the antibody construct and the proteolysis targeting module. The antibody construct can comprise an antibody to a tumor antigen or an immune cell antigen.

[0521] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a conjugate as described herein can be manufactured, for example, by lyophilizing the conjugate, mixing, dissolving, emulsifying, encapsulating, or entrapping the conjugate. The pharmaceutical compositions can also include the conjugates described herein in a free-base form or

pharmaceutically-acceptable salt form.

[0522] Methods for formulation of the conjugates described herein can include formulating any of the conjugates described herein with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, H buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the pharmaceutical compositions described herein can be lyophilized or in powder form for re- constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0523] Pharmaceutical compositions of the conjugates described herein can comprise at least an active ingredient (i.e., a conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0524] Pharmaceutical compositions as described herein often further can comprise more than one active compound as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. For example, the composition can comprise a conjugate and a checkpoint inhibitor, chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant. Such molecules can be present in combination in amounts that are effective for the purpose intended.

[0525] The compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0526] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the compositions described herein can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0527] For parenteral administration the conjugates can be formulated in a unit dosage injectable form (e.g., a solution, suspension or emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and no n- therapeutic. A vehicle can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.

Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives). [0528] Sustained-release preparations can also be prepared. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the antibody, and these matrices can be in the form of shaped articles (e.g., films or

microcapsules). Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L- glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene- vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-( - )-3- hydroxybutyric acid.

[0529] Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing a conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and/or stabilizers can be nontoxic to recipients at the dosages and

concentrations used. Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non- ionic surfactants or polyethylene glycol.

Therapeutic Applications

[0530] The pharmaceutical compositions, conjugates and methods of the present disclosure can be useful for a plurality of different subjects including, but are not limited to, a mammal, human, non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), non-domesticated animal (e.g., wildlife), dog, cat, rodent, mouse, hamster, cow, bird, chicken, fish, pig, horse, goat, sheep, rabbit, and any combination thereof.

[0531] The compositions, conjugates and methods described herein can be useful as a

therapeutic, for example a treatment that can be administered to a subject in need thereof. A therapeutic effect of the present disclosure can be obtained in a subject by reduction, suppression, remission, or eradication of a disease state, including, but not limited to, a symptom thereof. A therapeutic effect in a subject having a disease or condition, or pre-disposed to have or is beginning to have the disease or condition, can be obtained by a reduction, a suppression, a prevention, a remission, or an eradication of the condition or disease, or pre-condition or pre- disease state. [0532] In practicing the methods described herein, therapeutically-effective amounts of the compositions or conjugates described herein can be administered to a subject in need thereof, often for treating and/or preventing a condition or progression thereof. A pharmaceutical composition can affect the physiology of the subject, such as the immune system, inflammatory response, or other physiologic affect. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.

[0533] Treat and/or treating can refer to any indicia of success in the treatment or amelioration of the disease or condition. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treat can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0534] Prevent, preventing and the like can refer to the prevention of the disease or condition, e.g. , tumor formation, in the patient. For example, if an individual at risk of developing a tumor or other form of cancer is treated with the methods of the present disclosure and does not later develop the tumor or other form of cancer, then the disease has been prevented, at least over a period of time, in that individual. Prevent can also refer to preventing relapse in a patient.

[0535] A therapeutically effective amount can be the amount of a composition or an active component (i.e., a conjugate) thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment, and can be ascertainable by one skilled in the art using known techniques.

[0536] The conjugates described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the composition, the method of administration and other factors known to practitioners. The conjugates described herein can be prepared according to the description of preparation described herein.

[0537] Pharmaceutical compositions of the conjugates can be considerd useful with the methods described herein and can be administered to a subject in need thereof using a technique known to one of ordinary skill in the art which can be suitable as a therapy for the disease or condition affecting the subject. One of ordinary skill in the art would understand that the amount, duration and frequency of administration of a pharmaceutical composition described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been

administered, and the like.

[0538] The methods and compositions described herein can be for administration to a subject in need thereof. Often, administration of the compositions described herein can include routes of administration, non- limiting examples of administration routes include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or

intraperitoneally. Additionally, a pharmaceutical composition can be administered to a subject by additional routes of administration, for example, by inhalation, oral, dermal, intranasal, or intrathecal administration.

[0539] Compositions of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations. The one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof every 21 days, every 14 days, every 10 days, every 7 days, every 4 days or every day after the first administration over the course of a cycle. The additional administrations can also be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days, or less than 1 day after the first administration. The one or more administrations can occur more than once per day, more than once per week or more than once per month. Cycles of administration of a

pharmaceutical composition can be weekly, biweekly, every three weeks, monthly, every six weeks, every two months, or the like.

[0540] Suitable doses of an immune- stimulatory conjugate with a DAR of 1-8 can be from about 0.05 mg/kg to about 20 mg/kg or about 0.5 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 10 mg/kg. Doses of conjugates with greater DARs can be scaled accordingly.

Increased dosages and reduced side-effects

[0541] In certain embodiments, the conjugates can comprise two binding domains, one of which binds to a tumor antigen and another of which binds to a target on an immune cell such as an antigen presenting cell and can be administered in a dosage that is about 10%, about 25%, about 50%, about 100% or greater than an antibody from which one of the tumor antigen binding domains or binding domains that bind to an antigen on an immune cell, such as an antigen presenting cell (APC), is derived. For example, a common regimen for administering pertuzumab comprises 840 mg intravenous (IV) administered as an initial dose over 60 minutes, followed every 3 weeks thereafter by 420 mg IV over 30 to 60 minutes. An initial dosage of a conjugate having a binding domain of pertuzumab and a second binding domain binding to an immune cell antigen can range from 900 mg to 1700 mg or more and a maintenance dose can range from 450 mg to 900 mg or more. An increased initial dose and/or maintenance dose can be used with an immune stimulatory conjugate or pharmaceutical composition of this disclosure, such as bispecific tumor targeting compositions comprising a tumor antigen binding domain that binds a tumor antigen with at least 80% or 100% sequence identity to CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1,

MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin Bl, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GMl, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, , TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD-L1, VTCN1 (B7-H4), VISTA, or any fragment thereof. Antibodies that bind costimulatory molecules or other cell surface molecules on APCs can have small therapeutic windows and high dose-limiting toxicity. For example, CP-870,893 can be shown to have a maximum tolerated dosage of 0.2 mg/kg to 0.3 mg/kg. Using a bispecific immune- stimulatory conjugate of this disclosure can allow administration of a conjugate at greater than 0.2 mg/kg to 0.3 mg/kg that comprises a binding domain derived from CP-870,893 or any binding domain that binds to an antigen on an APC with at least 80% or 100% sequence identity to CD40, CD47, TNFR2, DEC-205, PD-L1, CD36 mannose scavenger receptor 1, DC-SIGN, CLEC9A,

CLEC12A, BDCA-2, OX40L, 41BBL, CD204, MARCO, CLEC5A, Dectin 1, Dectin 2,

CLECIOA, CD206, CD64, CD32A, CD 16 A, HVEM, CD38, CD32B, or a fragment thereof. [0542] In certain embodiments, using an immune- stimulatory conjugate of this disclosure can allow administration of a conjugate that comprises a binding domain that binds to an antigen on an antigen presenting cell at greater levels than an antibody alone comprising a binding domain that binds to that molecule on an antigen presenting cell. In certain embodiments, a bispecific immune- stimulatory conjugate that comprises a binding domain that binds to an antigen on an antigen presenting cell can be administered at levels equivalent to that of an antibody from which the binding domain is derived.

[0543] In certain embodiments, the immune- stimulatory conjugate can be administered at a dose higher than the maximum tolerated dose for that immune- stimulatory compound administered in the absence of attachment to an antibody construct.

[0544] In certain embodiments, administration of an immune stimulatory conjugate can be associated with fewer side effects than an antibody from which one of binding domains is derived. In certain embodiments, administration of the immune stimulatory conjugate can be associated with fewer side effects than when the immune- stimulatory compound is administered alone. In certain embodiments, administration of immune- stimulatory conjugate with a chemotherapeutic agent can be associated with fewer side effects than when the

chemotherapeutic agent is administered with the immune- stimulatory compound. In certain embodiments, the chemotherapeutic agent can be an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaloplatin, or carboplatin), or a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel). In some embodiments, the chemotherapeutic agent can be a nucleoside analog. In some embodiments, the chemotherapeutic agent can be gemcitabine. In certain embodiments, the additional therapeutic agent can be radiation therapy.

Diseases, Conditions and the Like

[0545] The pharmaceutical compositions, conjugates and methods provided herein can be useful for the treatment of a plurality of diseases, conditions, preventing a disease or a condition in a subject, preventing relapse of a disease or condition or other therapeutic applications for subjects in need thereof. Often the compositions, conjugates and methods provided herein can be useful for treatment of hyperplastic conditions, including but not limited to, neoplasms, cancers, tumors and the like.

[0546] A condition, such as a cancer, can be associated with expression of an antigen on the cancer cells. Often, the molecule expressed by the cancer cells can comprise an extracellular portion capable of recognition by a binding domain (e.g., an antibody or antigen-binding portion thereof) of the conjugate. An antigen expressed by the cancer cells can be a tumor antigen. A binding domain of the conjugate can recognize a tumor antigen. A tumor antigen can include for example, CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-Ll, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin Bl, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYPIBI, PLAVl, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, , TRAILl, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD-Ll, VTCN1 (B7-H4), VISTA, gpNMB, or any fragment thereof.

[0547] As described herein, an antigen binding domain portion of the conjugate can be configured to recognize an antigen expressed by a cancer cell, such as for example, a disease antigen, tumor antigen or a cancer antigen. Such antigens are known to those of ordinary skill in the art, or can be newly found to be associated with such a disease or condition, to be commonly associated with, and/or, specific to, such disease or condition. For example, a disease antigen, tumor antigen or a cancer antigen is, but is not limited to, CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-Ll, B7-H3, B7-DC (PD-L2), HLD-DR, carcinoembryonic antigen (CEA), TAG-72, EpCAM, MUC1, MUC15, MUC16, fo late-binding protein, A33, G250, pro state- specific membrane antigen (PSMA), ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, EGFRvIII (de2-7 EGFR), fibroblast activation protein (FAP), tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, Her-2/neu, p53 nonmutant, NY-ESO-1,

MelanA/MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, a Sarcoma translocation breakpoint protein, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin Bl, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GMl, mesothelin (MSLN), PSCA, MAGE Al, MAGE A3, sLe(animal), CYP1B1, PLAV1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, Legumain, Tie 3, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, , TRAIL 1, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, EPCAM, CA6, NAPI2B, TROP2, Claudin-6 (CLDN6), Claudin-16 (CLDN16), CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, Uroplakin-IB (UPK1B), LIV1, ROR1, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, PD-L1, VTCN1 (B7-H4), VISTA, or any fragment thereof.

[0548] Additionally, such tumor antigens can be associated with the following specific conditions and/or families of diseases or conditions, including but not limited to, cancers such as brain cancers, skin cancers, lymphomas, sarcomas, lung cancer, liver cancer, leukemias, uterine cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, kidney cancer,

hemangio sarcomas, bone cancers, blood cancers, testicular cancer, prostate cancer, stomach cancer, intestinal cancers, pancreatic cancer, and other types of cancers as well as pre-cancerous conditions such as hyperplasia or the like.

