Related Applications

[0001] This application claims priority to United States Provisional Patent Application Serial No. 61/445,455 filed on 22 February 2011, United States Provisional Patent Application Serial No. 61/443,103 filed on 15 February 201 1, and United States Provisional Patent

Application Serial No. 61/355,978 filed on 17 June 2010 the contents of which are incorporated in their entirety by reference herein.

Reference to Sequence Listing Submitted Via EFS-WEB

[0002] The entire content of the following electronic submission of the sequence listing via the USPTO EFS-WEB server, as authorized and set forth in MPEP §1730 II.B.2(a)(C), is incorporated herein by reference in its entirety for all purposes. The sequence listing is identified on the electronically filed text file as follows:

Technical Field

[0003] The invention relates to the field of passive immunization against influenza. More particularly, antibodies that bind near to the HA ₀ maturation cleavage site consensus sequence of influenza hemagglutinin A, including antibodies secreted by human cells.

Background Art

[0004] The hemagglutinin protein of influenza virus has a globular head domain which is highly heterogeneous among flu strains and a stalk region containing a fusion site which is needed for entry into the cells. The hemagglutinin protein (HA ₀ ) is activated to permit the fusion site to effect virulence by cleavage into HAi and HA ₂ portions which remain coupled using disulfide bonds but undergo a conformational change. This cleavage site contains a consensus sequence which is shared both by influenza A and influenza B and by the various strains of influenza A and B. [0005] Bianchi, E., et al, J. Virol. (2005) 79:7380-7388 describe a "universal" influenza B vaccine based on the consensus sequence of this cleavage site which was able to raise antibodies in mice when conjugated to the outer membrane protein complex of Neisseria meningitidis. Monoclonal antibodies which appear to bind to the consensus sequence were also described. In addition, successful passive transfer of antiserum was observed in mice. Prior vaccines, such as those described in WO2004/080403 comprising peptides derived from the M2 and/or HA proteins of influenza are subject to inducing antibodies that are either of weak efficacy or are not effective across strains.

Disclosure of the Invention

[0006] The invention provides monoclonal antibodies that bind an epitope shared across multiple strains of influenza, and more particularly that bind representatives of either or both Group 1 and Group 2 influenza A. Such antibodies are able to confer passive immunity in the event of a pandemic caused, for example, by a previously unidentified influenza strain or a strain against which protection is not conferred by the seasonal vaccines currently available. Since the antibodies bind across many strains, indicative of targeting an essential site and thus likely to be included even in previously unencountered strain, such a vaccine would be effective in such circumstances. Such antibodies are also useful to ameliorate or prevent infection in subjects for whom vaccination failed to produce a fully protective response or who are at high risk due to a weak immune system (e.g., the very young, the elderly, transplant patients, cancer or HIV chemotherapy treated patients).

[0007] Thus, in one aspect, the invention is directed to monoclonal antibodies or

immunoreactive fragments thereof that are broadly crossreactive with influenza A virus of Group 1 including HI, H2, H5, H6, H8, H9, HI 1, H13, H16 or Group 2 including H3 and H7 as type specimens, or that show cross-Group reactivity. The antibodies bind specifically to an epitope contained in the HA ₀ protein of the influenza virus and recognize the native trimeric form of HA. As is well understood in the art, non-immunoglobulin based proteins may have similar epitope recognition properties as an antibody and can also provide suitable embodiments, including binding agents based on fibronectin, transferrin, lipocalin, or nucleic acid based aptamers. [0008] In other aspects, the invention is directed to methods to use the antibodies and fragments of the invention for passively inhibiting viral infection in subjects. The invention is also directed to recombinant materials and methods to produce these antibodies or fragments.

Brief Description of the Drawings

[0009] Figures 1 A and IB show the results of binding by MAB53 and MAB8 with respect to HAo protein from various influenza clades tested by ELISA. Figure 1C shows that MAB53 binds to native trimer, expressed in HEK293 cells.

[0010] Figures 2A and 2B show the results of binding of MAB53 and MAB8 versus HA ₀ protein from various clades as tested by ForteBio ^® biosensor.

[0011] Figure 3A shows the extent of binding as tested by ELISA of MAB53 with respect to HAo as an intact protein and the cleavage fragment HAi. Figure 3B shows the extent of binding of MAB53 to a peptide denoted CP from HA ₂ .

[0012] Figures 4A and 4B show the results of a ForteBio ^® assay demonstrating that MAB53 competes with MAB8, but not with MAB30.

[0013] Figures 5A and 5B show CDR mapping according to Kabat number of MAB53 heavy and light chain variable regions. IGHV1-69*01 is SEQ ID NO:83 and IGKV3-20*01 is SEQ ID NO: 84.

[0014] Figure 6 shows neutralization of H1N1 by various amounts of MAB53, as measured by in vitro plaque assay.

[0015] Figures 7A and 7B show survival times for mice challenged with H1N1 (panel A) or H5N1 (panel B) as a function of administration of various amounts of MAB53.

[0016] Figure 8 shows the effect of post-infection treatment of H5N1 with MAB53.

Modes of Carrying Out the Invention

[0017] The present invention provides useful antibodies including providing effective means to identify cells that secrete such antibodies so that the relevant coding sequences can be retrieved and stored for subsequent and facile recombinant production of such antibodies. The method includes a binary logic based design of a screening procedure.

[0018] Such a procedure can readily be applied to human cells using, in particular, the CellSpot™ method described in U.S. patent 7,413,868, the contents of which are incorporated herein by reference. Briefly, the method is able to screen individual cells obtained from human (or other) subjects in high throughput assays taking advantage of labeling with particulate labels and microscopic observation. In one illustrative embodiment, even a single cell can be analyzed for antibodies it secretes by allowing the secreted antibodies to be adsorbed on, or coupled to, a surface and then treating the surface with desired antigens each coupled to a distinctive particulate label. The footprint of a cell can therefore be identified with the aid of a microscope. Using this technique, millions of cells can be screened for desirable antibody secretions and even rare antibodies, such as those herein desirable for passive influenza immunization across strains can be recovered. Since human subjects have existing antibodies to at least some influenza strains, and since the antibodies obtained by the method of the invention bind a conserved sequence, these antibodies serve the purpose of addressing new strains as well as strains with which human populations have experience.

