ALK5 INHIBITORS, CONJUGATES, AND USES THEREOF

STATEMENT REGARDING SEQUENCE LISTING

[0001] The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 860234_414WO.txt. The text file is 1.30 MB, was created on October 8, 2021, and is being submitted electronically via EFS-Web.

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 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.

[0003] Fibrosis is the formation of excess fibrous connective tissue or scar tissue in an organ or tissue in a reparative or reactive process. Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage, which include the lungs, liver, heart, and brain. Scar tissue blocks arteries, immobilizes joints and damages internal organs, wreaking havoc on the body's ability to maintain vital functions. Every year, millions of people are hospitalized due to the damaging effects of fibrosis. However, current therapeutics for treating fibrotic diseases are lacking or have drawbacks. Thus, there remains a considerable need for alternative or improved treatments for fibrotic diseases.

BRIEF SUMMARY

[0004] The disclosure provides, inter alia, compounds represented by the structure of Formula (I):

or a salt thereof, wherein the variable R ¹ , R ² , R ^a , R ^b , Q ^A , Q ^B , Q ³ , Q ⁴ , Q ⁵ , and m are as described herein.

[0005] In some embodiments, compounds disclosed herein are attached to a linker to form compound-linkers.

[0006] In some embodiments, compounds disclosed herein are covalently bound to an antibody construct or a targeting moiety, optionally via a linker. In some embodiments, compounds disclosed herein are covalently bound to an anti-ASGRl antibody or an antigen binding domain thereof.

[0007] In some embodiments, compounds disclosed herein are covalently bound to an antibody construct or a targeting moiety, the antibody or antigen binding domain thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (i) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1001, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1008, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1013; and the VL comprises a CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1018, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1023, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1033; (ii) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1001, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1006, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1013; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1018, a VL- CDR2 comprising the amino acid sequence of SEQ ID NO: 1023, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1033; (iii) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1002, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1009, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1014; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1019, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1026, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1034; (iv) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1001, a VH-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NOS: 1006-1008, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1013; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1018, a VL-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NOS: 1023-1025, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1033; (v) the VH comprises a CDR1 (VH- CDR1) comprising the amino acid sequence of SEQ ID NO: 1002, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1009, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1014; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1019, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1026 or SEQ ID NO: 1027, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1034; (vi) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1005, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1012, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1017; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1022, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1032, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1037; (vii) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1003, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1010, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1015; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1020, a VL-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NOS: 1028-1030, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1035; or (viii) the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1004, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1011, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1016; and the VL comprises a CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1021, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1031, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1036.

[0008] In some embodiments, the conjugate is represented by Formula (I): wherein: A is the anti-ASGRl antibody or antigen-binding fragment thereof, L is the linker; D _x is a compound of the disclosure, wherein the compound comprises an ALK5 inhibitor; n is selected from 1 to 20; and z is selected from 1 to 20. In some embodiments, n is an integer from 1 to about 10, or from 1 to about 5, or is 1 or 2, or is 1. In some embodiments, n is an integer from 1 to 10, or from 1 to 5, or is 1 or 2, or is 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, z is from 1 to about 10, or from 1 to about 9, or from 1 to about 8, or 2 to about 6, or about 3 to about 5, or about 4. In some embodiments, z is from 1 to 10, or from 1 to 9, or from 1 to 8, or 2 to 6, or about 3 to 5, or 4. In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0009] The disclosure provides an ALK5 inhibitor conjugate or salt thereof represented by the formula: wherein Antibody is an anti-ASGRl antibody comprising light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1131-1133 and 1244-1249, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1043-1088 and 1238-1243; light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1134-1137, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1089-1093 light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1143-1149, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1113-1125; light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1138-1141, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1094-1102; or light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence of SEQ ID NO: 1142, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence selected from any one of SEQ ID NOS: 1103-1112; as determined by the Kabat index, and L ³ -D is a linker-compound.

[0010] The disclosure provides pharmaceutical compositions of the compounds or conjugates described herein. [0011] The disclosure provides a method for treating cancer, comprising administering a compound, a conjugate, or a pharmaceutical composition as described herein to a subject in need thereof.

[0012] The disclosure provides a method for enhancing an immune response (e.g., an anti-cancer immune response) in a subject comprising administering a compound, a conjugate, or a pharmaceutical composition as described herein to a subject in need thereof.

[0013] The disclosure provides a method for treating fibrosis, comprising administering a compound, a conjugate, or a pharmaceutical composition as described herein to a subject in need thereof. In some embodiments, the fibrosis is cancer-associated. In some embodiments, the fibrosis is not cancer-associated. In some embodiments, the fibrosis is scleroderma. In some embodiments, the fibrosis is systemic fibrosis. In some embodiments, the fibrotic disease is steatohepatitis., e.g., non-alcoholic steatohepatitis (NASH).

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is a plot of % Reporter Activity versus amount of drug (Log nM), which shows the impact of structural variation on the activity of bicyclic pyrazole-based inhibitors, as conjugates.

[0015] Figure 2 is a plot of % Reporter Activity versus amount of drug (Log nM), which shows the impact of structural variation on the activity of pyrazole-based inhibitors, as conjugates.

[0016] Figure 3 is a plot of % Reporter Activity versus amount of drug (Log nM), which shows the impact of structural variation (carboxylate topology) on the activity of pyrazole-based inhibitors, as conjugates.

DETAILED DESCRIPTION

[0017] Activin receptor-like kinase 5 (ALK5), which is also commonly known as transforming growth factor beta receptor 1 (TGF-PR1), is a serine/threonine kinase transmembrane receptor. It is a part of the TGFβ signaling pathway and is involved in signal transduction from the cell surface to the cytoplasm. The TGFβ signaling pathway regulates gene expression of genes involved in cellular processes such as differentiation, apoptosis, wound healing, and cell growth. ALK5 and TGF-PR1 can be used interchangeably.

[0018] In the absence of TGFβ ligands, ALK5 remains a homodimeric cell surface receptor. However, ligand binding to type II TGFβ receptor (TGFβR2) induces the formation of the TGFβR1/TGFβR2 complex, which leads to phosphorylation of Mothers Against Decapentaplegic homolog 2 (Smad2) and Mothers Against Decapentaplegic homolog 3 (Smad3) and subsequent modulation of a number of downstream signaling targets involved in the regulation of gene expression. As such, inhibitors of ALK5 may be useful in altering or modulating the expression of genes involved in cancer, and thus, may be useful in treating and preventing cancer.

[0019] As used throughout this disclosure, a “modulator” of ALK5 is a compound which, when administered to a subject, provides the desired modulation of the target receptor. For example, the compound may function as a full or partial antagonist or agonist of the receptor, either by interacting directly or indirectly with the target receptor. The disclosure provides compounds, linkers, conjugates and pharmaceutical compositions for use in the treatment of disease. In some embodiments, the compounds of the disclosure modulate activin receptor-like kinase 5 (ALK5). In some embodiments, the compounds of the disclosure may act as ALK5 inhibitors.

[0020] The compounds, salts, and conjugates of the disclosure may be useful for treatment and/or prevention (e.g., vaccination) of cancer, an autoimmune disease, inflammation, fibrosis, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, an immunodeficiency, or an infectious disease.

[0021] In some embodiments, the compounds, salts, and conjugates have utility in the treatment of cancer either as single agents or in combination therapy. In some embodiments, the compounds, salts, and conjugates have utility as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. In some embodiments, the compounds and salts are incorporated into a conjugate that can be utilized, for example, to enhance an immune response. In some embodiments, the disclosure provides conjugates including a compound or salt described in the disclosure and an antibody construct.

[0022] In some embodiments, the compounds, salts, and conjugates have utility in the treatment or amelioration of a fibrotic disease, either as single agents or in combination therapy. In some embodiments, the compounds, salts, and conjugates have utility as single agent immunomodulators, vaccine adjuvants or in combination with conventional fibrotic disease therapies. In some embodiments, the compounds and salts are incorporated into a conjugate that can be utilized, for example, to enhance an immune response. In some embodiments, the disclosure provides conjugates including a compound or salt described herein and an antibody construct. Definitions

[0023] Prior to setting forth this disclosure in more detail, it may be helpful to an understanding thereof to provide definitions of certain terms to be used herein. Additional definitions are set forth throughout this disclosure. Unless specifically defined otherwise, the technical terms, as used throughout this disclosure, have their normal meaning as understood in the art. The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the disclosure. It is also to be understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.

[0024] As used in the specification and claims, the singular form “a,” “an,” and “the” includes plural references unless the context clearly dictates otherwise. It should be understood that the terms “a” and “an” as used throughout this disclosure refer to “one or more” of the enumerated components.

[0025] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives. As used throughout this disclosure, the terms “include” and “comprise” are used synonymously. Thus the phrase “comprising A or B” means including A, B, or A and B.

[0026] The phrase “at least one of’ when followed by a list of items or elements refers to an open-ended set of one or more of the elements in the list, which may, but does not necessarily, include more than one of the elements.

[0027] The term “about” as used throughout this disclosure in the context of a number refers to a range centered on that number and spanning 15% less than that number and 15% more than that number. The term “about” used in the context of a range refers to an extended range spanning 15% less than that the lowest number listed in the range and 15% more than the greatest number listed in the range.

[0028] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), irrespective of whether a specific numerical value or specific sub-range is expressly stated. Also, any number range recited in the disclosure relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. [0029] The phrase “targeting moiety” refers to a structure that has a selective affinity for or selectively binds to a target molecule relative to other non-target molecules. A targeting moiety may include, for example, an antibody, an antibody construct, a peptide, a polypeptide, a ligand, carbohydrate, a polynucleotide, an oligonucleotide, or a receptor or a binding portion thereof. The target biological molecule may be a biological receptor or other structure of a cell, such as a tumor antigen.

[0030] As used throughout this disclosure, the term “antibody” refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive toward, a specific antigen. The portion of the antibody that binds a specific antigen may be referred to as an “antigen binding domain.” An antibody can include, for example, polyclonal, monoclonal, and genetically engineered antibodies, and antigen binding fragments thereof. An antibody can be, for example, murine, chimeric, humanized, heteroconjugate, bispecific, diabody, triabody, or tetrabody.

[0031] As used throughout this disclosure throughout this disclosure, an “antigen binding domain” refers to a region of a molecule that specifically binds to an antigen. An antigen binding domain can be an antigen-binding portion of an antibody or an antibody fragment. An antigen binding domain can be one or more fragments of an antibody that can retain the ability to specifically bind to an antigen. An antigen binding domain can be an antigen binding fragment. In some embodiments, an antigen binding domain can recognize a single antigen. An antigen binding domain can recognize, for example, two or three antigens. An antigen binding fragment can include, for example, a Fab', F(ab') ₂ , Fab, Fv, rlgG, scFv, hcAbs (heavy chain antibodies), a single domain antibody, VHH, VNAR, sdAb, or nanobody.

[0032] As used throughout this disclosure, “specifically binds” and the like refers to the specific association or specific binding between the antigen binding domain and the antigen, as compared with the interaction of the antigen binding domain with a different antigen (i.e., non- specific binding). In some embodiments, an antigen binding domain that recognizes or specifically binds to an antigen has a dissociation constant (KD) of < <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 ^-8 M or less; from about 10 ^-8 M to about 10 ^-13 M; from about 10 ^-9 M to about 10 ^-13 M). Specific binding does not require that the antigen binding domain not associate with or bind to any other antigen, but rather that it preferentially associates with or binds to the target antigen of interest, as compared to off-target association with or binding to an unrelated antigen. [0033] As used throughout this disclosure, an “antibody construct” refers to a molecule, e.g., a protein, peptide, antibody or portion thereof, that contains an antigen binding domain and an Fc region (e.g., an Fc domain from within the Fc region).

[0034] As used throughout this disclosure, a “Fc domain” can be from within an Fc region of an antibody or from within a non-antibody molecule domain that can bind to an Fc receptor.

[0035] As used throughout this disclosure, a “tumor antigen” can be an antigenic substance associated with a tumor or cancer cell, and can trigger an immune response in a host.

[0036] As used throughout this disclosure, “identical” or “identity” refer to the similarity between a DNA, RNA, nucleotide, amino acid, or protein sequence to another DNA, RNA, nucleotide, amino acid, or protein sequence. Identity 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 can be 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. Percent (%) sequence identity with respect to a reference amino acid sequence can be 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. In some embodiments, the percent sequence identity values are generated using the NCBI BLAST 2.0 software as defined by Altschul et al., Nucleic Acids Res. 25:3389-3402, 2007, with the parameters set to default values.

[0037] As used throughout this disclosure, a compound or salt of the disclosure, e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, may be referred to as an “ALK5 inhibitor,” a drug, “D,” a compound, or a payload, “P,” particularly when referenced as part of a conjugate. In some embodiments, an ALK5 inhibitor inhibits the activity of ALK5 enzyme by about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% as compared to ALK5 activity in the absence of the inhibitor.

[0038] As used throughout this disclosure, “LP,” “linker-payload,” “LD,” “linker-ALK5 inhibitor,” “linker-drug,” or “linker-compound” may be used throughout this disclosure to refer to a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, bound to a linker.

[0039] As used throughout this disclosure, “conjugate” means a compound of the disclosure conjugated either directly or through a linker group to an antibody, an antibody construct, or a targeting moiety.

[0040] As used throughout this disclosure, drug-to-antibody ratio (“DAR”) refers to a particular number of compounds (ALK5 inhibitors) of a conjugate that are covalently attached or linked, directly or indirectly (via a linker), to an antibody, antibody construct, or targeting moiety. For a conjugate having more than one compound covalently attached or linked, the linked compounds may be the same or different. In some embodiments, a conjugate is represented by the following formula: wherein A is an antibody, an antibody construct, or a targeting moiety, L is a linker, D is a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and z is from 1 to about 20. In some embodiments, z ranges from 1 to about 10, from 1 to about 9, from 1 to about 8, from 2 to about 8, from 1 to about 6, from 1 to about 3 or from about 3 to about 5. In some embodiments, z is 2, about 3, about 4, about 5, about 6, about 7, or about 8. In further embodiments, conjugates are represented by the following formula: wherein A is an antibody, an antibody construct, or a targeting moiety, D is a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and z ranges from 1 to about 20. In some embodiments, z ranges from 1 to about 10, from 1 to about 9, from 1 to about 8, from 2 to about 8, from 1 to about 6, from 1 to about 3 or from about 3 to about 5. In some embodiments, z is 2, about 3, about 4, about 5, about 6, about 7, or about 8. A population of conjugates found in, for example, a composition or formulation will have an average DAR. In some embodiments, the average DAR for the conjugates of a composition or formulation will range from 1 to about 10, from 1 to about 9, from 1 to about 8, from 1 to about 6, from 1 to about 3, from about 2 to about 8, from about 2 to about 6, from about 2.5 to about 5.5, from about 2.5 to about 4.5, from about 2 to about 4, from about 3.5 to about 5.5, from about 3 to about 5, from about 3.5 to about 4.5, or from about 3 to about 4. In some embodiments, the average DAR for the conjugates of a composition or formulation will be about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8.

[0041] As used throughout this disclosure, a compound or salt of this disclosure, e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, may be referred to as a ALK5 inhibitor, a drug, D, a compound, or a payload, particularly when referenced as part of a conjugate. “LP,” “L-P,” or “linker-payload” may be used interchangeably throughout this disclosure to refer to a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, covalently bound to a linker, L.

[0042] As used throughout this disclosure, “alkyl” or “lower alkyl” means a straight chain or branched alkyl group having from 1 to 12 carbon atoms, in some embodiments from 1 to 10 carbon atoms, in some embodiments from 1 to 8 carbon atoms, in some embodiments from

1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 3 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, Ao-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0043] As used throughout this disclosure, “alkenyl” or “lower alkenyl” means a straight chain or branched alkenyl group having from 2 to 10 carbon atoms, in some embodiments from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. Alkenyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0044] As used throughout this disclosure, “alkynyl” or “lower alkynyl” means a straight chain or branched alkynyl group having from 2 to 10 carbon atoms, in some embodiments from

2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. Alkynyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond. Examples of lower alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0045] “Halo" or “halogen” refers to fluorine, chlorine, bromine, and iodine. [0046] "Hydroxy" refers to -OH.

[0047] “Cyano” refers to -CN.

[0048] “Amino” refers to -NH ₂ .

[0049] “Aminoalkyl” or “lower aminoalkyl” refers to a lower alkyl as defined above with one or more hydrogen atoms replaced with -NH ₂ . Examples of lower aminoalkyl groups include, but are not limited to, -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , and the like.

[0050] “Haloalkyl” or “lower haloalkyl” refers to a lower alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF ₃ , -CHF ₂ , and the like.

[0051] “Haloalkenyl” or “lower haloalkenyl” refers to a lower alkenyl as defined above with one or more hydrogen atoms replaced with halogen.

[0052] “Haloalkynyl” or “lower haloalkynyl” refers to a lower alkynyl as defined above with one or more hydrogen atoms replaced with halogen.

[0053] “Alkoxy” or “lower alkoxy” refers to a lower alkyl as defined above joined by way of an oxygen atom (i.e., -O-(lower alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0054] “Haloalkoxy” or “lower haloalkoxy” refers to a lower haloalkyl as defined above joined by way of an oxygen atom (i.e., -O-(lower haloalkyl). Examples of lower haloalkoxy groups include, but are not limited to, -OCF ₃ , and the like.

[0055] “Cycloalkyl” refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi- electrons in the ring do not give rise to aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0056] “Aryl” groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The terms "aryl" and "aryl groups" include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic- aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.

[0057] "Carbocyclyl," “carbocycle,” or "carbocyclic" refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring may give rise to aromaticity. In one embodiment, carbocycle includes cycloalkyl as defined above. In another embodiment, carbocycle includes aryl as defined above.

[0058] "Heterocyclyl," "heterocycle," or "heterocyclic" refers to aromatic and non- aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.

[0059] Heterocyclyl groups also include fused ring species including those having fused aromatic and non-aromatic groups. A heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring members. A heterocyclyl group as defined throughout this disclosure can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. [0060] "Heteroaryl" refers to aromatic ring moi eties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl groups" include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydro indolyl.

[0061] As used throughout this disclosure, the term “optionally substituted” refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to -OR ^a , -NR ^a R ^b , -S(O) ₂ R ^a or -S(O) ₂ OR ^a , halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R ^a and R ^b is, independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or R ^a and R ^b , together with the atom to which they are attached, form a 3-8 membered carbocycle or heterocycle.

[0062] “Isomer” is used throughout this disclosure to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of some embodiments of the invention. The isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable- isomers that are called “enantiomers.” Single enantiomers of a pure compound are optically active (i.e., they are capable of rotating the plane of plane polarized light and designated R or 5).

[0063] “Isolated optical isomer” means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure by weight. In some embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight. [0064] “Substantially enantiomerically or diastereomerically” pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0065] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled “(±)” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out). All compounds with an asterisk (*) adjacent to a tertiary or quarternary carbon are optically active isomers, which may be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.

[0066] 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, compounds described throughout this disclosure are intended to include all Z-, E- and tautomeric forms as well.

[0067] 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 throughout this disclosure, in some 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:

[0068] A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used throughout this disclosure a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used throughout this disclosure.

[0069] A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used throughout this disclosure a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used throughout this disclosure.

[0070] “Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 19.

[0071] Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as “acid addition salts”. Conversely, salts formed between bases in the cationic form and anions are referred to as “base addition salts.”

ALK5 Inhibitor Compounds

[0072] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. The compounds and salts thereof described in Formulas (I)-(IX) and Table 1 may be covalently bound, to a linker, L, which may further be covalently bound to an antibody, an antibody construct, or a targeting moiety.

[0073] In some embodiments, compounds are provided having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ^A is CR ^A or N;

Q ^B is CR ^B ;

Q ³ is N or CR ³ ;

Q ⁴ is N or CR ⁴ ;

Q ⁵ is N or CR ⁵ ;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl and R ^B together with the atoms to which they are attached, form a heterocyclic ring;

R ^a and R ^b are each H, or R ^a and R ^b , together with the atoms to which they are attached, form a heterocyclic ring; ring B is carbocycle or heterocycle;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ³ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁴ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁵ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are, at each occurrence, independently substituted with

0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-5.

[0074] In some embodiments, compounds are provided having the structure of Formula (II): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ³ is N or CR ³ ;

Q ⁴ is N or CR ⁴ ;

Q ⁵ is N or CR ⁵ ;

Q ⁶ is N or CR ⁶ ;

R ^a and R ^b are each H, or R ^a and R ^b , together with the atoms to which they are attached, form a heterocyclic ring;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ³ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁴ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁵ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁶ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; and m is 0-3.

[0075] In some embodiments of Formula (II), Q ⁶ is CR ⁶ when R ¹ is methyl and R ^a and R ^b , together with the atoms to which they are attached, form a heterocyclic ring. [0076] In some embodiments, compounds are provided having the structure of Formula

(III): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ⁶ is N or CR ⁶ ;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁶ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ , R ² , and R ⁶ are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; and m is 0-3. wherein Q ⁶ is CR ⁶ when R ¹ is methyl.

[0077] In some embodiments, compounds are provided having the structure of Formula (IV): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ⁶ is N or CR ⁶ ;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁶ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ , R ² , and R ⁶ are each substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; and m is 0-3.

[0078] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is H.

[0079] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is C 1-3 alkyl.

[0080] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is methyl.

[0081] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, R ¹ is ethyl or propyl.

[0082] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, R ¹ is C _1-3 haloalkyl.

[0083] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CFH2, -CF2H, or -CF ₃ .

[0084] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0.

[0085] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1-3.

[0086] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q ⁶ is N.

[0087] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q ⁶ is CR ⁶ . [0088] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is H.

[0089] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁶ is halo, C _1-3 alkyl, or C _1-3 haloalkyl.

[0090] In some embodiments, compounds are provided wherein the TGFβRl inhibitor is a compound having the structure of Formula (V): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ^a and R ^b are each H, or R ^a and R ^b , together with the atoms to which they are attached, form a heterocyclic ring;

Q ^A is CR ^A or N;

Q ³ is N or CR ³ ;

Q ⁴ is N or CR ⁴ ;

Q ⁵ is N or CR ⁵ ;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl;

R ^a and R ^b are each H, or R ^a and R ^b , together with the atoms to which they are attached, form a heterocyclic ring; ring B is carbocycle or heterocycle;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ³ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁴ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁵ is H, halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are, at each occurrence, independently substituted with 0- 3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-5.

[0091] In some embodiments, compounds are provided wherein the TGFβRl inhibitor is a compound having the structure of Formula (VI): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ^A is CR ^A or N;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl; ring B is carbocycle or heterocycle;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-5.

[0092] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heterocycle.

[0093] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heteroaryl.

[0094] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0095] In some embodiments, compounds are provided having the structure of Formula (VI-A): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ^A is CR ^A or N;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; wherein R ¹ and R ² are, at each occurrence, independently substituted with

0-3 R ¹⁰ ;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-2.

[0096] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is carbocycle.

[0097] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is aryl.

[0098] In some embodiments, compounds are provided having the structure of Formula

(VI-B): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ^A is CR ^A or N;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with

0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-4.

[0099] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q ^A is N. [0100] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q ^A is CR ^A .

[0101] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is H.

[0102] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is halo.

[0103] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is F.

[0104] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is C _1-3 alkyl, or C _1-3 haloalkyl.

[0105] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is H.

[0106] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is C 1-3 alkyl.

[0107] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is methyl.

[0108] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is ethyl or propyl.

[0109] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is C _1-3 haloalkyl.

[0110] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CFH2, -CF2H, or -CF ₃ .

[0111] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0.

[0112] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1-3.

[0113] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0.

[0114] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1-2. [0115] In some embodiments, compounds are provided, wherin the TGFβRl inhibitor is a compound having the structure of Formula (VII): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ^A is CR ^A or N;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl; ring B is carbocycle or heterocycle;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy; m is 0-3; and n is 0-5.

[0116] In some embodiments, compounds are provided having the structure of Formula (VII): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q ^A is CR ^A or N;

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl; ring B is carbocycle or heterocycle;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy; m is 0-3; and n is 0-5.

[0117] In some embodiments of Formula (VII), compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ¹ is not H or methyl when ring B is carbocycle; ring B is a five membered heteroaryl when R ¹ is H and Q ^A is N.

[0118] In some embodiments of Formula (VII), compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ¹ is not H or methyl when ring B is carbocycle; ring B is a five membered heteroaryl when R ¹ is H and Q ^A is N; and

R ⁷ is substituted with an acidic amino acid sidechain when R ¹ is methyl and Q ^A is

CR ^A

[0119] In some embodiments, compounds are provided having the structure of Formula

(VIII): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl; ring B is carbocycle or heterocycle;

R ¹ is H, ethyl, propyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy; m is 0-3; and n is 0-5; wherein R ¹ is ethyl, propyl, or C _1-3 haloalkyl when ring B is carbocycle.

[0120] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heterocycle.

[0121] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heteroaryl.

[0122] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0123] In some embodiments, compounds are provided having the structure of Formula (VIII- A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl;

R ¹ is H, ethyl, propyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy; m is 0-3; and n is 0-2.

[0124] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is carbocycle.

[0125] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is aryl.

[0126] In some embodiments, compounds are provided having the structure of Formula

(Vni-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ^A is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl;

R ¹ is ethyl, propyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-4.

[0127] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is H.

[0128] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is halo.

[0129] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is F.

[0130] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^A is C _1-3 alkyl, or C _1-3 haloalkyl.

[0131] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is H. [0132] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is ethyl or propyl.

[0133] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is C _1-3 haloalkyl.

[0134] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CFH2, -CF2H, or -CF ₃ .

[0135] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0.

[0136] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1-3.

[0137] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0.

[0138] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1-2.

[0139] In some embodiments, compounds are provided having the structure of Formula (IX): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: ring B is carbocycle or heterocycle;

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy; m is 0-3; and n is 0-5; wherein:

R ¹ is ethyl, propyl, or C _1-3 haloalkyl when ring B is carbocycle; and ring B is a 5-membered heteroaryl when R ¹ is H

[0140] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heterocycle.

[0141] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heteroaryl.

[0142] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is a 5-membered heteroaryl.

[0143] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0144] In some embodiments, compounds are provided having the structure of Formula (IX-A): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

R ¹ is H, C _1-3 alkyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-2.

[0145] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is carbocycle.

[0146] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is aryl.

[0147] In some embodiments, compounds are provided having the structure of Formula (IX-B):

R ¹ is ethyl, propyl, or C _1-3 haloalkyl;

R ² is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, or C _1-3 haloalkoxy; wherein R ¹ and R ² are, at each occurrence, independently substituted with 0-3 R ¹⁰ ;

R ⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;

R ⁹ is, at each occurrence, independently halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy;

R ¹⁰ is, at each occurrence, independently C _1-3 alkoxy or C _1-3 haloalkoxy; m is 0-3; and n is 0-4.

[0148] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is H.

[0149] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is C 1-3 alkyl.

[0150] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is methyl.

[0151] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is ethyl or propyl.

[0152] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is C _1-3 haloalkyl.

[0153] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹ is -CFH2, -CF2H, or -CF ₃ .

[0154] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0.

[0155] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1-3.

[0156] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0.

[0157] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1-2.