[0549] Non- limiting examples of cancers can include Acute lymphoblastic leukemia (ALL);

Acute myeloid leukemia; Adrenocortical carcinoma; Astrocytoma, childhood cerebellar or cerebral; Basal-cell carcinoma; Bladder cancer; Bone tumor, osteo sarcoma/malignant fibrous histiocytoma; Brain cancer; Brain tumors, such as, cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma; Brainstem glioma;

Breast cancer; Bronchial adenomas/carcinoids; Burkitt's lymphoma; Cerebellar astrocytoma;

Cervical cancer; Cholangiocarcinoma; Chondrosarcoma; Chronic lymphocytic leukemia;

Chronic myelogenous leukemia; Chronic myeloproliferative disorders; Colon cancer; Cutaneous

T-cell lymphoma; Endometrial cancer; Ependymoma; Esophageal cancer; Eye cancers, such as, intraocular melanoma and retinoblastoma; Gallbladder cancer; Glioma; Hairy cell leukemia;

Head and neck cancer; Heart cancer; Hepatocellular (liver) cancer; Hodgkin lymphoma;

Hypopharyngeal cancer; Islet cell carcinoma (endocrine pancreas); Kaposi sarcoma; Kidney cancer (renal cell cancer); Laryngeal cancer; Leukaemia, such as, acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myelogenous and, hairy cell; Lip and oral cavity cancer; Liposarcoma; Lung cancer, such as, non-small cell and small cell; Lymphoma, such as, AIDS- related, Burkitt; Lymphoma, cutaneous T-Cell, Hodgkin and Non-Hodgkin, Macroglobulinemia, Malignant fibrous histiocytoma of bone/osteosarcoma; Melanoma; Merkel cell cancer;

Mesothelioma; Multiple myeloma/plasma cell neoplasm; Mycosis fungoides; Myelodysplastic syndromes; Myelodysplastic/myeloproliferative diseases; Myeloproliferative disorders, chronic; Nasal cavity and paranasal sinus cancer; Nasopharyngeal carcinoma; Neuroblastoma;

Oligodendroglioma; Oropharyngeal cancer; Osteosarcoma/malignant fibrous histiocytoma of bone; Ovarian cancer; Pancreatic cancer; Parathyroid cancer; Pharyngeal cancer;

Pheochromocytoma; Pituitary adenoma; Plasma cell neoplasia; Pleuropulmonary blastoma; Prostate cancer; Rectal cancer; Renal cell carcinoma (kidney cancer); Renal pelvis and ureter, transitional cell cancer; Rhabdomyosarcoma; Salivary gland cancer; Sarcoma, Ewing family of tumors; Sarcoma, Kaposi; Sarcoma, soft tissue; Sarcoma, uterine; Sezary syndrome; Skin cancer (non- melanoma); Skin carcinoma; Small intestine cancer; Soft tissue sarcoma; Squamous cell carcinoma; Squamous neck cancer with occult primary, metastatic; Stomach cancer; Testicular cancer; Throat cancer; Thymoma and thymic carcinoma; Thymoma,; Thyroid cancer; Thyroid cancer, childhood; Uterine cancer; Vaginal cancer; Waldenstrom macroglobulinemia; Wilms tumor; and any combination thereof.

[0550] The invention provides any therapeutic compound or conjugate disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy may be by any mechanism disclosed herein, such as by stimulation of the immune system. The invention provides any therapeutic compound or conjugate disclosed herein for use in stimulation of the immune system, vaccination or immunotherapy, including for example enhancing an immune response. The invention further provides any therapeutic compound or conjugate disclosed herein for prevention or treatment of any condition disclosed herein, for example cancer, autoimmune disease, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiency or infectious disease (typically caused by an infectious pathogen). The invention also provides any therapeutic compound or conjugate disclosed herein for obtaining any clinical outcome disclosed herein for any condition disclosed herein, such as reducing tumour cells in vivo. The invention also provides use of any therapeutic compound or conjugate disclosed herein in the manufacture of a medicament for preventing or treating any condition disclosed herein. Embodiments:

1. An immune- stimulatory conjugate comprising:

(a) an immune- stimulatory compound that optionally binds to a protein active site to stimulate an immune response;

(b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein said antigen binding domain binds to at least a first antigen and wherein said Fc domain binds to an Fc receptor; and

(c) a linker, wherein said linker is covalently bound to said antibody construct and said linker is covalently bound to said immune- stimulatory compound; and

wherein the dissociation constant (K _d ) for binding of said Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody to said Fc receptor, wherein the control antibody is the antibody construct; and wherein the K _d for binding of said immune- stimulatory compound of the conjugate to said protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to said protein active site or wherein the EC50 or IC50 of said immune- stimulatory compound of the conjugate is no greater than 300-fold the EC50 or IC50 of a control compound, wherein said control compound is the unbound immune- stimulatory compound.

2. An immune- stimulatory conjugate comprising:

(a) an immune- stimulatory compound that optionally binds to a protein active site of a binding protein to stimulate an immune response by inhibition of the activity of said binding protein;

(b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein said antigen binding domain binds to at least a first antigen and wherein said Fc domain binds to an Fc receptor; and

(c) a linker, wherein said linker is covalently bound to said antibody construct and said linker is covalently bound to said immune- stimulatory compound; and wherein the dissociation constant (K _d ) for binding of said Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody to said Fc receptor, wherein the control antibody is the antibody construct; and wherein the K _d for binding of said immune- stimulatory compound of the conjugate to said protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to said protein active site or wherein the IC50 of said immune- stimulatory compound of the conjugate is no greater than 300- fold the IC50 of a control compound, wherein said control compound is the unbound immune- stimulatory compound 3. An immune- stimulatory conjugate comprising:

(a) an immune- stimulatory compound that optionally binds to a protein active site of a binding protein to stimulate an immune response by degradation of said binding protein;

(b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein said antigen binding domain binds to at least a first antigen and wherein said Fc domain binds to an Fc receptor; and

(c) a linker, wherein said linker is covalently bound to said antibody construct and said linker is covalently bound to said immune- stimulatory compound; wherein the dissociation constant (K _d ) for binding of said Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody to said Fc receptor, wherein the control antibody is the antibody construct; and wherein the K _d for binding of said immune- stimulatory compound of the conjugate to said protein active site is equal to, or up to no greater than 100 times the K _d for binding of a control compound to said protein active site or wherein the IC50 of said immune- stimulatory compound of the conjugate is no greater than 300- fold the IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

4. The immune- stimulatory conjugate of any one of claims 1 to 3, wherein the EC50 or IC50 of said immune- stimulatory compound of the conjugate is no greater than 100-fold the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

5. The immune- stimulatory conjugate of any one of claims 1 to 3, wherein the EC50 or IC50 of said immune- stimulatory compound of the conjugate is no greater than 10-fold the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

6. The immune- stimulatory conjugate of any one of claims 1 to 3, wherein the EC50 or IC50 of- said immune- stimulatory compound of the conjugate is equivalent to or less than the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

7. An immune- stimulatory conjugate of any one of claims 1 to 3, wherein the EC50 or IC50 on an antigen bearing cell is equivalent to or less than the EC50 or IC50 of a control compound but EC50 or IC50 of the immune- stimulatory conjugate is 5-fold greater or more than the EC50 or IC50 of the control compound for a non-antigen bearing cell. 8. The immune- stimulatory conjugate of any one of claims 1 to 3, wherein the K _d for binding of said immune- stimulatory compound of the conjugate to said protein active site is no greater than 50 times the K _d for binding of a control compound to said protein active site, wherein the control compound is the unbound immune- stimulatory compound.

9. The immune- stimulatory conjugate of any one of claims 1 to 3, wherein the K _d for binding of said immune- stimulatory compound of the conjugate to said protein active site is no greater than 10 times the K _d for binding of a control compound to said protein active site, wherein the control compound is the unbound immune- stimulatory compound.

10. The immune- stimulatory conjugate of any one of claims 1 to 3, wherein the K _d for binding of said immune- stimulatory compound of the conjugate to said protein active site is equivalent to or less than the K _d for binding of a control compound to said protein active site, wherein the control compound is the unbound immune- stimulatory compound.

11. An immune- stimulatory conjugate comprising:

(a) an immune- stimulatory compound that optionally binds to a protein active site to stimulate an immune response;

(b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein said antigen binding domain binds to a first antigen and wherein said Fc domain binds to an Fc receptor; and

(c) a linker, wherein said linker is covalently bound to said antibody construct and said linker is covalently bound to said immune- stimulatory compound; and

wherein the dissociation constant (K _d ) for binding of said Fc domain of the conjugate to an Fc receptor is equal to, or up to no greater than about 100 times the K _d for binding of a control antibody to said Fc receptor, wherein the control antibody is the antibody construct; and wherein the K _d for binding of said immune- stimulatory compound when bound to a 5- 100 atom linker to said protein active site is no greater than 100 times the K _d for binding of a control compound to said protein active site or wherein the EC50 or IC50 of said immune- stimulatory compound of the conjugate is no greater than 300-fold the EC50 or IC50 of a control compound, wherein the conrol compound is the unbound immune- stimulatory compound.

12. The immune- stimulatory conjugate of claim 11, wherein the the EC50 or IC50 of said immune- stimulatory compound when bound to a 5- 100 atom linker is no greater than 100-fold the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound. 13. The immune- stimulatory conjugate of claim 11, wherein the EC50 or IC50 of said immune- stimulatory compound when bound to a 5- 100 atom linker is no greater than 10-fold the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

14. The immune- stimulatory conjugate of claim 11, wherein the EC50 or IC50 of said immune- stimulatory compound when bound to a 5- 100 atom linker is equivalent to or less than the EC50 or IC50 of a control compound, wherein the control compound is the unbound immune- stimulatory compound.

15. The immune- stimulatory conjugate of any one of claims 11 to 14, wherein the K _d for binding of said immune- stimulatory compound when bound to a 5- 100 atom linker to said protein active site is no greater than 50 times the K _d for binding of a control compound to said protein active site, wherein the control compound is the unbound immune- stimulatory compound.

16. The immune- stimulatory conjugate of any one of claims 11 to 14, wherein the K _d for binding of said of said immune- stimulatory compound when bound to a 5- 100 atom linker to said protein active site is no greater than 10 times the K _d for binding of a control compound to said protein active site, wherein the control compound is the unbound immune- stimulatory compound.

17. The immune- stimulatory conjugate of any one of claims 11 to 14, wherein the K _d for binding of said immune- stimulatory compound when bound to a 5- 100 atom linker to said protein active site is equivalent to or less than the K _d for binding of a control compound to said protein active site wherein the control compound is the unbound immune- stimulatory compound.

18. The immune- stimulatory conjugate of any one of claims 1 to 17, wherein the conjugate further comprises an E3 ubiquitin ligase binding moiety.

19. The immune- stimulatory conjugate of claim 18, wherein the E3 ubiquitin ligase binding moiety binds to VHL, cereblon, or MDM2

20. An immune- stimulatory conjugate of claims 18 or 19, wherein the E3 ubiquitin ligase binding moiety is selected from compounds 1- 1, 1-2, 1-3, 1-4, 1-5, 1-6, and 2- 1.

21. The immune stimulatory conjugate of any one of claims 18 to 20, wherein said E3 ubiquitin ligase binding moiety is attached to said linker or is part of said linker. 22. The immune- stimulatory conjugate of claim 21, wherein said E3 ubiquitin ligase binding moiety is part of said linker, wherein said E3 ubiquitin ligase binding moiety is bound through a first 5-100 atom linker to said immune- stimulatory compound and said E3 ubiquitin ligase binding moiety is bound through a second 5-100 atom linker to said antibody construct.

23. The immune- stimulatory conjugate of any one of claims 1 to 22, wherein the immune- stimulatory compound is a kinase inhibitor and the protein active site is a kinase active site.

24. The immune- stimulatory conjugate of claim 23, wherein said linker is covalently bound to said kinase inhibitor at a position on said kinase inhibitor that is at or near the solvent interface of said kinase active site as determined by modeling of said kinase inhibitor in said kinase active site.

25. The immune- stimulatory conjugate of claim 23, wherein said linker is covalently bound to said kinase inhibitor at a position on the kinase inhibitor such that when the kinase inhibitor is bound to said active site, said linker extends out from the kinase active site into the solvent, as determined by modeling of said kinase inhibitor in said kinase active site.

26. The immune- stimulatory conjugate of any one of claims 23 to 25, wherein the kinase inhibitor is selected from an inhibitor of ALK, Bcr-Abl, BRAF, BTK, c-KIT, EGFR, ErbB2, JAK, MEK, MET, PDGFRB, RET, ROS 1, Syk, SRC, TGFpR2, TNIK, TNKS, TrkA, TrkB, TrkC, VEGF, VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, FGFR4, CSF1R, RON/MS T1R, TYR03, MERTK, AXL, ΡΙ3Κδ, ΡΒΚγ, MAP4K1, PERK, and combinations thereof.

27. The immune- stimulatory conjugate of any one of claims 1 to 22, wherein said immune- stimulatory compound is a toll- like receptor agonist, STING agonist, or RIG-I agonist.

28. The immune- stimulatory conjugate of claim 27, wherein the immune- stimulatory compound is a toll-like receptor agonist selected from a TLR1 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a TLR10 agonist.