[0019] The invention provides a method to identify a monoclonal antibody that binds to a location near the hemagglutinin (HA ₀ ) cleavage site consensus sequence. The method comprises contacting candidate monoclonal antibodies or fragments with: i) a peptide consisting essentially of an amino acid sequence upstream of or downstream of said consensus sequence, but lacking said consensus sequence; ii) a peptide consisting essentially of an amino acid sequence upstream of said consensus sequence and including said consensus sequence; and iii) a peptide consisting essentially of an amino acid sequence downstream of said consensus sequence and including said consensus sequence; wherein a monoclonal antibody that binds to the peptide of ii) and iii) but not to the peptide of i) is identified as a peptide that binds specifically to the HA ₀ cleavage site consensus sequence. Other combinations could also be used, as will be evident to the skilled artisan, as long as binary logic is followed. For example, i) could be a peptide consisting essentially of an amino acid upstream of the consensus sequence of a first strain and lacking the consensus sequence , with ii) being the whole HA ₀ sequence from the first strain and iii) being the whole HA ₀ sequence from a second strain. Shorter portions could also be used. For further confirmation, an isolated peptide from the conserved region can also be used, although the information derived from the larger protein domains is believed to be more informative regarding recognition of the intact antigen.

[0020] This method is not limited to employing the CellSpot™ technique, nor is it limited to human antibodies. The binary logic of this method can be employed in any alternative screening 40982

method. Likewise, it can be applied to other diversity libraries besides natural

immunoglobulins.

[0021] The method of the invention relies on binary logic wherein peptides that contain the desired consensus sequence and additional upstream and/or downstream portions are used as test peptides and their ability to complex antibodies as compared to regions lacking the consensus sequence is assessed. Thus, patterns are obtained whereby cells secreting the appropriate antibodies can be instantly identified.

[0022] In one illustrative embodiment, three antigens are used to assess the secreted antibody population. The first peptide is all or substantially all of the amino acid sequence upstream of the consensus sequence contained in HA ₀ and is coupled to a particulate label of, say, red. A second test antigen contains these upstream sequences, but contains also the consensus sequence and is labeled with particle of a different color, for example, blue. A third test peptide contains the consensus sequence and all or substantially all of the downstream regions of the HA ₀ protein and is labeled with a third color particulate, for example, green. (By upstream portion is meant toward the N-terminus from the consensus sequence and by downstream portion the continuation of the amino acid sequence from the consensus sequence toward the C-terminus. By "substantially all" is meant lacking only one or a few non-essential amino acids.) Antibodies that bind to the consensus sequence will bind both the green and blue particulate labeled peptides but will not bind the red labeled upstream sequence lacking the consensus sequence. If desired, the specificity can be confirmed by adding a fourth peptide representing only the downstream portion without the consensus sequence bound, for example, to a yellow particulate label, wherein the yellow particulate label will not be bound to the antibody. Of course, it does not matter whether the upstream or downstream portion is chosen as the negative control.

[0023] The cleavage site for various strains of influenza A and influenza B is known. For example, the above cited article by Bianchi, et ah, shows in Table 1 the sequence around the cleavage site of several such strains: Table 1 Consensus sequence of the solvent-exposed region of the influenza A and B maturational cleavage sites

Virus/subtype Strain Sequence ⁰

NVPEKQTR FGAIAGFIE

A/H3/HAo Consensus 1 GI

(SEQ ID NO:l) (SEQ ID NO: 2)

NI PS IQSR GLFGAIAGFIE

A/H1/HA ₀ Consensus 1

(SEQ ID NO:3) (SEQ ID NO: 4)

PAKLLKER FLE

B/HAo Consensus* I GFFGAIAG

(SEQ ID NO:5) (SEQ ID NO: 6) a The position of cleavage between HAi and HA ₂ is indicated by the arrow. * The consensus is the same for both the Victoria and Yamagata lineages.

[0024] As indicated, strict consensus occurs starting with the arginine residue upstream of the cleavage site and thus preferred consensus sequences included in the test peptides of the invention have the sequence RGI/L/F FGAIAGFLE (SEQ ID NO:7). It may be possible to use only a portion of this sequence in the test peptides.

[0025] Once cells that secrete the desired antibodies have been identified, it is

straightforward to retrieve the nucleotide sequences encoding them and to produce the desired antibodies on a large scale recombinantly. This also enables manipulation of the antibodies so that they can be produced, for example, as single-chain antibodies or in terms of their variable regions only.

[0026] The retrieved nucleic acids may be physically stored and recovered for later recombinant production and/or the sequence information as to the coding sequence for the antibody may be retrieved and stored to permit subsequent synthesis of the appropriate nucleic acids. The availability of the information contained in the coding sequences and rapid synthesis and cloning techniques along with known methods of recombinant production permits rapid production of needed antibodies in the event of a pandemic or other emergency.

[0027] Applicants have recovered multiple monoclonal antibodies that are immunoreactive with HAo protein of influenza from multiple clades (SEQ ID NOS:9-23, 26-40, 42-56, and 59-73). Other sequences include the amino acid sequence for the human IgGl heavy chain constant region (SEQ ID NO:8), the amino acid sequence for the human light chain constant kappa region (SEQ ID NO:24), the amino acid sequence for the human light chain constant lambda region (SEQ ID NO:25), the nucleotide sequence for the human heavy chain constant region (SEQ ID NO:41), the nucleotide sequence for the human light chain constant kappa region (SEQ ID NO:57), and the nucleotide sequence for the human light chain constant lambda region (SEQ ID NO:58).

[0028] Two of these mAbs, MAB53 and MAB8, have substantial crossreactivity among important, distantly related influenza clades. As shown in Figures 1 A and B, each of these binds to three different clades with reasonable or high affinity. MAB53 binds to HA ₀ from the HI, H9 and H7 clades and MAB8 binds to HAo protein from HI, H7 and H3 clades. The results shown in Figure 1 were obtained by ELISA assay against HA ₀ protein, and imply that the affinities are in the nanomolar range. Reactivity to native trimer of HA from all the Group 1 clades was verified using HA expressed in HEK293 cells with antibody binding measured by flow cytometry.

[0029] These results were confirmed using an alternative assay system, the biolevel interferometry based binding assay designated ForteBio ^® biosensor, as shown in Figures 2A and 2B. As measured by this more accurate assay, the affinities are as follows:

MAB53 / HI = 60 pM, H5 = 6 nM, H7 = 70 pM, H9 = 30 pM;

MAB8 / HI = 9 nM, H3 = 16 nM, H5 = 0.2 nM.