[0158] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ , the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety is -Y-(CR ¹¹ R ¹² ) _P -NHR ¹³ , -Y-(CR ¹¹ R ¹² ) _P -C(O)OR ¹³ , or -Y-(CR ¹¹ R ¹² ) _P -C(O)NHR ¹³ , wherein:

Y is -O-, -CH ₂ -, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ NR ¹⁴ -, -C(O)NR ¹⁴ -; -CH ₂ C(O)NR ¹⁴ -, -CH ₂ CH ₂ C(O)NR ¹⁴ -, -C(O)O-; -CH ₂ C(O)O-, -CH ₂ CH ₂ C(O)O-, or -CH ₂ CH ₂ NR ¹⁴ C(O)C(O)-,

R ¹¹ is at each occurrence, independently, H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or R ¹⁵ ;

R ¹² is at each occurrence, independently, H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or R ¹⁵ ;

R ¹³ is H, C _1-3 alkyl, or C _1-3 haloalkyl; or R ¹¹ at one occurrence and R ¹² at one occurrence, together with the atom to which they are attached, form a ring; or R ¹¹ at one occurrence and R ¹³ form a ring;

R ¹⁴ is H, halo, C _1-3 alkyl, or C _1-3 haloalkyl; and

R ¹⁵ is an amino acid side chain or -C _1-3 alkyl-C(O)OR ¹³ ; and p is 0-5.

[0159] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ , the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety, is -Y-(CR ¹¹ R ¹² ) _P -NHR ¹³ , -Y-(CR ¹¹ R ¹² ) _P -C(O)OR ¹³ , -Y-(CR ¹¹ R ¹² )p-C(O)NHR ¹³ , or -Y-(CR ¹¹ R ¹² ) _P -O-phenyl-C(O)-C _1-3 alkyl, wherein:

Y is -O-, -CH ₂ -, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ NR ¹⁴ -, -C(O)NR ¹⁴ -, -CH ₂ C(O)NR ¹⁴ -, -CH ₂ CH ₂ C(O)NR ¹⁴ -, -C(O)O-, -CH ₂ C(O)O-, -CH ₂ CH ₂ C(O)O-, -CH ₂ CH ₂ NR ¹⁴ C(O)C(O)-, -CH ₂ CH ₂ NR ¹⁴ C(O)-, -CH(C(O)OH)-, -CH ₂ CH ₂ NR ¹⁴ C(O)CH(NH ₂ )CH ₂ CH ₂ C(O)NR ¹⁴ -, -CH ₂ C(O)NR ¹⁴ CH ₂ CH ₂ NR ¹⁴ C(O)-, -CH ₂ C(O)-piperazinyl-C(O)-, -CH ₂ CH ₂ NR ¹⁴ -, or -CH ₂ CH ₂ NR ¹⁴ C(O)CH ₂ CH ₂ CH ₂ C(O)NR ¹⁴ -;

R ¹¹ is at each occurrence, independently, H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or R ¹⁵ ;

R ¹² is at each occurrence, independently, H, halo, C _1-3 alkyl, C _1-3 haloalkyl, or R ¹⁵ ;

R ¹³ is H, -S(O) ₂ -C _1-3 alkyl, C _1-3 alkyl, or C _1-3 haloalkyl; or R ¹¹ at one occurrence and R ¹² at one occurrence, together with the atom to which they are attached, form a ring; or R ¹¹ at one occurrence and R ¹³ form a ring;

R ¹⁴ is H, halo, C _1-3 alkyl, C _1-3 aminoalkyl or C _1-3 haloalkyl; and

R ¹⁵ is an amino acid side chain, -C _1-3 alkyl-C(O)OR ¹³ or -C _0-3 alkyl-CN; p is 0-5.

[0160] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ¹⁵ is -C _1-3 alkyl-C(O)OR ¹³ ;

[0161] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is -Y-(CR ¹¹ R ¹² ) _P -NHR ¹³ .

[0162] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is

- Y-(CR ¹¹ R ¹² ) _P -C(O)OR ¹³ . [0163] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is-Y-(CR ¹¹ R ¹² ) _P -O- phenyl-C(O)- C _1-3 alkyl.

[0164] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -O-.

[0165] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ -.

[0166] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -OCH ₂ CH ₂ -.

[0167] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is-OCH ₂ CH ₂ NR ¹⁴ -.

[0168] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ CH ₂ NR ¹⁴ C(O)-.

[0169] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH(C(O)OH)-.

[0170] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ CH ₂ NR ¹⁴ C(O)CH(NH ₂ )CH ₂ CH ₂ C(O)NR ¹⁴ -.

[0171] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ C(O)NR ¹⁴ CH ₂ CH ₂ NR ¹⁴ C(O)-.

[0172] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ C(O)-piperazinyl- C(O)-.

[0173] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ CH ₂ NR ¹⁴ -.

[0174] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is -CH ₂ CH ₂ NR ¹⁴ C(O)CH ₂ CH ₂ CH ₂ C(O)NR ¹⁴ -.

[0175] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is:

[0176] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ is:

[0177] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ , the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety, comprises a substitutable nitrogen atom.

[0178] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ⁷ , the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety, comprises a moiety that enhances cell permeability.

[0179] In some embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compound has a pKa of about 3.5 to about 5.5.

[0180] Exemplary compounds of the disclosure include those set forth in Table 1 and salts thereof (includin pharmaceutically acceptable salts thereof).

TABLE 1

[0181] 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, compounds described throughout this disclosure are intended to include all Z-, E- and tautomeric forms as well.

[0182] 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 some 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: [0183] The compounds disclosed throughout this disclosure, 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 some embodiments, 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. 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.

[0184] Unless otherwise stated, compounds described throughout this disclosure 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 disclosure.

[0185] The compounds of this 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, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ 0, ¹⁷ O, 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 disclosure, whether radioactive or not, are encompassed within the scope of the disclosure.

[0186] In some embodiments, the compounds disclosed throughout this disclosure have some or all of the ¹ H atoms replaced with ² 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.

[0187] 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.; 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.

[0188] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein 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. [0189] Compounds of the disclosure 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.

[0190] Included in the disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described throughout this disclosure. The compounds of the disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0191] The compounds described throughout this disclosure may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented throughout this disclosure include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0192] The methods and compositions described throughout this disclosure include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described throughout this disclosure may be in the form of pharmaceutically acceptable salts. In some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the disclosure. In addition, the compounds described throughout this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented throughout this disclosure are also considered to be disclosed herein.

[0193] In some embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the disclosure.

[0194] Prodrug forms of the compounds of this disclosure, wherein the prodrug is metabolized in vivo to produce a compound as set forth throughout this disclosure are included within the scope of the claims. In some cases, some of the compounds described throughout this disclosure may be a prodrug for another derivative or active compound.

[0195] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0196] In some embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In some embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In some embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In some embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0197] Cell permeability may be measured using any suitable procedure. For example, using the procedure described in Jin, et al, “Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations,” Journal of Pharmacological and Toxicological Methods 70 (2014) 188-194, the relevant teachings of which are incorporated herein by reference. In various embodiments, MDCK cells are used.

[0198] In some embodiments, the parent compound with the acidic moiety is retained within a cell for a longer duration than the same compound without the acidic moiety.

[0199] In some embodiments, the parent compound, with an acidic moiety, may be retained within the cell, i.e., drug residence, for 10% or longer, such as 15% or longer, such as 20% or longer, such as 25% or longer, such as 30% or longer, such as 35% or longer, such as 40% or longer, such as 45% or longer, such as 50% or longer, such as 55% or longer, such as

60% or longer, such as 65% or longer, such as 70% or longer, such as 75% or longer, such as

80% or longer, such as 85% or longer, or even 90% or longer relative to the same compound without an acidic moiety.

[0200] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0201] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fie ser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

Linkers and Linker-Payloads

[0202] The compounds and salts described herein may be bound to a linker, e.g., a peptide linker. In some embodiments, the linker is also bound to an antibody, an antibody construct, or a targeting moiety, and may be referred to as an antibody conjugate, an antibody construct conjugate, or a targeting moiety conjugate, respectively, or may be referred to simply as a conjugate. Linkers of the conjugates may not affect the binding of active portions of a conjugate, e.g., the antigen binding domains, Fc region or domains, target binding domain, antibody, targeting moiety, or the like, to a target, which can be a cognate binding partner, such as an antigen. A conjugate can comprise multiple linkers, each having one or more compounds attached. The multiple linkers can be the same linker or different linkers contained on a single conjugate or on separate conjugates.

[0203] As will be appreciated by skilled artisans, a linker connects one or more ALK5 inhibitors to an antibody or antigen-binding fragment thereof by forming a covalent linkage to the compound at one location and a covalent linkage to the antibody or antigen-binding fragment thereof at another location. The covalent linkages can be formed by reaction between functional groups on the linker and functional groups on the ALK5 inhibitor and on the antibody or antigen-binding fragment thereof. As used throughout this disclosure, the expression "linker" can include (i) unattached forms of the linker that can include a functional group capable of covalently attaching the linker to an ALK5 inhibitor and a functional group capable of covalently attached the linker to an antibody or antigen-binding fragment thereof; (ii) partially attached forms of the linker that can include a functional group capable of covalently attaching the linker to an antibody or antigen-binding fragment thereof and that can be covalently attached to an ALK5 inhibitor compound, or vice versa; and (iii) fully attached forms of the linker that can be covalently attached to both an ALK5 inhibitor compound and to an antibody or antigen-binding fragment thereof. In some embodiments, the functional groups on a linker and covalent linkages formed between the linker and an antibody or antigen-binding fragment thereof can be specifically illustrated as Rx and Rx respectively.

[0204] 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 or selectively 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.

[0205] A cleavable linker can include a valine-citrulline (Val-Cit) peptide, a valine- alanine (Vai-Ala) peptide, a phenylalanine-lysine (Phe-Lys) or other peptide, such as a peptide that forms a protease recognition and cleavage site. Such a peptide-containing linker can contain a pentafluorophenyl group. A peptide-containing linker can include a succimide or a maleimide group. A peptide-containing linker can include a para aminobenzoic acid (PABA) group. A peptide-containing linker can include an aminobenzyloxycarbonyl (PABC) group. A peptide- containing linker can include a PABA or PABC group and a pentafluorophenyl group. A peptide-containing linker can include a PABA or PABC group and a succinimide group. A peptide-containing linker can include a PABA or PABC group and a maleimide group.

[0206] A non-cleavable linker is generally protease-insensitive and insensitive to intracellular processes. A non-cleavable linker can include a maleimide group. A non-cleavable linker can include a succinimide group. A non-cleavable linker can be maleimido-alkyl-C(O)- linker. A non-cleavable linker can be maleimidocaproyl linker. A maleimidocaproyl linker can be A-maleimidom ethylcycloh exane-1 -carboxylate. A maleimidocaproyl linker can include a succinimide group. A maleimidocaproyl linker can include pentafluorophenyl group.

[0207] A linker can be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules. A linker can be a maleimide-PEG4 linker. A linker can be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules. A linker can be a combination of a maleimidocaproyl linker containing a pentafluorophenyl 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 lengthen the linker.

[0208] A linker can be a (maleimidocaproyl)-(valine-alanine)-(para- aminobenzyloxy carbonyl) linker. A linker can be a (maleimidocaproyl)-(valine-citrulline)-(para- aminobenzyloxy carbonyl) linker. A linker can be a (maleimidocaproyl)-(phenylalanine-lysine)- (para-aminobenzyloxy carbonyl) linker. A linker can be a linker suitable for attachment to an engineered cysteine (THIOMAB). A THIOMAB linker can be a (maleimidocaproyl)-(valine- citrulline)-(para-aminobenzyloxycarbonyl)-linker.

[0209] A linker can also contain segments of alkylene, alkenylene, alkynylene, polyether, polyester, polyamide, polyamino acids, peptides, polypeptides, cleavable peptides, and/or aminobenzyl-carbamates. 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-term in al amine acetylated, and a valine-citrulline, valine-alanine or phenylalanine-lysine 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: 1351) to an N-term in al GGG motif to regenerate a native amide bond. The linker created can therefore link to a moiety attached to the LPXTG recognition motif (SEQ ID NO: 1351) with a moiety attached to the N-terminal GGG motif. A linker can be a link created between an unnatural amino acid on one moiety reacting with oxime bond that was formed by modifying a ketone group with an alkoxyamine on another moiety. A moiety can be part of a conjugate. A moiety can be part of an antibody. A moiety can be part of an immune-stimulatory compound, such as ALK5 inhibitor. A moiety can be part of a binding domain. A linker can be unsubstituted or substituted, for example, with a substituent. A substituent can include, for example, hydroxyl groups, amino groups, nitro groups, cyano groups, azido groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, acyl groups, acyloxy groups, amide groups, and ester groups.

[0210] In the conjugates, a compound or salt of any one of Formulas (I)— (IX) and Table 1 is linked to the antibody by way of a linker(s), also referred to herein as L. L, as used throughout this disclosure, may be selected from any of the linker moieties discussed herein. The linker linking the compound or salt to the antibody construct of a conjugate 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. The linkers may be polyvalent such that they covalently link more than one compound or salt to a single site on the antibody construct, or monovalent such that covalently they link a single compound or salt to a single site on the antibody construct.

[0211] A linker can be polyvalent such that it covalently links more than one ALK5 compound to a single site on the antibody or antigen-binding fragment thereof, or monovalent such that it covalently links a single ALK5 compound to a single site on the antibody or antigen- binding fragment thereof.

[0212] In some embodiments for a compound of Formulas (I)— (IX) and Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, the compound may further comprise a linker (L), which results a linker-payload. The linker may be covalently bound to any position, valence permitting, on a compound of Formulas (I)— (IX) and Table 1, or a pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. For example, the linker may be bound to R ⁷ or R ⁸ . In some embodiments, a linker is bound to R ⁷ . In some embodiments, a linker is bound to a nitrogen atom, e.g., an amine, or oxygen atom, e.g., a hydroxyl, of a compound of Formulas (I)— (IX) and Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. The linker may comprise a reactive moiety, e.g., an electrophile that can react to form a covalent bond with a reactive moiety of an antibody, an antibody construct, or a targeting moiety, e.g., a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue. In some embodiments, a compound of Formulas (I)-(IX) and Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, may be covalently bound through the linker to an antibody, an antibody construct, or a targeting moiety.

[0213] In the conjugates, a compound of Formulas (I)— (IX) and Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, is linked to an antibody, an antibody construct, or a targeting moiety by way of a linker(s), also referred to herein as. L, as used throughout this disclosure, may be selected from any of the linker moieties discussed herein. The linker linking the compound or salt to an antibody, an antibody construct, or a targeting moiety of a conjugate 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. The linkers may be polyvalent such that they covalently link more than one compound or salt to a single site on an antibody, an antibody construct, or a targeting moiety, or monovalent, such that covalently they link a single compound or salt to a single site on an antibody, an antibody construct, or a targeting moiety.

[0214] Linkers of the disclosure (L) may have from about 10 to about 500 atoms in a linker, such as from about 10 to about 400 atoms, such as about 10 to about 300 atoms in a linker. In some embodiments, linkers of the disclosure have from about 30 to about 400 atoms, such as from about 30 to about 300 atoms in the linker.

[0215] As will be appreciated by skilled artisans, the linkers may link a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, of any one of Formulas (I)— (IX) and Table 1 to an antibody, an the antibody construct, or a targeting moiety by a covalent linkages between the linker and the antibody, the antibody construct, or the targeting moiety, and the compound, to form a conjugate. As used throughout this disclosure, 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 a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, the present invention and a functional group capable of covalently linking the linker to an antibody, an antibody construct, or a targeting moiety; (ii) partially conjugated forms of the linker that include a functional group capable of covalently linking the linker to the an antibody, the antibody construct, or the targeting moiety, and that is covalently linked to at least one compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, (s) or salt thereof(s) of any one of Formulas (I)— (IX) and Table 1, or vice versa; and (iii) fully conjugated forms of the linker that is covalently linked to both a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and an antibody, an antibody construct, or the targeting moiety. Some embodiments pertain. One embodiment pertains to a conjugate formed by contacting an antibody, an antibody construct, or a targeting moiety that binds a cell surface receptor or tumor- associated antigen expressed on a tumor cell with a linker- compound described herein under conditions in which the linker-compound covalently links to the antibody, the antibody construct, or the targeting moiety. Further embodiments pertain construct. One embodiment pertains to a method of making a conjugate formed by contacting a linker-compound under conditions in which the linker-compound covalently links to an antibody, anthe antibody construct, or a targeting moiety.

[0216] In some embodiments, a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, Salts described in the section entitled “Compounds” is covalently bound to a linker (L) to form a linker-payload ((L-P). The linker may be covalently bound to any position of the compound, valence permitting. The linker may comprise a reactive moiety, e.g., an electrophile that can react to form a covalent bond with a moiety of an antibody, an antibody construct, or a targeting moiety, such as, for example, a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue. In some embodiments, a linker-payload, comprising a compound or salt of a compound in the section entitled “Compounds” herein and a linker, L, is covalently bound through Lthe linker to an antibody, an antibody construct, or a targeting moiety. In some embodiments, any one of the compounds or salts described in the section entitled “Compounds” is covalently bound to a linker (L). The linker may be covalently bound to any position, valence permitting. The linker may comprise a reactive moiety, e.g., an electrophile that can react to form a covalent bond with a moiety of an antibody construct such as, for example, a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue. In some embodiments, a compound or salt of a compound in the section entitled “Compounds” herein is covalently bound through the linker to an antibody construct.

[0217] In some embodiments, a linker-payload, comprising an ALK5 inhibitor compound or salt thereof of this disclosure and a linker, L, is covalently bound through L to an antibody. In some embodiments, a linker-payload, comprising an ALK5 inhibitor compound or salt thereof of this disclosure and a linker, L, is covalently bound through L to an antibody construct. In still further embodiments, a linker-payload, comprising an ALK5 inhibitor compound or salt thereof of this disclosure and a linker, L, is covalently bound through L to a targeting moiety. In some embodiments, including in any of the aforementioned embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, L is a noncleavable linker. Alternatively, in some embodiments, including in any of the aforementioned embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, L is a cleavable linker, such as a linker cleavable by a lysosomal enzyme. In some embodiments, including in any of the aforementioned embodiments, the antibody, the antibody construct, or the targeting moiety may specifically bind to a tumor antigen. In some embodiments, including in any of the aforementioned embodiments, the antibody, antibody construct, or targeting moiety may further comprise a second antigen or target binding domain.

[0218] In some embodiments, an ALK5 inhibitor compound of this disclosure is covalently attached to an antibody, an antibody construct, or a targeting moiety. In some embodiments, an ALK5 inhibitor compound of this disclosure is covalently attached to an antibody. In some embodiments, an ALK5 inhibitor compound of this disclosure is covalently attached to an antibody construct. In certain other embodiments, the compound is covalently attached to a targeting moiety. In some embodiments, including in any of the aforementioned embodiments, the antibody, the antibody construct, or the targeting moiety may specifically bind to a tumor antigen. In some embodiments, including in any of the aforementioned embodiments, the antibody, antibody construct, or targeting moiety may further comprise a second antigen or target binding domain.

[0219] Exemplary polyvalent linkers that may be used to link compounds of the invention to an antibody construct are described. 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:

[0220] The methodology renders highly-loaded conjugates (DAR up to 20) whilst maintaining good physicochemical properties. This methodology can be utilized with an ALK5 compound as shown in the scheme below, where Drug' refers to the ALK5 compound.

[0221] To utilize the Fleximer® linker technology depicted in the scheme above, an aliphatic alcohol can be present or introduced into the ALK5 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.

[0222] In some embodiments, a moiety, construct, or conjugate described herein includes the symbol , which indicates the point of attachment, e.g., the point of attachment of a chemical or functional moiety to the compound, the point of attachment of a linker to a compound of the disclosure, or the point of attachment of a linker to an antibody, an antibody construct, or a targeting moiety.

[0223] By way of example and not limitation, some cleavable and noncleavable linkers that may be included in the conjugates are described below, in addition to any other described herein.

[0224] Sulfamide linkers may be used to link many compounds of the disclosure to an antibody construct. Sulfamide linkers are as described herein and e.g., U.S. Patent Publication Number 2019/0038765, the linkers of which are incorporated by reference herein

[0225] Cleavable linkers can be cleavable in vitro, in vivo, or both. Cleavable linkers can include chemically or enzymatically unstable or degradable linkages. Cleavable linkers can rely on processes inside the cell to liberate a compound of Formula (I), 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.

[0226] In some embodiments, L is a linker comprising a reactive moiety. In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, L is represented by the formula:

In some embodiments, L is represented by the formula: wherein each R ³⁰ is independently selected from optionally substituted C ₁ -C ₆ alkyl and optionally substituted phenyl, and RX is the reactive moiety. RX may comprise a leaving group. RX may be a maleimide. L may be further covalently bound to an antibody construct. In some embodiments, -L- is represented by the formula: wherein RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody construct, wherein on RX* represents the point of attachment to a residue of the antibody construct; and each R ³⁰ is independently selected from optionally substituted C ₁ -C ₆ alkyl and optionally substituted phenyl.

[0227] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and linker L; L comprises a methylene carbamate unit.

[0228] In some embodiments, for a linker-payload (L-P) comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and linker L-RX*; the L-P is part of a conjugate and RX* comprises a hydrolyzed succinamide moiety and is bound to a cysteine residue of an antibody, an antibody construct, or a targeting moiety. In some embodiments, including in any of the aforementioned embodiments, the antibody, antibody construct, or targeting moiety comprises an antigen binding domain that specifically binds to an antigen selected from ASGR1, ASGR2, LRRC15, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (Nectin-4). The antibody, antibody construct, or targeting moiety may specifically bind to ASGR1, ASGR2, LRRC15, MSLN, HER2, TROP2, or EPHA2. In some embodiments, including in any of the aforementioned embodiments, the antibody, antibody construct, or targeting moiety comprises an antigen binding domain that specifically binds to ASGR1.

[0229] By way of example and not limitation, some cleavable and noncleavable linkers that may be included in the conjugates are described below, in addition to any others described throughtout the application.

[0230] A linker can contain a chemically labile group such as hydrazone and/or disulfide groups. Linkers comprising chemically labile groups can exploit differential properties between the plasma and some cytoplasmic compartments. The intracellular conditions that can facilitate release of a compound any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof 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.

[0231] 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 a compound of the disclsoure once the antibody 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 drug. 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.

[0232] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and a linker L, -L comprises a hydrazone moiety. For example, L may be selected from: wherein M is selected from C ₁ -C ₆ alkyl, aryl, and -Q-C ₁ -C ₆ alkyl.

[0233] In some embodiments, for a linker-payload comprising a compound of any one of Formula (I), (II), (III), (IV), (V), (VI), or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and a linker L. In certain embodiments, L reacts with a compound of this disclosure to form a hydrazone moiety. For example, the compound may contain a hydrazineyl moiety and L may contain a ketone or aldehyde moiety, which react to form a hydrazone moiety. For example, L may be:

[0234] Hydrazone-containing linkers can contain additional cleavage sites, such as additional acid-labile cleavage sites and/or enzymatically labile cleavage sites. Conjugates including exemplary hydrazone-containing linkers can include, for example, the following structures: wherein D is a compound or salt of any one of Formulas (I)-(IX) and Table 1 and Ab is an antibody construct, respectively, and n represents the number of compound-bound linkers (LP) 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 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.

[0235] Other acid-labile groups that can be included in linkers include cis-aconityl- containing linkers, cis- Aconityl chemistry can use a carboxylic acid juxtaposed to an amide bond to accelerate amide hydrolysis under acidic conditions.

[0236] Cleavable linkers can also include a disulfide group. Disulfides can be thermodynamically stable at physiological pH and can be designed to release a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; 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 a compound of any one of Formulas (I)- (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; 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 pM. 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.

[0237] Conjugates comprising a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and including exemplary disulfide-containing linkers can include the following structures: wherein D is a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and Ab is an antibody, an antibody construct, or a targeting moiety, n represents the number of compounds bound to linkers (L) bound to the antibody, antibody construct, or targeting moiety and R is independently selected at each occurrence from, for example, hydrogen or alkyl. Increasing steric hindrance adjacent to the disulfide bond can increase the stability of the linker. Structures such as (Clla) and (CIIc) can show increased in vivo stability when one or more R groups is selected from a lower alkyl, such as methyl.

[0238] 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.

[0239] 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 a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, from an antibody, an antibody construct, or a targeting moiety conjugate 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.

[0240] The cleavable peptide can be selected from tetrapeptides such as Gly-Phe-Leu- Gly (SEQ ID NO: 1399), Ala-Leu- Ala-Leu (SEQ ID NO: 1400) or dipeptides such as Val-Cit, Vai-Ala, and Phe-Lys. Dipeptides can have lower hydrophobicity compared to longer peptides.

[0241] A variety of dipeptide-based cleavable linkers can be used with an antibody, an antibody construct, or a targeting moiety construct to form conjugates of a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, described herein. [0242] Enzymatically cleavable linkers can include a self-immolative spacer to spatially separate a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, from the site of enzymatic cleavage. The direct attachment of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, to a peptide linker can result in proteolytic release of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, or of an amino acid adduct of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, thereby impairing its activity. The use of a self- immolative spacer can allow for the elimination of the fully active, chemically unmodified compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, upon amide bond hydrolysis.

[0243] One self-immolative spacer can be a bifunctional parra-ami nobenzyl alcohol (PABA) group, which can link to a peptide through an amino group, forming an amide bond, while an amine containing compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, can be attached through carbamate functionalities to the benzylic hydroxyl group of the linker (to give a /?-amidobenzylcarbamate, PABC). The resulting pro-compound can be activated upon protease-mediated cleavage, leading to a 1,6-elimination reaction releasing the unmodified compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, carbon dioxide, and remnants of the linker group.

[0244] The following scheme depicts the fragmentation of p-amidobenzyl carbamate and release of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof: wherein D represents the unmodified drug or payload having the structure of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. [0245] In some embodiments, for a linker-payload comprising a compound of any one of

Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, L is represented by the formula: peptide wherein peptide comprises from one to ten amino acids, and represents the point of attachment to the compound (payload).

[0246] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, -L is represented by the formula: wherein peptide comprises from one to ten amino acids and RX is a reactive moiety, and represents the point of attachment to the compound (payload). The reactive moiety may be selected from an electrophile, e.g., an aβ-unsaturated carbonyl, such as a mal eimide, and a leaving group. In some embodiments, RX comprises a leaving group. In some embodiments, RX is a maleimide.

[0247] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, -L is represented by the formula: wherein peptide comprises from one to ten amino acids, L ⁴ is the C-terminus of the peptide and L ⁵ is selected from a bond, alkylene and heteroalkylene, wherein L ⁵ is optionally substituted with one or more groups independently selected from R ³² , RX is a reactive moiety; and R ³² is independently selected at each occurrence from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , -NO ₂ ; and C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , and -NO ₂ . The reactive moiety may be selected from an electrophile, e.g., an aβ-unsaturated carbonyl, such as a maleimide, and a leaving group. In some embodiments, RX comprises a leaving group. In some embodiments, RX is a maleimide.

[0248] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, the L-P is part of a conjugate and -L is represented by the formula: wherein Antibody is an antibody, an antibody construct, or a targeting moiety peptide comprised of one to about 10 amino acids, RX* is a reactive moiety that has reacted with a moiety on the antibody, antibody construct, or targeting moiety to form a conjugate, and represents the point of attachment to the compound (payload).