29. The immune- stimulatory conjugate of any one of claims 1 to 22, wherein said immune- stimulatory compound is selected from a pyrimidine, a purine, a guanine nucleoside, an 8- oxoadenine, an imidazoquinoline, a thiazoquinoline, a 2-amino imidazole, a furo[2,3-c]pyridine, a furo[2,3-c]quinoline, a 2-aminobenzimidazole, a 2-aminoquinoline, and a 2-aminobenzazepine. 30. The immune- stimulatory conjugate of any one of claims 1 to 22, wherein the target of the immune- stimulatory compound is a GCPR, an ion channel, a membrane transporter, a

phosphatase, or an ER protein.

31. The immune- stimulatory conjugate of any one of claims 1 to 22, wherein said immune- stimulatory compound is an antagonist of the GPCR A2aR, the sphingosine 1 -phosphate receptor 1, prostaglandin receptor EP3, prostanglandin receptor E2, Frizzled, CXCR4, or an LPA receptor.

32. The immune- stimulatory conjugate of any one of claims 1 to 22 wherein said immune- stimulatory compound is an ion channel agonist for CRAC, Kvl.3, or KCa3.1.

33. The immune- stimulatory conjugate of any one of claims 1 to 22, wherein said immune- stimulatory compound is an inhibitor of HSP90 or AAA-ATPase p97.

34. The immune- stimulatory conjugate of any one of claims 1 to 33, wherein said conjugate has immune- stimulatory activity with no or minimal cell processing.

35. The immune- stimulatory conjugate of any one of claims 1 to 34, wherein the linker is a non-cleavable linker.

36. The immune- stimulatory conjugate of any one of claims 1 to 34, wherein the linker is a Fleximer linker.

37. The immune- stimulatory conjugate of any one of claims 1 to 34, wherein the linker comprises a carbamate and one or more amide linkages.

38. The immune- stimulatory conjugate of any one of claims 1 to 34, wherein the linker is

, wherein R ^x is a reactive moiety and wherein R is hydrogen, alkyl, sulfonate and methyl sulfonate. 39. The immune- stimulatory conjugate of any one of claims 1 to 34, wherein said linker is attached to the antibody construct at a cysteine or lysine residue of said antibody construct.

40. The immune- stimulatory conjugate of any one of claims 1 to 39, wherein said first antigen is a tumor antigen.

41. The immune- stimulatory conjugate of any one of claims 1 to 39, wherein said first antigen is at least 80% homologous to CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC, HLD-DR, carcinoembryonic antigen, TAG-72, EpCAM, MUC1, fo late-binding protein, A33, G250, pro state- specific membrane antigen, ferritin, GD2, GD3, GM2, Le ^y , CA-125, CA19-9, epidermal growth factor, pl85HER2, IL-2 receptor, de2-7 EGFR, fibroblast activation protein, tenascin, metalloproteinases, endosialin, vascular endothelial growth factor, ανβ3, WT1, LMP2, HPV E6 E7, EGFRvIII, Her-2/neu, idiotype, MAGE A3, p53 nonmutant, NY-ESO-1, PMSA, GD2, CEA, MelanA/M ART 1 , Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyronsinase, survivin, PSA, hTERT, Sarcoma translocation breakpoints, EphA2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin Bl, polysialic acid, MYCN, RhoC, TRP-2, fucosyl GM1, mesothelin, PSCA, MAGE Al, sLe(animal), CYPIBI, PLAVl, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES 1, Sperm protein 17, LCK,

HMWMAA, AKAP-4, SSX2, XAGE 1, B7H3, Legumain, Tie 3, Page4, VEGFR2, MAD-CT-1, PDGFR-B, MAD-CT-2, ROR2, TRAIL 1, MUC16, MAGE A4, MAGE C2, GAGE, EGFR, CMET, HER3, MUC15, MSLN, CA6, NAPI2B, TROP2, CLDN18.2, RON, LY6E, FRA, DLL3, PTK7, LIV1, ROR1, or Fos-related antigen 1..

42. The immune- stimulatory conjugate of any one of claims 1 to 41, wherein said antibody construct further comprises a second targeting binding domain.

43. The immune- stimulatory conjugate of claim 42, wherein said targeting binding domain specifically binds an immune cell.

44. The immune- stimulatory conjugate of claim 42 or 43, wherein said targeting binding domain is conjugated to said antibody construct at a C-terminal end of said Fc domain.

45. The immune- stimulatory conjugate of any one of claims 1 to 44, wherein said antigen binding domain is from an antibody or non-antibody scaffold. 46. The immune- stimulatory conjugate of any one of claims 1 to 45, wherein said antigen binding domain is at least 97% homologous to an antigen binding domain from an antibody or non-antibody scaffold.

47. The immune- stimulatory conjugate of any one of claims 1 to 46, wherein said antibody construct is a human antibody or a humanized antibody.

48. The immune- stimulatory conjugate of any one of claims 1 to 47, wherein said Fc domain is an Fc domain variant comprising at least one amino acid residue change as compared to a wild type sequence of said Fc domain.

49. The immune- stimulatory conjugate of any one of claims 1 to 48, wherein said Fc domain is at least about 80% homologous to an Fc domain from an antibody, wherein the Fc domain from an antibody comprises amino acid residues 216 to 447 of SEQ ID NO: 898, amino acid residues 216 to 443 of SEQ ID NO: 899, or amino acid residues 216 to 444 of SEQ ID NO: 900.

50. The immune- stimulatory conjugate of any one of claims 1 to 49, wherein said Fc domain has at least one amino acid residue change as compared to wildtype, wherein said Fc domain is at comprises at least 80% homologous to SEQ ID NO: 296, and wherein said at least one amino acid residue change is:

a) F243L, R292P, Y300L, L235V, and P396L, wherein numbering of amino acid residues in said Fc domain is relative to SEQ ID NO: 898;

b) S239D and I332E, wherein numbering of amino acid residues in said Fc domain is relative to SEQ ID NO: 898; or

c) S298A, E333A, and K334A, wherein numbering of amino acid residues in said Fc domain is relative to SEQ ID NO: 898.

51. The immune- stimulatory conjugate of any one of claims 1 to 50, wherein said Fc domain has at least one amino acid residue change as compared to wildtype, wherein said Fc domain is at comprises at least 80% homologous to SEQ ID NO: 898, and wherein said at least one amino acid residue change is:

a) N297A, N297G, N297Q, N297D as in Kabat numbering and relative to SEQ ID NO: 898; or

b) K322A/L234A/L235A N296A as in Kabat numbering and relative to SEQ ID NO: 898; or

c) L234F/L235E/P331S N296A as in Kabat numbering and relative to SEQ ID NO:

898; or d) P329G/L234A/L235A as in Kabat numbering and relative to SEQ ID NO: 898.

52. The immune- stimulatory conjugate of any one of claims 1 to 51, wherein said K _d for binding of said antigen binding domain to said first antigen in the presence of said immune- stimulatory compound is less than about ΙΟΟηΜ and is equal to, or up to no greater than about 10 times the K _d of the binding of the antigen binding domain to said first antigen in the absence of the immune- stimulatory compound; and said K _d for binding of said Fc domain to said Fc receptor in the presence of said immune- stimulatory compound is equal to, or up to no greater than about 10 times said K _d for the binding of said Fc domain to said Fc receptor in the absence of said immune- stimulatory compound.

53. The immune- stimulatory conjugate of any one of claims 1 to 52, wherein said molar ratio of immune- stimulatory compound to antibody is less than 5.

54. The immune- stimulatory conjugate of any one of claims 1 to 53, wherein said linker is bound to said antibody construct at an amino acid residue that does not interfere with said Fc domain binding to said Fc receptor.

55. The immune- stimulatory conjugate of any one of claims 1 to 54, wherein said linker is not attached to an amino acid residue of said Fc domain selected from a group consisting of: 221, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 275, 276, 278, 280, 281, 283, 285, 286, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 305, 313, 318, 323, 324, 325, 327, 328, 329, 330, 331, 332, 333, 335, 336, 396, or 428, wherein numbering of amino acid residues in said Fc domain is according to the EU index as in Kabat.

56. The immune- stimulatory conjugate of any one of claims 1 to 55, wherein said Fc domain is selected from a group consisting of a human IgGl Fc domain, a human IgG2 Fc domain, a human IgG3 Fc domain, and a human IgG4 Fc domain.

57. The immune- stimulatory conjugate of any one of claims 1 to 56, wherein said conjugate induces the secretion of cytokines by an antigen presenting cell.

58. A pharmaceutical composition comprising an immune- stimulatory conjugate of any one of claims 1 to 57 and a pharmaceutically acceptable excipient.

59. A method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition of claim 58. General Schemes

Synthesis of Immune-Stimulatory Compound-Linkers and Immune-Modulatory Compound- Linker Constructs

[0551] An construct of a linker and an immune- stimulatory compound or an immune-modulatory compound (denominated ISC) can be synthesized by various methods. For example, ISC-linker constructs can be synthesized as shown in Scheme Bl.

Sche

R = NHS, pentafluorophenyl

ISC: immune-stimulatory compound

[0552] A PEGylated carboxylic acid (i) that has been activated for amide bond formation can be reacted with an appropriately substituted amine containing immune- stimulatory compound to afford an intermediate amide. Formation of an activated ester (ii) can be achieved by reaction the intermediate amide-containing carboxylic using a reagent such as N-hydroxysuccinimide or pentafluorophenol in the presence of a coupling agent such as diisopropylcarbodiimide (DIC) to provide compounds (ii).

[0553] An ISC-linker construct can be synthesized as shown in Scheme B2.

Scheme B2:

[0554] An activated carbonate such as (i) can be reacted with an appropriately substituted amine containing immune- stimulatory compound to afford carbamates (ii) which can be deprotected using standard methods based on the nature of the R ₃ ester group. The resulting carboxylic acid (iii) can then by coupled with an activating agent such as N-hydroxysuccinimide or

pentafluorophenol to provide compounds (iv).

[0555] A ISC-linker construct can be synthesized as shown in Scheme B3.

Scheme B3:

i-a; X = NHS ϋ

i-b; X = H

ISC: immune-stimulatory compound

[0556] An activated carboxylic ester such as (i-a) can be reacted with an appropriately

substituted amine containing immune- stimulatory compound to afford amides (ii). Alternatively, carboxylic acids of type (i-b) can be coupled to an appropriately substituted amine containing immune- stimulatory compound in the presence of an amide bond forming agent such as

dicyclohexycarbodiimde (DCC) to provide the desired ISC.

[0557] An ISC-linker construct can be synthesized by various methods such as that shown in Scheme B4.

Scheme B4:

ϋ

ISC: immune-stimulatory compound

[0558] An activated carbonate such as (i) can be reacted with an appropriately substituted amine containing immune- stimulatory compound to afford carbamates (ii) as the target ISC. [0559] An ISC-linker construct can also be synthesized as shown in Scheme B5.

Scheme B5:

[0560] An activated carboxylic acid such as (i-a, i-b, i-c) can be reacted with an appropriately substituted amine containing immune- stimulatory compound to afford amides (ii-a, ii-b, ii-c) as the target linkered immune- stimulatory compounds.

General Scheme for the Synthesis of Immune-Modulatory Conjugates Containing a PROTAC

[0561] An immune-modulatory conjugate containing a PROTAC (or PTM) as described herein can comprise an antibody construct Ab (such as an antibody) convalently attached via a linker (L) to a PROTAC, wherein the PROTAC comprises a ubiquitin E3 ligase binding group (E; also referred to as ULM), a spacer (S) and an immune-modulatory compound (K; also referred to as an IMC) (such as a kinase inhibitor). The general formula is: Ab— (L— (Ci-S-C ₂ )) _n , wherein Ab is the antibody construct, C ₁ -S-C ₂ is PROTAC or PTM, wherein, C ₂ is an E3 ubiquitin ligase binding group (E or ULM) covalently bound to a spacer group (s) that is covalently bound to Ci, an immune-modulatory compound (E or IMC), and L is a linker covalently bonded to the antibody construct and to the PROTAC; and n has a value from about 1 to about 8.