[0030] Both MAB53 and MAB8 are fully human antibodies, but similar antibodies characteristic of other species are also included in the invention. In the context of the invention, "antibodies" and their fragments include those portions of the molecule that are relevant for binding; thus, fragments would include variable regions only and "antibodies" as a general term would also be considered to include such fragments. Thus, F _a b fragments, F( _ab ') ₂ , and Fv fragments are included as well as recombinantly produced single chain antibodies, and fusions of such constructs to create bispecific agents. Chimeric, humanized and human antibodies are all within the scope of the present invention as are antibody mimics based on other protein scaffolds such as fibronectin, transferrin, or lipocalin. Likewise, multiple technologies now exist for making a single antibody-like molecule that incorporates antigen specificity domains from two separate antibodies (bi-specific antibody). Thus, a single antibody with very broad strain reactivity can be constructed using the Fab domains of individual antibodies with broad reactivity to Group 1 and Group 2 respectively. Suitable technologies have been described by Macrogenics (Rockville, MD), Micromet (Bethesda, MD) and Merrimac (Cambridge, MA). (See, e.g. , Orcutt KD, Ackerman ME, Cieslewicz M, Quiroz E, Slusarczyk AL, Frangioni JV, Wittrup KD. A modular IgG-scFv bispecific antibody topology, Protein Eng Des Sel (2010) 23:221-228; Fitzgerald J, Lugovskoy A. Rational engineering of antibody therapeutics targeting multiple oncogene pathways. MAbs. (2011) 1 :3(3); Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. (2009) 69:4941-4944.)

[0031] To identify the epitope to which MAB53 binds, ELISA assays were conducted with respect to uncleaved HA ₀ protein, the HAt fragment, and the HA ₂ fragment. As shown in Figures 3 A and B, while MAB53 binds with high affinity to HA ₀ , it does not bind HAi implying binding to the complementary HA2 fragment. To confirm this hypothesis, a peptide derived from HA ₂ was immobilized on a streptavidin coated plate using a C-terminal biotin.

Specifically, the sequence tested was RGLFGAIAGFIENGW (SEQ ID NO:74). Irrelevant flanking portions were also used. MAB53 was confirmed as capable of binding to this peptide. As MAB53 does not bind to HA ₀ when tested by Western blot, it is assumed that the dominant epitope is at least in part conformational in nature.

[0032] It has also been found that MAB8 and MAB53 bind to the same or nearby epitopes as demonstrated by their ability to compete with each other for binding to the HA ₀ protein of the HI clade. This was shown using a ForteBio ^® assay using 2 μg/ml of antibody and 50 nM HA ₀ from HI. As shown in Figure 4 A, the signal obtained from MAB53 bound to the

ForteBio ^® surface is augmented when 50 nM HA ₀ solution is added. However, when MAB8 is then added, no further signal occurs. Thus, MAB53 blocks the epitope bound by MAB8. As shown in Figure 4B, however, another antibody that is immunoreactive with HA ₀ , MAB30, binds, apparently, to a different epitope as the signal is enhanced when it is added to the coupled MAB53-HA ₀ .

[0033] Importantly, MAB53 and MAB8 differ in that MAB8 is released from the HA ₀ protein when the pH is lowered to 6, whereas MAB53 is not. This difference is significant as this appears predictive of neutralizing capability. In tests for the ability of MAB8 to neutralize H1N1 viral infection in a plaque reduction assay in MDCK target cells, low doses of MAB53 of 1-5 ng/ml neutralized infection by H1N1, by H7 3, H5N1 and H9N2. However, MAB8 does not neutralize infection by these strains. Thus, neutralizing strains may be preferentially selected by washing bound MAB or fragment at pH 6 during the primary screen, thus removing from HA ₀ MAB'S that are unlikely to remain bound as the antibody- virus complex enters the cell via the endosomal compartment and thus will be expected to have reduced ability to neutralize the virus.

[0034] For example, in the CellSpot method HA ₀ may be bound to solid support (fluorescent beads) and captured by the MAB or a mixture of MAB's, then washed at pH 6.

[0035] MAB53 is produced recombinantly and has been sequenced. The full-length sequences of the heavy chain and light chain are as follows:

Heavy Chain: QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQ GLEWMGGIIAIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARG MNYYSDYFDYWGQGSLVTVSPASTKGPSVFPLVPSSKSTSGGTAALGCLV DYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

(SEQ ID NO:75); and

Light Chain: EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQA PRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGG

GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG N SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

(SEQ ID NO:76).

[0036] The bold sequences are variable domains, and the un-bolded sequences represent the IgGl constant chain for the heavy chain and the kappa constant chain for the light chain.

[0037] In addition, these variable regions have been analyzed according to the Kabat CDR assessment based on matching framework regions. As shown in Figure 5 A, CDR1 , CDR2, and CDR3 of the IGHV1-69*01 heavy chain (SEQ ID NO:83) are GGIIRKYAIN (SEQ ID NO:77), GGIIAIFNTANYAQKFQG (SEQ ID NO:78) and ARGMNYYSDYFDY (SEQ ID NO:79), respectively. As shown in Figure 5B, CDR1, CDR2, and CDR3 of the IGKV3-20*01 light chain (SEQ ID NO:84) are RASQSVRSNNLA (SEQ ID NO:80), GASSRAT (SEQ ID NO:81) and QQYGSSPALT (SEQ ID NO:82), respectively.

[0038] As shown in Figure 6, MAB53 neutralizes H1N1 in vitro in a plaque assay. [0039] It has also been shown that mice pretreated with graded doses of MAB53 survive challenge with otherwise lethal titers of H1N1 and H5N1 viruses with 100% protection against H1N1 challenge, as shown in Figure 7. The potency is comparable to a prior art antibody described by Crucell which does not show activity against Group 2 strains. Throsby M., et ah, PLoS One. (2008) 3:e3942. Epub 2008 Dec 16. These are heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells.

[0040] As shown in Figure 7A, MAB53 provided full protection at 10 mg/kg; 90% survived at 2 mg/kg and 50% survived at 0.4 mg/kg. In comparison, the prior art antibody from Crucell gave full protection at 2 mg/kg, but only 20% survived when 0.7 mg/kg were administered. This is despite the fact that the lethality of the viral dose was less than that in the experiment shown in Figure 7A; only 90% of the mice died after infection, whereas in the experiment shown in Figure 7A, all the mice died at day 6. This demonstrates that MAB53 is highly potent.

[0041] Where challenge by H5N1 was substituted for challenge by H1N1, for MAB53 shown in Figure 7B, 10 mg/kg gave 80% survival; 2 mg/kg gave 60% survival and 0.4 mg/kg gave 50% survival. In comparison, for the prior art antibody, 100% survival was obtained at 5 mg/kg and 60%) survival at 1.7 mg/kg. Thus, the survival rates at 1.7 mg/kg and 2 mg/kg were comparable. In this case, the viral dose itself was slightly less potent in the mice tested with MAB53.