[0249] In further embodiments, L-P is part of a conjugate and -L- is represented by the formula: wherein peptide comprises from one to ten amino acids, L ⁴ is the C-terminus of the peptide and L ⁵ is selected from a bond, an alkylene and a heteroalkylene, each of which is optionally substituted with one or more groups independently selected from R ¹² ; the left represents the point of attachment to the compound (payload), RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety attached at the on the right to a residue of an antibody, an antibody construct, or a targeting moiety.

[0250] In some embodiments, L-P is part of a conjugate and -L- is represented by the formula: wherein peptide comprises from one to ten amino acids, L ⁴ represents the C-terminus of the peptide and L ⁵ is selected from a bond, alkylene and heteroalkylene, wherein L ⁵ is optionally substituted with one or more groups independently selected from R ³² ; RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of an antibody, an antibody construct, or a targeting moiety, wherein on RX* represents the point of attachment to the residue of the antibody, antibody construct, or targeting moiety; and R ³² is independently selected at each occurrence from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , -NO ₂ ; and C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , and -NO ₂ . In some embodiments, the peptide of L comprises Val-Cit or Vai-Ala.

[0251] In any of the aforementioned embodiments, -L is:

[0252] Heterocyclic variants of this self-immolative group may also be used.

[0253] The enzymatically cleavable linker can be a B-glucuronic acid-based linker. Facile release of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, 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 antibody construct conjugate of a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, to undergo aggregation due to the hydrophilic nature of B-glucuronides. In some embodiments, B-glucuronic acid-based linkers can link an antibody, an antibody construct, or a targeting moiety to a hydrophobic compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0254] The following scheme depicts the release of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, (D) from a conjugate of a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, containing a B-glucuronic acid-based linker: wherein Ab indicates an antibody, an antibody construct, or a targeting moiety.

[0255] A variety of cleavable β-glucuronic acid-based linkers useful for linking drugs such as auristatins, camptothecin analogues, 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. In some embodiments, an enzymatically cleavable linker is a β- galactoside-based linker. β-Galactoside is present abundantly within lysosomes, while the enzyme activity outside cells is low.

[0256] Additionally, a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, 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.

[0257] 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.

[0258] 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 a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein such ester groups can hydrolyze under physiological conditions to release a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. Hydrolytically degradable linkages can include 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 at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide.

[0259] A linker can contain an enzymatically cleavable peptide, for example, a linker comprising structural formula (Cilla), (Clllb), (CIIIc), or (Cllld): or a salt thereof, wherein: “peptide” represents a peptide (illustrated in N^C orientation, wherein peptide includes the amino and carboxy “termini”) that is cleavable by a lysosomal enzyme; T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or combinations thereof; R ^a is selected from hydrogen, alkyl, sulfonate and methyl sulfonate; R ^y is hydrogen or C _1-4 alkyl -(O) _r -(C _1-4 alkylene) _s -G ¹ or C _1-4 alkyl-(N)-[(C _1-4 alkylene)-G ¹ ] ₂ ; R ^z is C _1-4 alkyl-(O) _r -(C _1-4 alkylene) _s -G ² ; G ¹ is -SO ₃ H, -CO ₂ H, PEG 4-32, or a sugar moiety; G ² is -SO ₃ H, -CO ₂ H, or a 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 0 or 1; represents the point of attachment of the linker to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and * represents the point of attachment to the remainder of the linker.

[0260] In some embodiments, a peptide can be selected to contain natural amino acids, unnatural amino acids, or any combination thereof. In some embodiments, a peptide can be a tripeptide or a dipeptide. In particular embodiments, a dipeptide comprises L-amino acids, such as 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-Vai; Vai-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.

[0261] Exemplary embodiments of linkers according to structural formula (Cilla) are illustrated below (as illustrated, the linkers include a reactive group suitable for covalently linking the linker to an antibody, an antibody construct, or a targeting moiety): . . wherein indicates an attachment site of a linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0262] Exemplary embodiments of linkers according to structural formula (Clllb), (CIIIc), or (Cllld) that can be included in the conjugates can include the linkers illustrated below (as illustrated, the linkers include a reactive group suitable for covalently linking the linker to an antibody construct): . . . . wherein indicates an attachment site to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0263] The linker can contain an enzymatically cleavable sugar moiety, for example, a linker comprising structural formula (CIVa), (CIVb), (CIVc), (ClVd), or (CIVe):

1 or a salt thereof, wherein: qisOorl;risOorl;X is CH ₂ , O or NH; represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and * represents the point of attachment to the remainder of the linker. [0264] Exemplary embodiments of linkers according to structural formula (CIVa) that may be included in the antibody construct conjugates of a compound of any one of Formulas (I)- (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, 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 represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0265] Exemplary embodiments of linkers according to structural formula (CIVb) that may be included in the conjugates include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct): (CIVb.l) ) . wherein represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0266] Exemplary embodiments of linkers according to structural formula (CIVc) that may be included in the conjugates include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct): (CIVc.l) . wherein represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0267] Exemplary embodiments of linkers according to structural formula (ClVd) that may be included in the conjugates include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct): . (CIVd.6) wherein represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0268] Exemplary embodiments of linkers according to structural formula (CIVe) that may be included in the conjugates include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct): wherein represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0269] Although cleavable linkers can provide certain advantages, the linkers comprising the conjugate need not be cleavable. For non-cleavable linkers, the payload compound release may not depend on the differential properties between the plasma and some cytoplasmic compartments. The release of the payload compound can occur after internalization of the conjugate via antigen-mediated endocytosis and delivery to lysosomal compartment, where the antibody, antibody construct, or targeting moiety can be degraded to the level of amino acids through intracellular proteolytic degradation. This process can release a payload compound derivative (a metabolite of the conjugate containing a non-cleavable linker-heterocyclic compound), which is formed by the payload compound, the linker, and the amino acid residue or residues to which the linker was covalently attached. The payload compound derivative from 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 conjugates with a cleavable linker. Conjugates with non-cleavable linkers can have greater stability in circulation than conjugates with cleavable linkers. Non-cleavable linkers can include 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.

[0270] The linker can be non-cleavable in vivo, for example, a linker-payload comprising a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and a linker L. In certain embodiments, L is represented by any one of the formulas below: ( e) or salts thereof, wherein: R ^a is selected from hydrogen, alkyl, sulfonate and methyl sulfonate; R ^x is a reactive moiety including a functional group capable of covalently linking the linker to an antibody construct; and represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof. [0271] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and a linker L; -L is represented by the formula: wherein n = 0-9 and represents the point of attachment to the compound (payload).

[0272] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and a linker L; -L is represented by the formula: wherein RX comprises a reactive moiety, e.g., a maleimide or a leaving group, n = 0-9, and represents the point of attachment to the compound (payload).

[0273] In some embodiments, for a conjugate comprising a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, a linker L, and an antibody, an antibody construct, or a targeting moiety; -L- is represented by the formula:

RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety attached at the on the right to a residue of the antibody, antibody construct, or targeting moiety, on the left represents the point of attachment to the compound (payload), and n = 0-9.

[0274] Exemplary embodiments of linkers according to structural formula (CVa)-(Ve) that may be included in the conjugates 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 of the linker (L) to a compound of any one of Formulas (I)- (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof: .

[0275] Attachment groups that are used to attach the linkers to an antibody, an antibody construct, or a targeting moiety 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" mal eimides and "bridging disulfides" that can be used with ALK5 inhibitor compounds of this disclosure. Examples of cysteine based linkers are provided in PCT Patent Application Publication Number WO 2020/092385, the linkers of which are incorporated by reference herein.

[0276] Maleimide groups are frequently used in the preparation of conjugates because of their specificity for reacting with thiol groups of, for example, cysteine groups of an antibody, an antibody construct or a targeting moiety. The reaction between a thiol group of an antibody, an antibody construct or a targeting moiety and a drug with a linker (linker-aoyload) including a maleimide group proceeds according to the following scheme:

[0277] The reverse reaction leading to maleimide elimination from a thio- substituted succinimide may also take place. This reverse reaction is undesirable as the maleimide group may subsequently react with another available thiol group such as other proteins in the body having available cysteines. Accordingly, the reverse reaction can undermine the specificity of a conjugate. One method of preventing the reverse reaction is to incorporate a basic group into the linking group shown in the scheme above. Without wishing to be bound by theory, the presence of the basic group may increase the nucleophilicity of nearby water molecules to promote ring- opening hydrolysis of the succinimide group. The hydrolyzed form of the attachment group is resistant to deconjugation in the presence of plasma proteins. So-called “self-stabilizing” linkers provide conjugates with improved stability. A representative schematic is shown below:

[0278] The hydrolysis reaction schematically represented above may occur at either carbonyl group of the succinimide group. Accordingly, two possible isomers may result, as shown below: [0279] The identity of the base as well as the distance between the base and the maleimide group can be modified to tune the rate of hydrolysis of the thio- substituted succinimide group and optimize the delivery of a conjugate to a target by, for example, improving the specificity and stability of the conjugate.

[0280] Bases suitable for inclusion in a linker, e.g., any L with a maleimide group prior to conjugation to an antibody, an antibody construct, or a targeting moiety may facilitate hydrolysis of a nearby succinimide group formed after conjugation of the antibody, antibody construct, or targeting moiety to the linker. Bases may include, for example, amines (e.g., - N(R ²⁶ )(R ²⁷ ), where R ²⁶ and R ²⁷ are independently selected from H and Ci-6 alkyl), nitrogen- containing heterocycles (e.g., a 3- to 12-membered heterocycle including one or more nitrogen atoms and optionally one or more double bonds), amidines, guanidines, and carbocycles or heterocycles substituted with one or more amine groups (e.g., a 3- to 12-membered aromatic or non-aromatic cycle optionally including a heteroatom such as a nitrogen atom and substituted with one or more amines of the type -N(R ²⁶ )(R ²⁷ ), where R ²⁶ and R ²⁷ are independently selected from H or Ci-6 alkyl). A basic unit may be separated from a maleimide group by, for example, an alkylene chain of the form -(CH ₂ )m-, where m is an integer from 0 to 10. An alkylene chain may be optionally substituted with other functional groups as described herein.

[0281] A linker (L) with a maleimide group may include an electron withdrawing groups, such as -C(O)R, =O, -CN, -NO ₂ , -CX ₃ , -X, -C(O)OR, -C(O)NR ₂ , -C(O)R, -C(O)X, -SO ₂ R, -SO ₂ OR, -SO ₂ NHR, -SO ₂ NR2, -PO ₃ R2, -P(O)(CH ₃ )NHR, -NO, -NR ₃ ⁺ , -CR=CR ₂ , and -C≡CR, where each R is independently selected from H and C1-6 alkyl and each X is independently selected from F, Br, Cl, and I. Self-stabilizing linkers may also include aryl, e.g., phenyl, or heteroaryl, e.g., pyridine, groups optionally substituted with electron withdrawing groups, such as those described herein.

[0282] Examples of self-stabilizing linkers are provided in, e.g., U.S. Patent Application Publication Number US 2013/0309256, the linkers of which are incorporated by reference herein. It will be understood that a self-stabilizing linker useful in conjunction with the compounds of the disclosure may be equivalently described as unsubstituted maleimide- including linkers, thio- substituted succinimide-including linkers, or hydrolyzed, ring-opened thio- substituted succinimide-including linkers.

[0283] In some embodiments, for a linker-payload comprising a compound of any one of Formulas (I)— (IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and a linker L; -L comprises a self-stabilizing moiety.

For example, -L may be selected from:

[0284] In the scheme provided above, the bottom structure may be referred to as (maleimido)-DPR-Val-Cit-PAB, where DPR refers to diaminopropinoic acid, Vai refers to valine, Cit refers to citrulline, and PAB refers to para-aminobenzylcarbonyl. represent the point of attachment to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0285] 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 conjugates by full reduction of IgGs (to give 4 pairs of sulfhydryls from interchain disulfides, wherein the DAR can range from 1 to 8) followed by reaction with 4 equivalents of the alkylating agent. Conjugates containing "bridged disulfides" are also claimed to have increased stability.

[0286] Similarly, as depicted below, a mal eimide derivative that is capable of bridging a pair of sulfhydryl groups has been developed.

[0287] A linker of the disclosure, L, can contain the following structural formulas (CVIa), (CVIb), or (CVIc): or salts thereof, wherein: R ^q is H or -O-(CH ₂ CH ₂ O)n-CH3; x is O or 1, y is O or 1, CP is -CH ₂ CH ₂ CH ₂ SO ₃ H or -CH ₂ CH ₂ O-(CH ₂ CH ₂ O)II-CH3; R ^W is -O-CH ₂ CH ₂ SO ₃ H or -NH(CO)-CH ₂ CH ₂ O-(CH ₂ CH ₂ O)i2-CH3; and * represents the point of attachment to the remainder of the linker.

[0288] Exemplary embodiments of linkers according to structural formula (CVIa) and (CVIb), which can be included in linker-paylod and conjugate structures of this disclosure, include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct):

(CVIb.l) .

. wherein represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0289] Exemplary embodiments of linkers according to structural formula (CVIc), which can be included in linker-payload and conjugate structure of this disclosure, include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the linker to an antibody construct): c. .

[0290] wherein represents the point of attachment of the linker (L) to a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0291] Some exemplary linkers (L) are described in the following paragraphs. In some embodiments for a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, attachment of the linker is to a nitrogen of the compound and conjugation is to a cysteine residue of an antibody, an antibody construct, or targeting moiety. In certain embodiments, -L is represented by any one of the formulas set forth in Table 2 below. TABLE 2. EXEMPLARY LINKERS TARGETING CYSTEINE

wherein represents attachment to a nitrogen of a compound or salt of any one of Formula

(I), (IA), (IB), (IC), (ID), (IE), or Table 1. For linker LI 1, L ⁴ represents the C-terminus of the peptide and L ⁵ is selected from a bond, alkylene and heteroalkylene, wherein L ⁵ is optionally substituted with one or more groups independently selected from R ³⁰ , and R ³⁰ is independently selected at each occurrence from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , -NO ₂ ; and Ci-Cioalkyl, C2-Cioalkenyl, and C2-Cioalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, -OH, -CN, -O-alkyl, -SH, =O, =S, -S(O) ₂ OH, -NH ₂ , and -NO ₂ ; and RX represents a reactive moiety. The reactive moiety may be selected, for example, from an electrophile, e.g., an a,β-unsaturated carbonyl, such as a maleimide, and a leaving group. In certain embodiments, RX of any one of linkers LI to LI 1 is a maleimide. In certain further embodiments, RX is wherein RX is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a cysteine residue of an antibody, an antibody construct or a targeting moiety, wherein on RX* represents the point of attachment to such residue.

[0292] In some embodiments for a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, attachment of the linker is to a nitrogen of a compound of any one of Formulas (I)-(IX) or Table 1, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and conjugation is to a lysine residue of an antibody or other targeting moiety. In certain embodiments, -L is represented by the formulas set forth in Table 3 below. TABLE 3. EXEMPLARY LINKERS TARGETING LYSINE

WHEREIN REPRESENTS ATTACHMENT TO A NITROGEN OF A COMPOUND OF ANY ONE OF

FORMULAS (I)— (IX) OR TABLE 1, OR PHARMACEUTICALLY ACCEPTABLE ISOMER, TAUTOMER, RACEMATE, HYDRATE, SOLVATE, ISOTOPE, OR SALT THEREOF, AND RX REPRESENTS A REACTIVE MOIETY. IN CERTAIN EMBODIMENTS, RX OF LINKER L 12 OR L 13 IS A MALEIMIDE. IN CERTAIN

FURTHER EMBODIMENTS, RX IS WHEREIN RX IS A BOND, A SUCCINIMIDE MOIETY, OR A

HYDROLYZED SUCCINIMIDE MOIETY BOUND TO A LYSINE RESIDUE OF AN ANTIBODY, AN ANTIBODY CONSTRUCT OR A TARGETING MOIETY, WHEREIN ON RX* REPRESENTS THE POINT OF

ATTACHMENT TO SUCH RESIDUE.

[0293] As is known by skilled artisans, the linker selected for a particular conjugate may be influenced by a variety of factors, including the site of attachment to the antibody, antibody construct, or targeting moiety (e.g., lysine, cysteine, or other amino acid residues), 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, antibody construct, or targeting moiety/drug combination.

[0294] For example, cytotoxic conjugates have been observed to effect killing of bystander antigen-negative cells present in the vicinity of the antigen-positive tumor cells. The mechanism of the bystander effect by cytotoxic conjugates has indicated that metabolic products formed during intracellular processing of the conjugates may play a role. Neutral cytotoxic metabolites generated by metabolism of the conjugates in antigen-positive cells appear to play a role in bystander cell killing while charged metabolites may be prevented from diffusing across the membrane into the medium, or from the medium across the membrane and, therefore, cannot effect cell killing via the bystander effect. In some embodiments, a linker is selected to attenuate the bystander effect caused by cellular metabolites of the conjugate. In further embodiments, a linker is selected to increase the bystander effect.

[0295] The properties of the linker, or linker-payload, may also impact aggregation of a conjugate under conditions of use and/or storage. Generally, conjugates reported in the literature contain about 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 conjugate. In many instances, DARs higher than 3-4 could be beneficial as a means of increasing potency. In instances where the payload compound is more hydrophobic in nature, it may be desirable to select linkers that are relatively hydrophilic as a means of reducing conjugate aggregation, especially in instances where DARs greater than 3-4 are desired. Thus, in some embodiments, a linker incorporates chemical moi eties that reduce aggregation of the conjugates 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 conjugates. 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.

[0296] In preferred embodiments, aggregation of 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 about 35%, such as less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, or even less, as determined by size-exclusion chromatography (SEC). [0297] Exemplary Linker-Compounds (also referred to as linker-payloads) of this disclosure include those set forth in Table 4, and salts thereof (including pharmaceutically acceptable salts thereof).

Antibody, Antibody Construct, and Targeting Moiety

[0298] The disclosure provides conjugates for use in the treatment of disease. As used throughout this disclosure, “conjugate” refers to an antibody, antibody construct, or targeting moiety that is attached (i.e., conjugated) either directly or through a linker group to an ALK5 inhibitor compound described herein. Antibodies, antibody constructs, and targeting moieties in the disclosure have a selective affinity for a target molecule relative to other non-target molecules. The antibody, antibody construct, and/or a targeting moiety binds to a target molecule. The target molecule may be an antigen, such as a biological receptor or other structure of a cell such as a tumor antigen. The target genes and proteins disclosed herein may serve as antigen markers for the development and establishment of more specific disease treatment, for example, more specific anti-cancer immune response.

[0299] Antibodies, antibody constructs, targeting moieties and antigen binding domains thereof may each be individually combined with an ALK5 inhibitor compound of this disclosure, as described herein. In some embodiments, ALK5 inhibitor compounds of this disclosure are conjugated either directly or through a linker to an antibody, an antibody construct, a targeting moiety, or an antigen binding domain thereof, to form a conjugate.

[0300] Terms understood by those in the art of antibody technology are each given the meaning acquired in the art, unless expressly defined differently herein. An intact antibody comprises at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as an antigen binding fragment or portion (which includes an antigen binding domain) of an intact antibody that has or retains the capacity to bind a target molecule. A monoclonal antibody or antigen-binding portion thereof may be non-human, chimeric, humanized, or human, preferably humanized or human. Immunoglobulin structure and function are reviewed, for example, in Greenfield et al., Ed., Antibodies: A Laboratory Manual, Second Edition, Chapter 2 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2014).

[0301] For example, the terms “VL” and “VH” refer to the variable binding region from an antibody light and heavy chain, respectively. The variable binding regions are made up of discrete, well-defined sub-regions known as “complementarity determining regions” (CDRs) and “framework regions” (FRs). The term “CL” refers to an “immunoglobulin light chain constant region” or a “light chain constant region,” i.e., a constant region from an antibody light chain. The term “CH” refers to an “immunoglobulin heavy chain constant region” or a “heavy chain constant region,” which is further divisible, depending on the antibody isotype into CHI, CH2 , and CH3 (IgA, IgD, IgG), or CHI, CH2 , CH3, and CH4 domains (IgE, IgM).

[0302] An antigen binding domain of an antibody may comprise one or more light chain (LC) CDRs and one or more heavy chain (HC) CDRs. For example, an antigen binding domain of an antibody may comprise one or more of the following: a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), or a light chain complementary determining region 3 (LC CDR3). Another exemplary antigen binding domain may comprise one or more of the following: a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), or a heavy chain complementary determining region 3 (HC CDR3). As an additional example, an antigen binding domain of an antibody may comprise one or more of the following: LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3. In some embodiments, an antigen binding domain of an antibody includes all six CDRs, (i.e., LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3).

[0303] Antibody CDR sequences may be determined by one or more methods, including Kabat, Chothia, AbM, Contact, IMGT and AHo. Unless otherwise specified herein, CDR sequences are determined according to the Kabat method. Referenes to variable region or CDR numbering as in Kabat, amino acid position numbering as in Kabat, or CDR sequences determined according to the Kabat method, and variations thereof, refer to the numbering system used for heavy chain variable regions or light chain variable regions of the compilation of antibodies in Kabat et al. ((1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, an FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 and three inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra).

[0304] The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index, as in Kabat,” refers to the residue numbering of the human IgG 1 EU antibody.

[0305] Other numbering systems have been described, for example, by AbM (Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Dithel eds., 2d ed. 2010)), Chothia (see, Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17), Contact, IMGT (ImMunoGeneTics (IMGT) Information System® (see, Lafranc et al., 2003, Dev. Comp. Immunol. 27(l):55-77)), and AHon (see, Honegger and Plückthun , 2001, J. Mol. Biol. 309: 657-70) and are well understood by a person of ordinary skill in the art.

[0306] An antibody, an antibody construct, a targeting moiety or an antigen binding domain thereof of this disclosure may comprise an antibody light chain variable region having an amino acid sequence with at least one, about two, about three, about four, about five, about six, about seven, about eight, about nine or about ten modifications (e.g., insertion, deletion, mutation), provided that the modifications are not within the light chain CDRs. An antibody, an antibody construct, a targeting moiety or an antigen binding domain thereof of this disclosure may comprise an antibody light chain variable region having an amino acid sequence with at least one, two, three, four, five, six, seven, eight, nine or ten modifications (e.g., insertion, deletion, mutation), provided that the modifications are not within the light chain CDRs. In some embodiments, the light chain variable region amino acid sequence does not have more than about 25, about 20, about 15, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or 1 modification relative to the natural or original light chain variable region amino acid sequence, provided that the modifications are not within the light chain CDRs. In some embodiments, the light chain variable region amino acid sequence does not have more than 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 modification relative to the natural or original light chain variable region amino acid sequence, provided that the modifications are not within the light chain CDRs.

[0307] An antibody, an antibody construct, a targeting moiety or an antigen binding domain thereof of this disclosure may comprise a heavy chain variable region of an amino acid sequence having at least one, two, about three, about four, about five, about six, about seven, about eight, about nine, or about ten modifications (e.g., insertion, deletion, mutation), provided that the modifications are not within the heavy chain CDRs. An antibody may comprise a heavy chain variable region of an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine, or ten modifications (e.g., insertion, deletion, mutation), provided that the modifications are not within the heavy chain CDRs. In some embodiments, the heavy chain variable region amino acid sequence does not have more than about 25, about 20, about 15, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, 2, or 1 modification relative to the natural or original heavy chain variable region amino acid sequence, provided that the modifications are not within the heavy chain CDRs. In some embodiments, the heavy chain variable region amino acid sequence does not have more than 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 modification relative to the natural or original heavy chain variable region amino acid sequence, provided that the modifications are not within the heavy chain CDRs.

[0308] As used throughout this disclosure, a "Fab" (fragment antigen binding) is a fragment or portion of an antibody that binds to antigens and includes the variable region and CHI of the heavy chain linked to the light chain via an inter-chain disulfide bond. An antibody construct or targeting moiety may comprise an antigen binding fragment from an antibody. An antigen binding fragment from an antibody may include (i) an antigen binding fragment (Fab), which is a monovalent fragment comprising the VL, VH, CL and CHI domains, optionally comprising all or a portion (including at least one Cys residue) of a hinge region (Fab’); (ii) a F(ab') ₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a single-domain antibody (sdAb) or nanobody, which comprises a single monomeric variable antibody domain; or (iv) a Fv fragment comprising the VL and VH domains of a single arm of an antibody. Although the two domains of the Fv fragment, VL and VH, may be coded for by separate genes, they may be linked by a synthetic linker to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules referred to as as single chain variable fragments (scFv).

[0309] An antigen binding domain of an antibody construct or targeting moiety may be selected from any domain that binds the antigen, including from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, or a functional fragment thereof, for example, a heavy chain variable domain (VH) and a light chain variable domain (VL), or 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, or a recombinant T cell receptor. An antibody construct or targeting moiety may be in the form of a single chain antibody, an anticalin, a centyrin, an affibody, a knottin, a diabody, 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 recombinant T cell receptor, or a peptibody. [0310] An antibody may be of any class, e.g., IgA, IgD, IgE, IgG, and IgM. Several of these classes may be further subdivided into isotypes, e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy-chain constant regions (Fc) that corresponds to the different classes of immunoglobulins may be α, δ, ε, y, or μ. The light chains may be one of either kappa (K) or lambda (λ), based on the amino acid sequences of the constant domains. Antibody constructs may also include an antibody fragment or a recombinant form thereof, including single chain variable fragments (scFvs).

[0311] In particular embodiments, an antibody construct or targeting moiety may comprise an antigen-binding antibody fragment. An antibody fragment may include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI 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 VL and VH domains of a single arm of an antibody. Although the two domains of the Fv fragment, VL and VH, may be coded for by separate genes, they may be linked by a synthetic linker to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules.

[0312] In other embodiments, an antibody construct or targeting moiety may contain, for example, two, three, four, five, six, seven, eight, nine, ten, or more antigen binding domains. An antibody construct or targeting moiety may contain two antigen binding domains in which each antigen binding domain can recognize the same antigen. An antibody construct or targeting moiety may contain two antigen binding domains in which each antigen binding domain can recognizes a different antigen. In some embodiments, an antibody construct or targeting moiety may comprise an Fc fusion protein. In further embodiments, the antibody construct comprises an antigen binding domain and an Fc region or domain. In still further embodiments, an antibody construct or targeting moiety is an antibody, such as a chimeric, humanized, or human antibody.

[0313] In any of the embodiments disclosed herein, an antigen binding domain may specifically bind to a tumor antigen, such as ASGR2, LRRC15, mesothelin (MSLN), HER2, CEA, TROP2, EPHA2, p-cadherin, UPK1B, FOLH1, LYPD3, and PVRL4 (Nectin-4). An antigen binding domain may specifically bind to a molecule on an antigen presenting cell (APC). In certain embodiments, the antigen binding domain specifically binds to a human tumor antigen.

[0314] Further exemplary antibodies or antigen binding domains thereof can specifically bind to:

ASGR1, also known as asialoglycoprotein receptor 1, is a major subunit of asialoglycoprotein receptor. Asialoglycoprotein receptor is a hetero-oligomeric protein composed of major and minor subunits and is highly expressed on the surface of hepatocytes, several human carcinoma cell lines, and liver cancers. Asialoglycoprotein receptor mediates the endocytosis of plasma glycoproteins to which the terminal sialic acid residue on their complex carbohydrate moieties has been removed. The receptor recognizes terminal galactose and N- acetylgalactosamine units. After ligand binding to the receptor, the resulting complex is internalized and transported to a sorting organelle, where receptor and ligand are disassociated. The receptor then returns to the cell membrane surface. The asialoglycoprotein receptor may facilitate hepatic infection by multiple viruses including hepatitis B. ASGR1 includes mammalian ASGR1 proteins, e.g., mouse, rat, rabbit, guinea pig, pig, sheep, dog, non-human primate, and human. In some embodiments, ASGR1 refers to an alternatively spliced variant. In some embodiments, ASGR1 is a human ASGR1 having the amino acid sequence set forth in accession NP_001184145.1 (SEQ ID NO: 49) or NP_001662.1 (SEQ ID NO: 278).

CTLA4 protein (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), which is a protein receptor that acts as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in Tregs but only upregulated in conventional T cells after activation. CTLA4 acts as an "off " switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. The monoclonal antibody ipilimamab has been developed to target CTLA4;

Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), which is a cell surface receptor that plays a cell surface receptor that plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 is an immune checkpoint and guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells). The human IgG4 anti -PD-1 monoclonal antibody Opdivo® (nivolumab) and humanized antibody Keytruda® (pembrolizumab) have been developed to target PD-1. The antibodies pidilizumab (CT-011, Cure Tech) and BMS-936559 are in clinical development;

PD-L1 (programmed death-ligand 1), also known as CD274 (cluster of differentiation 274). PD-L1 is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. The binding of PD-L1 to PD-1 or B7.1 transmits an inhibitory signal which reduces the proliferation of CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene Bcl-2. The monoclonal antibodies atezolizumab, durvalumab, avelumab, and MDX-1106 have been developed to target PD-L1;

TNFR2 (tumor necrosis factor receptor 2), also known as TNFRSF1B (tumor necrosis factor receptor super family IB) and CD120b, 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 memstbrane-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. The mouse monoclonal antibodies against TNFR2 comprising one or more CDRs comprising the amino acid sequence of any one of SEQ ID NO: 1237 - SEQ ID NO: 1263, one or more variable regions comprising the amino acid sequence of any one of SEQ ID NOS: 1264 - SEQ ID NO: 1272, or a VH region comprising the amino acid sequence of SEQ ID NO: 1273 and a VL region comprising the amino acid sequence of SEQ ID NO: 1274 have been developed to target TNFR2;

0X40, also known as TNFRSF4 (tumor necrosis factor receptor superfamily, member 4), a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naive T cells, unlike CD28. 0X40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of 0X40 is dependent on full activation of the T cell; without CD28, expression of 0X40 is delayed and of fourfold lower levels. The monoclonal antibody Vonlerolizumab has been developed to target 0X40;

CD27 is a member of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is required for generation and long-term maintenance of T cell immunity. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. This receptor transduces signals that lead to the activation of NF-KB and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor. CD27-binding protein (SIVA), a proapoptotic protein, can bind to this receptor and is thought to play an important role in the apoptosis induced by this receptor. The monoclonal antibody Varlilumab has been developed to target CD27;

IL2RA encodes CD25, also known as IL2RA (interleukin-2 receptor alpha chain), which is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes. IL2RA is expressed in most B-cell neoplasms, some acute nonlymphocytic leukemias, neuroblastomas, mastocytosis and tumor infiltrating lymphocytes. It functions as the receptor for HTLV-1 and is consequently expressed on neoplastic cells in adult T cell lymphoma/leukemia. Its soluble form, called sIL-2R may be elevated in these diseases and is occasionally used to track disease progression. The humanized monoclonal antibody Zinbryta® (Daclizumab) has been developed to target CD25;

TNFRSF18 encodes GITR (glucocorticoid-induced TNFR-related protein), also known as TNFRSF18 (tumor necrosis factor receptor superfamily member 18) and AITR (activation- inducible TNFR family receptor), which is a protein that is a member of the tumor necrosis factor receptor (TNF-R) superfamily. GITR (glucocorticoid-induced tumor necrosis factor receptor) is a surface receptor molecule that has been shown to be involved in inhibiting the suppressive activity of T -regulatory cells and extending the survival of T-effector cells. The anti- GITR antibodies comprising one or more CDRs comprising the amino acid sequence of any one of SEQ ID NO: 1275 - SEQ ID NO: 1280, comprising a VH region comprising the amino acid sequence of SEQ ID NO: 1281 and a VL region comprising the amino acid of SEQ ID NO: 1282, and antibody TRX518 have been developed to target GITR;

LAG-3 (lymphocyte-activation gene 3) encodes a cell surface molecule with diverse biologic effects on T cell function. LAG-3 is an immune checkpoint receptor. The LAG3 protein, which belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated DI to D4. LAG-3 is expressed on activated T cells, natural killer cells, B cells and plasmacytoid dendritic cells. The anti-LAG-3 antibodies comprising one or more CDRs comprising the amino acid sequence of any one of SEQ ID NO: 1283 - SEQ ID NO: 1288, or comprising a VH region comprising the amino acid sequence of SEQ ID NO: 1289 and a VL region comprising the amino acid sequence of SEQ ID NO: 1290 have been developed to target LAG-3;

GARP (glycoprotein A repetitions predominant) is a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. The anti-GARP antibodies comprising one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1291 - SEQ ID NO: 1300 have been developed to target GARP;

4- IBB is a type 2 transmembrane glycoprotein belonging to the TNF superfamily, expressed on activated T Lymphocytes. 4-1BB can be expressed by activated T cells. 4-1BB expression can be found on dendritic cells, B cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. The anti-4-lBB antibodies comprising one or more CDRs comprising the amino acid sequence of any one of SEQ ID NO: 1301 - SEQ ID NO: 1306, or one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1307 - SEQ ID NO: 1312 have been developed to target 4- 1BB;

ICOS (Inducible T-cell COStimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated T cells. The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. ICOS forms homodimers and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation. The anti-ICOS antibodies comprising one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1313 - SEQ ID NO: 1316 have been developed to target ICOS;

CD70 is expressed on highly activated lymphocytes, such as in T- and B-cell lymphomas. CD70 is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for TNFRSF27/CD27. It is a surface antigen on activated, but not on resting, T and B lymphocytes. CD70 induces proliferation of co-stimulated T cells, enhances the generation of cytolytic T cells, and contributes to T cell activation. This cytokine is also reported to play a role in regulating B-cell activation, cytotoxic function of natural killer cells, and immunoglobulin synthesis. The monoclonal antibody Vorsetuzumab has been developed to target CD70;

PDGFRp (beta-type platelet-derived growth factor receptor) is a typical receptor tyrosine kinase, which is a transmembrane protein consisting of an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. The molecular mass of the mature, glycosylated PDGFRβ protein is approximately 180 kDA. The monoclonal antibody Rinucumab has been developed to target PDGFRβ;

CD73 (cluster of differentiation 73), known as ecto-5 '-nucleotidase (ecto-5'-NT, EC 3.1.3.5) is a glycosyl-phosphatidylinositol (GPI)-linked 70-kDa cell surface enzyme found in most tissues. CD73 commonly serves to convert AMP to adenosine. Ecto-5-prime-nucleotidase (5-prime-ribonucleotide phosphohydrolase; EC 3.1.3.5) catalyzes the conversion at neutral pH of purine 5-prime mononucleotides to nucleosides, the preferred substrate being AMP. The enzyme consists of a dimer of 2 identical 70-kD subunits bound by a glycosyl phosphatidyl inositol linkage to the external face of the plasma membrane. The enzyme is used as a marker of lymphocyte differentiation. The monoclonal antibody Oleclumab and the anti-CD73 antibodies comprising one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1317 and SEQ ID NO: 1318 have been developed to target CD73;

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase, is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism. The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions. CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system. The monoclonal antibody Daratumumab has been developed to target CD38;

Integrin αvβ3 is a type of integrin that is a receptor for vitronectin. Integrin αvβ3 consists of two components, integrin alpha V and integrin beta 3 (CD61), and is expressed by platelets. Integrin αvβ3 is a receptor for phagocytosis on macrophages or dendritic cells. The monoclonal antibodies Etaracizumab and Intetumumab have been developed to target Integrin αvβ3;

Integrin αvβ8, a VN receptor, is identified as a potential negative regulator of cell growth. The cytoplasmic domain of P8 is divergent in sequence, lacking all amino acid homology with the highly homologous cytoplasmic domains of the other av-associating integrin P subunits (Pl , P3, P5, and P6). The P8 cytoplasmic domain is divergent in function. αvβ8 has a restricted distribution and is most highly expressed in nonproliferating cell types. The anti- Integrin αvβ8 antibodies comprising one or both variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1319 and SEQ ID NO: 1320 have been developed to target Integrin αvβ8;

CD248 encodes endosialin. Endosialin is a member of the “Group XIV”, a novel family of C-type lectin transmembrane receptors which play a role not only in cell-cell adhesion processes but also in host defense. Endosialin has been associated with angiogenesis in the embryo, uterus and in tumor development and growth. Monoclonal antibody Ontuxizumab has been developed to target endosialin; FAP (fibroblast activation protein alpha) is a 170 kDa melanoma membrane-bound gelatinase, protein that in humans is encoded by the FAP gene. The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. This protein is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. The anti-FAP antibodies comprising one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1321 - SEQ ID NO: 1338 have been developed to target FAP;

Integrin av subunit associates with one of five integrin β subunits, β1, β3, β5, β6, or β8, to form five distinct αVβ heterodimers. The integrin αVβ heterodimers on the cell surface interact with cell adhesive proteins, such as collagen, fibrinogen, fibronectin, and vitronectin. These interactions play an important role in cell adhesion or migration, especially in tumor metastasis. Monoclonal antibody intetumumab and anti-Integrin av antibodies comprising one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1339 - SEQ ID NO: 1342 have been developed to target Integrin av; or

Integrin αvβ6 is an epithelial-specific integrin that is a receptor for the extracellular matrix (ECM) proteins fibronectin, vitronectin, tenascin and the latency associated peptide (LAP) of TGF-p. Integrin αvβ6 is not expressed in healthy adult epithelia but is upregulated during wound healing and in cancer. Integrin αvβ6 has been shown to modulate invasion, inhibit apoptosis, regulate the expression of matrix metalloproteases (MMPs) and activate TGF-pi. The anti-Integrin αvβ6 antibodies comprising one or more variable regions comprising the amino acid sequence of any one of SEQ ID NO: 1343 - SEQ ID NO: 1350 have been developed to target Integrin αvβ6.

[0315] As used throughout this disclosure, "an Fc region constant domain portion" or "Fc region portion" refers to the heavy chain constant region segment of the Fc fragment (the "fragment crystallizable" region or Fc region) from an antibody, which can in include one or more constant domains, such as CH ₂ , CH3, CH4, or any combination thereof. In some embodiments, an Fc region portion includes the CH ₂ and CH3 domains of an IgG, IgA, or IgD antibody and any combination thereof, or the CH3 and CH4 domains of an IgM or IgE antibody and any combination thereof.

[0316] By way of background, the Fc region is responsible for the effector functions of an immunoglobulin, such as ADCC (antibody-dependent cell-mediated cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), CDC (complement-dependent cytotoxicity) and complement fixation, binding to Fc receptors (e.g., CD16, CD32, FcRn), greater in vivo half-life relative to a polypeptide lacking an Fc region, protein A binding, and perhaps even placental transfer (see Capon et al., Nature 337:525, 1989).

[0317] An Fc region or domain may interact with different types of FcRs. The different types of FcRs may include, for example, FcyRI, FcyRIIA, FcyRIIB, FcyRIIIA, FcyRIIIB, FcaRI, FcpR, FcaRI, FcεRII, and FcRn. FcRs may be located on the membrane of certain immune cells including, for example, B lymphocytes, natural killer cells, macrophages, neutrophils, follicular dendritic cells, eosinophils, basophils, platelets, and mast cells. Once the FcR is engaged by the Fc domain, the FcR may initiate functions including, for example, clearance of an antigen- antibody complex via receptor-mediated endocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody dependent cell-mediated phagocytosis (ADCP), and ligand- triggered transmission of signals across the plasma membrane that can result in alterations in secretion, exocytosis, and cellular metabolism. FcRs may deliver signals when FcRs are aggregated by antibodies and multivalent antigens at the cell surface. The aggregation of FcRs with immunoreceptor tyrosine-based activation motifs (IT AMs) may sequentially activate SRC family tyrosine kinases and SYK family tyrosine kinases. IT AM comprises a twice-repeated YxxL sequence flanking seven variable residues. The SRC and SYK kinases may connect the transduced signals with common activation pathways.

[0318] In some embodiments, an Fc region or domain can exhibit reduced binding affinity to one or more Fc receptors. In some embodiments, an Fc region or domain can exhibit reduced binding affinity to one or more Fey receptors. In some embodiments, an Fc region or domain can exhibit reduced binding affinity to FcRn receptors. In some embodiments, an Fc region or domain can exhibit reduced binding affinity to Fey and FcRn receptors. In some embodiments, an Fc region or domain is an Fc null region or domain. In some embodiments, an Fc region or domain can exhibit reduced binding affinity to FcRn receptors but have the same or increased binding affinity to one or more Fey receptors as compared to a wildtype IgG. In some embodiments, an Fc region or domain can exhibit increased binding affinity to FcRn receptors but have the same or decreased binding affinity to one or more Fey receptors.

[0319] In some embodiments, an Fc domain is an Fc null domain or region. As used throughout this disclosure, an “Fc null” refers to a domain that exhibits weak to no binding to any of the Fey receptors. In some embodiments, an Fc null domain or region exhibits a reduction in binding affinity (e.g., increase in Kd) to Fey receptors of at least about 1000-fold. [0320] The Fc region or domain may have one or more, two or more, three or more, or four or more, or up to five amino acid substitutions that decrease binding of the Fc region or domain to an Fc receptor. In some embodiments, an Fc region or 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 region or domain to an Fc receptor, an Fc region or domain may comprise one or more amino acid substitutions that has the effect of reducing the affinity of the Fc domain or region to an Fc receptor.

[0321] In some embodiments, the Fc region or domain is an IgGl and the one or more substitutions in the Fc region or domain 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.

[0322] In some embodiments, the Fc region or domain 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 (IgGIVLPLL) according to the EU index of Kabat numbering. A modification can comprise a substitution at more than one amino acid residues, such as at 2 different amino acid residues including S239D/I332E (IgGIDE) according to the EU index of Kabat numbering. A modification can comprise a substitution at more than one amino acid residues, such as at 3 different amino acid residues including S298A/E333A/K334A (IgGl AAA) according to the EU index of Kabat numbering.

[0323] In some embodiments, the Fc region or domain can comprise a sequence of an IgG isoform that has been modified from the wild-type IgG sequence. In some embodiments, the Fc region or domain 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 region or domain 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 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. [0324] In some embodiments, an IgG Fc region or domain comprises at least one amino acid substitution that reduces its binding affinity to FcyRl, as compared to a wild-type or reference IgG Fc region or domain. A modification can comprise a substitution at F241, such as F241 A, 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.

[0325] In some embodiments, an IgG Fc region or domain comprises at least one amino acid substitution that increases its binding affinity to FcyRl, as compared to a wild-type or reference IgG Fc region or domain. A modification can comprise a substitution at A327 and P329, such as A327Q/P329A, according to the EU index of Kabat.

[0326] In some embodiments, the modification comprises substitution of one or more amino acids that reduce binding affinity of an IgG Fc region or domain 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.

[0327] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc region or domain 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.

[0328] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc region or domain 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 P331 A, 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.

[0329] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc region or domain 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 R301 A, 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.

[0330] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc region or domain 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.

[0331] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc region or domain 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.

[0332] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc region or domain to FcyRIIIA receptor. A modification can be substitution of F241 and F243, such as F241S/F243S or F241I/F243I, according to the EU index of Kabat.

[0333] In some embodiments, the modification comprises substitution of one or more amino acids that decreases binding affinity of an IgG Fc region or domain 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.

[0334] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc region or domain 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.

[0335] In some embodiments, the modification comprises substitution of one or more amino acids that increases binding affinity of an IgG Fc region or domain to FcyRIIIA receptor. A modification can be substitution of L235, F243, R292, Y300 and P396, such as L235V/F243L/R292P/Y300L/P396L (IgGIVLPLL) according to the EU index of Kabat. A modification can be substitution of S298, E333 and K334, such as S298A/E333A/K334A, according to the EU index of Kabat. A modification can be substitution of K246, such as K246F, according to the EU index of Kabat.

[0336] Other substitutions in an IgG Fc region or domain that affect its interaction with one or more Fey receptors are disclosed in U.S. Patent Nos. 7,317,091 and 8,969,526 (the disclosures of which are incorporated by reference herein).

[0337] In some embodiments, an IgG Fc region or domain comprises at least one amino acid substitution that reduces the binding affinity to FcRn, as compared to a wild-type or reference IgG Fc region or 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. [0338] A modification can comprise a substitution of one amino acid residue that increases the binding affinity of an IgG Fc region or domain for FcRn, relative to a wildtype or reference IgG Fc region or 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 region or 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).

[0339] In some embodiments, an antibody construct or targeting moiety of this disclosure comprises an Fc region that may comprise an Fc domain, wherein the Fc domain is found within the Fc region that interacts with Fc receptors. An Fc domain of an antibody construct may interact with Fc-receptors (FcRs) found on immune cells. An Fc domain may also mediate the interaction between effector molecules and cells, which can lead to activation of the immune system. An Fc region may be derived from IgG, IgA, or IgD antibody isotypes, and may comprise two identical protein fragments, which are derived from the second and third constant domains of the antibody’s heavy chains. In an Fc domain or region derived from an IgG antibody isotype, the Fc domain or region may comprise a highly conserved A-glycosylation site, which may be essential for FcR-mediated downstream effects. An Fc domain or region may be derived from IgM or IgE antibody isotypes, in which the Fc domain or region may comprise three heavy chain constant domains.

[0340] An antibody or Fc domain may be modified to acquire or improve at least one constant region-mediated biological effector function relative to an unmodified antibody or Fc domain, e.g., to enhance FcyR interactions. In some embodiments, a modification can increase CD32b binding (and support transdelivery in a PBMC assay) comprises a substitution at S267L and E329F (IgGILF, also known as SELF double mutant) according to the EU index of Kabat numbering. For example, an antibody with a constant region that binds to FcyRIIA, FcyRIIB and/or FcyRIIIA with greater affinity than the corresponding wild type constant region may be produced according to the methods described herein. An Fc domain that binds to FcyRIIA, FcyRIIB and/or FcyRIIIA with greater affinity than the corresponding wild type Fc domain may be produced according to the methods described herein.

[0341] In some embodiments, an Fc region or domain found in an antibody, antibody construct, or targeting moiety of the disclosure will be capable of mediating one or more of these effector functions or will lack one or more or all of these activities or have one or more of the effector activities increased or decreased by way of, for example, one or more mutations as compared to the unmodified Fc region or domain.

[0342] In addition, antibodies have a hinge sequence that is typically situated between the Fab and Fc region (but a lower section of the hinge may include an amino-terminal portion of the Fc region). By way of background, an immunoglobulin hinge acts as a flexible spacer to allow the Fab portion to move freely in space. In contrast to the constant regions, hinges are structurally diverse, varying in both sequence and length between immunoglobulin classes and even among subclasses. For example, a human IgGl hinge region is freely flexible, which allows the Fab fragments to rotate about their axes of symmetry and move within a sphere centered at the first of two inter-heavy chain disulfide bridges. By comparison, a human IgG2 hinge is relatively short and contains a rigid poly-proline double helix stabilized by four inter-heavy chain disulfide bridges, which restricts the flexibility. A human IgG3 hinge differs from the other subclasses by its unique extended hinge region (about four times as long as the IgGl hinge), containing 62 amino acids (including 21 prolines and 11 cysteines), forming an inflexible poly- proline double helix and providing greater flexibility because the Fab fragments are relatively far away from the Fc fragment. A human IgG4 hinge is shorter than IgGl but has the same length as IgG2, and its flexibility is intermediate between that of IgGl and IgG2.

[0343] In various embodiments, an antibody or antigen binding fragment thereof comprises two light chain polypeptides (light chains) and two heavy chain polypeptides (heavy chains), held together covalently by disulfide linkages.

[0344] The heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region typically comprises three domains, CHI, CH ₂ , and CH3. Nonlimiting exemplary heavy chain constant regions include human IgGl, human IgG2, human IgG3, and human IgG4 constant regions. In some embodiments, an antibody provided herein comprises an IgGl constant region. Exemplary heavy chain constant regions include human IgGl heavy chain constant region (SEQ ID NO: 1230), human IgGlnull heavy chain constant region (SEQ ID NO: 1231), mouse IgG2a heavy chain constant region (SEQ ID NO: 1233), and rat IgG2b heavy chain constant region (SEQ ID NO: 1235).

[0345] The light chain typically comprises a light chain variable region (VL) and a light chain constant region. Nonlimiting exemplary light chain constant regions include kappa and lambda constant regions. A nonlimiting exemplary human kappa constant region is shown in SEQ ID NO: 1232. Another exemplary light chain constant region is mouse kappa constant region shown in SEQ ID NO: 1234. Another exemplary light chain constant region is rat kappa constant region shown in SEQ ID NO: 1236.

[0346] The antigen-recognition regions of the antibody variable domains typically comprise six complementarity determining regions (CDRs), or hypervariable regions, that lie within the framework of the heavy chain variable region and light chain variable region at the N- terminal ends of the two heavy and two light chains.

[0347] In some embodiments, an antigen binding domain comprises a light chain complementary determining region 1 (LCDR1), a light chain complementary determining region 2 (LCDR2), a light chain complementary determining region 3 (LCDR3), a heavy chain complementary determining region 1 (HCDR1), a heavy chain complementary determining region 2 (HCDR2), and a heavy chain complementary determining region 3 (HCDR3). In some embodiments, an antibody may be a heavy-chain only antibody, in which case the antigen binding domain comprises HCDR1, HCDR2, and HCDR3, and the antibody lacks a light chain.

[0348] In some embodiments, an antibody or antigen binding fragment thereof of this disclosure may be identified by its heavy and/or light chain CDRs using any one of the following methods: Kabat, Chothia, AbM, Contact, IMGT, and/or Aho. In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof may be identified by CDRs provided in Tables 5 through 9. In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof may be identified by CDRs provided in Table 10.

Table 5. hzG2D Anti-ASGRl CDRs

Table 6. hzK2E Anti-ASGRl CDRs

Table 7. hzL4L Anti-ASGRl CDRs

Table 8. hzJ4F Anti-ASGRl CDRs

Table 9. hzH8K Anti-ASGRl CDRs

Table 10. Anti-Nectin4 CDRs

[0349] In some embodiments, an anti-LRRC15 antibody or antigen binding fragment thereof comprises: a) a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1580, a VH-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 1590- 1594, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1611, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1625, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1636, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1644; or b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1581, a VH- CDR2 comprising an amino acid sequence selected from SEQ ID NO: 1595-1597, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1612, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1626 or 1627, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1637, and a VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 1645-1649; or c) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1582, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1598, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1613 or 1614, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1628, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1638, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1650; or d) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1583, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1599-1602, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1615, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1629, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1639, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1651; or e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1580, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1603, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1616, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1625, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1636, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1644; or f) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1581, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1595, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1621, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1626, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1637, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1645; or g) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1581; a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1605, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1618, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1631, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1640, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1653; or h) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1584, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1604, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1617, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1630, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1639, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1652; or i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1585, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1606, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1619, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1632, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1641, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1654; or j) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1586, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1607, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1620, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1632, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1641, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1654; or k) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1587, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1608, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1622, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1633, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1641, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1655; or l) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1588, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1609, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1623, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1634, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1642, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1656; or m) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1589, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1610, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1624, a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1635, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1643, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1657.

[0350] In certain embodiments, an anti-LRRC15 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 1683-1725; and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOS: 1726-1746, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged. In further embodiments, an anti- LRRC15 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1750-1835, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from any one of SEQ ID NO:1836-1856, provided that the amino acid sequences of the VH-CDRs and VL- CDRs are unchanged.

[0351] In some embodiments, an anti-MSLN antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequences of the heavy chain variable region CDRs set forth in SEQ ID NO: 1658 and a light chain variable region comprising CDRs having the amino acid sequences of the light chain variable region CDRs set forth in SEQ ID NO: 1659. In some emboiments, the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequences of the heavy chain variable region CDRs set forth in SEQ ID NO: 1660. In some emboiments, the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequences of the heavy chain variable region CDRs set forth in SEQ ID NO: 1661. The CDRs can be identified, for example, via Kabat. For example, in embodiments wherein the CDRs are identified by Kabat, CDR 1 of the heavy chain is SEQ ID NO: 1662, CDR2 of the heavy chain is SEQ ID NO: 1663 or SEQ ID NO: 1664, CDR3 of the heavy chain is SEQ ID NO: 1665, CDR1 of the light chain is SEQ ID NO: 1666, CDR2 of the light chain is SEQ ID NO: 1667, and CDR3 of the light chain is SEQ ID NO: 1668. In some emboiments, an antibody comprising a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 1663 is more stable than an antibody comprising a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 1664.

[0352] In some emboiments, an anti-MSLN antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1658. In some emboiments, an antiMSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1661. In some emboiments, an anti-MSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1669. In some emboiments, an anti-MSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1670. In some emboiments, an anti-MSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1671. In some emboiments, the antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1672. In some emboiments, an anti-MSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1673. In some emboiments, an anti-MSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1674. In some emboiments, an anti-MSLN antibody comprises a VH comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1660.

[0353] In some embodiments, an anti-MSLN antibody comprises a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1659. In some emboiments, an anti-MSLN antibody comprises a VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1675. In some emboiments, an anti-MSLN antibody comprises a VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1676. In some emboiments, an anti-MSLN antibody comprises a VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1677. In some emboiments, an anti-MSLN antibody comprises a VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1678. In some emboiments, an anti-MSLN antibody comprises a VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1679.

[0354] The antibodies of the disclosure can comprise any combination of heavy chain variable region and light chain variable region as described throughout this disclosure. For example, the antibody can comprise a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NOs: 1658, 1661, 1669, 1670, 1671, 1672, 1673, 1674, or 1660, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NOs: 1659, 1675, 1676, 1677, 1678, or 1679. For example, an anti-MSLN antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1658 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1659 or SEQ ID NO: 1679; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1674 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1675; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1660 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1675; or a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1660 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1679.

[0355] In exemplary embodiments, an anti-MSLN antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1680 or SEQ ID NO: 1681 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1682.

[0356] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1862, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1865, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1866, provided that the amino acid sequences of the VH-CDRs i.e., SEQ ID NOS: 1859-1861) and VL-CDRs (i.e., SEQ ID NOS: 1862, 1863, and 1864) are unchanged. In some embodiments, the anti-Nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NO: 1867, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1868, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0357] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence selected from SEQ ID NOS: 1862, 1869, or 1870, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1871, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOS: 1872-1877, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1878, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOS: 1879- 1884, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0358] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1862, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1871, (b) a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 1872, or both (a) and (b).

[0359] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1862, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some embodiments, the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871, (b) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1873, or both (a) and (b). [0360] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1869, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871, (b) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1874, or both (a) and (b).

[0361] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1870, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871, (b) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1875, or both (a) and (b).

[0362] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1870, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871, (b) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1876, or both (a) and (b).

[0363] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:1860, a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1861, a light chain CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1869, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence comprising SEQ ID NO: 1864. In some such embodiments, the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871, (b) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1877, or both (a) and (b).

[0364] In some embodiments, an anti-Nectin-4 antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1865, and a light chain variable region (VL) comprising the amino acid of SEQ ID NO: 1866; or (b) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871, and a light chain variable region (VL) comprising the amino acid sequence selected from SEQ ID NOs: 1872-1877.

[0365] In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1872.

[0366] In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1873.

[0367] In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1874.

[0368] In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1875.

[0369] In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 1876. [0370] In some such embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1871 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID

NO: 1877.

[0371] In some embodiments, an anti-Nectin-4 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 1867, and a light chain comprising the amino acid sequence of SEQ ID NO:1868; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878, and a light chain comprising the amino acid sequence selected from SEQ ID NOS: 1879-1884.

[0372] In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878 and a light chain comprising the amino acid sequence of SEQ ID NO: 1879.

[0373] In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878 and a light chain comprising the amino acid sequence of SEQ ID NO: 1880.

[0374] In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878 and a light chain comprising the amino acid sequence of SEQ ID NO: 1881.

[0375] In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878 and a light chain comprising the amino acid sequence of SEQ ID NO: 1882.

[0376] In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878 and a light chain comprising the amino acid sequence of SEQ ID NO: 1883.

[0377] In some such embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1878 and a light chain comprising the amino acid sequence of SEQ ID NO: 1884.

[0378] In any of the aforementioned embodiments, the anti-Nectin-4 antibody or antigen binding fragment thereof is conjugated to a small molecule drug to form an antibody drug conjugate.

[0379] An antibody or antigen binding fragment thereof can be chimeric or humanized. Chimeric and humanized forms of non-human (e.g., murine) antibodies can be intact (full length) chimeric immunoglobulins, immunoglobulin chains or antigen binding fragments thereof (such as Fv, Fab, Fab', F(ab') ₂ or other target-binding subdomains of antibodies), which can contain sequences derived from non-human immunoglobulin. In general, the humanized antibody or antigen binding fragment thereof 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 framework (FR) regions are those of a human immunoglobulin sequence. A humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), an Fc domain, typically that of a human immunoglobulin sequence.

[0380] An antibody or antigen binding fragment thereof described throughout this disclosure can be a human antibody. As used throughout this disclosure, “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 and that typically do not express endogenous immunoglobulins. Human antibodies can be produced using transgenic mice incapable of expressing functional endogenous immunoglobulins, but capable of expressing 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.

[0381] An antibody or antigen binding fragment thereof described throughout this disclosure 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, one of which may be ASGR1.

[0382] An antibody or antigen binding fragment thereof described throughout this disclosure can be derivatized or otherwise modified. For example, derivatized antibodies can be modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or the like.

[0383] In some embodiments, an anti-Nectin-4 antibody of this disclosure is comprised of (a) a heavy chain variable region (VH) comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1859, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1860, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1861; and (b) a light chain variable region (VL) comprising a CDR1 (VL-CDR1) comprising the amino acid sequence selected from any one of SEQ ID NOS: 1862, 1869, or 1870, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1863, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1864.

[0384] In further embodiments, an anti-Nectin-4 antibody of this disclosure is comprised of (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1885, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1886, and a VH- CDR3 comprising the amino acid sequence of SEQ ID NO: 1887; and (b) a VL comprising a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1888, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1889, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1890.

[0385] In still further embodiments, an anti-Nectin-4 antibody of this disclosure is comprised of (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1891, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1892, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1893; and (b) a VL comprising a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1894, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1895, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1896.

[0386] In yet further embodiments, an anti-Nectin-4 antibody of this disclosure is comprised of (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1897, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1898, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1899; and (b) a VL comprising a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1900, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1901, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1902.

[0387] In yet further embodiments, an anti-Nectin-4 antibody of this disclosure is comprised of (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1903, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1904, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1905; and (b) a VL comprising a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1906, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1907, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1908.

[0388] In yet further embodiments, an anti-Nectin-4 antibody of this disclosure is comprised of (a) a VH comprising a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1909, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1910, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1911; and (b) a VL comprising a CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1912, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1913, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1914.

[0389] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises:

[0390] a heavy chain CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1001, a VH-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NOS: 1006-1008, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1013; and a light chain CDR1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO: 1018, a VL- CDR2 comprising the amino acid sequence selected from any one of SEQ ID NOS: 1023-1025, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1033;

[0391] a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1002, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1009, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1014; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 1019, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1026 or SEQ ID NO: 1027, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1034;

[0392] a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1005, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1012, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1017; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 1022, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1032, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1037;

[0393] a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1003, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1010, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1015; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 1020, a VL-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NOS: 1028-1030, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1035; or

[0394] a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1004, a VH- CDR2 comprising the amino acid sequence of SEQ ID NO: 1011, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1016; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 1021, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 1031, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1036. [0395] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1001, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1008, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1013; and the VL comprises a CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1018, a VL-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NO: 1023, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1033.

[0396] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1001, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1006, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1013; and the VL comprises a CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1018, a VL-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NO: 1023, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1033.

[0397] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO: 1002, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 1009, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1014; and the VL comprises a CDR1 (VL- CDR1) comprising the amino acid sequence of SEQ ID NO: 1019, a VL-CDR2 comprising the amino acid sequence selected from any one of SEQ ID NO: 1026, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 1034.

[0398] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1038, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1126, provided that the amino acid sequences of the VH-CDRs (i.e., SEQ ID NOS: 1001, 1006, and 1013) and VL-CDRs i.e., SEQ ID NOS: 1018, 1023, and 1033) are unchanged.

[0399] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1043-1088 and 1352-1357, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1131-1133 and 1358-1363, provided that the amino acid sequences of the VH- CDRs and VL-CDRs are unchanged.

[0400] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1354, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1361, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged. In further embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1353, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1361, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0401] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1354, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1362, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged. In further embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1353, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1362, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0402] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NO: 1039, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1127, provided that the amino acid sequences of the VH-CDRs (i.e., SEQ ID NOS: 1002, 1009, and 1014) and VL-CDRs (i.e., SEQ ID NOS: 1019, 1026, and 1034) are unchanged.

[0403] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1089-1093, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1134-1137, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0404] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1089, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1134, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged. In further embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1089, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1136, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0405] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1042, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1130, provided that the amino acid sequences of the VH-CDRs (i.e., SEQ ID NOS: 1005, 1112, and 1117) and VL-CDRs (i.e., SEQ ID NOS: 1022, 1032, and 1037) are unchanged.

[0406] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1113-1125, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1143-1149, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0407] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1040, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1128, provided that the amino acid sequences of the VH-CDRs (i.e., SEQ ID NOS: 1003, 1010, and 1015) and VL-CDRs (i.e., SEQ ID NOS: 1020, 1028, and 1035) are unchanged.

[0408] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1094-1102, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1138-1141, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0409] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1041, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1129, provided that the amino acid sequences of the VH-CDRs (i.e., SEQ ID NOS: 1004, 1011, and 1016) and VL-CDRs (i.e., SEQ ID NOS: 1021, 1031, and 1036) are unchanged.

[0410] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1103-1112, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1142, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[0411] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1038, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 1126.

[0412] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence selected from any one of SEQ ID NOS: 1043-1088 and 1352-1357, and a VL comprising an amino acid sequence selected from any one of SEQ ID NOS:1131-1133 and 1358-1363.

[0413] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0414] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0415] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0416] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0417] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1131. [0418] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0419] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0420] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0421] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0422] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0423] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0424] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0425] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0426] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0427] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0428] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1131. [0429] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0430] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0431] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0432] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0433] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0434] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0435] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0436] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0437] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0438] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0439] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1131. [0440] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0441] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0442] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0443] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0444] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0445] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0446] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0447] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0448] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0449] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0450] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1131. [0451] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0452] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0453] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0454] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0455] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0456] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0457] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0458] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0459] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0460] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0461] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1131. [0462] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0463] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0464] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1131.

[0465] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0466] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0467] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0468] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0469] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0470] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0471] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0472] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1132. [0473] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0474] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0475] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0476] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0477] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0478] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0479] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0480] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0481] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0482] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0483] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1132. [0484] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0485] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0486] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0487] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0488] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0489] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0490] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0491] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0492] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0493] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0494] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1132. [0495] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0496] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0497] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0498] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0499] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0500] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0501] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0502] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0503] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0504] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0505] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1132. [0506] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0507] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0508] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0509] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0510] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0511] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0512] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0513] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0514] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0515] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1132.

[0516] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1132. [0517] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0518] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0519] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0520] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0521] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0522] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0523] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0524] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0525] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0526] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0527] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1133. [0528] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0529] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0530] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0531] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0532] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0533] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0534] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0535] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0536] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0537] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0538] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1133. [0539] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0540] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0541] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0542] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0543] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0544] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0545] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0546] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0547] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0548] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0549] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1133. [0550] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0551] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0552] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0553] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0554] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0555] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0556] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0557] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0558] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0559] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0560] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1133. [0561] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0562] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0563] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0564] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0565] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0566] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0567] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0568] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1133.

[0569] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0570] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0571] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1358. [0572] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0573] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0574] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0575] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0576] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0577] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0578] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0579] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0580] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0581] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0582] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1358. [0583] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0584] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0585] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0586] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0587] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0588] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0589] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0590] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0591] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0592] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0593] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1358. [0594] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0595] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0596] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0597] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0598] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0599] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0600] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0601] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0602] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0603] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0604] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1358. [0605] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0606] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0607] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0608] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0609] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0610] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0611] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0612] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0613] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0614] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0615] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1358. [0616] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0617] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0618] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0619] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0620] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1358.

[0621] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0622] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0623] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0624] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0625] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0626] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1359. [0627] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0628] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0629] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0630] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0631] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0632] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0633] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0634] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0635] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0636] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0637] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1359. [0638] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0639] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0640] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0641] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0642] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0643] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0644] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0645] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0646] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0647] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0648] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1359. [0649] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0650] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0651] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0652] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0653] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0654] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0655] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0656] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0657] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0658] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0659] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1359. [0660] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0661] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0662] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0663] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0664] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0665] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0666] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0667] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0668] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0669] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0670] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1359. [0671] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0672] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1359.

[0673] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0674] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0675] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0676] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0677] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0678] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0679] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0680] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0681] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1360. [0682] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0683] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0684] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0685] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0686] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0687] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0688] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0689] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0690] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0691] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0692] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1360. [0693] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0694] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0695] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0696] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0697] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0698] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0699] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0700] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0701] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0702] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0703] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1360. [0704] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0705] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0706] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0707] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0708] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0709] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0710] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0711] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0712] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0713] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0714] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1360. [0715] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0716] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0717] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0718] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0719] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0720] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0721] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0722] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0723] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0724] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1360.

[0725] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1361. [0726] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0727] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0728] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0729] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0730] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0731] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0732] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0733] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0734] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0735] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0736] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1361. [0737] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0738] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0739] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0740] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0741] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0742] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0743] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0744] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0745] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0746] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0747] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1361. [0748] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0749] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0750] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0751] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0752] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0753] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0754] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0755] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0756] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0757] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0758] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1361. [0759] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0760] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0761] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0762] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0763] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0764] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0765] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0766] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0767] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0768] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0769] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1361. [0770] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0771] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0772] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0773] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0774] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0775] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0776] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1361.

[0777] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0778] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0779] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0780] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1362. [0781] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0782] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0783] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0784] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0785] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0786] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0787] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0788] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0789] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0790] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0791] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1362. [0792] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0793] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0794] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0795] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0796] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0797] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0798] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0799] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0800] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0801] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0802] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1362. [0803] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0804] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0805] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0806] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0807] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0808] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0809] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0810] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0811] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0812] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0813] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1362. [0814] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0815] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0816] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0817] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0818] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0819] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0820] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0821] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0822] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0823] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0824] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1362. [0825] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0826] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0827] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0828] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1362.

[0829] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1043 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0830] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1044 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0831] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1045 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0832] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1046 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0833] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1047 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0834] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1048 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0835] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1049 and a VL comprising the amino acid sequence of SEQ ID NO: 1363. [0836] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1050 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0837] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1051 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0838] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1052 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0839] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1053 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0840] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1054 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0841] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1055 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0842] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1056 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0843] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1057 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0844] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1058 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0845] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1059 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0846] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1060 and a VL comprising the amino acid sequence of SEQ ID NO: 1363. [0847] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1061 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0848] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1062 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0849] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1063 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0850] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1064 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0851] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1065 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0852] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1066 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0853] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1067 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0854] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1068 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0855] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1069 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0856] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1070 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0857] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1071 and a VL comprising the amino acid sequence of SEQ ID NO: 1363. [0858] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1072 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0859] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1073 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0860] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1074 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0861] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1075 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0862] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1076 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0863] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1077 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0864] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1078 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0865] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1079 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0866] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1080 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0867] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1081 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0868] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1082 and a VL comprising the amino acid sequence of SEQ ID NO: 1363. [0869] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1083 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0870] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1084 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0871] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1085 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0872] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1086 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0873] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1087 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0874] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1088 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0875] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1352 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0876] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1353 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0877] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1354 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0878] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1355 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0879] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1356 and a VL comprising the amino acid sequence of SEQ ID NO: 1363. [0880] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1357 and a VL comprising the amino acid sequence of SEQ ID NO: 1363.

[0881] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1039, and a VL comprising the amino acid sequence of SEQ ID NO: 1127.

[0882] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence selected from any one of SEQ ID NOS: 1089-1093, and a VL comprising the amino acid sequence selected from any one of SEQ ID NOS: 1134-1137.

[0883] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1089 and a VL comprising the amino acid sequence of SEQ ID NO: 1134.

[0884] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1090 and a VL comprising the amino acid sequence of SEQ ID NO: 1134.

[0885] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1091 and a VL comprising the amino acid sequence of SEQ ID NO: 1134.

[0886] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1092 and a VL comprising the amino acid sequence of SEQ ID NO: 1134.

[0887] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1093 and a VL comprising the amino acid sequence of SEQ ID NO: 1134.

[0888] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1089 and a VL comprising the amino acid sequence of SEQ ID NO: 1135.

[0889] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1090 and a VL comprising the amino acid sequence of SEQ ID NO: 1135. [0890] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1091 and a VL comprising the amino acid sequence of SEQ ID NO: 1135.

[0891] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1092 and a VL comprising the amino acid sequence of SEQ ID NO: 1135.

[0892] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1093 and a VL comprising the amino acid sequence of SEQ ID NO: 1135.

[0893] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1089 and a VL comprising the amino acid sequence of SEQ ID NO: 1136.

[0894] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1090 and a VL comprising the amino acid sequence of SEQ ID NO: 1136.

[0895] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1091 and a VL comprising the amino acid sequence of SEQ ID NO: 1136.

[0896] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1092 and a VL comprising the amino acid sequence of SEQ ID NO: 1136.

[0897] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1093 and a VL comprising the amino acid sequence of SEQ ID NO: 1136.

[0898] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1089 and a VL comprising the amino acid sequence of SEQ ID NO: 1137.

[0899] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1090 and a VL comprising the amino acid sequence of SEQ ID NO: 1137.

[0900] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1091 and a VL comprising the amino acid sequence of SEQ ID NO: 1137. [0901] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1092 and a VL comprising the amino acid sequence of SEQ ID NO: 1137.

[0902] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1093 and a VL comprising the amino acid sequence of SEQ ID NO: 1137.

[0903] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1042, and a VL comprising the amino acid sequence of SEQ ID NO: 1130.

[0904] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence selected from any one of SEQ ID NOS: 1113-1125, and a VL comprising the amino acid sequence selected from any one of SEQ ID NOS: 1143-1149.

[0905] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0906] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprises the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0907] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0908] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0909] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0910] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1144. [0911] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0912] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0913] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0914] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0915] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0916] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0917] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0918] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0919] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0920] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0921] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1145. [0922] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0923] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0924] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0925] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0926] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0927] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0928] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0929] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0930] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0931] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1146.

[0932] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1146. [0933] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0934] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0935] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0936] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0937] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0938] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0939] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0940] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0941] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0942] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0943] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1148. [0944] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0945] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0946] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0947] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0948] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0949] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0950] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0951] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0952] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1113 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0953] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1118 and a VL comprising the amino acid sequence of SEQ ID NO: 1149. [0954] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0955] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0956] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0957] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0958] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0959] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0960] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0961] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0962] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0963] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0964] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1114 and a VL comprising the amino acid sequence of SEQ ID NO: 1145. [0965] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0966] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0967] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1115 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0968] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0969] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0970] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1116 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0971] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0972] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0973] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1117 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0974] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0975] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1144. [0976] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1119 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0977] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0978] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0979] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1120 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0980] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0981] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0982] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1121 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0983] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1147.

[0984] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0985] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1122 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0986] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1147. [0987] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1148.

[0988] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1123 and a VL comprising the amino acid sequence of SEQ ID NO: 1149.

[0989] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0990] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0991] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1124 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0992] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1143.

[0993] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1144.

[0994] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1125 and a VL comprising the amino acid sequence of SEQ ID NO: 1145.

[0995] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1040, and a VL comprising the amino acid sequence of SEQ ID NO: 1128.

[0996] In some embodiments, an anti-ASGRl antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence selected from any one of SEQ ID NOS: 1094-1102, and a VL comprising the amino acid sequence selected from any one of SEQ ID NOS: 1138-1141. [0997] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1094 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[0998] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1095 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[0999] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1096 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1000] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1097 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1001] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1098 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1002] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1099 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1003] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1100 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1004] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1101 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1005] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1102 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1006] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1096 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1007] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1096 and a VL comprising the amino acid sequence of SEQ ID NO: 1140. [1008] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1096 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1009] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1098 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1010] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1100 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[ion] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1094 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1012] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1094 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1013] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1094 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1014] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1095 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1015] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1095 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1016] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1095 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1017] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1097 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1018] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1097 and a VL comprising the amino acid sequence of SEQ ID NO: 1139. [1019] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1097 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1020] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1097 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1021] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1098 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1022] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1098 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1023] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1098 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1024] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1099 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1025] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1099 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1026] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1099 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1027] In some such embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1099 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1028] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1100 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1029] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1100 and a VL comprising the amino acid sequence of SEQ ID NO: 1139. [1030] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1100 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1031] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1101 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1032] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1101 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1033] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1101 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1034] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1101 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1035] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1102 and a VL comprising the amino acid sequence of SEQ ID NO: 1138.

[1036] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1102 and a VL comprising the amino acid sequence of SEQ ID NO: 1139.

[1037] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1102 and a VL comprising the amino acid sequence of SEQ ID NO: 1140.

[1038] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1102 and a VL comprising the amino acid sequence of SEQ ID NO: 1141.

[1039] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1041, and a VL comprising the amino acid sequence of SEQ ID NO: 1129.

[1040] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence selected from any one of SEQ ID NOS: 1103-1112, and a VL comprising the amino acid sequence of SEQ ID NO: 1142. [1041] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1103 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1042] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1104 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1043] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1105 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1044] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1106 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1045] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1107 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1046] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1108 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1047] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1109 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1048] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1110 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1049] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1111 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1050] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1112 and a VL comprising the amino acid sequence of SEQ ID NO: 1142.

[1051] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1150, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1206, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[1052] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1155-1200, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1211-1213, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[1053] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1151, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1207, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[1054] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1201-1205, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from any one of SEQ ID NOS: 1214-1217, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[1055] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1154, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1210, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged. [1056] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1152, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1208, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[1057] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1153, and a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1209, provided that the amino acid sequences of the VH-CDRs and VL-CDRs are unchanged.

[1058] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1150, and a light chain comprising the amino acid sequence of SEQ ID NO: 1206.

[1059] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence selected from any one of SEQ ID NOS: 1155-1200, and a light chain comprising the amino acid sequence selected from any one of SEQ ID NOS: 1211-1213.

[1060] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1151, and a light chain comprising the amino acid sequence of SEQ ID NO: 1207.

[1061] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence selected from any one of SEQ ID NOS: 1201-1205, and a light chain comprising the amino acid sequence selected from any one of SEQ ID NOS: 1214-1217.

[1062] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1154, and a light chain comprising the amino acid sequence of SEQ ID NO: 1210. [1063] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1152, and a light chain comprising the amino acid sequence of SEQ ID NO: 1208.

[1064] In some embodiments, an anti- ASGR1 antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1153, and a light chain comprising the amino acid sequence of SEQ ID NO: 1209.

[1065] In any of the aforementioned antibody or antigen binding fragment thereof embodiments, the VH may be joined to a heavy chain constant region, such as a human IgGl constant region of SEQ ID NO: 1230 or 1231.

[1066] In any of the aforementioned antibody or antigen binding fragment thereof embodiments, the VL may be joined to a light chain constant region, such as a human kappa constant region of SEQ ID NO: 1232.

[1067] In any of the aforementioned embodiments, the antibody or antigen binding fragment thereof of this disclosure is conjugated to a small molecule drug to form an antibody drug conjugate. In some embodiments, the small molecule drug is a myeloid cell agonist (e.g., ALK5 inhibitor of this disclosure) as disclosed herein.

[1068] An antibody or antigen binding fragment thereof described herein can be a human antibody. As used throughout this disclosure, “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 and that typically do not express endogenous immunoglobulins. Human antibodies can be produced using transgenic mice incapable of expressing functional endogenous immunoglobulins, but capable of expressing 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.

[1069] An antibody or antigen binding fragment thereof described herein can be derivatized or otherwise modified. For example, derivatized antibodies can be modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or the like.

[1070] An antibody, antibody construct, or targeting moiety may be a derivatized antibody. For example, derivatized antibodies may be modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein.

[1071] An antibody construct may consist of two identical light protein chains and two identical heavy protein chains, all held together covalently by disulfide linkages. The N-terminal regions of the light and heavy chains together may form the antigen recognition site of an antibody. Structurally, various functions of an antibody may be confined to discrete protein domains. The sites that can recognize and can bind antigen may consist of three complementarities determining regions (CDRs) that may lie within the variable heavy chain region and variable light chain region at the N-terminal end of the heavy chain and the light chain. The constant domains may provide the general framework of the antibody and may not be involved directly in binding the antibody to an antigen, but may be involved in various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity and may bind Fc receptors. The constant domains may include an Fc region. The constant domains may include an Fc region or domain. The variable regions of natural light and heavy chains may have the same general structures, and each domain may comprise four framework regions, whose sequences can be somewhat conserved, connected by three hyper-variable regions or CDRs. The four framework regions (FR) may largely adopt a β-sheet conformation and the CDRs can form loops connecting, and in some embodiments forming part of, the P -sheet structure. The CDRs in each chain may be held in close proximity by the framework regions and with the CDRs from the other chain, may contribute to the formation of the antigen binding site.

[1072] An antibody construct may comprise a light chain of an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine or ten modifications and in some embodiments, 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 may comprise a heavy chain of an amino acid sequence having at least one, two, three, four, five, six, seven, eight, nine or ten modifications and in some embodiments, 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.

[1073] F(ab') ₂ and Fab' moieties may be produced by genetic engineering or by treating immunoglobulin (e.g., monoclonal antibody) with a protease such as pepsin and papain, and may include an antibody fragment generated by digesting immunoglobulin near the disulfide bonds existing between the hinge regions in each of the two H chains. The Fab fragment may also contain the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab' fragments may differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CHI domain including one or more cysteine(s) from the antibody hinge region.

[1074] An Fv may be the minimum antibody fragment which contains a complete antigen-recognition and antigen-binding site. This region may consist of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. In this configuration, the three CDRs of each variable domain may 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 three CDRs specific for an antigen) may recognize and bind to antigen, although the binding can be at a lower affinity than the affinity of the entire binding site.

[1075] An antibody, antibody construct, or targeting moiety may comprise an antigen binding domain that binds an antigen, wherein the antigen binding domain comprises:

(a) HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 6;

(b) HCDR1 comprising an amino acid sequence of SEQ ID NO: 7, HCDR2 comprising an amino acid sequence of SEQ ID NO: 8, HCDR3 comprising an amino acid sequence of SEQ ID NO: 9, LCDR1 comprising an amino acid sequence of SEQ ID NO: 10, LCDR2 comprising an amino acid sequence of SEQ ID NO: 11, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 12;

(c) 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: 16, LCDR2 comprising an amino acid sequence of SEQ ID NO: 17, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 18;

(d) HCDR1 comprising an amino acid sequence of SEQ ID NO: 19, HCDR2 comprising an amino acid sequence of SEQ ID NO: 20, HCDR3 comprising an amino acid sequence of SEQ ID NO: 21, LCDR1 comprising an amino acid sequence of SEQ ID NO: 22, LCDR2 comprising an amino acid sequence of SEQ ID NO: 23, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 24; (e) HCDR1 comprising an amino acid sequence of SEQ ID NO: 25, HCDR2 comprising an amino acid sequence of SEQ ID NO: 26, HCDR3 comprising an amino acid sequence of SEQ ID NO: 27, LCDR1 comprising an amino acid sequence of SEQ ID NO: 28, LCDR2 comprising an amino acid sequence of SEQ ID NO: 29, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 30;

(f) HCDR1 comprising an amino acid sequence of SEQ ID NO: 31, HCDR2 comprising an amino acid sequence of SEQ ID NO: 32, HCDR3 comprising an amino acid sequence of SEQ ID NO: 33, LCDR1 comprising an amino acid sequence of SEQ ID NO: 34, LCDR2 comprising an amino acid sequence of SEQ ID NO: 35, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 36;

(g) HCDR1 comprising an amino acid sequence of SEQ ID NO: 37, HCDR2 comprising an amino acid sequence of SEQ ID NO: 38, HCDR3 comprising an amino acid sequence of SEQ ID NO: 39, LCDR1 comprising an amino acid sequence of SEQ ID NO: 40, LCDR2 comprising an amino acid sequence of SEQ ID NO: 41, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 42;

(h) HCDR1 comprising an amino acid sequence of SEQ ID NO: 43, HCDR2 comprising an amino acid sequence of SEQ ID NO: 44, HCDR3 comprising an amino acid sequence of SEQ ID NO: 45, LCDR1 comprising an amino acid sequence of SEQ ID NO: 46, LCDR2 comprising an amino acid sequence of SEQ ID NO: 47, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 48;

(i) HCDR1 comprising an amino acid sequence of SEQ ID NO: 50, HCDR2 comprising an amino acid sequence of SEQ ID NO: 51, HCDR3 comprising an amino acid sequence of SEQ ID NO: 52, LCDR1 comprising an amino acid sequence of SEQ ID NO: 53, LCDR2 comprising an amino acid sequence of SEQ ID NO: 54, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 55;

(j) HCDR1 comprising an amino acid sequence of SEQ ID NO: 56, HCDR2 comprising an amino acid sequence of SEQ ID NO: 57, HCDR3 comprising an amino acid sequence of SEQ ID NO: 58, LCDR1 comprising an amino acid sequence of SEQ ID NO: 59, LCDR2 comprising an amino acid sequence of SEQ ID NO: 60, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 61;

(k) HCDR1 comprising an amino acid sequence of SEQ ID NO: 62, HCDR2 comprising an amino acid sequence of SEQ ID NO: 63, HCDR3 comprising an amino acid sequence of SEQ ID NO: 64, LCDR1 comprising an amino acid sequence of SEQ ID NO: 65, LCDR2 comprising an amino acid sequence of SEQ ID NO: 66, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 67;

(l) HCDR1 comprising an amino acid sequence of SEQ ID NO: 68, HCDR2 comprising an amino acid sequence of SEQ ID NO: 69, HCDR3 comprising an amino acid sequence of SEQ ID NO: 70, LCDR1 comprising an amino acid sequence of SEQ ID NO: 71, LCDR2 comprising an amino acid sequence of SEQ ID NO: 72, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 73;

(m) HCDR1 comprising an amino acid sequence of SEQ ID NO: 74, HCDR2 comprising an amino acid sequence of SEQ ID NO: 75, HCDR3 comprising an amino acid sequence of SEQ ID NO: 76, LCDR1 comprising an amino acid sequence of SEQ ID NO: 77, LCDR2 comprising an amino acid sequence of SEQ ID NO: 78, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 79;

(n) HCDR1 comprising an amino acid sequence of SEQ ID NO: 74, HCDR2 comprising an amino acid sequence of SEQ ID NO: 75, HCDR3 comprising an amino acid sequence of SEQ ID NO: 76, LCDR1 comprising an amino acid sequence of SEQ ID NO: 80, LCDR2 comprising an amino acid sequence of SEQ ID NO: 81, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 82;

(o) HCDR1 comprising an amino acid sequence of SEQ ID NO: 199, HCDR2 comprising an amino acid sequence of SEQ ID NO: 200, HCDR3 comprising an amino acid sequence of SEQ ID NO: 201, LCDR1 comprising an amino acid sequence of SEQ ID NO: 202, LCDR2 comprising an amino acid sequence of SEQ ID NO: 203, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 204;

(p) HCDR1 comprising an amino acid sequence of SEQ ID NO: 205, HCDR2 comprising an amino acid sequence of SEQ ID NO: 206, HCDR3 comprising an amino acid sequence of SEQ ID NO: 207, LCDR1 comprising an amino acid sequence of SEQ ID NO: 208, LCDR2 comprising an amino acid sequence of SEQ ID NO: 209, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 210;

(q) HCDR1 comprising an amino acid sequence of SEQ ID NO: 211, HCDR2 comprising an amino acid sequence of SEQ ID NO: 212, HCDR3 comprising an amino acid sequence of SEQ ID NO: 213, LCDR1 comprising an amino acid sequence of SEQ ID NO: 214, LCDR2 comprising an amino acid sequence of SEQ ID NO: 215, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 216; (r) HCDR1 comprising an amino acid sequence of SEQ ID NO: 217, HCDR2 comprising an amino acid sequence of SEQ ID NO: 218, HCDR3 comprising an amino acid sequence of SEQ ID NO: 219, LCDR1 comprising an amino acid sequence of SEQ ID NO: 220, LCDR2 comprising an amino acid sequence of SEQ ID NO: 221, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 222;

(s) HCDR1 comprising an amino acid sequence of SEQ ID NO: 223, HCDR2 comprising an amino acid sequence of SEQ ID NO: 224, HCDR3 comprising an amino acid sequence of SEQ ID NO: 225, LCDR1 comprising an amino acid sequence of SEQ ID NO: 226, LCDR2 comprising an amino acid sequence of SEQ ID NO: 227, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 228;

(t) HCDR1 comprising an amino acid sequence of SEQ ID NO: 229, HCDR2 comprising an amino acid sequence of SEQ ID NO: 230, HCDR3 comprising an amino acid sequence of SEQ ID NO: 231, LCDR1 comprising an amino acid sequence of SEQ ID NO: 232, LCDR2 comprising an amino acid sequence of SEQ ID NO: 233, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 234;

(u) HCDR1 comprising an amino acid sequence of SEQ ID NO: 235, HCDR2 comprising an amino acid sequence of SEQ ID NO: 236, HCDR3 comprising an amino acid sequence of SEQ ID NO: 237 LCDR1 comprising an amino acid sequence of SEQ ID NO: 238, LCDR2 comprising an amino acid sequence of SEQ ID NO: 239, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 240;

(v) HCDR1 comprising an amino acid sequence of SEQ ID NO: 241, HCDR2 comprising an amino acid sequence of any one of SEQ ID NOS: 242-244, HCDR3 comprising an amino acid sequence of SEQ ID NO: 245, LCDR1 comprising an amino acid sequence of SEQ ID NO: 246, LCDR2 comprising an amino acid sequence of any one of SEQ ID NOS: 247- 249, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 250;

(w) HCDR1 comprising an amino acid sequence of SEQ ID NO: 251, HCDR2 comprising an amino acid sequence of SEQ ID NO: 252, HCDR3 comprising an amino acid sequence of SEQ ID NO: 253, LCDR1 comprising an amino acid sequence of SEQ ID NO: 254, LCDR2 comprising an amino acid sequence of SEQ ID NO: 255 or 256, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 257;

(x) HCDR1 comprising an amino acid sequence of SEQ ID NO: 258, HCDR2 comprising an amino acid sequence of SEQ ID NO: 259, HCDR3 comprising an amino acid sequence of SEQ ID NO: 260, LCDR1 comprising an amino acid sequence of SEQ ID NO: 261, LCDR2 comprising an amino acid sequence of SEQ ID NO: 262, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 263;

(y) HCDR1 comprising an amino acid sequence of SEQ ID NO: 264, HCDR2 comprising an amino acid sequence of SEQ ID NO: 265, HCDR3 comprising an amino acid sequence of SEQ ID NO: 266, LCDR1 comprising an amino acid sequence of SEQ ID NO: 267, LCDR2 comprising an amino acid sequence of any one of SEQ ID NOS: 268-270, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 271; or

(z) HCDR1 comprising an amino acid sequence of SEQ ID NO: 272, HCDR2 comprising an amino acid sequence of SEQ ID NO: 273, HCDR3 comprising an amino acid sequence of SEQ ID NO: 274, LCDR1 comprising an amino acid sequence of SEQ ID NO: 275, LCDR2 comprising an amino acid sequence of SEQ ID NO: 276, or LCDR3 comprising an amino acid sequence of SEQ ID NO: 277.

[1076] An antibody construct may comprise an antigen binding domain that specifically binds an antigen, wherein the antigen binding domain comprises:

(a) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 83, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 84;

(b) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 85, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 86;

(c) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 87, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 88;

(d) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 89, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 90;

(e) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 91, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 92;

(f) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 93, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 94;

(g) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 95, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 96;

(h) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 97, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 98;

(i) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 99, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 100;

(j) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 101, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 102; (k) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 101, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 103;

(l) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 104, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 105;

(m) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 106, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 107;

(n) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 109, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 108;

(o) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 110, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 108;

(p) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 111, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 112;

(q) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 113, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 114;

(r) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 115, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 116;

(s) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 117, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 118;

(t) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 117, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 119;

(u) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 117, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 120;

(v) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 117, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 121;

(w) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 117, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 122; (x) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 123, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 124;

(y) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 125, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 126;

(z) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 127, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 128;

(aa) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 130, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 129;

(bb) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 131, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 132;

(cc) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 133, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 134;

(dd) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 135, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 136;

(ee) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 137, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 138;

(ff) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 140, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 139;

(gg) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 141, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 142;

(hh) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 143, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 144;

(ii) ii) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 145, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 146;

(jj) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 147, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 148; (kk) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 149, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 150;

(11) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 151, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 153;

(mm) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 152, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 153;

(nn) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 154, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 155;

(oo) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 156, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 157;

(pp) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 158, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 159;

(qq) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 160, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 161;

(rr) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 162, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 163;

(ss) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 164, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 167;

(tt) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 164, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 168;

(uu) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 165, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 167;

(vv) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 165, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 168;

(ww) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 166, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 167; (xx) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 166, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 168;

(yy) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 171, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 172;

(zz) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 174, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 173;

(aaa) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 175, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 176;

(bbb) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 177, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 178;

(ccc) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 179, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 180;

(ddd) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 181, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 182;

(eee) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 183, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 184;

(fff) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 185, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 186;

(ggg) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 187, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 188;

(hhh) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 189, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 190;

(iii) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 191, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 192;

(jjj) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 193, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 194; (kkk) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 195, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 196;

(111) a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 197, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 198; or

(mmm)a VH sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 285, and a VL sequence having at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to an amino acid sequence of SEQ ID NO: 286.

Attachment of Linkers to an Antibody, an Antibody Construct, or a Targeting Moiety

[1077] In some embodiments, including in any of the aforementioned embodiments, the antibody, antibody construct, or targeting moiety can be used to generate a conjugate with an ALK5 inhibitor compound of this disclosure as described herein.

[1078] The conjugates described herein may comprise a linker, e.g., a peptide linker. Linkers of the conjugates and methods may not affect the binding of active portions of a conjugate (e.g., active portions include antigen binding domains, Fc region or domains, target binding domains, antibodies, compounds, inhibitors or the like) to a target, which can be a cognate binding partner such as an antigen. A linker can form a linkage between different parts of a conjugate, e.g., between an antibody construct or targeting moiety and a compound of the disclosure. In some embodiments, a conjugate comprises multiple linkers. In some embodiments, wherein a conjugate comprises multiple linkers, the linkers may be the same linkers or different linkers.

[1079] A linker may be bound to an antibody construct or targeting moiety by a bond between the antibody construct targeting moiety and the linker. A linker may be bound to an anti-tumor antigen antibody construct by a bond between the anti-tumor antigen antibody construct and the linker. A linker may be bound to a terminus of an amino acid sequence of an antibody construct, or could be bound to a side chain modification to the antibody construct, such as the side chain of a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue. A linker may be bound to a terminus of an amino acid sequence of an Fc region of an antibody construct, or may be bound to a side chain modification of an Fc region of an antibody construct, such as the side chain of a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue. A linker may be bound to a terminus of an amino acid sequence of an Fc region or domain of an antibody construct, or may be bound to a side chain modification of an Fc region or domain of an antibody construct, such as the side chain of a lysine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamine, a non-natural amino acid residue, or glutamic acid residue.

[1080] A linker may be bound to an antibody construct at a hinge cysteine. A linker may be bound to an antibody construct at a light chain constant domain lysine. A linker may be bound to an antibody construct at an engineered cysteine in the light chain. A linker may be bound to an antibody construct at an Fc region lysine. A linker may be bound to an antibody construct at an Fc region or domain lysine. A linker may be bound to an antibody construct at an Fc region cysteine. A linker may be bound to an antibody construct at an Fc region or domain cysteine. A linker may be bound to an antibody construct at a light chain glutamine, such as an engineered glutamine. A linker may be bound to an antibody construct at an unnatural amino acid engineered into the light chain. A linker may be bound 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, for example, a linker of a conjugate. Engineered amino acids may be added to a sequence of existing amino acids. Engineered amino acids may be substituted for one or more existing amino acids of a sequence of amino acids.

[1081] A linker may be conjugated to an antibody construct via a sulfhydryl group on the antibody construct. A linker may be conjugated to an antibody construct via a primary amine on the antibody construct. A linker may be conjugated to an antibody construct via residue of an unnatural amino acid on an antibody construct, e.g., a ketone moiety.

[1082] In some embodiments, when one or more linkers are bound, e.g., covalently, to an antibody construct at sites on the construct, an Fc region or domain of the antibody construct can bind to Fc receptors. In some embodiments, an antibody construct bound to a linker or an antibody construct bound to a linker bound to a compound of the disclosure, retains the ability of the Fc region or domain of the antibody to bind to Fc receptors. In some embodiments, when a linker is connected to an antibody construct, the antigen binding domain of an antibody construct bound to a linker or an antibody construct bound to a linker bound to a compound of the disclosure can bind its antigen. In some embodiments, when a linker is connected to an antibody construct at the sites described herein, a target binding domain of an antibody construct bound to a linker or an antibody construct bound to a linker bound to a compound of the disclosure can bind its antigen.

[1083] In some embodiments, a linker or linker bound to a compound of the disclosure may be attached to an amino acid residue of an IgG Fc region or domain selected from: 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246,

247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276,

278, 280, 281, 283, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302,

305, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,

336, 396, 428, or any subset thereof, wherein numbering of amino acid residues in the Fc region or domain is according to the EU index as in Kabat.

[1084] In some embodiments, a linker or linker bound to a compound of the disclosure is not attached to an amino acid residue of an IgG Fc region or domain selected from: 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246,

247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276,

278, 280, 281, 283, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302,

305, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,

336, 396, 428, or any subset thereof, wherein numbering of amino acid residues in the Fc region or domain is according to the EU index as in Kabat.

Lysine-based Bioconjugation

[1085] 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 a compound of the disclosure, 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 (mAb) and linker-payload, e.g., 10 equivalents, following Scheme A below (Conjugate = antibody conjugate). Monomer content and drug-antibody construct ratios (molar ratios) can be determined by methods described herein.

Cysteine-based Bioconjugation

[1086] 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 a compound of the disclosure and a linker 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 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-payload 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 (mAb) and linker- payload, e.g., 7 equivalents, using the conditions described in Scheme B below (Conjugate = antibody conjugate). Monomer content and drug-antibody ratios can be determined by methods described herein.

Pharmaceutical Formulations

[1087] The compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof. Pharmaceutical compositions may comprise at least the compositions described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents. The composition may comprise the conjugate having an antibody construct and a compound of the disclosure. The composition may comprise the conjugate having an antibody construct and a compound of the disclosure. The composition may comprise the conjugate having an antibody construct, a target binding domain, and a compound of the disclosure. The composition may comprise any conjugate described herein. In some embodiments, the antibody construct is an anti-LRRC15 antibody. A conjugate may comprise an anti-LRRC15 antibody and a compound of this disclosure. In some embodiments, the antibody construct is an anti-ASGRl antibody. A conjugate may comprise an anti-ASGRl antibody and a compound of this disclosure. A pharmaceutical composition can comprise at least the compounds, salts or conjugates described herein and one or more of buffers, antibiotics, steroids, carbohydrates, drugs (e.g., chemotherapy drugs), radiation, polypeptides, chelators, adjuvants and/or preservatives.

[1088] Pharmaceutical compositions may be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation may be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate may be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions may also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.

[1089] Methods for formulation of the conjugates may include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some embodiments, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates may be lyophilized or in powder form for re- constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[1090] Pharmaceutical compositions of the conjugates may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredients may 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.

[1091] Pharmaceutical compositions as often further may comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds may have complementary activities that do not adversely affect each other. For example, the composition may comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant. Such molecules may be present in combination in amounts that are effective for the purpose intended.

[1092] The compositions and formulations may be sterilized. Sterilization may be accomplished by filtration through sterile filtration.

[1093] The compositions may be formulated for administration as an injection. Non- limiting examples of formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension. The suspension may also contain suitable stabilizers. Injections may be formulated for bolus injection or continuous infusion. Alternatively, the compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[1094] The phrases “parenteral administration” and “administered parenterally” as used throughout this disclosure 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 intrastemal injection and infusion.

[1095] 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.

[1096] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used throughout this disclosure 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: (a) sugars, such as lactose, glucose and sucrose; (b) starches, such as com starch and potato starch; (c) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (d) powdered tragacanth; (e) malt; (f) gelatin; (g) talc; (h) excipients, such as cocoa butter and suppository waxes; (i) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (j) glycols, such as propylene glycol; (k) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (1) esters, such as ethyl oleate and ethyl laurate; (m) agar; (n) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (o) alginic acid; (p) pyrogen-free water; (q) isotonic saline; (r) Ringer's solution; (s) ethyl alcohol; (t) phosphate buffer solutions; and (u) other non-toxic compatible substances employed in pharmaceutical formulations.

[1097] 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, p-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.

[1098] For parenteral administration, the compounds, salts or conjugates may be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles may be inherently non- toxic, and non-therapeutic. Vehicles may be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used. Liposomes may be used as carriers. The vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[1099] Sustained-release preparations may be also be prepared. Examples of sustained- release preparations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound, salt or conjugate, and these matrices may be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices may include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and y 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.

[1100] Pharmaceutical formulations may be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer. This formulation may be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and/or stabilizers may be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and/or stabilizers may 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.

[1101] Pharmaceutical formulations of the conjugates may have an average drug- antibody construct ratio (“DAR”) selected from about 1 to about 20 or from about 1 to about 10, wherein the drug is a compound or salt of any one of Formulas (I)— (IX) and Table 1. In some embodiments, the average DAR of the formulation is from about 2 to about 8, such as from about 3 to about 8, such as from about 3 to about 7, such as about 3 to about 5 or such as about 2. In some embodiments, a pharmaceutical formulation has an average DAR of about 3, about 3.5, about 4, about 4.5 or about 5.

Therapeutic Applications

[1102] The compositions, conjugates and methods of the 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.

[1103] The compositions, conjugates and methods 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 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.

[1104] In practicing the methods described herein, therapeutically-effective amounts of the compositions, and conjugates 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, an inflammatory response, or other physiologic affect. A therapeutically-effective amount can vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. [1105] Treat and/or treating 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.

[1106] Prevent, preventing and the like 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 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. Preventing can also refer to preventing re-occurrence of a disease or condition in a patient that has previously been treated for the disease or condition, e.g., by preventing relapse.

[1107] A therapeutically effective amount (also referred to as an effective amount) can be the amount of a composition (e.g., conjugate or compound) or an active component 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 and the teachings provided herein.

[1108] The conjugates that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disease or condition 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 compositions can be prepared according to the description of preparation described herein.

[1109] Pharmaceutical compositions can be used in 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 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 treatments the subject is receiving or has received, and the like.

[1110] The methods and compositions can be for administration to a subject in need thereof. Often, administration of the compositions 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.

[1111] Compositions and conjugates of the 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 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. The administrations can be weekly, biweekly (every two weeks), every three weeks, monthly or bimonthly.

[1112] The compositions, conjugates and methods provided herein may be useful for the treatment of a plurality of diseases, conditions, preventing a disease or a condition in a subject or other therapeutic applications for subjects in need thereof. Often the compositions, conjugates and methods provided herein may be useful for treatment of hyperplastic conditions, including but not limited to, neoplasms, cancers, tumors and the like. The compositions, conjugates and methods provided herein may be useful in specifically targeting TGFβi, TGFβRl, TGFβR2, or combinations thereof. The compositions and methods provided herein may be useful in inhibiting TGFβi, TGFβRl, TGFβR2, or combinations thereof. In one embodiment, the compounds of the disclosure activate or enhance an immune response. In another embodiment, the conjugates of the disclosure activate or enhance an immune response.

[1113] A condition, such as a cancer, may be associated with expression of a molecule on the cancer cells. Often, the molecule expressed by the cancer cells may comprise an extracellular portion capable of recognition by the antibody construct of the conjugate. A molecule expressed by the cancer cells may be a tumor antigen. An antibody construct of the conjugate may recognize a tumor antigen. [1114] In some embodiments, the antigen binding domain specifically binds to an antigen that is at least 80% identical to an antigen on a T cell, a B cell, a stellate cell, an endothelial cell, a tumor cell, an APC, a fibroblast cell, a fibrocyte cell, or a cell associated with the pathogenesis of fibrosis. In some embodiments, the antigen binding domain specifically binds to an antigen that is at least 80% identical to an antigen on a T cell, an APC, and/or a B cell. In some embodiments, the antigen binding domain may specifically bind to an antigen that is at least 80% identical to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, CLTA4, PD-1, 0X40, LAG-3, GITR, GARP, CD25, CD27, PD-L1, TNFR2, ICOS, 41BB, CD70, CD73, CD38, or VTCN1. In some embodiments, the antigen binding domain specifically binds to an antigen that is at least 80% identical to an antigen on a stellate cell, an endothelial cell, a fibroblast cell, a fibrocyte cell, or a cell associated with the pathogenesis of fibrosis or cancer. In some embodiments, the antigen binding domain may specifically bind to an antigen that is at least 80% identical to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, PDGFRβ, integrin αvβ1, integrin αvβ3, integrin αvβ6, integrin αvβ8, Endosialin, FAP, ADAM12, MMP14, PDPN, CDH11 and F2RL2, In some embodiments, the antigen binding domain may specifically bind to an antigen that is at least 80% identical to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, FAP, ADAM12, MMP14, PDPN, CDH11 and F2RL2, In some embodiments, the antigen binding domain specifically binds to an antigen that is at least 80% identical to an antigen on a tumor cell, a tumor antigen. In some embodiments, the antigen binding domain specifically binds to an antigen that is at least 80% identical to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, MUC16, UPK1B, VTCN1, TMPRSS3, TMEM238, Clorfl86, TMPRSS4, CLDN6, CLDN8, STRA6, MSLN or CD73.

[1115] In some embodiments, the antigen binding domain specifically binds to an antigen on a T cell, a B cell, a stellate cell, an endothelial cell, a tumor cell, an APC, a fibroblast cell, a fibrocyte cell, or a cell associated with the pathogenesis of fibrosis. In some embodiments, the antigen binding domain specifically binds to an antigen on a T cell, an APC, and/or a B cell. In some embodiments, the antigen binding domain may specifically bind to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, CLTA4, PD-1, 0X40, LAG-3, GITR, GARP, CD25, CD27, PD-L1, TNFR2, ICOS, 41BB, CD70, CD73, CD38 or VTCN1. In some embodiments, the antigen binding domain specifically binds to an antigen on a stellate cell, an endothelial cell, a fibroblast cell, a fibrocyte cell, or a cell associated with the pathogenesis of fibrosis or cancer. In some embodiments, the antigen binding domain may specifically bind to an antigen selected from the group consisting of, ASGR1, ASGR2, LRRC15, PDGFRβ, integrin αvβ1, integrin αvβ3, integrin αvβ6, integrin αvβ8, Endosialin, FAP, ADAM12, MMP14, PDPN, CDH11 and F2RL2. In some embodiments, the antigen binding domain may specifically bind to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, FAP, ADAM12, LRRC15, MMP14, PDPN, CDH11 and F2RL2. In some embodiments, the antigen binding domain specifically binds to an antigen on a tumor cell, a tumor antigen. In some embodiments, the antigen binding domain specifically binds to an antigen selected from the group consisting of ASGR1, ASGR2, LRRC15, MUC16, UPK1B, VTCN1, TMPRSS3, TMEM238, Clorfl86, TMPRSS4, CLDN6, CLDN8, STRA6, MSLN or CD73.

[1116] Additionally, such antigens may be derived from the following specific conditions and/or families of 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, hemangiosarcomas, 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.

[1117] Non-limiting examples of cancers may include Acute lymphoblastic leukemia (ALL); Acute myeloid leukemia; Adrenocortical carcinoma; Astrocytoma, childhood cerebellar or cerebral; Basal-cell carcinoma; Bladder cancer; Bone tumor, osteosarcoma/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.

[1118] Non-limiting examples of fibrosis or fibrotic diseases include adhesive capsulitis, arterial stiffness, arthrofibrosis, atrial fibrosis, cirrhosis, Crohn’s disease, collagenous fibroma, cystic fibrosis, Desmoid-type fibromatosis, Dupuytren’s contracture, elastofibroma, endomyocardial fibrosis, fibroma of tendon sheath, glial scar, idiopathic pulmonary fibrosis, keloid, mediastinal fibrosis, myelofibrosis, nuchal fibroma, nephrogenic systemic fibrosis, old myocardial infarction, Peyronie’s disease, pulmonary fibrosis, progressive massive fibrosis, nonalcoholic steatohepatitis (otherwise known as NASH), radiation-induced lung injury, retroperitoneal fibrosis, scar, scleroderma/systemic sclerosis.

[1119] 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.

EXAMPLES

List of Abbreviations

[1120] As used above, and throughout this disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: lo

General Synthetic Schemes and Examples

[1121] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. 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 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. SCHEME 1 : PREPARATION OF ALK5 INHIBITORS OF FORMULA (I)

[1122] In one method, compounds of Formula (I) are prepared according to Scheme 1. Specifically, bromo-substituted pyrazoles (i) are reacted with an aryl- or heteroaryl -b or onic acid (or ester) (iii) in the presence of an appropriate transition metal catalyst (e.g. palladium-based) to generate compounds of Formula (I). Alternatively, bromo-substituted pyrazoles can be converted to a boronic ester, or ester, (ii) via a borylation reaction. The resultant compound (ii) can then be coupled with an appropriate aryl- or heteroaryl-halide (or pseudohalide) (iv) to generate compounds of Formula (I).

SCHEME 2: METHOD A

PREPARATION OF ALK5 INHIBITORS OF FORMULA (III)

[1123] In one method, compounds of Formula (III) are prepared according to Schemes 2.1, 2.2, and 2.3. More specific example embodiments are shown below for each step of Schemes 2.1, 2.2, and 2.3. Scheme 2,1 : Synthetic procedure for the preparation of heteroaryl boronic ester intermediates

Scheme 2,2: Synthetic procedure for the preparation of bicyclic-pyrazolyl bromide intermediates

Scheme 2,3: Synthetic procedure for the preparation of ALK5 inhibitors of Formula (III)

SCHEME 3 : METHOD B

PREPARATION OF ALK5 INHIBITORS OF FORMULA (IV)

In one method, compounds of Formula (IV) are prepared according to Schemes 3.1 and

3.2. More specific example embodiments are shown below for each step of Schemes 3.1 and

3.2. Scheme 3,1: Synthetic procedure for the preparation of monocyclic-pyrazolyl bromide intermediates

Scheme 3,2: Synthetic procedure for the preparation of ALK5 inhibitors of Formula (IV) SCHEME 5 : METHOD D

PREPARATION OF ALK5 INHIBITORS OF FORMULA (VII)

[1124] NH ₂ -R ⁷ - is R ⁷ - wherein NH ₂ is a reactive group of R ⁷ capable of attachment to a linker, an antibody, an antibody construct, or a targeting moiety and R ⁷ is the remainder of R ⁷ . PG is a protecting group.

SCHEME 6: METHOD E

PREPARATION OF ADDITIONAL ALK5 INHIBITORS OF FORMULA (VII)

Ak is an alkyl chain.

EXAMPLE 1

SYNTHESIS OF COMPOUNDS ACCORDING TO METHOD A

Example 1A

Synthesis of a TFA salt of 4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-

Pyrrolo[ 1,2-b]1pyrazol-3-yl)quinolin-3-yl)oxy)butan-l -amine (Compound 3, 1)

Step 1 : Preparation of benzyl (4-((6-bromoquinolin-3-yl)oxy)butyl)carbamate

To a solution of 6-bromoquinolin-3-ol (500.0 mg, 2.2 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) with an inert atmosphere of nitrogen, was added benzyl 7V-(4- hydroxybutyl)carbamate (491.2 mg, 2.2 mmol, 1.0 equiv.), triphenylphosphine (864.6 mg, 3.3 mmol, 1.5 equiv.), diisopropyl azodicarboxylate (666.6 mg, 3.3 mmol, 1.5 equiv.) with stirring at 0°C. The resulting solution was stirred for 5 h at 50°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 100 mL of water and extracted with 3x100 mL of di chloromethane and the organic layers were combined, washed with 3x100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 400 mg (42%) of benzyl (4-((6-bromoquinolin- 3-yl)oxy)butyl)carbamate was obtained as a white solid. MS m/z [M+H] ⁺ (ESI): 429. Step 2: Preparation of (4-((6-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)quinolin- 3- yl)oxy)butyl)carbamate

[1125] To a solution of benzyl benzyl (4-((6-bromoquinolin-3-yl)oxy)butyl)carbamate (100.0 mg, 0.23 mmol, 1.0 equiv.) in 1,4-dioxane (4.0 mL) with an inert atmosphere of nitrogen, was added bis(pinacolato)diboron (71.1 mg, 0.28 mmol, 1.2 equiv.), [l,l'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (33.6 mg, 0.046 mmol, 0.2 equiv.) and potassium acetate (67.6 mg, 0.69 mmol, 3.0 equiv.). The resulting solution was stirred for 2 h at 110°C. The reaction mixture was cooled to 25°C with a water/ice bath and diluted with 20 mL of water. The resulting mixture was extracted with ethyl acetate 3x 20 mL and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product without further purification was used at next step directly. 85 mg (77%) of (4-((6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinolin-3-yl)oxy)butyl)carbamate was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 477.

Step 3: Preparation of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate

[1126] To a solution of methyl 6-methylpyridine-2-carboxylate (3.0 g, 19.8 mmol, 1.0 equiv.) in ethyl acetate (45.0 mL) with an inert atmosphere of nitrogen, was added sodium hydride (1.6 g, 39.6 mmol, 2.0 equiv.). The resulting solution was stirred for 12 h at 55°C and then quenched by the addition of ice/water. The resulting solution was extracted with 2x50 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 2.4 g (58%) of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate was obtained as a colorless oil. MS m/z [M+H] ⁺ (ESI): 208.

Step 4: Preparation of ethyl (E)-3-(6-methylpyridin-2-yl)-3-((2-oxopyrrolidin-l- yl)imino)propanoate

[1127] To a solution of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate (1.5 g, 7.2 mmol, 1.0 equiv.) in pyridine (30.00 mL) with an inert atmosphere of nitrogen, was added 1- aminopyrrolidin-2-one hydrochloride (1.2 g, 8.6 mmol, 1.2 equiv.). The resulting solution was stirred for 20 h at 25°C. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 25 min); Detector, UV 254 nm. 1.4 g (67%) of ethyl (E)-3-(6- methylpyridin-2-yl)-3-((2-oxopyrrolidin-l-yl)imino)propanoat e was obtained as a white oil. MS m/z [M+H] ⁺ (ESI): 290.

Step 5: Preparation of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolor[1,2-b1]pyra zole-3- carboxylic acid

[1128] To a solution of ethyl (E)-3-(6-methylpyridin-2-yl)-3-((2-oxopyrrolidin-l-yl) imino)propanoate (1.0 g, 3.5 mmol, 1.0 equiv.) in toluene (20.0 mL) with an inert atmosphere of nitrogen, was added sodium ethoxide (476.0 mg, 7.0 mmol, 2.0 equiv.). The resulting solution was stirred for 24 h at 80°C. LCMS showed the reaction was completed. It was followed by the addition of Imol/L hydrochloric acid dropwise with stirring adjust pH to 4. The resulting solution was stirred for 3 h at 25°C. The pH of the reaction was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The resulting solution was diluted with 100 mL of water and extracted with 3x200 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 520 mg (62%) of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazole-3 -carboxylic acid was obtained as a yellow oil. MS m/z [M+H] ⁺ (ESI): 244.

Step 6: Preparation of 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihvdro-4H-pyrrolo[L2-Z >1pyrazole

[1129] To a solution of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazole- 3-carboxylic acid (200.0 mg, 0.82 mmol, 1.0 equiv.) in V,7V-dimethylformamide (5.0 mL) with an inert atmosphere of nitrogen, was added N-bromosuccinimide (445.0 mg, 2.5 mmol, 3.0 equiv.). The resulting solution was stirred for 16 h at 25°C. The resulting solution was diluted with 20 mL of water and extracted with 3x20 mL of dichloromethane and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 170 mg (75%) of 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazole was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 278.

Step 7: Preparation of benzyl (4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihvdro-4H- pyrrolo[ 1,2-b]1pyrazol-3-yl)quinolin-3-yl)oxy)butyl)carbamate

[1130] To a solution of 3-bromo-2-(6-methylpyri din-2 -yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazole (100.0 mg, 0.36 mmol, 1.0 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added (4-((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin - 3-yl)oxy)butyl)carbamate (205.0 mg, 0.43 mmol, 1.2 equiv.), [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (52.6 mg, 0.072 mmol, 0.2 equiv.) and sodium carbonate (116.6 mg, 1.1 mmol, 3.0 equiv.). The resulting solution was stirred for 4 h at 80°C. The reaction mixture was cooled to 25 °C with a water/ice bath and diluted with 10 mL of water and extracted with 3x10 mL of di chloromethane and the organic layers were combined, washed with 3x10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 110 mg (56%) of benzyl (4-((6-(2- (6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazol-3-yl)quinolin-3-yl)oxy)butyl) carbamate was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 548.

Step 8: Preparation of a TFA salt of 4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-

Pyrrolo[ 1,2-b]]pyrazol-3-yl)quinolin-3-yl)oxy)butan-l -amine (Compound 3, 1 To a solution of benzyl (4-((6-(2-(6-methylpyri din-2 -yl)-5,6-dihy dro-4H-pyrrolo[ 1,2-b] pyrazol-3- yl)quinolin-3-yl)oxy)butyl)carbamate (60.0 mg, 0.11 mmol, 1.0 equiv.) trifluoroacetic acid (2.0 mL) with inert atmosphere of nitrogen, the resulting solution was stirred for 4 h at 50°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 10 mL of di chloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 19 mg (43%) of 4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazol-3-yl)quinolin-3-yl)oxy)butan-l -amine TFA salt (Compound 3.1) was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 414. ¹ H NMR (300 MHz, Methanol-d4) δ: 1.87-1.96 (m, 4H), 2.46 (s, 3H), 2.67-2.83 (m, 2H), 2.95-3.00 (m, 2H), 3.10-3.20 (m, 2H), 4.18- 4.22 (m, 2H), 4.27-4.35 (m, 2H), 7.25-7.39 (m, 2H), 7.40-7.54 (m, 1H), 7.62-7.68 (m, 1H), 7.69- 7.82 (m, 2H), 7.83-7.85 (m, 1H), 8.50 (s, 1H). Example IB

Synthesis of a TFA salt of A-(2-aminoethyl)-6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-d ihvdro- 4H-pyrrolor[ 1,2-b1]pyrazol-3-yl)quinoline-3 -carboxamide (Compound 3, 15)

[1132] Compound 3.15 was prepared according to synthetic Method A with the appropriate starting materials, as shown below.

Step 1 : Preparation of benzyl (2-(6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-

Pyrrolo[ 1,2-b]1pyrazol-3-yl)quinoline-3-carboxamido)ethyl)carbamate

[1133] To solution of 3-bromo-2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-47/- pyrrolo[ 1,2-b] pyrazole (160.0 mg, 0.5 mmol, 1.0 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added benzyl (2-(6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline-3-carboxamido)ethyl)carbamate (285.2 mg, 0.6 mmol, 1.2 equiv.), [l,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.1 mg, 0.1 mmol, 0.2 equiv.) and sodium carbonate (159.0 mg, 1.5 mmol, 3.0 equiv.). The resulting solution was stirred for 10 h at 80°C. The reaction mixture was cooled to 25°C with a water/ice bath and diluted with 50 mL of water and extracted with 3x50 mL of di chloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 140 mg (47%) of benzyl (2-(6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazol-3-yl)quinoline-3-carboxamido)ethyl)carbamate was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 583.

Step 2: Preparation of A-(2-aminoethyl)-6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-d ihvdro-4H- pyrrolo[ 1,2-b]1pyrazol-3-yl)quinoline-3-carboxamide TFA salt (Compound 3,15)

[1134] To a solution of benzyl (2-(6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazol-3-yl)quinoline-3-carboxamido)ethyl)carbamate (116.0 mg, 0.2 mmol, 1.0 equiv.) trifluoroacetic acid (2.0 mL) with inert atmosphere of nitrogen, the resulting solution was stirred for 4 h at 50°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 10 mL of di chloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 55 mg (62%) of N-(2-aminoethyl)-6-(2-(6-(difluoromethyl)pyridin- 2-yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazol-3-yl)quinoline-3-carboxamide TFA salt (Compound 3.15) was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 449; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.71-2.81 (m, 2H), 3.12-3.16 (m, 2H), 3.21-3.25 (m, 2H), 3.74-3.78 (m, 2H), 4.31 (t, J= 7.5 Hz, 2H), 6.19-6.57 (m, 1H), 7.59 (d, J= 6.9 Hz, 1H), 7.89-8.00 (m, 3H), 8.04-8.16 (m, 2H), 8.94 (d, J= 2.1 Hz, 1H), 9.30 (d, J= 2.1 Hz, 1H).

Example 1C

Synthesis of a TFA salt of 2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihvdro-4H-pyr rolo r[ 1,2-b1]pyrazol-3-yl)quinoxalin-2-yl)ethan-l -amine (Compound 3,22)

Compound 3.22 was prepared according to synthetic Method A with the appropriate starting materials, as shown below.

Step 1 : Preparation of benzyl (2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-

Pyrrolo[ 1,2-b]1pyrazol-3-yl)quinoxalin-2-yl)ethyl)carbamate

[1135] To a solution of 3-bromo-2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazole (208 mg, 0.48 mmol, 1.2 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added benzyl (2-(7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoxalin-2-yl)ethyl)carbamate (130.0 mg, 0.4 mmol, 1.0 equiv.), [l,l'-Bis (diphenylphosphino)ferrocene]dichloropalladium(II) (58.0 mg, 0.08 mmol, 0.2 equiv.), sodium carbonate (127.2 mg, 1.2 mmol, 3 equiv.). The resulting solution was stirred for 6 h at 80°C. The reaction mixture was cooled to 25°C with a water/ice bath and diluted with 50 mL of water and extracted with 3x50 mL of di chloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 102 mg (47%) of benzyl (2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-py rrolo[ 1,2-b] pyrazol-3- yl)quinoxalin-2-yl)ethyl)carbamate was obtained a yellow solid. MS m/z [M+H] ⁺ (ESI): 559. Step 2: Preparation of 2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-

Pyrrolor[ 1,2-b1]pyrazol-3-yl)quinoxalin-2-yl)ethan-l -amine TFA salt (Compound 3,22)

[1136] To a solution of benzyl (2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro- 4H-pyrrolo[ 1,2-b] pyrazol-3-yl)quinoxalin-2-yl)ethyl)carbamate (102.0 mg, 0.18 mmol, 1.0 equiv.) in trifluoroacetic acid (3.0 mL) with inert atmosphere of nitrogen, the resulting solution was stirred for 4 h at 50°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 20 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 55 mg (71%) of 2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6- dihydro-4H-pyrrolo[ 1 ,2-b]pyrazol-3-yl)quinoxalin-2-yl)ethan- l -amine TFA salt (Compound 3.22) was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 425; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.72-2.82 (m, 2H), 3.13-3.17 (m, 2H), 3.43-3.47 (m, 2H), 3.56-3.60 (m, 2H), 4.30-4.35 (m, 2H), 7.63-7.69 (m, 1H), 7.71-7.83 (m, 1H), 7.98-8.09 (m, 3H), 8.10-8.13 (m, 1H), 8.82 (s, 1H).

Examples 1D-1V

[1137] The compounds in Table 17 were prepared according to synthetic Method A in a manner similar to that described within for Examples 1 A-1C.

TABLE 17

EXAMPLE 2 SYNTHESIS OF COMPOUNDS ACCORDING TO METHOD B

Example 2 A

Synthesis of a TFA salt of 4-((6-(3-(6-methylpyridin-2-yl)- 1H-pyrazol-4-yl)quinolin-3-yl)oxy) butan-l-amine (Compound 4,1)

Compound 4.1

[1138] Compound 4.1 was prepared according to synthetic Method B with the appropriate starting materials, as shown below.

Step 1 : Preparation of (E)-3-(dimethylamino)-l-(6-methylpyridin-2-yl)prop-2-en-l-on e

[1139] To a solution of l-(6-methylpyridin-2-yl)ethanone (270.0 mg, 2.0 mmol, 1.0 equiv.) in (dimethoxy- methyl)dimethylamine (262.2 mg, 2.2 mmol, 1.1 equiv.) with an inert atmosphere of nitrogen, The resulting solution was stirred for 7 h at 105°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 100 mL of water and extracted with 3x100 mL of di chloromethane and the organic layers were combined, washed with 3x100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 305 mg (80%) of (E)-3- (dimethylamino)-l-(6-methylpyridin-2-yl)prop-2-en-l-one was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 191. Step 2: Preparation of 2-methyl-6-(1H-pyrazol-3-yl)pyridine

[1140] To a solution of (E)-3 -(dimethylamino)- l-(6-methylpyri din-2 -yl)prop-2-en-l -one (190.0 mg, 1.0 mmol, 1.0 equiv.) in ethanol (5.0 mL) with an inert atmosphere of nitrogen, was added hydrazine hydrate (2.0 mL). The resulting solution was stirred for 20 h at 25°C and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 150 mg (90%) of 2-methyl-6-(1H-pyrazol-3-yl)pyridine was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 160.

Step 3: Preparation of 2-(4-bromo-1H-pyrazol-3-yl)-6-methylpyridine

[1141] To a solution of 2-methyl-6-( 1H-pyrazol-3-yl)pyridine (318 mg, 2.0 mmol, 1.0 equiv.) in dichloromethane (6.0 mL) with an inert atmosphere of nitrogen, was added N- bromosuccinimide (391.6 mg, 2.2 mmol, 1.1 equiv.). The resulting solution was stirred for 4 h at 25°C. The resulting solution was diluted with 20 mL of water and extracted with 3x20 mL of dichloromethane and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 430 mg (90%) 2-(4-bromo-1H-pyrazol-3-yl)-6- methylpyridine was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 238. Step 4: Preparation of tert-butyl 4-b romo-3 -(6-methylpyridin-2-yl)- 1H-pyrazole- l -carboxyl ate 89%

[1142] To a solution of 2-(4-bromo- 1H-pyrazol-3-yl)-6-methylpyridine (474.0 mg, 2.0 mmol, 1.0 equiv.) in tetrahydrofuran (8.0 mL) with an inert atmosphere of nitrogen, was added di-tert-butyl pyrocarbonate (523.7 mg, 2.4 mmol, 1.2 equiv.), triethylamine (303.0 mg, 3.0 mmol, 1.5 equiv.). The resulting solution was stirred for 4 h at 25°C. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of di chloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 600 mg (89%) of tert-butyl 4-bromo-3 -(6-methylpyri din-2-yl)- 1H-pyrazole-l- carboxylate was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 338.

Step 5: Preparation of tert-butyl 4-(3-(4-(((benzyloxy)carbonyl)amino)butoxy)quinolin-6-yl)-3-

(6-methylpyridin-2-yl)- 1H-pyrazole- 1 -carboxylate

[1143] To a solution of tert-butyl 4-bromo-3 -(6-methylpyri din-2-yl)-l 1H-pyrazole-1- carboxylate (202.0 mg, 0.6 mmol, 1.0 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added (4-((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin - 3-yl)oxy)butyl)carbamate (343.0 mg, 0.72 mmol, 1.2 equiv.), [l,l'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (87.7 mg, 0.12 mmol, 0.2 equiv.), sodium carbonate (190.8 mg, 1.8 mmol, 3.0 equiv.). The resulting solution was stirred for 2 h at 80°C. The reaction mixture was cooled to 25°C with a water/ice bath and diluted with 20 mL of water and extracted with 3x20 mL of dichloromethane and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 230 mg (63%) of tert-butyl 4-(3-(4- (((benzyloxy)carbonyl)amino)butoxy)quinolin-6-yl)-3-(6-methy lpyridin-2-yl)-1H-pyrazole-l- carboxylate was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 608.

Step 6: Preparation of 4-((6-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinolin-3-y l)oxy)butan-

1-amine TFA salt (Compound 4,1)

[1144] To a solution of (4-((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin -3- yl)oxy)butyl)carbamate (200.0 mg, 0.33 mmol, 1.0 equiv.) in trifluoroacetic acid (5.0 mL) with an inert atmosphere of nitrogen, the resulting solution was stirred for 3 h at 50°C. The resulting solution was diluted with 10 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 80 mg (65%) of 4-((6-(3-(6-methylpyridin-2- yl)-1H-pyrazol-4-yl)quinolin-3-yl)oxy)butan-l -amine TFA salt was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 374. ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 1.91-1.99 (m, 4H), 2.82 (s, 3H), 3.04-3.09 (m, 2H), 4.23-4.27 (m, 2H), 7.56 (d, J= 8.7 Hz, 1H), 7.65 (d, J= 8.7 Hz, 1H), 7.74 (d, J= 7.8 Hz, 1H), 7.88-7.91 (m, 1H), 8.01-8.04 (m, 2H), 8.17-8.22 (m, 2H), 8.69 (s, 1H).

EXAMPLE 3

SYNTHESIS OF COMPOUNDS ACCORDING TO METHOD C

Example 3 A

Synthesis of a TFA salt of 2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-

Pyrrolor[ 1,2-b1]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-l-yl)ethan-l -amine (Compound 6,3)

Compound 6.3

Compound 6.3 was prepared according to synthetic Method C with the appropriate starting materials, as shown below.

Step 1 : Preparation of (2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-pyrrolol[ 1,2-b1] pyrazol-3-yl)boronic acid

[1145] To a solution of 3-bromo-2-(6-(difluorornethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazole (100.0 mg, 0.3 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) with an inert atmosphere of nitrogen, was added 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (296.2 mg, 1.6 mmol, 5.0 equiv.). The reaction mixture was cooled to -78°C by the addition of n- butyllithium (51.0 mg, 0.8 mmol, 2.5 equiv.) to the reaction at -78°C. The resulting solution was stirred for 3 h at -78°C. The reaction was then quenched by the addition of water/ice. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 60 mg (68%) of (2-(6-(difluoromethyl)pyridin- 2-yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazol-3-yl)boronic acid was obtained as a white solid. MS m/z [M+H] ⁺ (ESI): 280.

Step 2: Preparation of benzyl (2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-b]1pyrazol-3 -yl)-2-fluorophenyl)- 1H-pyrazol - 1 -yl)ethyl)carbamate

[1146] To a solution of benzyl (2-(4-(5-bromo-2-fluorophenyl)- l7/-pyrazol- l - yl)ethyl)carbamate (220.0 mg, 0.5 mmol, 1.0 equiv.) in 1,2-dimethoxy ethane (5.0 mL) with an inert atmosphere of nitrogen, was added (2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1,2-b] pyrazol-3-yl)boronic acid (220.2 mg, 0.8 mmol, 1.5 equiv.), Tetrakis(triphenylphosphine)palladium (60.8 mg, 0.05 mmol, 0.1 equiv.), Cesium fluoride (159.8 mg, 1.1 mmol, 2.0 equiv.). The resulting solution was stirred for 2 h at 80°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 50 mL of water and extracted with 3x50 mL of di chloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 174 mg (58%) of benzyl (2-(4-(5-(2- (6-(difhioromethyl)pyri din-2 -yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazol-3-yl)-2-fluorophenyl)- 1H-pyrazol-l-yl)ethyl)carbamate was obtained as a white solid. MS m/z [M+H] ⁺ (ESI): 573. Step 3: Preparation of a TFA salt of 2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-

Pyrrolo[ 1,2-b]1pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-l-yl)ethan-l -amine (Compound 6,3)

[1147] To a solution of benzyl (2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro- 4H-pyrrolo[ 1,2-b] pyrazol-3-yl)-2-fluorophenyl)- 1H-pyrazol-l-yl)ethyl)carbamate (174.0 mg, 0.304 mmol, 1.0 equiv.) in trifluoroacetic acid (3 mL), the resulting solution was stirred for 4 h at 50°C. The reaction mixture was cooled to 25°C with a water/ice bath, diluted with 10 mL of di chloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 87 mg (65%) of 2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-Z>]pyrazol-3 -yl)-2-fluorophenyl)- 1 H-pyrazol - 1 -yl)ethan- 1 -amine TFA salt (Compound 6.3) was obtained as a white solid. MS m/z [M+H] ⁺ (ESI): 439; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.69-2.77 (m, 2H), 3.05-3.09 (m, 2H), 3.47 (t, J= 5.6 Hz, 2H), 4.27 (t, J= 7.2 Hz, 2H), 4.49 (t, J= 6.0 Hz, 2H), 6.35-6.62 (m, 1H), 7.09-7.20 (m, 2H), 7.57-7.61 (m, 2H), 7.75-7.77 (m, 1H), 7.86 (s, 1H), 7.93-7.97 (m, 1H), 8.06 (s, 1H).

Examples 3B-3D

[1148] The compounds in Table 18 were prepared according to synthetic Method A in a manner similar to that described within for Examples 3 A.

TABLE 18 EXAMPLE 4

SYNTHESIS OF COMPOUNDS ACCORDING TO METHOD D

Example 4 A

Synthesis of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)p henyl)-1H-pyrazol-l- v1)ethan-l -amine (Compound 7,2)

Compound 7.2 was prepared according to synthetic Method D with the appropriate starting materials, as shown below.

Step 1 : Preparation of 2-(2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-y l)phenyl)- 1H-pyrazol - I -yl)ethyl)i soindoline- 1 , 3 -di one

[1149] To a solution of 2-(4-[2-fluoro-5-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4- yl]phenyl]pyrazol-l-yl)ethanol (600.0 mg, 1.65 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) with an inert atmosphere of nitrogen, was added phthalimide (485.1 mg, 3.3 mmol, 2.0 equiv.), triphenyl phosphine (657.5 mg, 2.5 mmol, 1.5 equiv.), diisopropyl azodiformate (505.0 mg, 2.5 mmol, 1.5 equiv.) with stirring at 0°C. The resulting solution was stirred for 4 h at 25°C. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 20 min); Detector, UV 254 nm. 450 mg (55%) 2-(2-(4-(2-fluoro-5-(3-(6- methylpyri din-2 -yl)- 1 H-pyrazol -4-yl )phenyl )- 1 H-pyrazol - 1 -yl)ethyl)isoindoline- 1 ,3 -di one was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 493.

Step 2: Preparation of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)p henyl)- 1H- pyrazol- 1 -vDethan- 1 -amine

[1150] To a solution of 2-(2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4- yl)phenyl)-1H-pyrazol-l-yl)ethyl)isoindoline-l, 3-dione (450.0 mg, 0.9 mmol, 1.0 equiv.) in ethanol (4.0 mL) with an inert atmosphere of nitrogen, was added hydrazine hydrate (2.0 mL). The resulting solution was stirred for 1 h at 70°C in an oil bath, cooled to 25°C with a water/ice bath and concentrated under reduced pressure. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 240 mg (73%) of 2-(4-(2-fhioro-5-(3-(6-methylpyri din-2 -yl)-1H-pyrazol -4-yl)phenyl)- 1H-pyrazol-1- yl)ethan-l -amine (Compound 7.2) was obtained as a white solid. MS m/z [M+H] ⁺ (ESI): 363; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.52 (s, 3H), 3.07-3.11 (m, 2H), 4.23 (t, J= 6.0 Hz, 2H), 7.05-7.17 (m, 2H), 7.21-7.27 (m, 2H), 7.59-7.67 (m, 2H), 7.74-7.82 (m, 2H), 8.01 (s, 1H).

Examples 4B-4W

[1151] The compounds in Table 19 were prepared according to synthetic Method D in a manner similar to that described within for Example 4A. TABLE 19

EXAMPLE 5

SYNTHESIS OF COMPOUNDS ACCORDING TO METHOD E

Example 5 A

Synthesis of a TFA salt of (M-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H -

Pyrazol-4-yl)phenyl)-1H-pyrazol-l-yl)ethyl)amino)-5-oxope ntanoic acid (Compound 7,14)

Compound 7.14

[1152] Compound 7.14 was prepared according to synthetic Method E with the appropriate starting materials, as shown below. Step 1 : Preparation of methyl (M-4-((tert-butoxycarbonyl)amino)-5-((2-(4-(2-fluoro-5-(3-(6 - methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-l-yl) ethyl)amino)-5-oxopentanoate

[1153] To a solution of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4- yl)phenyl)-1H-pyrazol-l-yl)ethan-l -amine (150.0 mg, 0.41 mmol, 1.0 equiv.) in tetrahydrofuran (3.0 mL) with an inert atmosphere of nitrogen, was added N,A-carbonyldiimidazole (79.4 mg, 0.49 mmol, 1.2 equiv.), methyl (4S)-4-(benzylcarbamoyl)-4-[(tert- butoxycarbonyl)amino]butanoate (107.0 mg, 0.41 mmol, 1.0 equiv.). The resulting solution was stirred for 6 h at 25°C. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 20 min); Detector, UV 254 nm. 120 mg (48%) of methyl fS')-4-((tert- butoxycarbonyl)amino)-5-((2-(4-(2-fluoro-5-(3-(6-methylpyrid in-2-yl)-1H-pyrazol-4-yl)phenyl)- 1H-pyrazol-l-yl)ethyl)amino)-5-oxopentanoate was obtained as a yellow solid. MS m/z [M+H] ⁺ (ESI): 606.

Step 2: Preparation of a TFA salt of methyl (M-4-amino-5-((2-(4-(2-fluoro-5-(3-(6- methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-l-yl) ethyl)amino)-5-oxopentanoate TFA salt (Compound 7,13)

[1154] To a solution of methyl (5)-4-((tert-butoxycarbonyl)amino)-5-((2-(4-(2-fluoro-5-

(3 -(6-methylpyridin-2-yl)- 1H-pyrazol-4-yl)phenyl)- 1H-pyrazol - 1 -yl)ethyl)amino)-5- oxopentanoate (138.0 mg, 0.23 mmol, 1.0 equiv.) in dichloromethane (4.0 mL) with an inert atmosphere of nitrogen, was added trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at 25°C. The reaction mixture was diluted with 10 mL of di chloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% r(s, 1H), 8.03 (s, 1H), 8.11-8.18 (m, 2H). MS m/z [M+H] ⁺ (ESI): 506; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.02-2.09 (m, 2H), 2.35-2.39 (m, 2H), 2.78 (s, 3H), 3.59-3.64 (m, 4H), 3.82-3.87 (m, 2H), 4.33-4.41 (m, 2H), 7.20-7.22 (m, 2H), 7.53-7.66 (m, 1H), 7.70-7.72 (m, 2H), 7.88 (s, 1H), 8.02 (s, 1H), 8.10-8.15 (m, 2H).

Step 3: Preparation of (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-l H- pyrazol-4-yl)phenyl)-lH-pyrazol-l-yl)ethyl)amino)-5-oxopenta noic acid TFA salt, Compound 7.14

[1155] To a solution of Compound 7.13 (190.0 mg, 0.38 mmol, 1.0 equiv.) in tetrahydrofuran/water (2.0 mL/2.0 mL) with an inert atmosphere of nitrogen, was added lithium hydroxide monohydrate (31.9 mg, 0.76 mmol, 2.0 equiv.). The resulting solution was stirred for 6 h at 25°C. The pH of the reaction was adjusted to 7 with trifluoroacetic acid. The resulting mixture was concentrated under vacuum and purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 50.0% in 15 min); Detector, UV 254 nm. 70 mg (38%) of (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-l H-pyrazol-4-yl)phenyl)-lH- pyrazol-l-yl)ethyl)amino)-5-oxopentanoic acid TFA salt, Compound 7.14 was obtained as a yellow semi-solid. MS m/z [M+H] ⁺ (ESI): 492; ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 2.02-2.09 (m, 2H), 2.36-2.39 (m, 2H), 2.79 (s, 3H), 3.61-3.65 (m, 1H), 3.79-3.87 (m, 2H), 4.39-4.43 (m, 2H), 7.19-7.22 (m, 2H), 7.55 (d, J= 8.0 Hz, 1H), 7.66-7.72 (m, 2H), 7.89 (s, 1H), 8.03 (s, 1H), 8.11-8.18 (m, 2H). Examples 5C-5K

[1156] The compounds in Table 20 were prepared according to synthetic Method E in a manner similar to that described within for Examples 5 A and 5B.

TABLE 20 EXAMPLE 6

Enzyme Inhibition Assay and TGFβ Reporter Assay

Materials and General Procedures

[1157] TGFβ/SMAD Signaling Pathway SBE reporter cell line was obtained from BPS Bioscience. Cells were passed, expanded, and stored in liquid nitrogen as per the supplier's instructions with the exception that growth media is changed to DMEM-C with Geneticin (DMEM supplemented with 10% fetal bovine serum, 1X NEAA, ImM Pyruvate, 2mM glutamine, 50 pg/mL penicillin, 50 U/mL streptomycin and 400 pg/mL of Geneticin). The assay media was MEM supplemented with 0.5% fetal bovine serum, IX NEAA, ImM Pyruvate, 50 pg/mL penicillin and 50 U/mL streptomycin.

[1158] Compounds of Formula (I) were assayed to measure their activity as ALK5 inhibitors.

Enzyme Inhibition Assay

[1159] ALK5 enzyme inhibition assays were performed by Reaction Biology Corp (Malvern, PA). 1 mg/mL of peptide substrate (casein) and 10 uM ATP were prepared in a mixture of fresh reaction buffer. The kinase was delivered into the substrate solution which was gently mixed. Compounds in 100% DMSO were added to the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range) and the mixture was incubated for 20 min at room temperature. ³³ P-ATP (Specific activity 10 uCi/uL) was added into the reaction mixture to initiate the reaction and the reaction mixture was incubated for 2 hours at room temperature. Radioactivity was detected by filter-binding method and kinase activity data were expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. ICso values and curve fits were obtained using Prism (GraphPad Software). Compounds having an ICso value between 0.1 nM and 25 nM are denoted as ++++, 25 nM and 100 nM as +++, 100 nM and 1000 nM as ++, and 1000 nM to 10,000 nM as + in Table 21 below. TABLE 21

INHIBITION OF ALK5 BY COMPOUNDS DESCRIBED HEREIN.

*ND = No Data TGFP Reporter Assay

[1160] TGFβ/SMAD Signaling Pathway SBE reporter cell line was obtained from BPS Bioscience. Cells were passed/expanded/stored in liquid nitrogen per supplier’s instruction with the exception that growth media was changed to DMEM-C with Geneticin (DMEM supplemented with 10% fetal bovine serum, 1X NEAA, ImM Pyruvate, 2mM glutamine, 50 pg/mL penicillin, 50 U/mL streptomycin and 400 pg/mL of Geneticin). The assay media was MEM supplemented with 0.5% fetal bovine serum, 1X NEAA, ImM Pyruvate, 50 pg/mL penicillin and 50 U/mL streptomycin.

[1161] Reporter cells were harvested from the tissue culture flasks by incubation in small quantity of Versene at room temperature for three to five minutes after the media in the flask was removed and cells rinsed with PBS. Cells were counted and diluted in the assay media at ~0.8 x 10 ⁶ cells/mL then 50 μL/well were added to 96-well assay plate. Test samples (at desired concentrations diluted in assay media) were added to assay plate containing the 50μL/well of cells (or media only), 50μL per well, and incubated for 5-6 hours at 37°C in a 5% CO ₂ humidified incubator. After that time, 15uL of TGFβ diluted to 12.5ng/mL in the assay media was added to the plate. Controls included TGFβ titration (from 25 to 0 ng/mL) without inhibitors, and media only (without cells, inhibitor or TGFβ). Plates were incubated at 37°C in a 5% CO ₂ humidified incubator for 18h. Luciferase substrate solution was subsequently added at 75 μL per well, incubated in dark with shaking at room temperature for 10 min, and luminescence was measured using a luminometer. Compounds having an EC50 value between 0.1 nM and 25 nM are denoted as ++++, 25 nM and 100 nM as +++, 100 nM and 1000 nM as ++, and 1000 nM to 10,000 nM as + in Table 22 below.

TABLE 22.

TGFB REPORTER ACTIVITY BY COMPOUNDS DESCRIBED HEREIN.

*ND = No Data

EXAMPLE 7

SYNTHESIS OF LINKER-MODIFIED PAYLOADS

Example 7 A

Synthesi s of (S)- 1 -(2, 5 -dioxo-2, 5 -dihy dro- 1H-pyrrol- 1 -yl)- 17-(((S)-3 -methyl- 1 -((($)- 1 -((4-((((4- ((7-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[ 1,2-b]1pyrazol-3-yl)quinoxalin-2- yl)oxy)butyl)carbamoyl)oxy)methyl)phenyl)amino)-l-oxo-5-urei dopentan-2-yl)amino)-l- oxobutan-2-yl (carbamoyl )-15-oxo-3,6,912-tetraoxa- 16-azaicosan-20-oic acid, trifluoroacetate salt (Compound CIII.c.10- 3,1)

Preparation of Compound CIII.c.lQ-3.1

Step 1:

[1162] T ert-Butyl (S)- 1 -(2, 5 -di oxo-2, 5 -dihydro- I H-pyrrol - 1 -yl)- 17 -(((S)-3 -methyl- 1 -

(((5)-l-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl )amino)-l-oxo-5-ureidopentan-2- yl)amino)-l-oxobutan-2-yl)carbamoyl)-15-oxo-3,6,9,12-tetraox a-16-azaicosan-20-oate (78 mg, 0.0739 mmol) and Compound 3.2 (3 x HC1 salt) (38.7 mg, 0.0741 mmol) were combined in DMF (4.0 mL). DIEA (66 mg, 0.512 mmol) was added and the mixture was stirred in a sealed vial at room temperature for 2 hours. The reaction mixture was purified by reverse phase liquid chromatography using 2 x 2 mL injections (150mm x 20mm, 100A, 5 uM, C18 Aq Redi-Sep column 10 65% Acetonitrile in Water (0.1%TFA)). Product peak (MS: Calculated for

C67H90N13O16 1332.66, found m/z = 667.0 [M+2H] ²⁺ ) was collected and lyophilized, resultant solid was carried on directly into the next step (mass recovered was not recorded).

Step 2:

[1163] The TFA salt from the previous step was treated with 1 : 1 TFA:DCM (1.0 mL). After 10 minutes the mixture was concentrated under reduced pressure. The resulting residue was dissolved in DMF (2.0 mL) and purified using the same reverse phase chromatography conditions as in the previous step (10 60% gradient) to give Compound CIII.c.10-3.2 TFA salt. 20.4 mg (18% over two steps). MS: Calculated for C63H82N13O16 1276.59, found m/z = 1276.6 [M+H] ⁺

Examples 7B-7O

[1164] The compounds in Table 23 were prepared in a manner similar to that described Example 7 A using the appropriate compounds as starting material.

TABLE 23

EXAMPLE 8

PRODUCTION OF EXEMPLARY ASGR1 ANTIBODIES

[1165] ASGR1 4A2 Heavy and Light chain DNA was cloned into separate expression vectors for human IgGl antibody production. The heavy chain vector construct and the light chain vector construct were transiently co-expressed in the ExpiCHO™ system to generate 4A2 IgGl antibody. The protein from the harvested ExpiCHO™ supernatant was purified to homogeneity using protein A column on GE AKTA Pure™ system and confirmed for purity using analytical HPLC-SEC. If needed, additional purification was performed on a preparative SEC column to remove aggregates. ASGR1 72G9 and 176H4 IgGl antibodies were created in the same manner. The sequences for the heavy chain and lights chains for the 4A2, 72G9 and 176H4 antibodies are set forth in WO ₂ 017/058944, which is incorporated herein by reference in its entirety and for all purposes.

[1166] Additionally, hybridomas producing monoclonal antibodies (mAbs) specific for human ASGR1 were prepared from Balb/C mice immunized with ASGRl-AviHis at a service provider using their propriety protocol. Antibody heavy and light chain sequences were obtained, amplified, and cloned. Clone supernatants containing the expressed mAbs were screened for binding to a human ASGRl-IgGlFc fusion protein, and those with a positive signal as measured by enzyme linked immunosorbent assay (ELISA) were screened for cell binding on HepG2 cells (which express ASGR1). Based on the initial selection criteria, sixteen (16) mAbs were expressed and isolated. The isolated mAbs were further analyzed for the additional characteristics including, for example, titer, low aggregate content following protein A purification, high titer, lack of cross-blocking of ligand GalNac, calcium sensitivity, and cross- reactivity with rat ASGR1 protein. A total of five (5) clones (G2D, K2E, J4F, L4L and H8K) exhibiting strong signals in these assays were humanized and subjected to epitope binning as compared to known anti-ASGR mAbs 4A2, 72G9 and 4F3 (see, e.g., PCT Publication Nos. WO 2017/058944 and WO 2014/023709), referred to herein as ASGR1 mAb-A, ASGR1 mAb- B, and ASGR1 mAb-C, respectively. mAb G2D Humanization

[1167] For humanization of the G2D VH region (SEQ ID NO: 1038), the 3 CDR loops as defined by Kabat were grafted into the human germline sequence VH1-03 with JH6 to generate hzG2D VH (SEQ ID NO: 1043). In addition, several variants of hzG2D VH were constructed to contain one or more mouse back mutations in framework region 1 (FR1), in CDR2, at the junction of framework region 3 (FR3) with CDR2, in FR3, or any combination thereof (see SEQ ID NOS: 1044-1051 and 1082-1088). Several of the humanized heavy chains were further changed by adding mutations in CDR2, namely N54Q or G55A, to remove a potential deamidation site (see SEQ ID NOS: 1052-1081).

[1168] For humanization of the G2D VL region (SEQ ID NO: 1126) of clones 1-16, 19-

21, 26-29, 31, and 33, the 3 CDR loops as defined by Kabat were grafted into the human germline sequence VKI-L1 with JK4 to generate hzG2D VL _a (SEQ ID NO: 1131). In addition, mutations were introduced into humanized light chains at the CDR2/FR3 junction, namely D56S or D56E, to remove a potential isomerization site (see SEQ ID NOS: 1132-1133).

[1169] For humanization of the G2D VL region (SEQ ID NO: 1126) of clones 22, 23, 30,

32, and 34-37, the 3 CDR loops as defined by Kabat were grafted into the human germline sequence VKI-02 with JK4 to generate hzG2D VLb (SEQ ID NO: 1361). In addition, a mutation was introduced into humanized light chains at the CDR2/FR3 junction, namely D56S, to remove a potential isomerization site (see SEQ ID NO: 1362).

[1170] For humanization of the G2D VL region (SEQ ID NO: 1126) of clones 24 and 25, the 3 CDR loops as defined by Kabat were grafted into the human germline sequence VKI-A20 with JK4 to generate hzG2D VL _C (SEQ ID NO: 1363).

[1171] Variable heavy region sequences were cloned into a vector containing a signal peptide sequence and human IgGl constant region (SEQ ID NO: 1230), while variable light chain regions were cloned into a vector containing a signal peptide sequence and a human kappa light chain constant region (SEQ ID NO: 1232). A total of twenty two humanized heavy chains were paired with six humanized light chains to generate mAbs analyzed for the desirable characteristics noted above.

TABLE 24

CHARACTERIZATION OF HUMANIZED G2D CLONES mAb K2E Humanization

[1172] Germline VH1-46 with JH6 was used for CDR grafting the variable heavy chain (SEQ ID NO: 1039) and germline VKI-L1 with JK2 was used for CDR grafting the variable light chain (SEQ ID NO: 1127). CDR grafting was done using Kabat defined CDRs to generate hzK2E VH (SEQ ID NO: 1089) and hzK2E VL (SEQ ID NO: 1134). Several variants of hzK2E VH (SEQ ID NOS: 1090-1093) and hzK2E VL (SEQ ID NO: 1135) containing mouse framework back mutations were generated, and the sequences determined using a 3D structural model for potential influence of residues on the CDR structure. In addition, mutations were introduced into humanized light chains at the CDR2/FR3 junction, namely D56E, to remove a potential isomerization site (see SEQ ID NOS: 1136-1137). Variable heavy region sequences were cloned into a vector containing a signal peptide sequence and IgGl constant region. Variable light regions were cloned into a vector containing a signal peptide sequence and kappa constant region.

[1173] Five humanized heavy chains were individually paired with each of four different humanized light chains to generate mAbs analyzed for the desirable characteristics noted above (see Table 25). The humanized sequences were further modified by adding an additional mutation in the light chain CDR2/FR3 junction, namely D56E, to remove a potential isomerization site.

TABLE 25

CHARACTERIZATION OF HUMANIZED K2E CLONES mAb L4L Humanization

[1174] Germline VH4-31 with JH6 was used for CDR grafting the variable heavy chain (SEQ ID NO: 1040) and germline VKI-02 with JK4 were used for CDR grafting the variable light chain (SEQ ID NO: 1128). CDR grafting was done using Kabat defined CDRs to generate hzL4L VH (SEQ ID NO: 1094) and hzL4L VL (SEQ ID NO: 1138). Several variants of hzL4L VH (SEQ ID NOS: 1095-1102) containing mouse framework back mutations were generated, and the sequences determined using a 3D structural model for potential influence of residues on the CDR structure. Variable heavy region sequences were cloned into a vector containing a signal peptide sequence and IgGl constant region. Variable light regions were cloned into a vector containing a signal peptide sequence and kappa constant region.

[1175] Nine humanized heavy chains were individually co-transfected individually with four different humanized light chains (see Table 26) into the ExpiCHO™ expression system in a 30 mL culture, using the parental chimeric antibody, L4L, as a benchmark. The supernatant containing the antibody was purified and further characterized. Humanized sequences hzL4L-10 through hzL4L-14 were further modified by adding additional mutations in the light chain CDR2/FR3 junction, namely D56S (SEQ ID NO: 1139), D56E (SEQ ID NO: 1140) or G57A (SEQ ID NO: 1141), to remove a potential isomerization site. There was a reduction in percent purity, as measured by analytical size-exclusion chromatography (% protein of interest (POI)), seen with the chimeric and hzL4L-l, -2 and -6. Surprisingly, the G27Y mutation appears to help stabilize the structure, resulting in a more homogenous recovery (see Table 26).

TABLE 26

CHARACTERIZATION OF HUMANIZED L4L CLONES mAb H8K Humanization

[1176] Germline VH with JH6 was used for CDR grafting the variable heavy chain (SEQ ID NO: 1041) and germlines VL with JK4 were used for CDR grafting the variable light chain (SEQ ID NO: 1129). CDR grafting was done using Kabat defined CDRs to generate hzH8K VH (SEQ ID NO: 1103) and hzH8K VL (SEQ ID NO: 1142). Several variants containing mouse framework back mutations were generated (SEQ ID NOS: 1104-1112), and the sequences determined using a 3D structural model for potential influence of residues on the CDR structure. Variable heavy region sequences were cloned into a vector containing a signal peptide sequence and IgGl constant region. Variable light regions were cloned into a vector containing a signal peptide sequence and kappa constant region.

[1177] Ten humanized heavy chains were individually co-transfected with one humanized light chain into the ExpiCHO™ expression system in a 30 mL culture, using the parental chimeric antibody, H8K, as a benchmark. The supernatant was purified and further characterized as shown in Table 27. TABLE 27

HUMANIZED H8K CLONES J4F Humanization

[1178] Germline VH1-46 with JH6 was used for CDR grafting the variable heavy chain (SEQ ID NO: 1042) and germline VL with JK4 was used for CDR grafting the variable light chain (SEQ ID NO: 1130). CDR grafting was done using Kabat defined CDRs to generate hzJ4F VH (SEQ ID NO: 1113) and hzJ4F VL (SEQ ID NO: 1143). Several variants containing mouse framework back mutations were generated (SEQ ID NOS: 1114-1125 for VH and SEQ ID NOS: 1144-1149 for VL), and the sequences determined using a 3D structural model for potential influence of residues on the CDR structure. Variable heavy region sequences were cloned into a vector containing a signal peptide sequence and IgGl constant region. Variable light regions were cloned into a vector containing a signal peptide sequence and kappa constant region.

[1179] Thirteen humanized heavy chains were each individually co-transfected with each of seven different humanized light chains into the ExpiCHO™ expression system in a 30mL culture, using the parental chimeric antibody, J4F, as a benchmark. Humanized variants hzJ4F-l through hzJ4F-20 showed reduced binding compared to the parent chimeric mAb J4F (see Table 28). Therefore, additional humanized variable region sequences were designed to screen for hzJ4F heavy chain and light chain combinations (hzJ4F-21 - hzJ4F-58) with binding similar to or better than the chimeric parent mAb J4F.

TABLE 28

HUMANIZED J4F CLONES

EXAMPLE 9

Generation of Antibody-TGFβ Inhibitor Conjugates through Partial Reduction of Native Disulfide Bonds of Non-Engineered Antibodies

The linker payloads in Example 7 and Table 23 were covalently attached to an anti- ASGR1 antibody. The mAh (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 mAh solution was transferred to a tared 50 mL conical tube. The mAh concentration was determined to be 3-8 mg/mL by A280. To the mAh 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, a linker-payload (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 7V-ethyl maleimide (3.0 equivalents, 100 mM DMA) was added. After an additional 15 minutes of stirring, N-acetyl cysteine (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 the disclosure.

EXAMPLE 10

General Procedure for the Determination of the Drug-Antibody -Ratios

Hydrophobic Interaction Chromatography

10 μL of 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 pM 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.

EXAMPLE 11 CONJUGATE ACTIVITY

Effect of Anti-ASGR1-ALK5 Inhibitor Conjugates on TGFβ Production

[1180] Anti-ASGRl antibodies conjugated to an ALK5 inhibitor were tested via a cell reporter assay. Briefly, HEK293 SBE-LUC reporter cells transfected to stably express full length human ASGR1 were seeded in 96 well plates at 40,000 cells/well in an assay media of minimum essential media containing 0.5% fetal bovine serum, 1% nonessential amino acids, 1% sodium pyruvate and 1% Pen/Strep. Anti-ASGRl -ALK5 inhibitor conjugates and controls were added to wells in a dose titration ranging from 5 pM to 0.064 nM to HEK293 SBE-LUC and ASGR1- HEK293 SBE-LUC cells. After incubating for 6 hours at 37°C in a 5% CO ₂ environment, human TGFβi (PeproTech Inc.) was added to a final concentration of 1.6 ng/ml followed by an additional 18 hour incubation under the same conditions. Luciferase Steady-Gio® reagent (Promega Corporation) was added at 70pl/well and incubated with shaking for 10 minutes. Luciferase activity was determined by measuring luminescence with an EnVision® Plate Reader (Perkin-Elmer Inc.). Data were fit with a four-parameter non-linear regression to calculate IC50 values using Prism Software v7.04 (GraphPad Inc.).

[1181] Table 29 shows that anti-ASGRl-ALK5 inhibitor conjugates could efficiently inhibit TGFβi -mediated luciferase expression as compared to an unconjugated anti-ASGR antibody (mAb-A) alone. Furthermore, the ASGR1-ALK5 inhibitor conjugates were more potent than the ALK5 inhibitors alone.

[1182] The potency of the antibody drug conjugates track proportionally with the activity observed for the non-conjugated small molecule activity within the cell-based reporter assay. For examples in which the observed activity of a small molecule is low when assessed by the small molecule cell-based reporter assay and high by measure within the small molecule cell-free enzymatic inhibition assay, it is believed, without being bound by theory, that this can most often be attributed to the molecule possessing low cell permeability. In these cases, the rank order of potency of the applicable antibody drug conjugate tracks more closely with the observed activity within the small molecule cell-free enzymatic inhibition assay.

TABLE 29

ASGR1-ALK5 INHIBITOR CONJUGATE INHIBITION OF TGFB 1 -MEDIATED LUCIFERASE

EXPRESSION

[1183] Monoclonal antibodies (mAbs) ASGR1 mAb-A, ASGR1 mAb-B, and ASGR1 mAb-C correspond to anti-ASGR mAbs 4A2, 72G9 and 4F3, respectively (see, e.g., PCT Publication Nos. WO 2017/058944 and WO 2014/023709).

EXAMPLE 12:

CACO-2 PERMEABITLITY ASSAY

[1184] Cell membrane permeability of compounds of the disclosure is determined with the Caco-2 Permeability Assay.

Preparation of Caco-2 Cells

[1185] Cell culture medium (25mL) is added to a Transwell reservoir. Cell culture medium (50μL) is added to each well of a 96-well HTS transwell plate and the plate then incubated at 37°C and 5% CO ₂ for 1 hour, before cell seeding. Caco-2 cells are diluted with culture medium, to 6.86xl0 ⁵ cells/mL and 50μL of cell suspension are dispensed into the filter well of the plate. Cells are cultivated for 14-18 days in a cell culture incubator at 37°C, 5% CO ₂ , 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating.

Assessment of Cell Monolayer Integrity

[1186] Medium is removed from the reservoir and from each well, and replaced with prewarmed fresh culture medium. Transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA) and the plate returned to the incubator once the measurement was complete. The TEER value is calculated according to the following equation: [1187] TEER measurement (ohms) x Area of membrane (cm ² ) = TEER value (ohm»cm ² )

[1188] A TEER value greater than 230 ohm»cm ² indicates a suitable Caco-2 monolayer.

Preparation of Solutions

HBSS (25mM HEPES, pH7,4)

[1189] HEPES (5.958g) and sodium hydrogen carbonate (0.35g) are added to pure water (900mL), using sonication to dissolve solids, if required. HBSS (lOx, 100mL) is added to the solution, which is then placed on a stirrer. The pH is slowly adjusted to 7.4, by addition of sodium hydrate. The final solution is filtered before use.

Compound working solution (5μM)

[1190] A solution of compound - test or control (metoprolol, erythromycin or cimetidine) - (lOmM) is prepared and 6μL was added to DMSO (54μL) in the same well to obtain ImM stock solutions. Transport buffer (597μL) is loaded into each well of a 96 well plate. 3μL of 2mM solution is added to each well to prepare the compound working solution.

Plates are shaken at 1000rpm for 10 min.

Drug Transport Assay

[1191] The apical to basolateral and basolateral to apical direction assays are performed simultaneously. The Caco-2 plates are removed from the incubator, the monolayer washed twice with pre-warmed HBSS (25mM HEPES, pH 7.4) and then incubated at 37°C for 30 minutes.

Rate of drug transport - apical to basolateral direction (A → B)

[1192] Working solution (108μL) is added to the Transwell insert (apical compartment), and transfer 8μL sample immediately from the apical compartment to 72μL transport buffer and 240μL of acetonitrile containing IS (100nM alprazolam, 200nM Caffeine and 100nM tolbutamide) in a new 96-well plate as the initial donor sample (A-B). The plates are vortexed at 1000 rpm for 10 minutes. The wells in the receiver plate (basolateral compartment) are filled with transport buffer (300μL). Rate of drug transport - basolateral to apical direction (B → A)

[1193] Working solution (308μL) is added to the receiver plate wells (basolateral compartment), and transfer 8μL sample immediately from the basolateral compartment to 72μL transport buffer and 240μL of acetonitrile containing IS (100nM alprazolam, 200nM Caffeine and 100nM tolbutamide) in a new 96-well plate as the initial donor sample (B-A). The plates are vortexed at 1000 rpm for 10 minutes. The Transwell insert (apical compartment) is filled with transport buffer (100μL).

[1194] The multiwell insert plate is placed into the basolateral receiver plate, and incubated at 37°C for 2 hours.

[1195] A sample from the donor side (8μL, apical compartment for Ap→ B1 flux, and basolateral compartment for Bl → Ap flux) is transferred to a mixture of transport buffer (72μL) and quenching solvent (240μL) in new 96-well plates.

[1196] A sample from the receiver side (80μL, basolateral compartment for Ap→ B1 flux, and apical compartment for Bl→ Ap flux) is transferred to a mixture of acetonitrile (240μL) and IS (100nM alprazolam, 200nM caffeine and 100nM tolbutamide) in new 96-well plates.

[1197] The plates are vortexed for 10 minutes at 1000 rpm and then centrifuged at 4,000 rpm for 30 minutes. 100μL of the supernatant is transferred to a new 96-well plate, taking care not to disturb the pellet. Pure water ( 100μL) is added to all samples for analysis by LC-MS/MS. All incubations are performed in duplicates.

[1198] Lucifer yellow working solutions are prepared by diluting the stock solution with HBSS (25mM HEPES, pH7.4) to a final concentration of 100pM. 100μL of the Lucifer yellow solution is added to the Transwell insert (apical compartment). The wells in the receiver plate (basolateral compartment) are filled with HBSS (300μL, 25 mM HEPES, pH 7.4) and incubated at 37°C for 30 minutes. An 80μL aliquot is removed directly from the basolateral wells and transferred to new 96 wells plates. Measure Lucifer Yellow fluorescence (to monitor monolayer integrity) in a fluorescence plate reader at 485nM excitation and 530nM emission.

Data analysis

[1199] All calculations are carried out using Microsoft Excel. Peak areas are determined from extracted ion chromatograms. Lucifer yellow leakage

[1200] Lucifer yellow leakage of monolayer is calculated according to the following equation: is the fluorescence intensity in the acceptor well (0.3mL) is the fluorescence intensity in the donor well (O.lmL)

[1201] Lucifer yellow (LY) leakage percentage amount transported values should be less than 1.5%.

Apparent permeability (Papp)

[1202] Apparent permeability (Papp) can be calculated for drug transport assays using the following equation

P app is apparent permeability (cm/s x IO" ⁶ ) dQ/dt is the rate of drug transport (pmol/second)

A is the surface area of the membrane (cm ² )

D o is the initial donor concentration (nM; pmol/cm ³ )

Efflux ratio

[1203] Efflux ratio can be determined using the following equation: is the apparent permeability coefficient for the basolateral to apical direction is the apparent permeability coefficient for the apical to basolateral direction

Mass balance (% recovery)

[1204] Mass balance (% recovery) can be determined using the following equation: Materials

[1205] Test compounds are prepared as described in the disclosure.

[1206] Caco-2 cells are obtained from the American type culture collection (ATCC, Number HTB-37).

[1207] Hepes, Penicillin, Streptomycin, Trypsin/EDTA and DMSO are purchased from Solarbio. Fetal bovine serum, Hank’s balanced salt solution (HBSS) and Non-essential amino acids (NEAA) are purchased from Gibco by Thermo Fisher Scientific. Dulbecco’s Modified Eagle’s Medium (DMEM) is purchased from Coming Corporation. HTS Transwell-96 Well (Cat. No. 3391) Permeable Supports are purchased from Corning Corporation. Millicell Epithelial Volt-Ohm measuring system is purchased from Millipore. Cellometer® Vision is purchased from Nexcelom Bioscience LLC. Infinite 200 PRO microplate reader is purchased from Tecan. MTS2/4 orbital shaker is purchased from IKA Labortechnik.

EXAMPLE 13

ANTIBODY DRUG CONJUGATES

[1208] The structure of Antibody -Drug Conjugates (ADCs) in Figures 1-3 are described in Tables 30-32 below. In the Figures, Ab control A corresponds to mAb.A and Ab control B corresponds to mAb.B.

TABLE 30

ANTIBODY DRUG CONJUGATES OF FIGURE 1 TABLE 31

ANTIBODY DRUG CONJUGATES OF FIGURE 2

TABLE 32

ANTIBODY DRUG CONJUGATES OF FIGURE 3

The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Provisional Patent Application No. 63/090,174 filed on October 9, 2020, and U.S. Provisional Patent Application No. 63/217,187 filed on June 30, 2021 are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.