[0562] In the following exemplary scheme, the immune-modulatory compound (E in this scheme) is a kinase inhibitor. Scheme 1: deprotect

couple

deprotect

0-NH HN-© conjugate

[0563] A kinase inhibitor containing a free amine functional group can be acylated with a multifunctional amino acid derivative such as aspartate or glutamate using standard amide bond coupling reactions such as HATU in DMF containing and amine base to provide intermediates (ii). Deprotection of compounds (ii) using known methods for the conversion of carboxylic esters to carboxylic acids, such as hydrogenation when R = Bn can provide compounds (iii) which can be coupled to an E3 ubiquitin ligase such as a group that binds VHL or cereblon to provide PROTACs (iv). Compounds that bind VHL may be hydroxyproline compounds such as those disclosed in WO 2013/106643, and other compounds described in US 2016/0045607, WO 2014187777, US 20140356322, and US 9,249,153. Compounds that bind to cereblon include thalidomide, lenalidomide, pomalidomide and analogs thereof. Other small molecule compounds that bind to cereblon are also known, e.g., the compounds disclosed as an in US2016/0058872 and US2015/0291562. The amine protecting group can be converted to intermediates (v) using appropriate reagents such as TFA when PG = Boc. Acylation of amines (v) by activated linker reagents (X* = NHS) or by direct amide bond coupling can provide linked-PROTAC (L-C) compounds (vi) which can subsequently be conjugated to an antibody using known methods as described herein.

Schem

[0564] Alternatively, a kinase inhibitor containing a free amine functional group can be acylated with a multi-functional amino acid derivative such as lysine using standard amide bond coupling reactions such as HATU in DMF containing and amine base to provide intermediates (vii). Deprotection of compounds (vii) using known methods, such as hydrogenation when R = Cbz can provide compounds (ix) which can be coupled to an E3 ubiquitin ligase to provide

PROTACs (x). The second amine protecting group (PG ₂ ) can be converted to intermediates (v) using appropriate reagents such as TFA when PG = Boc. Acylation of amines (xi) by activated linker reagents (X* = NHS) or by direct amide bond coupling can provide linked-PROTAC compounds (xii) which can subsequently be conjugated to an antibody using known methods as described herein. FIGURE DESCRIPTIONS

[0565] FIGURE 1 illustrates a schematic of a conjugate comprising an antibody and a second binding domain. The antibody contains two heavy chains as shown in dark gray and two light chains as shown in light gray. A portion of the heavy chains contain Fc domains (705 and 720). The antibody comprises a binding domain comprising two antigen binding sites (710 and 715). The second binding domain is attached to the antibody (780 and 785; black spheres), for example, at the C-terminus of the heavy chains.

[0566] FIGURE 2 illustrates a schematic of an exemplary conjugate. The conjugate comprises an antibody, which contains two heavy chains as shown in dark gray and two light chains as shown in light gray. The antibody comprises a binding domain comprising two antigen binding sites (910 and 915), and a portion of the heavy chains contain Fc domains (905 and 920). The immune- stimulatory compounds (930 and 940; black stars) are attached to the antibody by linkers (960 and 970; black line). A second binding domain is attached to the antibody (980 and 985; black spheres), for example, at the C-terminus of the heavy chains.

[0567] FIGURE 3 illustrates a schematic of an exemplary conjugate. The conjugate comprises the Fc region of an antibody with the heavy chains shown in dark gray, and two scaffolds as shown in light gray. The conjugate comprises a first binding domain comprising two antigen binding sites (1110 and 1115) in the scaffolds, and a portion of the heavy chains contain Fc domains (1105 and 1120). The immune- stimulatory compounds (1130 and 1140; black starts) are conjugated to the Fc domains by linkers (1160 and 1170; black lines). A second binding domain is attached to the conjugate (1180 and 1185; black spheres), for example, at the C-terminus of the heavy chains.

[0568] FIGURE 4 illustrates a schematic of an exemplary conjugate. The conjugate comprises the F(ab') ₂ region of an antibody with the Fab portions of heavy chains shown in dark gray and light chains shown in light gray, and two scaffolds as shown in the darkest gray. The conjugate comprises a first binding domain comprising two antigen binding sites (1310 and 1315), and a portion of two scaffolds contain Fc domains (1340 and 1345). The immune- stimulatory compounds (1330 and 1340; black stars) are attached to the conjugate by linkers (1360 and 1370; black lines). A second binding domain is attached to the Fc domains (1380 and 1385; black spheres).

[0569] FIGURE 5 illustrates a schematic of an exemplary conjugate. The conjugate contains two scaffolds as shown in light gray and two scaffolds as shown in dark gray. The conjugate comprises a first binding domain comprising two antigen binding sites (1510 and 1515), and a portion of the two dark gray scaffolds contain Fc domains (1540 and 1545). The immune- stimulatory compounds (1530 and 1540; black stars) are conjugated to the conjugate by linkers (1560 and 1570; black lines). A second binding domain is attached to the conjugate (1580 and 1585; black spheres).

[0570] FIGURE 6 illustrates a schematic of a conjugate comprising an antibody and a second binding domain. The antibody contains two heavy chains as shown in dark gray and two light chains as shown in light gray. A portion of the heavy chains contain Fc domains (1705 and 1720). The antibody comprises a binding domain comprising two antigen binding sites (1710 and 1715). The second binding domain is attached to the antibody (1780 and 1785; black spheres), for example, at the C-terminus of the light chains.

[0571] FIGURE 7 illustrates a schematic of an exemplary conjugate. The conjugate comprises an antibody, which contains two heavy chains as shown in dark gray and two light chains as shown in light gray. The antibody comprises a binding domain comprising two antigen binding sites (1910 and 1915), and a portion of the heavy chains contain Fc domains (1905 and 1920). The immune- stimulatory compounds (1930 and 1940; black stars) are conjugated to the antibody by linkers (1960 and 1970; black lines). A second binding domain is attached to the antibody (1980 and 1985; black spheres), for example, at the C-terminus of the light chains.

[0572] FIGURE 8 illustrates a schematic of an exemplary conjugate. The conjugate comprises an Fc region of an antibody shown indark gray, and two scaffolds as shown in light gray. The conjugate comprises a first binding domain comprising two antigen binding sites (2110 and 2115) in the scaffolds, and a portion containing Fc domains (2105 and 2120). The immune- stimulatory compounds (2130 and 2140; black stars) are conjugated to the antibody construct by linkers (2160 and 2170; black lines). A second binding domain is attached to the antibody (2180 and 2185; black spheres).

[0573] FIGURE 9 illustrates a schematic of an exemplary conjugate. The conjugate comprises the F(ab')2 region of an antibody with heavy chains shown in dark gray and light chains shown in light gray, and two scaffolds as shown in darkest gray. The conjugate comprises a first binding domain comprising two antigen binding sites (2310 and 2315), and a portion of two scaffolds contain Fc domains (2340 and 2345). The immune- stimulatory compounds (2330 and 2340; black stars) are conjugated to the antibody by linkers (2360 and 2370; black lines). A second binding domain is attached to the antibody (2380 and 2385; black spheres), for example, at the C- terminus of the light chains.

[0574] FIGURE 10 illustrates a schematic of an exemplary conjugate. The conjugate contains two scaffolds as shown in light gray and two scaffolds as shown in dark gray. The conjugate comprises a first binding domain comprising two antigen binding sites (2510 and 2515), and a portion of the two dark gray scaffolds contain Fc domains (2540 and 2545). The immune- stimulatory compounds (2530 and 2540; black stars) are conjugated to the antibody construct by linkers (2560 and 2570; black lines). A second binding domain is attached to the conjugate (2580 and 2585; black spheres).

[0575] FIGURE 11 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (2705 and 2720). The antibody comprises a binding domain comprising two antigen binding sites shown in black (2710 and 2715).

[0576] FIGURE 12 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (2925 and 2930). The antibody comprises a first binding domain comprising two antigen binding sites shown in black (2910 and 2915). The antibody comprises a second binding domain comprising two single chain variable fragments (2905 and 2920) attached to a C- terminus of the light chains. A single chain variable fragment can be attached to a light chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a light chain at a light chain variable domain of the single chain variable fragment.

[0577] FIGURE 13 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain Fc domains (3120 and 3125). The antibody comprises a first binding domain comprising two antigen binding sites shown in black (3110 and 3115). The antibody comprises a second binding domain comprising two single chain variable fragments (3130 and 3135) attached to a C- terminus of the heavy chains. A single chain variable fragment can be attached to a heavy chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a heavy chain at a light chain variable domain of the single chain variable fragment.

[0578] FIGURE 14 illustrates a schematic of an antibody construct comprising an antibody. The antibody contains two heavy chains and two light chains. A portion of the heavy chains contain

Fc domains (3330 and 3335). The antibody comprises a first binding domain comprising two antigen binding sites shown in black (3310 and 3315). The antibody comprises a second binding domain comprising two single chain variable fragments (3320 and 3325) attached to a C- terminus of the light chains. A single chain variable fragment can be attached to a light chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a light chain at a light chain variable domain of the single chain variable fragment. The antibody comprises a third binding domain comprising two single chain variable fragments (3340 and 3345) attached to a C-terminus of the heavy chains. A single chain variable fragment can be attached to a heavy chain chain at a heavy chain variable domain of the single chain variable fragment. A single chain variable fragment can be attached to a heavy chain at a light chain variable domain of the single chain variable fragment.

[0579] FIGURE 15A sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with an amine handle (right top).

[0580] FIGURE 15B shows the x-ray crystal structure and binding orientation (pdb code 5D7A) of the immune- stimulatory compound as a ball- and- stick model as described in FIGURE 15A in a TNIK (TRAF2 and NCK- interacting protein kinase) active site. Cysl08 (bottom left) and Glnl57 (top right) of the TNIK protein are labeled. The dashed lines represent non-covalent bonds between the immune- stimulatory compound and the active site of TNIK. FIGURE 15B indicates that the terminal oxygen on the immune- stimulatory compound interacts with Gin 157 of the TNIK active site with a non-covalent bond length of about 2.9 A. Further, FIGURE 15B indicates that one of the nitrogen atoms of the compound interacts with the Cysl08 at the carboxyl group of the cysteine residue with a non-covalent bond length of about 3.1 A, and another nitrogem atom of the compound interacts with the amine group of the cysteine residue with a non-covalent bond length of about 3.2 A.

[0581] FIGURE 15C shows a close up of the binding orientation of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 15A in a TNIK active site, where the linker and antibody portions are pointing away and sitting outside of the active site. The modeling indicates that positioning of a linker on the 4-position of the benzimidazole of the left- hand compound of FIGURE 15A would extend from the active site and not interfere with the active site interactions of the compound as depicted in FIGURE 15B and FIGURE 15C.

[0582] FIGURE 16 sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with an amine handle and linker surrogate (right). The structure on the right illustrates that the immune- stimulatory compound is predicted to sit in the enzyme active site, whereas the amine handle and linker surrogate are predicted to sit outside of the enzyme active site, in the solvent.

[0583] FIGURE 17A sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with a linker surrogate (left side of molecule on right). FIGURE 17A indicates that the TGFpRl EC ₅₀ of the compound on the left is 14 nM, and that the TGFPR2 EC ₅₀ is 5 nM. The R group on the right figure is a hydrogen atom.

[0584] FIGURE 17B shows the x-ray crystal structure and binding orientation (pdb code 5E91) of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 17A in a TGFPR2 (transforming growth factor, beta receptor II) active site. Cys396 of the TGFPR2 is depicted in the upper right corner of the figure. [0585] FIGURE 17C shows a close up of the binding orientation of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 17 A in a TGFPR2 active site, where the linker and antibody construct portions are pointing away and sitting outside of the active site. Asn332 (upper right) and His328 (bottom right) of the TGFPR2 active site are also labeled. A bond length of 2.9 A is shown between an oxygen atom of the compound and the active site. Other bond lengths labeled include 2.8 A.

[0586] FIGURE 18A sets forth a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with an amine handle (upper left in molecule on right). FIGURE 18A indicates that the TNKS 1 IC ₅₀ of the compound on the left is 13 nM, and that the TNKS2 IC ₅₀ is 5 nM.

[0587] FIGURE 18B shows the x-ray crystal structure and binding orientation (pdb code 3KR8) of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 18A in a TNKS (tankyrase) active site. Glyl l85 and Serl221 are labeled on the active site of TNKS. The figure indicates that an oxygen atom of the compound interacts with Glyl 185 and Serl221 with a non-covalent bond length of about 2.9 A.

[0588] FIGURE 18C shows a close up of the binding orientation of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 18A in a TNKS active site, where the linker and antibody construct portions are pointing away and sitting outside of the active site, including the trifluoromethyl group of the compound.

[0589] FIGURE 19A shows a structure of an immune- stimulatory compound (left) and an immune- stimulatory compound with two amine handles (on right side of molecule on the right). FIGURE 19A indicates that the TNKS 1 IC ₅₀ of the compound on the left is 8 nM, and that the TNKS 2 ICso is 2 nM.

[0590] FIGURE 19B shows the x-ray crystal structure and binding orientation (pdb code 4191) of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 19A with dual site binding in the TNKS (tankyrase) active site. Aspl 198, Glyl 185, and Tyrl213 are labeled for the active site of TNKS. The figure indicates that an oxygen atom of the compound interacts with Aspl 198 with a non-covalent bond length of about 3.2 A. Another oxygen atom of the compound interacts with Tyrl213 with a non-covalent bond length of about 2.9 A. Both a nitrogen atom and oxygen atom of the compound interact with Glyl 185 with a non-covalent bond length of about 2.8 A and 2.7 A, respectively.

[0591] FIGURE 19C shows a close up of the binding orientation of the immune- stimulatory compound as a ball-and-stick model as described in FIGURE 19A in a TNKS active site, where the linker and antibody portions are pointing away and sitting outside of the active site. The figure indicates that the compound interacts with Aspl 198 at a non-covalent bond length of about 3.2 A (middle). The figure indicates that the compound interacts with Tyrl213 at a non-covalent bond length of about 2.9 A (left).

[0592] FIGURE 20A illustrates a schematic of an exemplary conjugate and its molecular target. The conjugate comprises an antibody (3405) attached to a linker (3410) that is attached to a drug (3415) at the opposite end of the antibody (3405). The molecular target (3420) has an active site (3425) that is complementary to the drug (3415).

[0593] FIGURE 20B illustrates a schematic of an active exemplary conjugate that is bound to the the molecular target's active site. The drug (3415) sits within the active site of the molecular target (3420). The linker (3410) and antibody (3405) sit outside of the active site (3430, represented by the dashed line).

[0594] FIGURE 20C illustrates a schematic of an active drug (3415) and linker (3410) that is bound to the molecular target (3420). The linker (3410) sits outside of the active site (3430, the dashed line is the boundary of the active site).

[0595] FIGURE 20D illustrates a schematic of an active drug (3415) that is bound to the molecular target (3420). The active drug sits inside the active site (3430, the dashed line is the boundary of the active site).

[0596] FIGURE 21A shows the results of an assay for degradation of TFGpR2 by an anti-HER2 antibody-TGFpR2-VHL PROTAC conjugate. Plasmid expressing HER2 was transfected into HEK293 cells, and the cells were treated with DMSO, PROTAC T-20, HER2 antibody (IgGl), or Her2 Antibody-Protac conjugate (050-T11020). Whole cell lysates were prepared from cells after 2 (left blot), 24 (middle blot), or 48 (right blot) hours incubation and quantitated with a BCA assay. Equal amounts of lysates were run on protein gels, transferred to PVDF, and TGFPR2 (top), TGFpRl (middle), or control actin (bottom) was detected using commercially available reagents. At both tested concentrations of the conjugate, the level of target TGFPR2 was diminished at 24 and 48 hours of treatment as demonstrated by the diminished signal of TGFPR2 in the lanes containing 050-T11020. For the 2 hour blot, from left to right, the lanes represent DMSO; T-20 5 μΜ; 050 IgG 1 μΜ; 050-T11020 1 μΜ; and 050-T11020 0.5 μΜ. For the 24 hour blot, from left to right, the lanes represent DMSO; T-20 5 μΜ; 050 IgG 0.5 μΜ; 050 IgG 1 μΜ; 050-T11020 0.5 μΜ; and 050-T11020 1 μΜ. For the 48 hour blot, from left to right, the lanes represent PBS; 050 IgG 1 μΜ; 050-T11020 1 μΜ; and 050-T11020 0.5 μΜ.

[0597] FIGURE 21B provides a quantification of the western blot data for TGFPR2 shown in FIG 21 A. To quantitate the amount of protein degradation, the signals on the Western blot were normalized to actin loading control and data was presented as a percent of matched control on the y-axis, which is labeled from 0 to 140 in intervals of 20. A thick black line denotes 100 precent. The medium-gray bars at the left of each data set represent the data obtained at 2 hours of treatment. The darkest gray bars in the middle of each data set represent the data obtained at 24 hours. The lightest gray bars at the right of each data set represent the data obtained at 48 hours. On the x-axis, from the left to right, the data sets are T20 5 μΜ; 050-11020 0.5 μΜ; and 050- 11020 1 μΜ.

[0598] FIGURE 21C provides a quantification of the western blot data for TGFpRl shown in FIGURE 21 A. To quantitate the amount of protein degradation, the signals on the Western blot were adjusted to actin loading control and data was presented as a percent of matched control on the y-axis, which is labeled as 0 to 200 in intervals of 20. The medium-gray bars at the left of each data set represent the data obtained at 2 hours of treatment. The darkest gray bars in the middle of each data set represent the data obtained at 24 hours. The lightest gray bars on the right of each data set represent the data obtained at 48 hours. On the x-axis, from the left to right, the data sets are T20 5 μΜ; 050-11020 0.5 μΜ; and 050-11020 1 μΜ. Consistent with the western blot data, the amount of TGFpRl protein remained fairly constant throughout the treatment period.

[0599] FIGURE 22A and FIGURE 22B show the results of an assay for antigen targeted degradation of TGFPR2 by an antibody conjugate with PROTACs having VHL or Cereblon E3 binding moieties. BT474 cells were plated and treated the following day with either a T-15 PROTAC or a T-20 PROTAC, a conjugate of a HER2 antibody TGFpR2-VHL binding

PROTAC (050-T05020), a conjugate of a HER2 antibody TGFpR2-Cereblon binding PROTAC (050-T05015), or a conjugate of a TROP2 antibody TGFpR2-VHL binding PROTAC (130- T05020). Whole cell lysates were prepared 24 hours after treatment and quantitated with a BCA assay. Equal amounts of lysates were run on protein gels, transferred to PVDF, and TGFPR2 and actin were detected using commercially available reagents. FIGUGRE 22A shows that HER2- antigen specific degradation was found with both the HER2 binding PROTAC conjugates, but not with the control TROP2-binding PROTAC conjugate, as indicated by the retained signal of the TGFPR2 protein (top blot; actin control is bottom blot). The lanes, from left to right, represent DMSO; T-15 300 nM; T-20 300 nM; PBS; unlabeled; 050-T05015 0.5 mM; 050- T05020 0.5 μΜ; and 130-T05020 0.5 μΜ.

[0600] FIGURE 22B provides a quantitation of FIGURE 22A, and was determined by normalizing the TGFPR2 signals to actin loading control. The data are presented as a percent of vehicle control on the y-axis, which is labeled as 0 to 120 in intervals of 20. The x-axis, from left to right, represents T-15 300 nM; T-20 300 nM; 050-T05015; 050-T0520; and 130-T05020. The thick black line is at 100 of the y-axis.

[0601] FIGURE 23A and FIGURE 23B show the results of an assay for cellular levels of TGFpR2 and TGFpRl in the presence of a TGFpR2/TGFpRl-VHL PROTAC (T-20) with or without the addition of a proteasome inhibitor. Normal human lung fibroblasts were treated with or without proteasome inhibitor MG-132 followed by the addition of DMSO or T-20. Whole cell lysates were prepared and then quantitated with a BCA assay. Equal amounts of lysates were run on protein gels and transferred to PVDF membrane. TGFpRl, TGFPR2, and actin were detected using commercially available reagents. FIGURE 23A provides the western blot results of the assay. The results demonstrate that the addition of the proteasome inhibitor protected TGFpRl and TGFPR2 against degradation induced by T-20, as indicated by rescue of the TGFPR2 and TGFpR2 signals by addition of MG-132 in the presence of T-20. TGFpR2 is the top row, TGFpRl is the middle row, and actin is the bottom row. The left blots lanes represent, from left to right, MG132 concentrations of 0 (shown as -); 10; and 50 followed by addition of DMSO. The right blots represent, from left to right, MG132 concentrations of 0 (shown as -); 10; and 50 μΜ followed by addition of 5 μΜ T-20.

[0602] FIGURE 23B provides quantification of the results of the FIGURE 23A, and was obtained by adjusting the western signal to the actin loading control. The data are presented as a percent of the matched vehicle control on the y-axis, which is labeled from 0 to 100 at intervals of 10. The light gray bars represent the data for TGFPR2 and the dark gray bars represent the data for TGFpRl. The x-axis, from left to right, is labeled as T-20; T-20 + 10 μΜ MG132; and T-20 + 50 μΜ MG132.

EXAMPLES

[0603] The following examples illustrate the various methods of making and assaying compounds and conjugates described herein. It is understood that one skilled in the art may be able to make these compounds and conjugates by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make compounds and conjugates in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

EXAMPLE 1

[0604] Synthesis of (S)-Nl-(4-(5-amino-6-((4-morpholinopyridin-3-yl)carbamoyl)py razin-2- yl)benzyl)-2-(6-(4-((2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)me thyl)-cyclohexane-l- carboxamido)hexanamido)-N5-(2-(3-(((S)-l-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan -2-yl)amino)-3- oxopropoxy)ethyl)pentanediamide (Compound 1-1)

Step A: Preparation oflnt lB-1

Int 1 B-1

[0605] HATU (3.54 g, 9.36 mmol) was added to a solution containing 1.64 g (7.5 mmol) of 3- amino-6-bromopyrazine-2-carboxylic acid in 25 mL of DMF. The reaction was stirred for 5 minutes before adding 2.5 mL (22.5 mmol) of N-methylmorpholine and 1.68 g (9.36 mmol) of 4- morpholinopyridin-3-amine. The reaction mixture was stirred for 16 h then quenched with 10 mL of saturated NH ₄ C1 solution and then 10 mL of water. The mixture was extracted with EtOAc three times; the combined organics were washed with brine and then dried over a ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% CH ₃ OH / dichloromethane) to afford compound Int lB-1 as a yellow solid. Step B: Preparation of Int 1B-2

Int 1 B-1 Int 1 B-2

[0606] A solution containing 1.5 g (4.0 mmol) of 3-amino-6-bromo-N-(4-morpholinopyridin-3- yl)pyrazine-2-carboxamide and 1.1 g (4.4 mmol) of (4-(2-(((tert-butoxy)carbonyl)- amino)methyl)phenyl)boronic acid in 25 mL of dioxane and 4.0 mL of 2N a ₂ C0 ₃ (8.0 mmol) was degassed and back filled with nitrogen three times. 295 mg (0.4 mmol) of PdCl ₂ (dppf) was added and the reaction vessel was degassed with nitrogen twice. The reaction mixture was then heated at 90 °C for 3 h then cooled and stirred overnight then filtered through a plug of Celite ^® . The filtrate was diluted with EtOAc, washed with water and then brine, and dried over Na ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% MeOH / dichloromethane) to afford 1.3 g of compound Int 1B-2 as a white solid. LCMS (M+H) = 506.

Step C: Preparation of Int 1B-3

2 HCl

Int 1 B-2 Int 1 B-3

[0607] A solution containing 1.2 g (2.4 mmol) of Int 1B-2 in 25 mL of EtOAc was added 10 mL of 4N HCl in dioxane at room temperature. The reaction was stirred for 3h and the solvent was evaporated. The resulting solid was triturated three times with toluene to provide the desired amine salt which was used without purification. LCMS (M+H) = 406. Step D: Preparation of Int 1B-4

[0608] To a solution containing 112 mg (0.276 mmol) of Int 1B-3 and 93 mg (0.276 mmol) of Boc-L-glutamic acid 5-benzyl ester in 2 mL of DMF was added 105 mg (0.276 mmol) of HATU and 0.06 mL (0.55 mmol) of N-methylmorpholine. The reaction mixture was stirred for 16 h then quenched with 1 mL of saturated NH ₄ C1 solution and 1 mL of water. The mixture was extracted with EtOAc three times; the combined organic s were washed with brine and then dried over a ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% CH ₃ OH / dichloro methane) to afford 160 mg of compound Int 1B-4 as a yellow solid. LCMS (M+H) = 725.

Step E: Preparation of Int 1B-5

[0609] A solution containing 100 mg (0.14 mmol) of Int 1B-4 in 20 mL of 1: 1 THF - EtOH was degassed and back filled with nitrogen three times. 100 mg of 20% Pd(OH) ₂ was added and the mixture was degassed two additional times. The reaction mixture was stirred for 16 h then filtered through Celite with EtOAc. Removal of the solvent and trituration with toluene afforded 75 mg of Int 1B-5 which was used directly in the next step. LCMS (M+H) = 635. Step F: Preparation oflnt 1B-6

[0610] To a solution containing 75 mg (0.12 mmol) of lnt 1B-5 and 82 mg (0.15 mmol) of (2S,4R)-l-((S)-2-(3-(2-aminoethoxy)propanamido)-3,3-dimethyl butanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide in 1.0 mL of DMF was added 66 mg (0.15 mmol) of BOP reagent and 0.026 mL (0.24 mmol) of diisopropylethylamine. The reaction mixture was stirred for 16 h then quenched with 1 mL of saturated NaHC0 ₃ solution and 1 mL of water. The mixture was extracted with EtOAc three times; the combined organic extracts were washed with brine and then dried over a ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% CH ₃ OH / dichloromethane) to afford 58 mg of the desired compound as a yellow solid which was immediately dissolved in 5 mL of EtOAc then treated with 1 mL of 4 N HC1 in dioxane at room temperature and the reaction was stirred for 3h. The solvent was removed under reduced pressure and the residue was azeotroped three times with toluene then stirred with ether and filtered to afford 43 mg of (S)-2-amino- N ¹ -(4-(5 -amino-6-((4- morpholinopyridin-3-yl)carbamoyl)pyrazin-2-yl)benzyl)-N5-(2- (3-(((S)-l-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)- 3,3-dimethyl-l-oxobutan-2- yl)amino)-3-oxopropoxy)-ethyl)pentanediamide trihydrochloride as bright yellow crystalline solid. LCMS (M+H) = 1062.

[0611] Int 1B-6 is PROTAC T-015 Step G: Preparation of Compound 1-1

Compound 1-

[0612] A solution containing 43 mg (0.037 mmol) of (S)-2-amino-N ¹ -(4-(5-amino-6-((4- morpholinopyridin-3-yl)carbamoyl)pyrazin-2-yl)benzyl)-N5-(2- (3-(((S)-l-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)- 3,3-dimethyl-l-oxobutan-2- yl)amino)-3-oxopropoxy)ethyl)pentanediamide trihydrochloride was combined with (16 mg, 0.037 mmol) of LC-smcc (succinimidyl 4-(N-maleimidomethyl)cyclohexane-l-carboxy-(6- amidocaproate)) in 1.5 mL of DCM and DIPEA (0.064 mL, 0.36 mmol). After stirring overnight, the reaction became cloudy and LCMS indicated the presence of product. The reaction was concentrated then taken up in a minimum amount of THF and water. The mixture was neutralized with saturated NaHC0 ₃ and the mixture was chromatographed (30 g, CI 8, H ₂ 0 to CH ₃ CN, liquid load) to provide Compound 1-1 (31.8, mg) as a yellow solid after lyophilization from CH ₃ CN/H ₂ 0. 1H NMR (CD ₃ OD) δ 9.46 (s, IH), 8.84 (s, IH), 8.78 (s, IH), 8.26 (d, J=8.5Hz, IH), 8.03 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.26 (d, J=5.5Hz, IH), 6.78 (s, 2H), 4.66 (s, IH), 4.59 (m, 2H), 4.46 (t, J=7.0Hz, 4H), 4.37 (m, 2H), 3.88 (d, J=11.5Hz, IH), 3.81-3.70 (m, 5H), 3.69 (t, J=5.5Hz, 2H), 3.55-3.49 (m, 3H), 3.11 (t, J=11.5Hz, 2H), 3.10-3.01 (m, 5H), 2.50 (t, J=15.0Hz, 2H), 2.33 (s, 3H), 2.35- 2.22 (m, 6H), 2.11-2.01 (m, 4H), 1.94 (m, 1H), 1.76-1.58 (m, 8H), 1.50-1.25 (m, 8H), 1.11 (s, 9H), 1.05-0.95 (m, 4H). LCMS (M+H) = 1395.6.

[0613] The following compounds were prepared in an analogous manner to that described for the synthesis of Compound 1-1 by substituting the appropriate aryl boronic acid in step B and E3 ligase ligand / spacer group in step E.

TABLE 12. Exemplary Compounds

TABLE 13. Exemplary Compounds

y l)carbamo y l)pyrazin- 2- yl)phenethy 1) -

2- (6-(4-((2,5-dioxo-2,5-diliydro-lH- pyrrol- 1 -yl)methyl)cyclohexane- 1 - carboxamido)hexanamido)-N5-(2-(3- (((S)-l-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)- 3 , 3 -dimethyl- 1 -oxobutan- 2- yl) amino ) -

3- oxopropoxy)ethyl)pentanediamide

ArB(OH) ₂ ^ - B(OH) ₂

E3 Ligand

M+l 1408

EXAMPLE 2

[0614] Synthesis of 3-amino-6-(4-(2-((2S)-2-(6-(4-((2,5-dioxo-2,5-diliydro-lH-py rrol-l- yl)methyl)cyclohexane-l-carboxamido)hexanamido)-6-(2-((2-(2, 6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)acetamido)hexanamido)ethyl)phenyl)- N-(4-morpholinopyridin-3- yl)pyrazine-2-carboxamide (Compound 2-1)

Step A: Preparation oflnt 7B-1

Int 1 B-1

Int 7B-1

[0615] A solution containing 3.0 g (8.0 mmol) of 3-amino-6-bromo-N-(4-morpholinopyridin-3- yl)pyrazine-2-carboxamide and 2.6 g (8.8 mmol) of (4-(2-(((tert-butoxy)carbonyl)- amino)ethyl)phenyl)boronic acid in 50 mL of dioxane and 8 mL of 2N a ₂ C0 ₃ (16.0 mmol) was degassed and back filled with nitrogen three times. 600 mg (0.8 mmol) of PdCl ₂ (dppf) was added and the reaction vessel was degassed with nitrogen twice. The reaction mixture was then heated at 90 °C for 3 h then cooled and stirred overnight then filtered through a plug of Celite ^® . The filtrate was diluted with EtOAc, washed with water and then brine, and dried over Na ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% MeOH / dichloromethane) to afford 2.5 g of compound Int 1.2a as a brown solid. The material was dissolved in 100 mL of 1: 1 THF : EtOH was degassed and back filled with nitrogen three times. 500 mg of 20% Pd(OH) ₂ was added and the mixture was degassed two additional times. The reaction mixture was stirred for 16 h then filtered through Celite with EtOAc. Removal of the solvent afforded 2.0g of lnt 7B-1 which was used directly in the next step. LCMS (M+H) = 420.

Step B: Preparation oflnt 7B-2

Int 7A-1 Int 7B-2

[0616] To a solution containing 228 mg (0.60 mmol) of Boc-L-Lys(Z)-OH in 5 mL of DMF was added 228 mg (0.60 mmol) of HATU and the reaction was stirred for 5 minutes before the addition of 210 mg (0.50 mmol) of lnt 7B-1 and 121 mg (1.2 mmol) of N-methylmorpholine. The reaction mixture was stirred for 3h then quenched with 5 mL of saturated NaHC0 ₃ solution and 2 mL of water. The mixture was extracted with EtOAc three times; the combined organics were washed with brine and then dried over a ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% CH ₃ OH / dichloromethane) to afford 190 mg of compound Int 7B-2 as a yellow solid. LCMS (M+H) = 782.

Step C: Preparation of Int 7B-3

Int 7B-3

[0617] A solution containing 164 mg (0.21 mmol) of Int 7B-2 in 10 mL of methanol was degassed three times while back filling with nitrogen before the addition of 50 mg of 5% Pd on carbon. A balloon of hydrogen was added and the reaction was stirred for 3h then filtered through Celite with EtOAc. Removal of the solvent afforded 40 mg of Int 7B-3 as a yellow solid. 1H NMR (CD ₃ OD) δ 9.48 (s, 1H), 8.77 (s, 1H), 8.28 (d, J=5.6Hz, 1H), 8.02 (d, J=8.0Hz, 2H), 7.40 (d, J=8.0Hz, 2H), 7.28 (d, J=5.2Hz, 1H), 3.98-3.79 (m, 5H), 3.51 (m, 2H), 3.04 (t, J=4.8Hz, 4H), 2.90 (t, J=5.1Hz, 2H), 2.62 (t, J=7.2Hz, 2H), 1.68 (m, 1H), 1.51 (s, 9H), 1.44-1.22 (m, 5H). LCMS (M+H) = 648.3.

[0618] To a solution containing 58 mg (0.09 mmol) of Int 7B-3 and 30 mg (0.09 mmol) of 2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)aceti c acid in 1 mL of DMF was added 48 mg (0.11 mmol) of BOP reagent and 0.047 mL (0.27 mmol) of diisopropylethylamine. The reaction mixture was stirred for 16 h then quenched with 1 mL of saturated NaHC0 ₃ solution and 1 mL of water. The mixture was extracted with EtOAc three times and the combined organic extracts were washed with brine and then dried over a ₂ S0 ₄ . The solvent was then evaporated and the residue was chromatographed (0% to 20% CH ₃ OH / dichloro methane) to afford 60 mg of the desired compound which was immediately dissolved in 4 mL of EtOAc and 1 mL of methanol then treated with 2 mL of 4 N HCl in dioxane at room temperature and the reaction was stirred for 2h. The solvent was removed under reduced pressure and the yellow solid was evaporated three times from diethyl ether to afford 49 mg of Int 7B-4 as bright yellow crystalline solid. LCMS (M+H) = 862.

[0619] Int 7B-4 is PROTAC T-20. Ste E: Preparation of Compound 2-1

[0620] To a solution containing 43 mg (0.05 mmol) of (S)-2-amino-N ¹ -(4-(5-amino-6-((4- morpholinopyridin-3-yl)carbamoyl)pyrazin-2-yl)benzyl)-N5-(2- (3-(((S)-l-((2S,4R)-4-hydroxy-2-

((4-(4-methylthiazol-5-yl)benzyl)carbam

yl)amino)-3-oxopropoxy)ethyl)pentanediamide trihydrochloride as bright yellow crystalline solid which was combined with (32 mg, 0.07 mmol) of LC-smcc (succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxy-(6-amidocaproate)) in 3 mL of DCM and DIPEA (0.13 mL, 0.7 mmol). After stirring overnight, the reaction became cloudy and LCMS indicated the presence of product. The reaction was concentrated then taken up in a minimum amount of THF and water. The mixture was neutralized with saturated NaHC0 ₃ and the mixture was

chromatographed (30 g, CI 8, H ₂ 0 to CH ₃ CN, liquid load) to provide Compound 2-1 as a yellow solid after lyophilization from CH ₃ CN/H ₂ 0. LCMS (M+H) = 1194.3.

EXAMPLE 3

TRAF2 And NCK Interacting Kinase (TNIK) Inhibitors

[0621] Synthesis of 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hex anamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl((6-((8-(((ls,4s )-4-hydroxy- cyclohexyl)oxy)quinazolin-2-yl)amino)-lH-benzo[d]imidazol-4- yl)methyl)carbamate (Compound 1C)

Step A: Preparation oflnt lC-1

Int 1C-1

[0622] 4-bromo-lH-benzo[d]imidazol-6-amine (903 mg, 4.26 mmol) was dissolved in a mixture of 15 mL THF, 8 mL of H ₂ 0 and 20 mL of MeOH. Solid NaHC0 ₃ (716 mg, 8.52 mmol) was added and the mixture was stirred for 15 min before adding 1.4 g (6.39 mmol) of Boc ₂ 0. The reaction mixture was concentrated and covered with MeOH to give a fine dark suspension. Silica gel was then added and the mix was concentrated to dryness. Silica gel column chromatography (ISCO 125 g, DCM to 20% MeOH/DCM) provided the desired material (1.1 g) as a yellow solid. 1H NMR (CDC1 ₃ ) δ 8.48 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 1.69 (s, 9H).

Step B: Preparation oflnt lC-2

Int 1C-1 Int 1C-2

[0623] To a mixture containing Int lC-1 (0.979 g, 2.37 mmol) in 25 mL of DMF was added 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.137 g, 0.237 mmol) and Zn(CN) ₂ (0.418 g, 3.56 mmol). The mixture was purged with N ₂ for 10 minutes. Palladium(II) acetate (0.053 g, 0.237 mmol) was then added and the mixture purged with N ₂ for 10 min then heated to 80°C. After 5h the reaction was cooled and diluted with EtOAc and filtered through Celite. Chromatography (24 g Gold silica, DCM to 20% MeOH/DCM) gave tert-butyl (4-cyano-lH-benzo[d]imidazol-6- yl)carbamate gave the desired product as a pale pink solid which was used directly in the next step.

Step C: Preparation oflnt lC-3

[0624] H Cube: 22 mL of 30% concentrated NH ₄ OH was diluted to 200 mL with MeOH. Half of this solution was used to prime and wash the H-cube lines and 2N NH ₄ OH in MeOH (88 ml) was used to dissolved the sample. Used 70 x 4 mm Ra-Ni column, 60°C, 10 psi, 1 ml/min, 0.026 molar in NH ₄ OH/MeOH for 4h (recirculate) on the H-cube instrument when LCMS showed product with some SM remained. The sample was concentrated and placed under high vacuum for 16h. Chromatography (40 g silica, Gold, DCM to 80: 18:2 DCM: MeOH :NH ₄ OH) gave a partial separation and 440 mg of the desired product as a white solid which was used directly in the next step without additional purification. LCMS (M+H) = 263.

Step D: Preparation oflnt lC-4

H ₂ N

Int 1 C-3 Int 1 C-4

[0625] To an ice-cold mixture of lnt lC-3 and 3 mL saturated NaHC0 ₃ in 17 mL of THF was added benzyl chloroformate (0.29 mL, 2.0 mmol) dropwise. The reaction mixture was stirred for 3h, then concentrated, covered with EtOAc and filtered through Na ₂ S0 ₄ , concentrated with silica gel and dry loaded onto a 24 g silica Gold cartridge. Elution with 100% heptanes to 100% EtOAc gave 450 mg of Int lC-4 as a white solid. 1H NMR (CDC1 ₃ ) d 8.52 (s, 1H), 8.29 (s, 1H), 7.6-7.3 (m, 11H), 6.60 (bs, 1H), 5.55 (s, 2H), 5.25 (s, 2H), 4.61 (s, 2H), 1.56 (s, 9H).

Step E: Preparation of Int lC-5

CbzHN

Int 1 C-4 Int 1 C-5

[0626] To a suspension of benzyl 4-((((benzyloxy)carbonyl)amino)methyl)-6-((tert- butoxycarbonyl)amino)-lH-benzo[d]imidazole-l-carboxylate (161 mg, 0.303 mmol) in 10 mL of MeOH was added K ₂ CO ₃ (84 mg, 0.606 mmol). The reaction was stirred at room temperature for lh when TLC showed the reaction to be complete. Chromatography (4 g silica, Gold, DCM to 20% MeOH/DCM) gave the mon-deprotected compound (141.8, mg) as a white solid. This material was dissolved in 9 mL of DCM and treated with 1 mL of TFA. The reaction was stirred at room temperature for lh then concentrated. The residue taken up in DCM and treated with 1 mL of Et ₃ N. The reaction was concentrated and chromatographed (4 g silica gel, Gold, DCM to

80: 18:2 DCM:MeOH:NH40H) to give 115 mg of Int lC-5 as a pale yellow semi-solid. 1H NMR (CDCI ₃ ) δ 7.70 (s, 1H), 7.25 (m, 5H), 6.72 (s, 1H), 6.42 (s, 1H), 5.87 (bs, 1H), 5.05 (s, 2H), 4.44

(s, 2H).

Step F: Preparation of Int lC-6

Int 1C-5

Int 1C-6

[0627] A mixture containing 56 mg (0.188 mmol) of Int lC-5 and 96 mg (0.244 mmol) of 8- (((ls,4s)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2- chloroquinazoline in 2 mL of isopropanol was heated in a microwave tube for 2h at 150°C. The reaction was cooled and 0.5 mL of water was added. Tetrabutylammonium fluoride (564 μΐ, 0.564 mmol) was added and the mixture was stirred for 2h. The solvent was concentrated then partitioned between EtOAc and NaHC0 ₃ . The EtOAc was washed with water then brine and dried ( a ₂ S0 ₄ ), filtered and concentrated. The material was adsorbed onto silica gel using DCM then concentrated.

Chromatography (24 g silica gel, Gold, DCM to 10% MeOH/DCM) to give 41 mg of Int lC-6 as a yellow solid. 1H NMR (CD ₃ OD) δ 9.12 (s, IH), 9.05 (bs, IH), 8.06 (s, IH), 7.41-7.06 (m, 9H), 5.13 (s, 2H), 4.89 (s, IH), 4.71 (bs, 2H), 3.86 (bs, IH), 2.20-2.07 (m, 4H), 1.89-1.80 (m, 2H), 1.73 (t, J=12Hz, 2H). LCMS (M+H) = 539.6.

Step G: Preparation of Compound lC-7

[0628] A mixture containing benzyl ((6-((8-(((ls,4s)-4-hydroxycyclohexyl)oxy)quinazolin-2- yl)amino)-lH-benzo[d]imidazole-4-yl)methyl)carbamate (181 mg, 0.336 mmol) was combined with water (2 ml) and 4 N HCl in dioxane (2 ml) in a microwave tube then heated in a microwave for 2h at 100°C. The solvents were removed under reduced pressure and saturated NaHC0 ₃ was added to make the free-base. This mixture was loaded onto a 100 g C18 column using a minimum of MeOH to finish the loading. Elution with H ₂ 0 to CH ₃ CN (TFA modifier) gave 121 mg of Int lC-7 as yellow solid after co-evaporation with DCM and heptane. 1H NMR (D ₂ 0) δ 9.12 (s, IH), 8.97 (s, IH), 8.53 (s, IH), 7.48 (d, J=2.0Hz, IH), 7.42 (dd, J=2.0, 8.0Hz, IH), 7.34 (d, J=8.0Hz, IH), 7.30 (m, 3H), 4.70 (s, IH), 4.44 (s, 2H), 3.80 (m, IH), 1.94 (m, 2H), 1.67 (m, 6H). LCMS (M+H) = 405.3. Step H: Preparation of Compound 1 C

[0629] To a solution containing 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzy l (4-nitrophenyl) carbonate (45.6 mg, 0.062 mmol) in 1 mL of DMF was added 618 uL of a 0.1 M solution of (ls,4s)-4-((2- ((4-(aminomethyl)-lH-benzo[d]imidazol-6-yl)amino)quinazolin- 8-yl)oxy)cyclohexan-l-ol (618 0.062 mmol) and N,N-diisopropylethylamine (21.53 μΐ, 0.124 mmol). The reaction was stirred for 16h then concentrated. The residue was chromatographed (30 g C18, H ₂ 0 to CH ₃ CN, liquid loaded using a mixture of THF, saturated NaHC0 ₃ (aq) and H ₂ 0 to give 25 mg of

Compound 1C as a yellow solid. 1H NMR (CD ₃ OD) δ 9.12 (s, IH), 9.07 (bs, IH), 8.06 (s, IH), 7.56 (d, J=8.0Hz, 2H), 7.40 (d, J=8.0Hz, IH), 7.33-7.22 (m, 4H), 7.12 (bs, IH), 6.76 (s, 2H), 5.08 (s, 2H), 4.89 (m, IH), 4.82 (s, 2H), 4.72 (m, 2H), 4.49 (m, IH), 4.15 (d, J=7.5Hz, IH), 3.86 (bs, IH), 3.44 (m, 3H), 3.22-3.08 (m, 4H), 2.26 (t, J=7.5Hz, 2H), 2.18-2.03 (m, 6H), 1.89 (m, 3H), 1.73 (m, 3H), 1.65-1.51 (m, 7H), 1.30 (3H), 0.96 (m, 6H). LCMS (M+H) = 1003.9.

EXAMPLE 4

Generation of Antibody- TGFb Inhibitor Conjugates through Partial Reduction of Native

Intrachain Disulfide Bonds of Non-Engineered Antibodies

[0630] The mAb (3-8 mg/mL in PBS) was exchanged into HEPES (100 mM, pH 7.0, 1 mM DTP A) via molecular weight cut-off centrifugal filtration (Millipore, 30 kDa). The resultant mAb solution was transferred to a tared 50 mL conical tube. The mAb concentration was determined to be 3-8 mg/mL by A ₂₈ o. To the mAb solution was added TCEP (2.0-4.0 equivalents, 1 mM stock) at room temperature and the resultant mixture was incubated at 37 °C for 30-90 minutes, with gentle shaking. Upon being cooled to room temperature, a stir bar was added to the reaction tube. With stirring, the linker-pay load from Examples 1 and 2 (5-10 equivalents, 10 mM DMSO) was added dropwise. The resultant reaction mixture was allowed to stir at ambient temperature for 30-60 minutes, at which point N-ethyl maleimide (3.0 equivalents, 100 mM DMA) was added. After an additional 15 minutes of stirring, N-acetylcysteine (6.0-11.0 equivalents, 50 mM HEPES) was added. The crude ADC was then exchanged into PBS and purified by preparative SEC (e.g. HiLoad 26/600, Superdex 200pg) using PBS as the mobile phase. The pure fractions were concentrated via molecular weight cut-off centrifugal filtration (Millipore, 30 kDa), sterile filtered, and transferred to 15 mL conical tubes. Drug-antibody construct ratios (molar ratios) were determined by methods described in Example 4 below.

EXAMPLE 5

General Procedure for the Determination of the Drug- Antibody-Ratios [0631] Hydrophobic Interaction Chromatography

[0632] 10 μL· oΐ a 6 mg/mL solution of a conjugate is injected into an HPLC system set-up with a TOSOH TSKgel Butyl-NPR™ hydrophobic interaction chromatography (HIC) column (2.5 μΜ particle size, 4.6 mm x 35 mm) attached. Then, over the course of 18 minutes, a method is run in which the mobile phase gradient is run from 100% mobile phase A to 100% mobile phase B over the course of 12 minutes, followed by a six-minute re-equilibration at 100% mobile phase A. The flow rate is 0.8 mL/min and the detector is set at 280 nM. Mobile phase A is 1.5 M ammonium sulfate, 25 mM sodium phosphate (pH 7). Mobile phase B is 25% isopropanol in 25 mM sodium phosphate (pH 7). Post-run, the chromatogram is integrated and the molar ratio is determined by summing the weighted peak area.

Mass Spectrometry

One microgram of immune- stimulatory conjugate (antibody construct immune- stimulatory compound conjugate) is injected into an LC/MS such as an Agilent 6550 iFunnel Q-TOF equipped with an Agilent Dual Jet Stream ESI source coupled with Agilent 1290 Infinity UHPLC system. Raw data is obtained and is deconvoluted with software such as Agilent MassHunter Qualitative Analysis Software with BioConfirm using the Maximum Entropy deconvolution algorithm. The average mass of the conjugates is calculated by the software, which used top peak height at 25% for the calculation. This data is then imported into another program to calculate the molar ratio of the conjugates such as Agilent molar ratio calculator

EXAMPLE 6

Determination of K _d Values for antigens and FcgRs

[0633] K _d is measured using surface plasmon resonance assays using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25 °C with immobilized antigen CM5 chips at ^" 10 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 μg/mL (~0.2 μΜ) before injection at a flow rate of 5 μΕ/ητίηυίε to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25 °C at a flow rate of approximately 25 μΕ/ηιίη. Association rates (k _on ) and dissociation rates (koff) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (IQ) is calculated as the ratio k ₀ ff/k _on . See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 106 M- l s- 1 by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation=295 nm; emission=340 nm, 16 nm band-pass) at 25 °C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop- flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO™

spectrophotometer (ThermoSpectronic) with a stirred cuvette.

EXAMPLE 7

PBMC Screening Assay

[0634] Materials and general procedures. Human peripheral blood mononuclear cells (PBMC) were obtained from BenTek, frozen at 25 x 10 ⁶ cell/mL in 10 % DMSO (Sigma) prepared in fetal bovine serum (Gibco) and stored in liquid nitrogen. For the culture, PBMC were thawed quickly in a 37 °C water bath and diluted into pre-warmed RPMI 1640 (Lonza) supplemented with 10% fetal bovine serum, 2 mM glutamine, 50 μg/mL penicillin, 50 U/mL streptomycin (all from Gibco) and centrifuged for 5 minutes at 500 x g. PBMC were suspended into the growth media described above and cultured at a concentration of 1 x 10 ⁶ cells per mL at 37 °C in a 5% C0 ₂ incubator.

[0635] General procedure for in vitro small molecule screening. PBMC were thawed, suspended at a concentration of 1 x 10 ⁶ cell/mL in growth media and 200 was aliquoted into each well of a 96-well plate for a total of 0.2 x 10 ⁶ cells per well. PBMC were incubated for approximately 16-18 hours at 37 °C in a 5% C0 ₂ humidified incubator. PBMC plates were centrifuged at 500 x g for 5 minutes and the growth media was removed. 150 of twelve concentrations ranging from 1000 to 0.000238 nM of small molecules prepared in growth media were added to PBMC in duplicate and incubated for 24 hours at 37 °C in a 5% C0 ₂ incubator. Prior to supernatant harvest, cells were spun at 500 x g for 5 minutes to remove cell debris. TNF-a activity was assessed in the supernatant by ELISA (eBioscience) or HTRF (CisBio) per the manufacturer's instructions. The optical density at 450 nm and 570 nm (ELISA) or luminescence (HTRF) was analyzed using an Envision (Perkin Elmer) plate reader.

EXAMPLE 8

General Procedure for measuring the Kd of kinase inhibitor by BLI

[0636] Measurement of the Kd for a kinase target is determined using the following reactants: (1) immune- stimulatory conjugate, (2) non-conjugated immune- stimulatory compound-linker constructs, and (3) non-conjugated immune- stimulatory control compound is performed using an Octet Red 96 instrument (ForteBio) with a biotin coated biosensor chip. As a negative control and baseline setting for the conjugate, the unconjugated control antibody is also included as a binding reactant (4). Purified, active, recombinant strep-tagged protein kinase domain is immobilized onto the bio-sensor surface at several concentrations. The analysis for each reactant is performed in the following steps: (1) baseline acquisition (60 s); (2) loading of the kinase domain onto the biotin coated biosensor (120 s); (3) second baseline acquisition (60 s); (4) association of the reactant (120 s); and (5) dissociation of reactant (480-900 s). The control reactant (1) is used at 6 concentrations of 3-fold concentration series diluted from a DMSO stock into PBS buffer for incubations. Data are analyzed using Octet Data Analysis Software 9.0 (ForteBio) and fitted to the 1: 1 binding model. Equilibrium dissociation constants (K _D ) are calculated by the ratio of k _on to k _Dff . Reactants (2-4) are then used at 6 concentrations of 3-fold concentration series bracketing the observed Kd for reactant (1). Reactant (3) is diluted from a DMSO stock into PBS buffer for incubations. The antibody reactants (2) and (4) are diluted for incubations into PBS/0. l%BSA/0.02%Tween 20. Data for reactants (2-4) are analyzed using Octet Data Analysis Software 9.0 (ForteBio) and fitted to the 1: 1 binding model. Equilibrium dissociation constants (K _D ) are calculated by the ratio of k _on to k _D ff.

EXAMPLE 9

CEA-TNIK Immune-stimulatory Compounds Retain Inhibitor Affinity for TNIK

[0637] The K _d for CEA-TNIK immune- stimulatory conjugates with TNIK inhibitors and the inhibitors as free, control compounds are determined using Bio-layer Inter ferometry with an Octet Red instrument (ForteBio) as follows. Dual N-terminal tagged (strep, GST) active kinase TNIK kinase (aa 1-367) is expressed as a recombinant protein by baculo virus in sf9 insect cells and purified by a GST-affinity column. The TNIK kinase is captured onto the surface of biotin- coated biosensor wells at several different loading concentrations. The analysis for each reactant is performed in the following steps: (1) baseline acquisition (60 s); (2) loading of the kinase domain onto the biotin coated biosensor (120 s); (3) second baseline acquisition (60 s); (4) association of the reactant (120 s); and (5) dissociation of reactant (480-900 s). First, the control compound is used at 6 concentrations of 3-fold concentration series diluted from a DMSO stock into PBS buffer for incubations. Data are analyzed using Octet Data Analysis Software 9.0 (ForteBio) and fitted to the 1: 1 binding model. Equilibrium dissociation constants (K _D ) are calculated by the ratio of k _on to k _D ff. Next, the CEA-TNIK conjugates are then used at 6 concentrations of 3-fold concentration series bracketing the observed K _d for reactant (1).

Reactant (3) is diluted from a DMSO stock into PBS buffer for incubations. The antibody reactants (2) and (4) are diluted for incubations into PBS/0. l%BSA/0.02%Tween 20. Data for reactants (2-4) are analyzed using Octet Data Analysis Software 9.0 (ForteBio) and fitted to the 1: 1 binding model. Equilibrium dissociation constants (K _D ) are calculated by the ratio of k _on to k ₀ ff. The results show that the K _d of the tested CEA-TNIK immune- stimulatory conjugates is measured at 1-10 times the K _d of its control compound.

EXAMPLE 10

Immune-Stimulatory Conjugates Inhibit Signaling by A2aR without Processing

[0638] To demonstrate immune- stimulatory conjugates do not require extensive processing for activity, immune- stimulatory conjugates with A2aR inhibitors are tested in a short-term cell- based assay for antagonism of signaling by a cell surface GPCR. CHO transfectants expressing human A2aR are seeded into 96-well white bottom plates at 2-3xl0 ⁴ cells/well in the absence of G418 20 hours prior to assay. Equimolar titrations of immune- stimulatory compounds and immune- stimulatory conjugates (conjugates containing the immune- stimulatory compounds at DARs 2 to 4) are added to the cells, incubated for 15-30 minutes, followed by addition of 10 nM adenine and 10 further minutes of incubation. Irrelevant immune- stimulatory compounds and conjugates are used as negative controls. (In some experiments, adenine deaminase (3U/ml) and adenosine 5' [ ,β-methylene] diphosphate (50uM) are added along with test items to lower cAMP baseline for the assay.) After the 10-minute incubation, cAMP levels are measured by an HTRF assay using a GS cAMP Assay Kit (CisBio) and an Envision multi-modal plate reader (Perkin-Elmer). The results show that the immune- stimulatory conjugates inhibit the cAMP increase generated by A2aR activation within minutes indicating that little to no processing is needed for immune- stimulatory activity and do so with IC50s close to those of the non- conjugated immuno stimulatory compound.

EXAMPLE 11

General Procedure for Determining Protein Degradation by Immune-Modulatory

Conjugates Containing Proteolysis targeting modules

[0639] Proteolysis targeting modules (PTMs) and immune-modulatory compounds are prepared as described above. Conjugates of PTMs and antibody constructs are prepared as described in Example 4. The average DAR is about 4.

[0640] Cells are plated, allowed to adhere, and treated with vehicle, an inhibitor, a PROTAC or an immune-modulatory conjugate in the presence or absence of proteasome inhibitor, such as

MG-132. After treatment, media is aspirated and cells are rinsed with ice cold PBS. Ice cold lysis buffer (20 mM TrisHCl pH 7.5, 150 mM NaCl, 1% Triton X-100, 2 mM EDTA and 10% glycerol) containing phosphatase and protease inhibitors is added to wells and cells are removed from the plate using a cell scraper. Lysates are transferred to a 1.5 ml tube and rocked for one hour at 4°C with vortexing every -15 minutes. Tubes are spun at 8500xg for 10 minutes and supernatants are drawn into an insulin needle twice. Cell lysates are frozen at -80°C. Protein concentration is determined using a BCA assay and equal amounts of samples are boiled with reducing loading buffer. The samples are then subjected to electrophoresis on 4-20%

polyacrylamide gels which are then transferred to PVDF membranes. Blocking and staining are done in 5% w/v soy milk PBS with 0.05% Tween 20 and washing using PBS with 0.05% Tween.

For PROTACs and immune-modulatory conjugates targeting TGFPR2, blots are incubated overnight with rocking at 4°C with 1:200 primary anti-TGFpR2 antibody (Santa Cruz, sc-17791).

For PROTACs and immune-modulatory conjugates targeting TGFpRl, blots are incubated overnight with rocking at 4°C with 1:3000 primary anti-TGFpRl antibody (R&D, MAB5871).

Loading controls are detected with 1: 15000 diluted primary antibody incubation at room temperature for 1 hour with rocking (Tubulin - Abeam, ab7291 ; Actin - Abeam, ab8224).

Secondary antibodies are diluted 1: 10000 and blots are incubated for 1 hour at room temperature with rocking (Jackson ImmunoResearch, 115-035-003 or 112-035-003). ECL reagent is used to detect the signal and blots are imaged using the ChemiDoc MP (Biorad). Analysis of densitometry is done using the ImageLab software and signals are adjusted based on loading control.

EXAMPLE 12

Degradation of TFGPR2 by a TGFpR2-VHL PROTAC Conjugated to an Anti-HER2

Antibody.

[0641] Protac T-20 was prepared as described in Example 2. Pertuzumab was used as the HER2 antibody. Her2 Antibody-Protac conjugate (050-T11020; Compound 2.1 (Example 2)) was prepared by attachment of maleimidomethylcyclohexane-l-carboxylate linker to T-20 to form a linker-T-20 construct (T11020) followed by conjugation of Tl 1020) to the Her2 antibody generally following the protocol in Example 4 for interchain cysteine conjugation. The average drug loading was about 2 to 4.

[0642] Plasmid expressing HER2 was transfected into HEK293 cells using commercially available materials and conditions. Twenty four hours after transfection, cells were treated with DMSO, PROTAC T-20, HER2 antibody (IgGl), or Her2 Antibody-Protac conjugate (050- Tl 1020). Whole cell lysates were prepared from cells after 2, 24, or 48 hours incubation and quantitated with a BCA assay. Equal amounts of lysates were run on protein gels, transferred to PVDF, and TGFPR2 was detected using commercially available reagents. To quantitate the amount of protein degradation, the signals on the Western blot were adjusted to actin loading control and data is presented as a percent of matched control. Referring to FIGURE 21A, FIGURE 21B, and FIGURE 21C, at both tested concentrations, 0.5uM and luM of conjugate, the level of target TGFPR2 was diminished at 24 and 48 hours of treatment, while TGFPR2.

EXAMPLE 13

Antigen Targeted Degradation of TGFpR2 by an Antibody Conjugate using VHL and

Cereblon E3 Binding Moieties

[0643] A HER2 antigen positive, TROP2 antigen negative cell line BT474 was used to demonstrate antigen specific delivery of PROTAC conjugates.

[0644] Protac T-15 and T-20 were prepared as described above in Examples 1 and 2, respectively. Pertuzumab was used as the Her2 antibody. Sacituzumab was used as the Trop2 antibody. Her2 Antibody-Protac conjugates (050-T05015 and 050-T05020) were prepared by attachment of an MC-VC-PAB linker to T-15 or T-20 for form T05015 and T05020 constructs, respectively, followed by conjugation to the Her2 antibody generally following the protocol in Example 4 for interchain cysteine conjugation. The average drug loading was about 2 to 4. Trop2-Protac conjugate (130-T05020) was similarly prepared.

[0645] BT474 cells were plated and treated the following day with either a small molecule (T-15 or T-20), a conjugate of a HER2 antibody TGFpR2-VHL binding PROTAC (050-T05020), a conjugate of a HER2 antibody TGFpR2-Cereblon binding PROTAC (050-T05015) or a conjugate of a TROP2 antibody TGFpR2-VHL binding PROTAC (130-T05020). Whole cell lysates were prepared 24 hours after treatment and quantitated with a BCA assay. Equal amounts of lysates were run on protein gels, transferred to PVDF, and TGFPR2 and actin were detected using commercially available reagents. Quantitation of protein bands was performed and Western signal was adjusted to actin loading control and data is presented as a percent of vehicle control. Referring to FIGURE 22A and FIGURE 22B, HER2-antigen specific degradation was found with both the HER2 binding PROTAC conjugates, but not with the control TROP2- binding PROTAC conjugates.

EXAMPLE 14

Lowered Cellular Level of TGFpR2 and TGFpRl by a TGFpR2/TGFpRl-VHL PROTAC is Proteasome Inhibitor Sensitive.

[0646] Normal human lung fibroblasts were treated with or without proteasome inhibitor MG- 132 followed by the addition of DMSO or T-20. Whole cell lysates were prepared and then quantitated with a BCA assay. Equal amounts of lysates were run on protein gels and transferred to PVDF membrane. TGFpRl, TGFPR2, and actin were detected using commercially available reagents. Western signal was adjusted to actin loading control and data is presented as a percent of the matched vehicle control. Referring to FIGURE 23A and FIGURE 23B, addition of the proteasome inhibitor protected TGFpRl and TGFPR2 against degradation induced by T-20.