[0042] As shown in Figure 8, MAB53 (10 mg/kg) was administered as a post-infection treatment at day +3 against the high pathology H5N1 strain. The control antibody is isotype matched but does not recognize any flue antigen. The infection and treatment protocol is the same as that for Figure 7 A, but given at day +3 instead of day -1.

[0043] Pepscan analysis was performed, establishing that MAB53 and CR6261 bind to similar regions of HA, but different epitopes (data not shown). This is consistent with the different activity of the two antibodies.

[0044] Thus, MAB53 and antibodies that bind to the same epitope under the same conditions are effective as passive vaccines suitable for protection of populations against epidemics and pandemics, and for prophylactic or therapeutic use against seasonal influenza for patients with a weakened immune system. SEQUENCE LISTING

NVPEKQTR (SEQ ID NO:l)

GIFGAIAGFIE (SEQ ID NO:2)

NIPSIQSR (SEQ ID N0:3)

GLFGAIAGFIE (SEQ ID N0:4)

PAKLLKER (SEQ ID N0:5)

GFFGAIAGFLE (SEQ ID N0:6)

RGI/L/F FGAIAGFLE (SEQ ID N0:7).

Human IgGl HC amino acid sequence of constant region (SEQ ID NO:8)

ASTKGPSVFPLVPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

MAB1 HC amino acid sequence of variable domain (SEQ ID NO: 9)

QVQLQESGPGLVKPSETLSLICRVSGGS I SSHYWSWIRQPPGKGLEWIGYISYRGRS NHNPSLGRRVSMS IDTSENQFSLNLSSVIAADTAVYYCARDATGIREINALDIWGQG TTVTVSS

MAB8 HC amino acid sequence of variable domain (SEQ ID NO: 10)

EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYTMSWVRQAPGQGLEWVSS ITRTSSN IYYADSVEGRFTISRDNAKNSLYLQMHSLRVEDTAVYYCARISGWGPVPFDYWGQG TLI VSS

MAB30 HC amino acid sequence of variable domain (SEQ ID NO:l 1)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRIRNKAAI YTTEYAASVKGRFTISRDDLKSSVYLQMNSLKTDDTAIYYCARSYGYFDYWGQGTLV TVSS

MAB42 HC amino acid sequence of variable domain (SEQ ID NO: 12)

QVQLVQSGAEV KPGASVKVSCKASGYSFNGYYMHWVRQAPGQGLEWMGWINLSSGG TDYAQKFQGWVTLTRDTS ITTAYMELSSLRSNDTAVYYCARIRPRTGGLDSWGQGTL VIVSS MAB48 HC amino acid sequence of variable domain (SEQ ID NO: 13)

QVQLVQSGAEVKKPGSSVKVSCKASGVTFTAYAISWVRQAPGRGLEWMGGISPLFGI VNFGQNFQGRVTITADKSTGAAYMELSSLSSEDTAMYYCARGPYYYDRSHLDYWGQG TLVTVSS

MAB49 HC amino acid sequence of variable domain (SEP ID NO: 14)

QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGI IGMFGT TNYAQKFQGRVTI ADE FTS TAYMELTS LRSDDTAMY YCARDRNYYAS GT YDHWGQG TLVTVSS

MAB52 HC amino acid sequence of variable domain (SEP ID NO: 15)

QVLLVQSGAEVKKPGSSV ISCKASGGTFSNYAISWVRQAPGQGLDWMGRI I PIFGT ANYAQKFQGRLTITADESTSTAYMELSSLRSEDTAVFYCAITKPGSVYALDVWGQGT TVTVSS

MAB53 HC amino acid sequence of variable domain (SE ID NO: 16)

QVQLVQSGAEVRKPGSSVKVSCKVSGGI IRKYAINWVRQAPGQGLEWMGGI IAIFNT ANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGS LVTVSP

MAB285 HC amino acid sequence of variable domain (SEP ID NO: 17)

QVQLVQSGAEVKKPGASVKVSCRASGYTFTGYYMQWVRQAPGQGLEWMGFINANTGV TNFAQKFQGRVTLTRDTS ISTAYMELRRLTSADTAVYYCARAPQWLSYSFDIWGQGT MVTVSS

MAB321 HC amino acid sequence of variable domain (SEP ID NO: 18)

EVQLVESGAEVRSPGASVKLSCKASAYTFINYYLHWVRQAPGQRLEWMG INPDSGV TEYAQTFQGRVT TRDTSINTAYLDLERLTSDDTAVYYCARGFIPWGGKYFYLDYWG QGTLVTVSS

MAB322 HC amino acid sequence of variable domain (SEP ID NO: 19)

QVQLQQSGPGLVKPSQTLSLTCSVSGSFIRSGDYNWS IRQPPGKGLEWIGYIDNSG STHYNPSLKSRVS ISVDTSK HLSLKLSFVTDADTGVYYCAGEQASDSRGNYYYYA DVWGQGTPVTVSS MAB375 HC amino acid sequence of variable domain (SEQ ID NO:20)

QVQLQQSGPGLMKPSETLSLSCTVSGDSVSSFYWSWIRQSPGKGLEWIGYLLYSGNT KYNPSLKSRATISRDTSKNQLSLELTSLTAADTAVYYCARWRWRHGGDLDV GQGT MVTVSS

MAB376 HC amino acid sequence of variable domain (SEQ ID NO:21)

QVQLVQSGGDLVQPGGSLRLSCAVSGFIFRKYIMSWVRQAPGKGPEWVAVISSSGDR TFYADSVEGRFIVSRDNSKDTLFLQMNSLRTEDTAMYYCAKDLLGFCSGGDCLKVFD LWGRGTMVTVSS

MAB377 HC amino acid sequence of variable domain (SEQ ID NO:22)

QVQLLQSGPGLIKASETLSLSCSVSNDSVSNYYWSWIRQSPEKGLEWIGYLLYSGNT KYNPSLKSRAI ISRDMSKNQLSLRVTSVTAADTAIYYCARWRWRFGGDMD GQGT AVTVST

MAB378 HC amino acid sequence of variable domain (SEQ ID NO:23

QVQLQQSGPGLIKPSETLSLSCSVSGDSV NYYWSWIRQPPEKGLEWIGYLQYSGST KYNPSLKSRVTISRDTSKNQLSLKLTSVTAADTAIYYCARWRWRHGGDMDVWGQGT AVTVSS

Human LC amino acid sequence of constant kappa region (SEQ ID NO:24)

RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Human LC amino acid sequence of constant lambda region (SEQ ID NO:25

GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTWPAECS

MAB1 LC amino acid sequence (SEP ID ΝΟ:26Ί

DIQMTQSPSSLSASGGDRVTITCRASQSVSTYLNWYQQKPGKAPNLLVYAVSNLQRG VPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQSYSDPLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSS TLTLS KAD YEKHKVYACEVTHQGLS S PVTKS FNRGEC

MAB8 LC amino acid sequence (SEQ ID NO:27

DIQMTQSPSSLSASVGDRVTITCRASQTISKYLNWYQQKPGRAPKLLIYSASSLQSG VPSRFTGSGSGTDFTLTITSLQPEDFATYYCQQSYRPSQITFGPGTKVDIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB30 LC amino acid sequence (SEP ID NO:28

DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGNAPNLLIYKASSLESG VPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDTYSPTFGQGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB42 LC amino acid sequence (SEP ID NO:29)

QSALTQPASVSGSAGQSITISCTGTSSDVGAYNFVSWYQHHPGKAPKLMIYDVDNRP SGVSNRFSGSKSGDTASLTISGLQAEDEADYYCSSYRRNGPWVFGGGTKLTVLGQPK AAPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQ SNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTWPAECS

MAB48 LC amino acid sequence (SEP ID ΝΟ:3(Τ)

EIVLTQSPGTLSLSPGERATLSCRASQSVGSSDLAWYQQKPGQAPRLLIYGASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYVSSPLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLN FYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB49 LC amino acid sequence (SEP ID NP:31

DIQMTQSPSSLSASVGDRVTITCRASQSISRYLNWYQQKPGKAPKLLIYSASSLQSG VPSRFGGSGSGTDFTLTISSLQPEDFALYYCQQTYSIPITFGQGTRLDFKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDS DSTYSLSSTLTLSKADYE HKVYACEVTHQGLSSPVTKSFNRGEC

MAB52 LC amino acid sequence (SEP ID NG:32)

DIQMTQSPSSLSASVGDRVTITCRASQTISTYLNWYQQKPGKAPNLLIYTASSLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDAPTWTFGPGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB53 LC amino acid sequence (SEP ID NP:33 ^{^} )

EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC MAB285 LC amino acid sequence (SEQ ID NO:34

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNPVNWYQQLPGTAPRLLIYSNNQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYCTSWDDSLNAWVFGGGTRLTVLGQPK AAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQ SNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTWPAECS

MAB321 LC amino acid sequence (SEP ID ΝΟ:35

DIVLTQSPPSLSASVGDRVTITCRASQSINNYLNWYQQKPGNAPRILIYGASSLVSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRPLYTFGPGTQLDVKRTVAAPS VFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEDS DST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB322 LC amino acid sequence (SEQ ID NO:36

DIVMTQSPSSLSASVGDRVTITCRASESISAYLNWYQHTPGRAPKLLIYAASSLETG VPSRFSGSGSGTEFTLTISGLQPEDFVTYYCQQTYNTPRTFGQGTKVEIKRTVAAPS VFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB375 LC amino acid sequence (SEP ID NO:37)

DIQMTQSPSFLSASVGDRVTFTCRASQGIASSLAWYQQKAGKAPKLLIYAASTLEDG VPSRFSGSGFGTEFTLTITSLQPEDFATYYCHQWSYPRTFGPGTTVDINR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB376 LC amino acid sequence (SEQ ID NO:38

DIQMTQSPSTLSASVGDTVTITCRASQSISTWLAWFQQKPGRAPKLLIYQASSLEGG VPSRFSGSGSGTDFNLTISGLQPDDFATYYCLQYNTYSKSFGQGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

MAB377 LC amino acid sequence (SEQ ID NO:39)

DIQMTQSPSFLSASVGDRVTITCRASQGIATSLAWYQQKPGKAPRLLIYAASTLESG VPSRFSGGGSGTDFTLTISSLQPEDFAVYYCQQWSYPRTFGPGTKLDVKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW VDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC MAB378 LC amino acid sequence (SEP ID NO:40

DIQMTQSPSFLSASVGDRVTMTCRASQGISSYLAWYQQKPGKAPKLLIYAASTLESG VPSRFSGSGSGTEFTLTISSLQPEDFAIYYCQQWGYPRTFGPGTKVDIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Human IgGl HC nucleotide sequence of constant region (introns are underlined) (SEQ ID NO:41

GCCTCCACCAAGGGCCCATCAGTCTTCCCCCTGGCACCCTCTACCAAGAGCACCTCT GGGGGCACAACGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG GGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTTGGTGAGAGGCCAGCACAGGGAGGGAGGGTGTCTGCTGGAAGCCAGGCT CAGCGCTCCTGCCTGGACGCATCCCGGCTATGCAGTCCCAGTCCAGGGCAGCAAGGC AGGCCCCGTCTGCCTCTTCACCCGGAGGCCTCTGCCCGCCCCACTCATGCTCAGGGA GAGGGTCTTCTGGCTTTTTCCCCAGGCTCTGGGCAGGCACAGGCTAGGTGCCCCTAA CCCAGGCCCTGCACACAAAGGGGCAGGTGCTGGGCTCAGACCTGCCAAGAGCCATAT CCGGGAGGACCCTGCCCCTGACCTAAGCCCACCCCAAAGGCCAAACTCTCCACTCCC TCAGCTCGGACACCTTCTCTCCTCCCAGATTCCAGTAACTCCCAATCTTCTCTCTGC AGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGGTAAGCCAGC CCAGGCCTCGCCCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCA GGGACAGGCCCCAGCCGGGTGCTGACACGTCCACCTCCATCTCTTCCTCAGCACCTG AACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA TGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGC AC CAGGAC TGGCTGAATGGC AAGGAGTAC AAGTGC AAGGT CTC C AAC AAAG C C C TCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGTGGGACCCGTGGGGTGC GAGGGCCACATGGACAGAGGCCGGCTCGGCCCACCCTCTGCCCTGAGAGTGACCGCT GTACCAACCTCTGTCCCTACAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCC CCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAG CTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAA TGA MAB1 HC variable domain nucleotide sequence (SEQ ID NO:42)

CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTCATCTGCAGAGTCTCTGGTGGCTCGATCAGTAGTCATTACTGGAGCTGGATCCGG CAGCCCCCAGGGAAGGGACTGGAGTGGATTGGATATATTTCTTATAGGGGGAGAAGC AACCACAATCCTTCCCTTGGGAGACGAGTCTCTATGTCAATAGACACGTCGGAGAAC CAGTTCTCCCTGAACCTGAGCTCTGTGATCGCTGCGGACACGGCCGTATATTACTGT GCGAGAGATGCTACTGGGATCAGAGAAATCAATGCTCTTGATATCTGGGGCCAAGGG ACAACGGTCACCGTCTCTTCA

MAB8 HC variable domain nucleotide sequence (SEQ ID NO:43)

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGTTTCACTTTCAGTACCTATACTATGAGTTGGGTCCGC CAGGCTCCAGGGCAGGGGCTAGAGTGGGTCTCGTCCATTACTAGGACTAGTAGTAAT ATATACTACGCAGACTCAGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAAG AACTCACTGTATCTGCAGATGCATAGCCTGAGAGTCGAAGACACGGCTGTGTATTAC TGTGCGAGAATCAGCGGGGTAGTGGGACCTGTCCCCTTTGACTACTGGGGCCAGGGA ACCCTGATCACCGTCTCCTCT

MAB30 HC variable domain nucleotide sequence (SEP ID NQ:44

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGAGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACCACTACATGGACTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAGAAATAAAGCTGCCATT TACACCACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGAT TTAAAGAGCTCAGTGTATCTGCAAATGAACAGTCTGAAAACCGACGACACGGCCATA TATTACTGTGCTAGGAGCTATGGATACTTTGACTACTGGGGCCAGGGAACCCTGGTC ACCGTCTCCTCA

MAB42 HC variable domain nucleotide sequence CSEO ID NO:45~)

CAGGTGCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGATATTCCTTCAACGGCTACTATATGCACTGGGTGCGA CAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATCAACCTGAGCAGTGGTGGC ACAGATTATGCACAGAAATTTCAGGGGTGGGTCACTTTGACCAGGGACACGTCCATC ACCACAGCCTACATGGAGTTGAGCAGCCTGAGATCGAACGACACGGCCGTGTATTAC TGTGCGAGAATTAGACCTCGCACTGGTGGACTTGACTCCTGGGGCCAGGGAACCCTG GTCATCGTCTCCTCA

MAB48 HC variable domain nucleotide sequence (SEQ ID NO:46)

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAA GTCTCCTGCAAGGCTTCTGGAGTCACCTTCACCGCCTATGCTATCAGTTGGGTGCGA 40982

CAGGCCCCTGGACGAGGGCTTGAGTGGATGGGAGGGATCAGCCCTTTGTTTGGAATA GTAAATTTCGGACAGAACTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACG GGCGCAGCCTACATGGAGCTGAGCAGCCTGAGCTCTGAGGACACGGCCATGTATTAC TGTGCGAGAGGACCCTATTATTACGATAGAAGTCACCTAGACTACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA

MAB49 HC variable domain nucleotide sequence (SEQ ID NQ:47)

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAG GTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTATGCTATTAGCTGGGTGCGA CAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCGGTATGTTTGGAACA ACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATTCACG AGCACAGCCTACATGGAGCTGACCAGCCTGAGATCTGACGACACGGCCATGTATTAC TGTGCGAGAGACCGAAATTACTATGCTTCGGGGACTTATGACCACTGGGGCCAGGGA ACCCTGGTCACCGTCTCCTCA

MAB52 HC variable domain nucleotide sequence (SEP ID NO:48

CAAGTGCTGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGTCCTCGGTGAAT ATCTCTTGCAAGGCTTCTGGAGGCACTTTCAGCAACTATGCTATCTCCTGGGTGCGA CAGGCCCCTGGACAAGGTCTTGACTGGATGGGAAGGATCATCCCTATCTTTGGAACA GCAAACTACGCACAGAAATTCCAGGGCAGACTCACCATTACCGCGGACGAATCCACG AGCACAGCCTACATGGAACTGAGCAGCCTGAGATCTGAAGACACGGCCGTGTTTTAC TGTGCGATTACTAAACCGGGGTCTGTCTACGCTTTGGACGTCTGGGGCCAAGGGACC ACGGTCACCGTCTCCTCA

MAB53 HC variable domain nucleotide sequence (SEQ ID NO:49)

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAGGAAGCCGGGGTCCTCGGTGAAG GTCTCCTGCAAGGTTTCTGGAGGCATCATTAGGAAATATGCTATCAACTGGGTGCGA CAGGCCCCCGGACAAGGGCTTGAGTGGATGGGAGGGATCATCGCTATCTTTAATACA GCAAACTATGCACAGAAATTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACG AGCACAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAAGACACGGCCCTTTATTAC TGTGCGAGAGGAATGAATTACTACAGTGACTACTTTGACTACTGGGGCCAGGGAAGC CTTGTCACCGTCTCCCCA

MAB285 HC variable domain nucleotide sequence (SEQ ID NO:50

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCCGGGCTTCTGGATACACCTTCACCGGCTACTATATGCAGTGGGTGCGG CAGGCCCCTGGCCAAGGGCTTGAGTGGATGGGATTCATCAATGCTAACACTGGTGTC ACAAACTTTGCTCAGAAGTTTCAGGGCAGGGTCACCTTGACCAGGGACACGTCCATC AGCACAGCCTACATGGAGCTGAGGAGGCTGACATCTGCCGACACGGCCGTGTATTAC TGTGCGAGAGCGCCCCAGTGGTTATCGTATTCTTTTGATATCTGGGGCCAAGGGACA ATGGTCACCGTCTCCTCA

MAB321 HC variable domain nucleotide sequence (SEP ID ΝΟ:5 Π

GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAGGAGCCCTGGGGCCTCAGTGAAG CTCTCCTGCAAGGCTTCTGCATACACCTTCATCAACTACTATCTGCACTGGGTGCGA CAGGCCCCTGGACAAAGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGTC ACAGAATATGCACAGACATTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATC AATACAGCCTACCTGGACCTGGAGAGACTGACATCTGACGACACGGCCGTATATTAC TGTGCGAGAGGTTTTATTCCTTGGGGTGGGAAGTACTTCTACCTTGACTACTGGGGC CAGGGAACCCTGGTCACCGTCTCCTCA

MAB322 HC variable domain nucleotide sequence (SEP ID NO:52 ^{^} )

CAGGTACAGCTGCAGCAGTCAGGGCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCACCTGCAGTGTATCTGGTAGTTTCATCAGAAGTGGAGATTATAATTGGAGTTGG ATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCGATAATAGCGGG AGCACCCACTACAACCCGTCCCTCAAGAGTCGAGTTAGCATATCAGTGGACACGTCC AAGAACCACTTGTCCCTGAAGCTGAGTTTTGTGACTGACGCAGACACGGGCGTGTAT TACTGTGCCGGAGAACAAGCGTCTGATAGTCGTGGTAATTACTACTACTACGCTATG GACGTCTGGGGCCAAGGGACCCCGGTCACCGTCTCCTCA

MAB375 HC variable domain nucleotide sequence (SEP ID NP:53

CAGGTGCAGCTGCAGCAGTCGGGCCCCGGACTGATGAAGCCTTCGGAGACCCTGTCC CTCAGCTGCACTGTCTCTGGTGACTCCGTCAGTAGTTTTTATTGGAGTTGGATTCGG CAGTCTCCAGGAAAGGGACTGGAGTGGATTGGGTATTTGCTTTACAGTGGGAATACC AAGTATAATCCGTCCCTCAAGAGTCGAGCCACCATATCAAGAGACACGTCCAAGAAC CAGTTGTCCCTGGAGTTGACCTCTCTGACCGCTGCGGACACGGCCGTCTACTATTGT GCGAGAGTGGTGAGATGGCGACATGGTGGCGATTTGGACGTCTGGGGCCAAGGGACC ACGGTCACCGTCTCCTCA

MAB376 HC variable domain nucleotide sequence (SEP ID NP:54)

CAGGTGCAGCTGGTGCAGTCCGGGGGGGACTTGGTCCAGCCGGGGGGGTCCCTGAGA CTGTCATGTGCAGTCTCTGGATTCATCTTTAGAAAATATATCATGAGTTGGGTCCGG CAGGCTCCAGGGAAGGGGCCGGAGTGGGTCGCAGTTATTAGTTCTAGTGGTGACCGG ACATTCTACGCCGACTCCGTGGAGGGCCGCTTCATCGTCTCCAGAGACAATTCCAAG GACACACTGTTTCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCATGTATTAC TGTGCGAAAGACCTTTTGGGATTTTGTAGTGGTGGTGATTGCCTGAAGGTCTTCGAT CTCTGGGGCCGAGGCACCATGGTCACTGTCTCCTCA MAB377 HC variable domain nucleotide sequence (SEP ID NO:551

CAGGTGCAGCTGCTGCAGTCGGGCCCAGGACTGATAAAGGCTTCGGAGACCCTGTCT CTCAGCTGCAGTGTCTCTAATGACTCCGTCAGTAATTATTATTGGAGTTGGATCCGG CAGTCCCCAGAGAAGGGACTGGAGTGGATTGGGTATTTGCTTTATAGTGGGAATACC AAGTACAATCCCTCCCTCAAGAGTCGAGCCATCATATCAAGAGACATGTCCAAAAAT CAGTTGTCCCTCAGAGTGACTTCTGTGACCGCTGCGGACACGGCCATATATTATTGT GCGCGAGTGGTGAGATGGCGATTTGGTGGTGATATGGACGTCTGGGGTCAAGGGACC GCGGTCACCGTCTCCACA

MAB378 HC variable domain nucleotide sequence (SEP ID NO:56 ^{^} )

CAGGTGCAGCTGCAGCAGTCGGGCCCAGGACTGATAAAGCCTTCGGAGACCCTGTCT CTCAGCTGCTCTGTCTCTGGTGACTCCGTCAATAATTATTATTGGAGTTGGATCCGG CAGCCCCCAGAGAAGGGACTGGAGTGGATTGGGTATCTGCAGTATAGTGGGAGTACA AAGTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAAGAGACACGTCCAAAAAC CAGTTGTCCCTGAAGCTGACCTCTGTGACCGCTGCGGACACGGCCATATATTATTGT GCGAGAGTGGTGAGATGGCGACATGGTGGGGATATGGACGTCTGGGGCCAAGGGACC GCGGTCACCGTCTCCTCT

Human LC nucleotide sequence of constant kappa region (SEP ID NP:57)

CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCTAGCGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAA GCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGC TCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

Human LC nucleotide sequence of constant lambda region fSEP ID NP:58)

GGTCAGCCCAAGGCTGCCCCCTCTGTCACTCTGTTCCCGCCCTCTAGCGAGGAGCTT CAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTG ACAGTGGC C TGGAAGGC AGATAGCAGC C C CGTCAAGGCGGGAGTGGAGAC CAC CAC A CCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCT GAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGTCCCTGCAGAATGCTCT

MAB1 LC variable domain nucleotide sequence (SEP ID NP:59

GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGGAGGAGACAGAGTC ACCATCACTTGCCGGGCAAGTCAGAGTGTTAGTACGTATTTAAATTGGTATCAGCAG AAACCAGGGAAAGCCCCTAACCTCCTGGTCTATGCTGTATCCAATTTACAACGTGGC GTGCCATCAAGGTTCAGTGGCAGTGGATCTGGGACACATTTCACTCTCACAATCAGC AGTCTGCAACCTGAGGATTTCGCAACTTACTACTGTCAACAGAGTTACAGTGACCCT CTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA

MAB8 LC variable domain nucleotide sequence (SEP ID NO: 60)

GACATCCAGATGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTAGGAGACAGAGTC ACCATCACTTGCCGGGCAAGTCAGACCATTAGCAAGTATTTAAATTGGTATCAGCAG AAGCCAGGGAGAGCCCCTAAACTCCTGATCTACTCTGCGTCCAGTTTGCAAAGTGGG GTCCCATCAAGGTTCACTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACC AGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGACCCTCC CAGATCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA

MAB3Q LC variable domain nucleotide sequence (SEQ ID NO:61)

GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTC ACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGTTGGTTGGCCTGGTATCAGCAG AAACCAGGGAACGCCCCTAACCTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGG GTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGC AGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATGATACTTATTCT CCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA

MAB42 LC variable domain nucleotide sequence (SEQ ID NO:62)

CAGTCTGCCCTGACTCAGCCTGCCTCCGGGTCTGGGTCTGCTGGACAGGCGATCACC ATCTCCTGCACTGGAACCGGCACTGACGTCTGTGCTTATAACTTTGTCTCCTGGTAC CAACACCACCCCGGCGAAGCCCCCAAACTCATGATTTATGATGTCGATAATCGGCCC TCATGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGTAACACGGCCTCCCTGACC ATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTACTACTGCAGCTCATATAGAAGG AACGGCCCTTGCTTGTTCGGCGGAGGGACCAAGCTGACCGTCCTG

MAB48 LC variable domain nucleotide sequence (SEQ ID NO:63)

GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCC ACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAGCGACTTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATATATGGTGCATCCAGCCGGGCCACT GGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC AGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGTCAGTTCA C C C C T C AC TTT CGG C GGAGGGAC C AAGGTGGAGAT C AAG

MAB49 LC variable domain nucleotide sequence (SEQ ID NO:64)

GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTC ACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAGCAG AAACCAGGGAAAGCCCCTAAACTCCTGATCTATTCTGCATCCAGTTTGCAAAGTGGG GTCCCATCAAGGTTCGGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC AGTCTGCAACCTGAAGATTTTGCACTTTACTACTGTCAACAGACTTACAGTATCCCG ATCACCTTCGGCCAAGGGACACGACTGGACTTTAAA

MAB52 LC variable domain nucleotide sequence (SEP ID NO:65)

GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTC ACTATCACTTGCCGGGCAAGTCAGACCATTAGCACCTATTTAAATTGGTATCAGCAG AAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCAGTTTGCAAAGCGGG GTCCCATCAAGATTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC AGTCTGCAACCTGAAGATTTTGCAACTTATTACTGTCAACAGAGTTACGATGCCCCC ACGTGGACCTTCGGCCCAGGGACCAAGGTGGAAATCAAA

MAB53 LC variable domain nucleotide sequence (SEP ID NO:66

GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCC ACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGAAGCAACAACTTAGCCTGGTACCAG CACAAACCTGGCCAGGCTCCCAGGCTCCTCATCTTTGGTGCATCCAGCAGGGCCACT GGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC AGCAGACTGGAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTATGGTAGCTCA CCTGCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA

MAB285 LC variable domain nucleotide sequence (SEP ID NO:67)

CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACC ATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTAATCCTGTAAACTGGTACCAG CAGCTCCCAGGAACGGCCCCCAGACTTCTCATCTATAGTAATAATCAGCGGCCCTCA GGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATC AGTGGGCTCCGGTCCGAGGATGAGGCTGATTACTACTGTACATCATGGGATGACAGC CTGAATGCTTGGGTGTTCGGCGGGGGGACCAGGCTGACCGTCCTA

MAB321 LC variable domain nucleotide sequence (SEQ ID NO:68

GATATCGTGTTGACTCAGTCTCCACCCTCCCTGTCTGCATCTGTGGGGGACAGAGTC ACCATCACTTGCCGGGCAAGTCAGAGCATTAATAACTACTTAAATTGGTATCAACAG AAACCAGGGAACGCCCCAAGAATACTAATCTATGGTGCATCCAGTTTGGTAAGTGGG GTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCCTCACCATCAGC AGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACCGGCCCCTG TACACTTTTGGCCCGGGGACCCAGCTGGATGTCAAA

MAB322 LC variable domain nucleotide sequence (SEP ID NO:69

GATATCGTGATGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTGGGAGACAGAGTC ACCATCACTTGCCGGGCAAGTGAGAGCATTAGCGCTTATTTAAATTGGTATCAGCAC ACACCAGGGAGAGCCCCTAAGCTCCTGATCTATGCTGCCTCCAGTTTGGAAACTGGG GTCCCATCAAGGTTCAGTGGCAGTGGATCTGGCACAGAATTCACTCTCACCATCAGC GGTCTGCAACCTGAAGATTTTGTCACTTACTACTGTCAACAGACTTACAATACCCCT CGGACCTTCGGCCAAGGGACCAAGGTGGAAATCAAA

MAB375 LC variable domain nucleotide sequence (SEP ID NP:7(T)

GATATCCAGATGACCCAGTCTCCATCCTTCTTGTCTGCATCTGTGGGAGACAGAGTC ACCTTCACTTGCCGGGCCAGTCAGGGCATTGCCAGTTCTTTAGCCTGGTATCAGCAA AAAGCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCTTCTACTTTGGAAGATGGG GTCCCATCAAGGTTCAGCGGCAGTGGATTTGGGACAGAATTCACTCTCACAATCACC AGCCTGCAGCCTGAAGATTTTGCAACCTATTACTGTCATCAGGTGAATAGTTACCCT CGGACTTTCGGCCCTGGGACCACAGTGGATATCAAC

MAB376 LC variable domain nucleotide sequence (SEP ID NO:71

GATATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTGGGAGACACAGTC ACCATCACTTGCCGGGCCAGTCAGAGTATTAGTACTTGGTTGGCCTGGTTTCAGCAG AAACCAGGGAGAGCCCCTAAACTCCTGATCTATCAGGCGTCTAGTTTGGAAGGTGGG GTCCCATCAAGGTTCAGCGGCAGTGGGTCTGGGACAGACTTCAACCTCACCATCAGC GGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTACAATATAACACTTATTCG AAGTCATTCGGCCAAGGGACCAAGGTGGAAATCAAAC

MAB377 LC variable domain nucleotide sequence (SEP ID NP:72

GATATCCAGATGACCCAGTCTCCATCCTTCTTGTCTGCATCTGTCGGAGACAGAGTC ACCATCACCTGCCGGGCCAGTCAGGGCATTGCCACTTCTTTAGCCTGGTATCAGCAA AAACCTGGGAAAGCCCCGAGGCTCCTGATCTATGCTGCATCCACTTTGGAAAGTGGG GTCCCATCAAGGTTCAGCGGCGGTGGATCTGGGACAGACTTCACTCTCACAATCAGC AGTCTGCAGCCCGAAGATTTTGCTGTTTATTACTGTCAACAGGTTAACTCCTATCCT CGGACTTTCGGCCCTGGGACCAAACTGGATGTCAAAC

MAB378 LC variable domain nucleotide sequence (SEP ID NP:73

GATATCCAGATGACCCAGTCTCCATCCTTCTTGTCTGCATCTGTAGGAGACAGAGTC ACCATGACCTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAA AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCGACTTTGGAAAGTGGG GTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGC AGCCTGCAGCCCGAAGATTTTGCAATTTATTACTGTCAACAGGTTAATGGTTACCCT CGGACTTTCGGCCCTGGGACCAAAGTGGATATCAAAC RGLFGAIAGFIENGW (SEP ID NO:74.

MAB53 Heavy Chain (SEP ID NO:75

QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQGLEWMGGIIAIFNT ANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGS LVTVSPASTKGPSVFPLVPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNWHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

MAB53 Light Chain (SEP ID NO:76)

EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

GGIIRKYAIN (SEQ ID NG:77)

GGIIAIFNTANYAQKFQG (SEQ ID NQ:78)

ARGMNYYSDYFDY (SEQ ID NG:79)

RASQSVRSN LA (SEQ ID NP:80)

GASSRAT (SEQ ID NO:81)

QQYGSSPALT (SEQ ID NG:82)

IGHV1-69*01 (SEQIDNG:83)

QVQLVQSGAEVRK PGSSVKVSCKVSGGIIRKYAINWVRQAPGQG

LEWMGG11AIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMN

YYSDYFDYWGQGSLVTTVS

IGKV3-20*01 (SEQ ID NG:84)

EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIK