WO2019079762A1 - Methods of antibody discovery using transcriptomes and compositions derived therefrom - Google Patents

Methods of antibody discovery using transcriptomes and compositions derived therefrom Download PDF

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Publication number
WO2019079762A1
WO2019079762A1 PCT/US2018/056774 US2018056774W WO2019079762A1 WO 2019079762 A1 WO2019079762 A1 WO 2019079762A1 US 2018056774 W US2018056774 W US 2018056774W WO 2019079762 A1 WO2019079762 A1 WO 2019079762A1
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Prior art keywords
seq
amino acid
acid sequence
set forth
light chain
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PCT/US2018/056774
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French (fr)
Inventor
Yang Liu
Pan Zheng
Hung-Yen Chou
Peng Zhang
Lei Young
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Children's National Medical Center
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Priority to CN201880082663.9A priority Critical patent/CN111492066A/en
Publication of WO2019079762A1 publication Critical patent/WO2019079762A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C40B40/08—Libraries containing RNA or DNA which encodes proteins, e.g. gene libraries
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids

Definitions

  • the present disclosure relates to The present disclosure relates to a method of identifying and producing antibody-based cancer therapies.
  • methods of identifying nucleic acid sequences that encode antibodies or antibody fragments from a transcriptome or genomic DNA sequences of a sample comprise steps of:
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • such methods can further comprise a step of:
  • exemplary methods can comprise steps of:
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • Steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c).
  • transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments.
  • Suitable antibody fragments include: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and/or a constant region of the antibody.
  • such nucleic acid sequences encode variable heavy chain and/or variable light chain portions of the antibody.
  • the screening step comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation: wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
  • Exemplary screening methods include performing FASTQ, MIXCR, and/or VDJtools functions on the transcriptome data.
  • It may be advantageous to align amino acid sequences before screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
  • One, non- limiting example of a function that aligns clonal sequences comprises performing an immunoSEQ function.
  • Samples for use in the disclosed methods are tissue sample from a subject having a hyperproliferative cell disorder.
  • Contemplated samples include, but are not limited to, cancer tissues from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and/or skin cutaneous carcinoma.
  • Another embodiment of the disclosure is a computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample, the method comprising: in a system comprising at least one processor and a memory,
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • the at least one processor can be further configured to (d) identify a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
  • the processor can repeat the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences one or more times.
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • Steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c).
  • the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
  • the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the sample is determined, at least in part, by the following equation: i 3 ⁇ 4 ⁇ f Ci logZjCi)
  • the screening the transcriptome of a series of samples for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
  • Screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences. Alignment of clonal sequences comprises performing an immunoSEQ function.
  • Contemplated samples include tissue samples from subjects having
  • hyperproliferative cell disorders such as: a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
  • the first set of nucleic acids that encode an antibody or antibody fragment encode an antibody capable of binding one or a plurality of cells from the sample and/or subject.
  • the disclosure further describes a method of compiling a set of nucleic acid sequences encoding an antibody or antibody fragment from a sample, the method comprising:
  • a method of designing an antibody or antibody fragment capable of binding to an epiptope on a cell from a sample comprises:
  • a composition comprising an antibody or antibody fragment comprises at least one CDR sequence obtained from performing any of the methods described above.
  • a library of antibodies comprising at least one amino acid sequence obtaining from performing any of the methods described above.
  • a non-transitory computer program product encoded on computer-readbale storage medium comprising instructions for:
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • the non- transitory computer program product of claim 30 further comprises instructions for a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
  • CDR complementarity determining region
  • an instruction is included for repeating the step of identifying a nucleic acid sequence encoding at least one
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • nucleic acid sequence [0053] g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score; and [0054] h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject
  • Steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c).
  • the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
  • the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation:
  • Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
  • the screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
  • the screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
  • the alignment of clonal sequences comprises performing an immunoSEQ function.
  • the sample is a tissue sample from a subject having a hyperproliferative cell disorder, such as cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
  • the method of validating antibody specificity uses immunofluorescence methods known in the art by comparing its binding to cancer and normal tissues.
  • compositions of antibodies are broadly reactive to cancer tissues but rarely to normal tissues.
  • compositions of the cancer-specific antibodies have amino acid sequence identified in sequence ID 1-9.
  • compositions of antibodies are narrowly specific for tissues from which the antibody sequence were composited based immunoseq data.
  • immunoseq-derived high abundance antibody sequences comprise CDR1, CDR2 and CDR3 as well as somatically mutated sequences.
  • immunoseq-derived high abundance antibody sequences comprise one of the sequences in sequence ID 19.
  • antibodies constructed from sequences in claims 42-48 for cancer diagnosis comprising staining of tissues by immunohistochemistry of immunofluorescence.
  • Such uses are contemplated for cancer therapy.
  • the disclosed uses include: antibodies modified for optimal antibody-dependent cellular cytotoxicity or antibody-dependent cellular phagocytosis and/or antibody-drug conjugates.
  • the antibodies are used an component of bi-specific antibodies.
  • the antibodies are used as key component of chimeric antigen-receptor T cells (CART). Other aspects of the disclosure are described in the detailed description.
  • the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2206, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2208, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2210, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2216, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2218, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2220.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2226, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2228, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2230, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2236, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2238, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2240.
  • a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2226
  • a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2228
  • a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2246, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2248, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2250, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2256, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2258, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2260.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2266, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2268, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2270, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2276, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2278, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2280.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2286, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2288, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2290, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2296, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2298, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2300.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2306, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2308, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2310, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2316, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2318, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2320.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2326, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2328, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2330, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2336, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2338, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2340.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2346, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2348, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2350, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2356, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2358, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2360.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2366, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2368, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2370, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2376, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2378, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2380.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2386, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2388, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2390, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2396, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2398, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2400.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2406, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2408, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2410, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2416, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2418, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2420.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2426, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2428, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2430, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2436, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2438, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2440.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2446, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2448, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2450, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2456, a light chain
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2466, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2468, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2470, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2476, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2478, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2480.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2490, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2496, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2498, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2500.
  • a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486
  • a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488
  • a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2506, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2508, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2510, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2516, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2518, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2520.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2526, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2528, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2530, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2536, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2538, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2540.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2546, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2548, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2550, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2556, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2558, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2560.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2566, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2568, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2570, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2576, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2578, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2580.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2586, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2588, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2590, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2596, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2598, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2600.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2606, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2608, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2610, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2616, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2618, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2620.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2626, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2628, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2630, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2636, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2638, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2640.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2646, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2648, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2650, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2656, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2658, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2660.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2666, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2668, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2670, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2676, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2678, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2680.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2686, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2688, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2690, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2696, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2698, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2700.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2706, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2708, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2710, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2716, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2718, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2720.
  • the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2204, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2204, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2214, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2214.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2224, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2224, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2234, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2234.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2244, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2244, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2254, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2254.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2264, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2264, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2274, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2274.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2284, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2284, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2294, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2294.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2304, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2304, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2314, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2314.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2324, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2324, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2344, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2344, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2354, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2354.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2364, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2364, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2374, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2374.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2384, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2384, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2394, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2394.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2404, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2404, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2414, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2414.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2424, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2424, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2444, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2444, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2454, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2454.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2464, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2464, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2474, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2474.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2484, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2484, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2494, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2494.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2504, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2504, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2514, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2514.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2524, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2524, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2534, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2534.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2544, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2544, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2554, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2554.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2564, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2564, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2574, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2574.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2584, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2584, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2594, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2594.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2604, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2604, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2614, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2614.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2624, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2624, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2634, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2634.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2644, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2644, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2654, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2654.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2664, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2664, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2674, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2674.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2684, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2684, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2694, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2694.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2704, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2704, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2714, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2714.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2202, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2202, and/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2212, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2212.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2222, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2222, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2232, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2232.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2242, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2242, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2252, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2252.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2262, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2262, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2272, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2272.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2282, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2282, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2292, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2292.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2302, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2302, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2312, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2312.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2322, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2322, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2332, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2332.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2342, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2342, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2352, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2352.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2362, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2362, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2372, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2372.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2382, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2382, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2392, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2392.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2402, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2402, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2412, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2412.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2422, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2422, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2432, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2432.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2442, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2442, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2452, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2452.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2462, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2462, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2472, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2472.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2482, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2482, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2492, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2492.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2502, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2502, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2512, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2512.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2522, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2522, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2532, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2532.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2542, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2542, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2552, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2552.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2562, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2562, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2572, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2572.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2582, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2582, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2592, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2592.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2602, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2602, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2612, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2612.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2622, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2622, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2632, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2632.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2642, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2642, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2652, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2652.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2662, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2662, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2672, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2672.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2682, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2682, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2692, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2692.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2702, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2702, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2712, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2712.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2202, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2212. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2222, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2232. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2242, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2252. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2262, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2272.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2282, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2292. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2302, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2312. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2322, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2332. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2342, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2352.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2362, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2372. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2382, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2392. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2402, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2412. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2422, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2432.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2442, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2452. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO:
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2472.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2482, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2492.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2502, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2512.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2522, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2532.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2542, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2552. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2562, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2572. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2582, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2592. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2602, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2612.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2622, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2632. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2642, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2652. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2662, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2672. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2682, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2692. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2702, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2712.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2202. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2212. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2222. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2232. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2242. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2252. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2262. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
  • composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2272. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2282. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2292. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2302. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2312. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2322. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2332.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2342. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2352. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2362. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2372. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2382. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2392. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2402.
  • composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2412. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2422. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
  • composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2442. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2452. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2462. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2482. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2492. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2502.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2512. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2522. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2532. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2542. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2552. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2562. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2572.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2582. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2592. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising 2602. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2612. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2622. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2632. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2642.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2652. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2662. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2672. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2682. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2692. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2702. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2712.
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of a Fab, a Fab', a F(ab')2, an Fv, a domain antibody, and a single-chain antibody.
  • the antibody, or antigen binding portion fragment thereof is classified as an isotype selected from the group consisting of an IgG, an IgM, an IgD, an IgA, and an IgE.
  • the disclosure features an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, that competes with the antibody, or antigen binding portion thereof, of any one of the preceding aspects or embodiments.
  • the antibody, or antigen binding portion thereof is humanized.
  • the tantibody, or antigen binding fragment thereof, of any one of the aspects or embodiments herein, and a pharmaceutically acceptable carrier in one embodiment, is lyophilized.
  • a vector comprises the nucleic acid.
  • a host cell comprises the vector.
  • the host cell is a prokaryotic cell or a eukaryotic cell.
  • the eukaryotic cell is a protist cell, an animal cell, a plant cell, a fungal cell, a yeast cell, a mammalian cell, an avian cell, or an insect cell.
  • the mammalian cell is a CHO cell or a COS cell.
  • Figure 1 (A-G) shows a computational framework for estimating and filtering the immunoglobulin sequences based on RNAseq data from TCGA database.
  • Figure 1A is a schematic diagram of rearranged sequences detection and selection from TCGA cohorts and lung cancer frozen tissues for curated extend and experimental validation.
  • Figure IB is a graph that shows the abundance of immunoglobulin aligned reads count (left) and clonotypes count (right) among different tumor samples.
  • Figure 1C is a graph that shows the CDR3 sequences clonality among different tumor types.
  • Figure ID is a graph that shows the distribution of the ratio of aligned immunoglobulin transcripts to total RNAseq reads across all samples from TCGA LUAD cohorts.
  • the sample (TCGA-L9-A444-01A) has the highest abundance of Immunoglobulin transcripts is marked in red and chosen for further study.
  • Figure IE is a graph that shows the distribution of clone fraction value of all immunoglobulin arrangement clonotypes from the most abundant sample (TCGA-L9-A444-01A). The red dots indicated with arrows depict the clonotypes chosen for proof-of-concept studies based on high abundance and high alignment scores.
  • Figure IF is a table that shows selected sequences with annotated information and gene usage for further extend analysis and experimental validation.
  • Figure 1G is a graph that shows expression of recombinant antibodies based on random pairing from 3 heavy and 6 light chains were expressed with transient transfection.
  • Figure 2 shows results of immunofluorescence experiments that demonstrate recombinant antibodies reconstructed from CDR3 sequences from an LUAD patient cross-react with unrelated LUSC and LUAD tissues.
  • Figure 2A shows reactivity of CDR3-based antibodies to unrelated LUSC and LUAD tissues.
  • LUSC (sample 427) was recognized by H1L7, H2L5, H2L6, H2L7, H2L8 and H2L9 whereas LUAD (Sample 429) was recognized by H1L5, H1L7, H1L9, H2L5, H2L6, H2L7, H2L8, H2L9, and H3L9.
  • Figure 2B shows H2L5 and H2L7 binds to 2/2 LUAD tissues and 3/3 LUSC tissues. Isotype control of mouse IgG2a k was included.
  • Figure 3 (A-D) shows results of immunofluorescence experiments that demonstrate H2L7 binds a broad range of malignant tissues but shows limited binding to normal tissues.
  • Figure 3A shows that H2L7 has limited binding to normal tissues. H2L7 does not react to most normal tissues although some non-cell surface binding was observed against normal parotid gland, normal pancreas tissue, normal testis tissue, normal lymph node tissue, and normal spleen tissue.
  • Figure 3B shows that H2L7 shows broad cross-reactivity against multiple malignant tissues, including colon adenocarcinoma, esophagus adenocarcinoma, stomach adenocarcinoma, ovary adenocarcinoma, Soft tissue giant cell tumor, liver hepatocellular carcinoma, breast invasive ductal carcinoma, skin squamous cell carcinoma, testis seminoma, LUAD and LUSC.
  • Figure 3C shows selective images depicting H2L7 binds to lung squamous cell carcinoma but not its normal adjacent tissue (NAT).
  • Figure 3D is a graph that shows H2L7 binds to 16/16 lung squamous cell carcinoma and 4/16 of NATs. P values in D were calculated by a fisher exact test.
  • Figure 4 (A-C) shows recombinant antibodies derived from targeted genomic sequence of LUAD (sample 463) and LUSC (sample 427) showed limited cross-reactivities.
  • Figure 4A is a table that shows selected sequences with annotated information and gene usage for further extend analysis and experimental validation.
  • Figure 4B is a graph that shows recombinant antibodies from heavy and light chains derived from LUAD and LUSC samples were expressed with transient transfection.
  • Figure 4C show results from
  • H5L12 derived from LUAD sample 463 recognizes 2/2 LUAD tissues whereas H6L13, which was derived from LUSC sample 427, shows very specific binding to LUSC tissue of which it was derived from.
  • Figure 5 shows antibody pool of 13 recombinant antibodies generated by random pairing of 3 heavy chains and 6 light chains binds to LUSC and LUAD tissues.
  • Isotype control of mouse IgG2a k was included as a control.
  • an element means one element or more than one element, e.g. , a plurality of elements.
  • an amino acid sequence with a modified amino acid is understood to include the options of an amino acid with a modified sidechain, a an amino acid with a modified backbone, and an amino acid with a modified sidechain and a modified backbone.
  • about is used herein to mean within the typical ranges of tolerances in the art.
  • “about” can be understood as about 2 standard deviations from the mean.
  • about means +10%, +9%, +8%, +7%, +6%, +5%, ⁇ 4%, +3%, +2%, +1%, +0.9%, +0.8%, +0.7%, +0.6%, +0.5%, 0.4%, 0.3%, +0.2%, +0.1% or +0.05%.
  • about means +5%.
  • polypeptide refers to any polymeric chain of amino acids.
  • peptide and protein are used interchangeably with the term polypeptide and also refer to a polymeric chain of amino acids.
  • polypeptide encompasses native or artificial proteins, protein fragments and polypeptide analogs of a protein sequence.
  • a polypeptide may be monomeric or polymeric.
  • isolated protein or "isolated polypeptide” is a protein or polypeptide that by virtue of its origin or source of derivation is not associated with naturally associated components that accompany it in its native state; is substantially free of other proteins from the same species; is expressed by a cell from a different species; or does not occur in nature.
  • a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components.
  • a protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.
  • An example of an isolated polypeptide is an isolated antibody, or antigen- binding portion thereof.
  • recovering refers to the process of rendering a chemical species such as a polypeptide substantially free of naturally associated components by isolation, e.g., using protein purification techniques well known in the art.
  • telomere binding in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A” and the antibody, will reduce the amount of labeled A bound to the antibody.
  • a particular structure e.g., an antigenic determinant or epitope
  • antibody as used herein, broadly refers to any immunoglobulin
  • each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • CL The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • Immunoglobulin molecules can be of any type ⁇ e.g., IgG, IgE, IgM, IgD, IgA and IgY), class ⁇ e.g., IgG 1, IgG2, IgG 3, IgG4, IgAl and IgA2) or subclass.
  • antigen binding portion or "antigen binding fragment” of an antibody (or simply “antibody portion” or “antibody fragment”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may also be bispecific, dual specific, or multi- specific formats; specifically binding to two or more different antigens.
  • binding fragments encompassed within the term "antigen -binding portion" or "antigen binding fragment” of an antibody 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; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546, Winter et al, PCT publication WO 90/05144 Al herein incorporated by reference), which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR).
  • CDR complementarity determining region
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" or "antigen binding fragment" of an antibody.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994) Structure 2: 1121-1123).
  • Such antibody binding portions are known in the art (Kontermann and Dubel eds., Antibody Engineering (2001) Springer- Verlag. New York. 790 pp. (ISBN 3-540-41354-5).
  • antibody construct refers to a polypeptide comprising one or more the antigen-binding portions of the invention linked to a linker polypeptide or an immunoglobulin constant domain.
  • Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen- binding portions.
  • Such linker polypeptides are well known in the art (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994) Structure 2: 1121-1123).
  • An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences are known in the art and represented below.
  • an "isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities.
  • An isolated antibody may have cross-reactivity to other antigens from other species.
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • chimeric antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.
  • CDR-grafted antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.
  • Kabat numbering Kabat definitions and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and , Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3.
  • the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.
  • the terms “acceptor” and “acceptor antibody” refer to the antibody or nucleic acid sequence providing or encoding at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or 100% of the amino acid sequences of one or more of the framework regions.
  • the term “acceptor” refers to the antibody amino acid or nucleic acid sequence providing or encoding the constant region(s).
  • the term “acceptor” refers to the antibody amino acid or nucleic acid sequence providing or encoding one or more of the framework regions and the constant region(s).
  • the term "acceptor” refers to a human antibody amino acid or nucleic acid sequence that provides or encodes at least 80%, preferably, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the framework regions.
  • an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues that does (do) not occur at one or more specific positions of a human antibody.
  • acceptor framework region and/or acceptor constant region(s) may be, e.g., derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well-known in the art, antibodies in development, or antibodies commercially available).
  • CDR refers to the complementarity determining region within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions.
  • CDR set refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md.
  • CDRs defined according to any of these systems although preferred embodiments use Kabat or Chothia defined CDRs.
  • canonical residue refers to a residue in a CDR or framework that defines a particular canonical CDR structure as defined by Chothia et al. (J. Mol. Biol. 196:901-907 (1987); Chothia et al, J. Mol. Biol. 227:799 (1992), both are incorporated herein by reference). According to Chothia et ah , critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.
  • the terms “donor” and “donor antibody” refer to an antibody providing one or more CDRs.
  • the donor antibody is an antibody from a species different from the antibody from which the framework regions are obtained or derived.
  • the term “donor antibody” refers to a non- human antibody providing one or more CDRs.
  • framework or “framework sequence” refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations.
  • the six CDRs also divide the framework regions on the light chain and the heavy chain into four sub- regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4.
  • a framework region represents the combined FR's within the variable region of a single, naturally occurring immunoglobulin chain.
  • a FR represents one of the four sub- regions, and FRs represents two or more of the four sub- regions constituting a framework region.
  • fragment is defined as a physically contiguous portion of the primary structure of a biomolecule.
  • the biomolecule is an antibody or a polypeptide sequence that binds an antigen recognized by the antibody.
  • a fragment may be defined by a contiguous portion of the amino acid sequence of a protein and may be at least 3-5 amino acids, at least 6-10 amino acids, at least 11-15 amino acids, at least 16-24 amino acids, at least 25-30 amino acids, at least 30-45 amino acids and up to the full length of the protein minus a few amino acids.
  • a fragment is defined by a contiguous portion of the nucleic acid sequence of a polynucleotide and may be at least 9-15 nucleotides, at least 15-30 nucleotides, at least 31-45 nucleotides, at least 46-74 nucleotides, at least 75-90 nucleotides, and at least 90-130 nucleotides.
  • fragments of biomolecules are immunogenic fragments.
  • the term "functional fragment” means any portion of a polypeptide or amino acid sequence that is of a sufficient length to retain at least partial biological function that is similar to or substantially similar to the wild-type polypeptide or amino acid sequence upon which the fragment is based. If the fragment is a functional fragment of an antibody or antibody-like molecule, the fragment can be immunogenic and therefore possess a binding avidity for one or a plurality of antigens.
  • a functional fragment of a polypeptide associated with the extracellular matrix is a polypeptide that comprises 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity of any polypeptide disclosed in Table 1 and has sufficient length to retain at least partial binding affinity to one or a plurality of ligands that bind to the amino acid sequence in Tables 1 through 17
  • the fragment is a fragment of any amino acid sequence disclosed in Table 1 and has a length of at least about 10, about 20, about 30, about 40, about 50 , about 60, about 70, about 80, about 90, or about 100 contiguous amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 50 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 100 amino acids. In some
  • the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 150 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 200 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 250 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 300 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 350 amino acids. In some embodiments,
  • the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 400 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 450 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 500 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 550 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 600 amino acids. In some embodiments,
  • the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 650 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 700 amino acids. In some embodiments, the fragment is a fragment of any polypeptide disclosed in Tables 1 through 17 and has a length of at least about 750 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 800 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 850 amino acids.
  • the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 900 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 950 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 1000 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 1050 amino acids. In some
  • the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of no more than the aforementioned alternative number of amino acids in this paragraph.
  • the composition or pharmaceutical is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of no more than the aforementioned alternative number of amino acids in this paragraph.
  • compositions of the disclosure include any one or more conservative substitutions disclosed in Table A.
  • human heavy chain and light chain acceptor sequences are selected from the sequences described in the tables below.
  • the term "germline antibody gene” or “gene fragment” refers to an immunoglobulin sequence encoded by non- lymphoid cells that have not undergone the maturation process that leads to genetic rearrangement and mutation for expression of a particular immunoglobulin. (See, e.g., Shapiro et al., Crit. Rev. Immunol. 22(3): 183-200 (2002); Marchalonis et al., Adv Exp Med Biol. 484: 13-30 (2001)).
  • hyperproliferative disorder is meant to refer to those diseases and disorders characterized by hyperproliferation of cells or cells that exhibit a dysfunction in their growth cycle.
  • the hyperproliferative disease is a dysplasia or cancer.
  • hyperproliferative disorder refer to a disorder
  • fibroproliferative disorders such as involving connective tissues, as well as other disorders characterized by fibrosis, including for example, rheumatoid arthritis, insulin dependent diabetes mellitus, glomerulonephritis, cirrhosis, and scleroderma), smooth muscle proliferative disorders (such as atherosclerosis and restinosis), chronic inflammation, and epithelial cell proliferative disorders (for example, psoriasis; keratosis; acne; comedogenic lesions; verracous lesions such as verruca plana, plantar warts, verruca acuminata, and other verruciform lesions marked by proliferation of epithelial cells; folliculitis and pseudofolliculitis; keratoacanthoma; callos
  • the hyperproliferative disease is a cancer derived from the gastrointestinal tract or urinary system.
  • a hyperproliferative disease is a cancer of the adrenal gland, bladder, bone, bone marrow, brain, spine, breast, cervix, gall bladder, ganglia, gastrointestinal tract, stomach, colon, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, or uterus.
  • the term hyperproliferative disease is a cancer chosen from: lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas
  • hyperproliferative disorder is a glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, or skin cutaneous carcinoma.
  • hyperproliferative-associated protein is meant to refer to proteins that are associated with a hyperproliferative disease.
  • the hyperproliferative-associated protein is an antigen expressed on the cell that has a dysfunctional growth cycle.
  • the cell having a dysfunctional growth cycle is cancerous.
  • the hyperproliferative-associated protein is an antigen that is expressed on a hyperproliferative cell in an abundance that is higher as compared to a normal cell. In some embodiments, the hyperproliferative-associated protein is an antigen that is expressed on a hyperproliferative cell but absent on a normal cell. In some embodiments, the hyperproliferative cell is a cell from a sample from a cancer patient. In some embodiments, the hyperproliferative cell is a cell from a tissue or solid tumor that is cancerous. In some embodiments, the cancer is
  • key residues refer to certain residues within the variable region that have more impact on the binding specificity and/or affinity of an antibody, in particular a humanized antibody.
  • a key residue includes, but is not limited to, one or more of the following: a residue that is adjacent to a CDR, a potential glycosylation site (can be either N- or O-glycosylation site), a rare residue, a residue capable of interacting with the antigen, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region, a residue within the Vernier zone, and a residue in the region that overlaps between the Chothia definition of a variable heavy chain CDR1 and the Kabat definition of the first heavy chain framework.
  • host cell as used herein is intended to refer to a cell into which exogenous DNA has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell, but, to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell” as used herein.
  • host cells include prokaryotic and eukaryotic cells selected from any of the phyla of living creatures.
  • Eukaryotic cells include protist, fungal, plant and animal cells. Other embodiments include cells include but are not limited to the prokaryotic cell line E.Coli; mammalian cell lines CHO, HEK 293 and COS; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.
  • Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose.
  • the term "humanized antibody” is an antibody or a variant, derivative, analog or fragment thereof which immunospecifically binds to an antigen of interest, and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementary determining region (CDR) having substantially the amino acid sequence of a non-human antibody.
  • FR framework
  • CDR complementary determining region
  • the term “substantially” in the context of a CDR refers to a CDR having an amino acid sequence at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to the amino acid sequence of a non-human antibody CDR.
  • a humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab') 2, FabC, Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
  • a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • a humanized antibody contains both the light chain as well as at least the variable domain of a heavy chain.
  • the antibody also may include the CHI, hinge, CH2, CH3, and CH4 regions of the heavy chain.
  • a humanized antibody only contains a humanized light chain. In some embodiments, a humanized antibody only contains a humanized heavy chain. In specific embodiments, a humanized antibody only contains a humanized variable domain of a light chain and/or humanized heavy chain.
  • the humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including without limitation IgG 1, IgG2, IgG3 and IgG4.
  • the humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains may be selected to optimize desired effector functions using techniques well- known in the art.
  • the framework and CDR regions of a humanized antibody need not correspond precisely to the parental sequences, e.g., the donor antibody CDR or the consensus framework may be mutagenized by substitution, insertion and/or deletion of at least one amino acid residue so that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. In a preferred embodiment, such mutations, however, will not be extensive. Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences.
  • the term "consensus framework" refers to the framework region in the consensus immunoglobulin sequence.
  • the term "consensus immunoglobulin sequence” refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (See e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of
  • each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.
  • Vernier zone refers to a subset of framework residues that may adjust CDR structure and fine-tune the fit to antigen as described by Foote and Winter (1992, J. Mol. Biol. 224:487-499, which is incorporated herein by reference). Vernier zone residues form a layer underlying the CDRs and may impact on the structure of CDRs and the affinity of the antibody.
  • epitope includes any polypeptide determinant capable of specific binding to a an antibody or antigen-binding portion thereof.
  • epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics.
  • an epitope may be a linear or sequential epitope, i.e., a linear sequence of amino acids, of the primary structure of the antigen.
  • an epitope may be a conformational epitope having a specific three-dimensional shape when the antigen assumes its secondary structure.
  • the conformational epitope may comprise non-linear, i.e., non- sequential, amino acids of the antigen.
  • an epitope is a region of an antigen that is bound by an antibody or antigen-binding portion thereof.
  • an antibody or antigen-binding portion thereof is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macro molecules.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further in Section II C, below), antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom H.R., (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith W.E., (2002) Clin. Biochem. 35:425-445; Gavilondo J.V., and Larrick J.W. (2002) BioTechniques 29: 128-145; Hoogenboom H., and Chames P.
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • crystal refers to an antibody, or antigen-binding portion thereof, that exists in the form of a crystal.
  • Crystals are one form of the solid state of matter, which is distinct from other forms such as the amorphous solid state or the liquid crystalline state.
  • Crystals are composed of regular, repeating, three-dimensional arrays of atoms, ions, molecules (e.g. , proteins such as antibodies), or molecular assemblies (e.g. , antigen/antibody complexes). These three-dimensional arrays are arranged according to specific mathematical relationships that are well-understood in the field.
  • the fundamental unit, or building block, that is repeated in a crystal is called the asymmetric unit. Repetition of the asymmetric unit in an arrangement that conforms to a given, well-defined
  • crystallographic symmetry provides the "unit cell” of the crystal. Repetition of the unit cell by regular translations in all three dimensions provides the crystal. See Giege, R. and Ducruix, A. Barrett, Crystallization of Nucleic Acids and Proteins, a Practical Approach, 2nd ea., pp. 20 1- 16, Oxford University Press, New York, New York, (1999)."
  • polynucleotide refers to a polymeric form of two or more nucleotides, either ribonucleotides or deoxvnucleotides or a modified form of either type of nucleotide.
  • the term includes single and double stranded forms of DNA but preferably is double- stranded DNA.
  • isolated polynucleotide as used herein shall mean a polynucleotide
  • the "isolated polynucleotide” is not associated with all or a portion of a polynucleotide with which the "isolated polynucleotide” is found in nature; is operably linked to a polynucleotide that it is not linked to in nature; or does not occur in nature as part of a larger sequence.
  • vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid refers to a circular double stranded DNA loop into which additional DNA segments may be ligated.
  • viral vector Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome.
  • Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g. , bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • Other vectors e.g. , non-episomal mammalian vectors
  • vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”).
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and vector may be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g. , replication defective retroviruses, adenoviruses and adeno- associated viruses), which serve equivalent functions.
  • operably linked refers to a juxtaposition wherein the components described are in a relationship permitting them to function in their intended manner.
  • a control sequence "operably linked" to a coding sequence is ligated in such a way that expression of the coding sequence is achieved under conditions compatible with the control sequences.
  • "Operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest.
  • expression control sequence refers to polynucleotide sequences which are necessary to effect the expression and processing of coding sequences to which they are ligated.
  • Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e. , Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion.
  • the nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences include promoters and transcription termination sequence.
  • control sequences is intended to include components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
  • Protein constructs of the present disclosure may be expressed, and purified using expression vectors and host cells known in the art, including expression cassettes, vectors, recombinant host cells and methods for the recombinant expression and proteolytic processing of recombinant polyproteins and pre-proteins from a single open reading frame (e.g. , WO 2007/014162 incorporated herein by reference).
  • Transformation refers to any process by which exogenous DNA enters a host cell. Transformation may occur under natural or artificial conditions using various methods well known in the art. Transformation may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method is selected based on the host cell being transformed and may include, but is not limited to, viral infection, electroporation, lipofection, and particle bombardment. Such "transformed” cells include stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome. They also include cells which transiently express the inserted DNA or RNA for limited periods of time.
  • host cell is intended to refer to a cell into which exogenous DNA has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell, but, to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell” as used herein.
  • host cells include prokaryotic and eukaryotic cells selected from any of the Kingdoms of life. Preferred eukaryotic cells include protist, fungal, plant and animal cells.
  • host cells include but are not limited to the prokaryotic cell line E.Coli; mammalian cell lines CHO, HEK 293 and COS; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.
  • Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation ⁇ e.g., electroporation, lipofection).
  • Enzymatic reactions and purification techniques may be performed according to
  • inhibitor and its various grammatical forms is used to refer to a restraining, blocking, or limiting of the range or extent of a certain biological event or effect.
  • a multispecific antibody that, when administered to a patient for treating a subject infection, is sufficient to effect treatment of the disease ⁇ e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease or its related
  • the "effective amount” may vary depending on the agent, how it is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.
  • An effective amount includes an amount that results in a clinically relevant change or stabilization, as appropriate, of an indicator of a disease or condition.
  • Effective amount refers to an amount of a compound, material, or composition, as described herein effective to achieve a particular biological result such as, but not limited to, biological results disclosed, described, or exemplified herein.
  • Such results may include, but are not limited to, the effective reduction of symptoms associated with any of the disease states mentioned herein, as determined by any means suitable in the art.
  • the effective amount of the composition may be dependent on any number of variables, including without limitation, the species, breed, size, height, weight, age, overall health of the subject, the type of formulation, the mode or manner or administration, the type and/or severity of the particular condition being treated, or the need to modulate the activity of the molecular pathway induced by association of the analog to its receptor.
  • the appropriate effective amount can be routinely determined by those of skill in the art using routine optimization techniques and the skilled and informed judgment of the practitioner and other factors evident to those skilled in the art.
  • An effective dose of the antibodies or mutants or variants described herein may provide partial or complete biological activity as compared to the biological activity induced by the wild-type or naturally occurring polypeptides upon which the antibodies or mutants or variants are derived.
  • a therapeutically effective dose of the antibodies or mutants or variants described herein may provide a sustained biochemical or biological affect and/or an increased resistance to degradation when placed in solution as compared with the normal affect observed when the naturally occurring and fully processed translated protein is administered to the same subject.
  • an “immunoconjugate” is an antibody or multispecific antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • administer means to give or to apply.
  • administering includes in vivo administration.
  • linker refers to a chemical moiety that connects one peptide to another, e.g., one antibody to another. Linkers can also be used to attach antibodies to labels or solid substrates.
  • a linker can include amino acids. Linkers can be straight or branched, saturated or unsaturated carbon chains. They can also include one or more heteroatoms within the chain.
  • enriched or enrichment means an increased number or the process of identifying an portion of transcriptome with an increased number of nucleic acid sequences (e.g. RNA sequences). In some embodiments, the term is relative to the number of Ig-like sequences or CDR3 seqeunces (or sequneces honmolgous thereto) in a transcriptome of a sample.
  • the term is used to modify the number of Ig-like sequences or CDR3 seqeunces (or sequneces honmolgous thereto) in a transcriptome or the genomic deoxyribonucleic acid (DNA) of a sample and corresponds to the abundance of nucleic acid sequences in genomic DNA or a transciptome that encode Ig-like sequences or CDR3 seqeunces.
  • composition refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered.
  • a pharmaceutical composition of the present disclosure can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. To administer an antibody according to the disclosure by certain routes of administration, it may be necessary to coat the antibody with, or coadminister the antibody with, a material to prevent its inactivation. For example, the antibody may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a
  • Pharmaceutically acceptable carriers includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g. by injection or infusion).
  • compositions according to the disclosure may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It
  • the term "subject” is used throughout the specification to describe an animal to which one or more compositions comprising the antibody or antibodies disclosed herein.
  • the animal is a human.
  • the term "patient” may be
  • the term "patient” will refer to human patients suffering from a particular disease or disorder.
  • the subject may be a human suspected of having or being identified as at risk to develop cancer.
  • the subject is suspected of having or has been diagnosed with cancer.
  • the subject may be a human suspected of having or being identified as at risk to develop cancer or a hyperproliferative disorder.
  • the subject may be a mammal.
  • the subject may be a non-human animal.
  • mammal encompasses both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.is used herein to refer to an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g. , a monkey, and a
  • the subject is a human, such as a human being treated or assessed for a hyperproliferative disorder; or a human having an HIV infection that would benefit from a multispecific antibody as described herein.
  • the subject is a subject in need thereof, meaning that the subject is is need of the treatment being administered.
  • salt refers to acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Examples of these acids and bases are well known to those of ordinary skill in the art. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
  • salts of the compositions comprising either an antibody or antibody-like molecule may be formed by reacting the free base, or a salt, enantiomer or racemate thereof, with one or more equivalents of the appropriate acid.
  • pharmaceutical acceptable salts of the present disclosure refer to derivatives or amino acid sequences comprising at least one basic group or at least one basic radical.
  • pharmaceutical acceptable salts of the disclosed compositions comprise a free amino group, a free guanidino group, a pyrazinyl radical, or a pyridyl radical that forms acid addition salts.
  • the pharmaceutical acceptable salts of the present disclosure refer to modified amino acids that are acid addition salts of the subject compounds with (for example) inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4- aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, hetero aromatic carboxylic acids, such as nicotinic acid or
  • mono- or poly-acid addition salts may be formed.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying.
  • the reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
  • the salts may be those that are physiologically tolerated by a patient.
  • Salts according to the present disclsoure may be found in their anhydrous form or as in hydrated crystalline form (i.e., complexed or crystallized with one or more molecules of water).
  • the compositions or pharmaceutical compositions comprise crystalline forms or lyophilized forms of the antibodies, antibody-like molecules or salts thereof.
  • treat or “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms.
  • treat or “treating” as used herein further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
  • Humanization and primatization refer to in cases where the tri-specific fusion antibody or the three antibodies forming the tri-specific fusion antibody are non-human antibodies, the antibody can be "humanized” to reduce immunogenicity to a human recipient.
  • Methods for humanizing non-human antibodies have been described in the art. See, e.g., Jones et al., Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-327 (1988);
  • tri-specific fusion antibodies are formed from aany of the fragments or antibody sequences disclosed herein.
  • a bi-specific or tri-specific fusion antibody or the three antibodies forming the fusion can be "primatized” to reduce immunogenicity to another primate, non- human recipient, e.g., a rhesus recipient.
  • Residues from the variable domain of a donor antibody are "imported" into a nonhuman primate recipient immunoglobulin molecule, resulting in antibodies in which some hypervariable region residues and possibly some FR residues of a nonhuman primate antibody are substituted by residues from analogous sites of donor antibodies.
  • primatized antibodies can be made for use in a desirable primate species by using a recipient immunoglobulin having non-primate sequences or sequences from a different primate species by introducing the Fc fragment, and/or residues, including particularly framework region residues, from the desirable primate, into the recipient immunoglobulin.
  • affinity maturation is meant when one or more hypervariable region residues of an antibody can be substituted to select for variants that have improved biological properties relative to the parent antibody by employing, e.g., affinity maturation using phage or yeast display.
  • affinity maturation using phage or yeast display.
  • the Fab region of an anti-cancer antigen can be mutated at several sites selected based on available structural information to generate all possible amino substitutions at each site.
  • the antibody variants thus generated are displayed in a monovalent fashion from phage particles or on the surface of yeast cells. The displayed variants are then screened for their biological activity (e.g. binding affinity).
  • operably linked refers to the linkage of the two components such that expression of the gene is under the control of a promoter with which it is spatially connected.
  • a promoter may be positioned 5' (upstream) or 3' (downstream) of a gene under its control.
  • the distance between the promoter and a gene may be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance may be accommodated without loss of promoter function.
  • the term refers to the protein having the signal peptide incorporated as part of the protein in a manner that it can function as a signal peptide.
  • the term refers to the coding sequences arranged such that the translation of the coding sequence produces a protein having the signal peptide incorporated as part of the protein in a manner that it can function as a signal peptide.
  • conservative amino acid substitutions may be defined as set out in Tables A, B, or C below.
  • Anitbodies, antibody-like molecules and derivative, mutants, variants ans salts thereof include those amino acid sequence wherein conservative amino acid substitutions
  • compositions and pharmaceutical compositions of the disclosure comprise 1, 2, 3, 4, 5 or more conservative amino acid substitutions.
  • Amino acids can be classified according to physical properties and contribution to secondary and tertiary protein structure.
  • a conservative substitution is recognized in the art as a substitution of one amino acid for another amino acid that has similar properties. Exemplary conservative substitutions are set out in Table A.
  • conservative amino acids can be grouped as described in Lehninger,
  • amino acids disclosed described herein are intended to include polypeptides bearing one or more insertions, deletions, or substitutions, truncation or any combination of amino acid residues as well as modifications other than insertions, deletions, or substitutions of amino acid residues.
  • sample refers to a biological sample obtained or derived from a source of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheo alveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
  • a biological sample is or comprises bodily fluid.
  • a sample is a "primary sample" obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • body fluid e.g., blood, lymph, feces etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semipermeable membrane.
  • Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc. in some embodiments, the methods disclosed herein do not comprise a processed sample. In some embodiments, the methods disclosed herein comprise taking a sample from water or other environmental surface, processing the sample to include a known volume, and exposing the sample to the antibody, antibody fragments, system, or
  • compositions disclosed herein are compositions disclosed herein.
  • transcriptome means nucleic acid sequences that are transcribed by one or a plurality of cells in a sample.
  • the sample comprises one or a plurality of hyperproliferative cells.
  • whole blood means blood that is taken directly from the subject and unprocessed by filtration or additives prior to manipulation, in some
  • whole blood may comprise anti-coagulants. In some embodiments, whole blood is free of anti-coagulants.
  • sequence identity is determined by using the stand-alone executable BLAST engine program for blasting two sequences (bl2seq), which can be retrieved from the National Center for Biotechnology Information (NCBI) ftp site, using the default parameters (Tatusova and Madden, FEMS Microbiol Lett., 1999, 174, 247-250; which is incorporated herein by reference in its entirety).
  • sequence identity is synonymous with a measured “sequence identity.”
  • sequence identity refers to a disclosed nucleic acid sequence or amino acid sequence possessing a homology to a disclosed sequence over its entire length.
  • clonality score refers to the number solution obtained after solving for the IgH number described corresponding to those nucleci acid sequences from samples or those samples, whether they be cancer tissue, with more extensive clonal expansion of B lymphocytes. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.1 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.15 or higher.
  • the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.2 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.25 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.3 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.4 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.5 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.6 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.6 or higher.
  • the disclosure relates to a method of A method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome or genomic DNA sequence of a sample comprising: a. screening the transcriptome or genomic DNA sequence of the sample for enriched nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; b. calculating a clonality score of the sample; c.
  • the method further comprises a step of: (d) identifying a nucleic acid sequence encoding at least one
  • the method further comprises further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences from the sample.
  • the method further comprises further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences from the sample based upon one or a combination of: the clonality score, the presence or abundance of CDR3 or Ig-like nucleic acid sequence enrichment in the sample and alignment of the CDR sequence to the CDR3 or Ig-like nucleic acid sequence in the sample.
  • the method further comprises a step of:screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score of the seris of control samples;
  • identifying the most enriched CDR3 sequences from a sample or series of samples and. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject, wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c) corresponding to those subparts in the claims; and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h) corresponding to those steps in the claims disclosed herein.
  • CDR complementarity determining region
  • the control set of samples is from a publicly available database of transcriptomes.
  • the publicly available database comprises transcriptomes from known cancer tissue.
  • the publicly available database comprises transcriptomes from known cancer tissue that is capable of being sorted based upon cancer type.
  • the publicly available database comprises transcriptomes from known cancer tissue from one or a combination of cancer tissues identified herein.
  • the publicly available database comprises transcriptomes from known cancer tissue is the TGCA database.
  • the disclosure also relates to a computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample, the method comprising: in a system comprising at least one processor and a memory, a. screening, by the at least one processor, the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; b.
  • the method further comprises a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
  • CDR complementarity determining region
  • the sample is a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
  • a method of designing an antibody or antibody fragment capable of binding to an epiptope on a cell from a sample comprising: (a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25; and repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample; (b) cloning the one or plurality of nucleic acids in a vector or synthesizing the antibody from solid state chemical synthesis; and if the one or plurality of nucleic acid sequences are cloned into a vector, (c) transforming the vector into a host ceil and (d) allowing a time period to elapse sufficient for the host cell to recombinantly produce the encoded antibody or antibody fragment.
  • CDR complementarity determining region
  • the disclosure also relates to methods of treating a subject diagnosed or suspected of having a hyperproliferative disorder comprising administering any one or combination of the pharmaceutical compositions diclosed herein to the subject.
  • the pharmaceutical compositoipn comprises an effective amount of antibodies or antibody fargments disclosed herein or salts thereof.
  • the hyperproliferative disorder is a cancer chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
  • the disclosure relates to a computer-implemented method of detecting, cataloguing or compiling one or a plurality of nucleic acid sequences encoding one or a plurality of antibodies or antibody fragments from a transcriptome of a sample.
  • the method comprises a device that accesses the internet, the device capable to executing one or more steps of a method comprising: identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome of a subject comprising: screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
  • the disclosure relates to a system comprising a processor that performs a computer-implemented method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome of a subject comprising: screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
  • the disclosure relates to a system comprising a processor that performs a computer-implemented method of detecting exit behavior of a user of a user device that accesses the internet, the method comprising: screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score; and obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid
  • the disclosure relates to a system including at least one processor and a computer readable memory, said computer readable memory having stored thereon program code for detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment from a transcriptome of a sample, and a means for storing data associated with a user of a user device
  • the disclosure relates to a system that comprises at least one processor, a program storage, such as memory, for storing program code executable on the processor, and one or more input/output devices and/or interfaces, such as data communication and/or peripheral devices and/or interfaces.
  • the user device and computer system or systems are communicably connected by a data communication network, such as a Local Area Network (LAN), the Internet, or the like, which may also be connected to a number of other client and/or server computer systems.
  • a data communication network such as a Local Area Network (LAN), the Internet, or the like
  • the user device and client and/or server computer systems may further include appropriate operating system software.
  • the disclosure relates to a computer-implemented method of identifying sequences from a transcripotome or genomic DNA of a sample that are nucleic acid seqeunces that encode antibodies or antibody fragments that more effectively bind cancer tissue than antibodies or antibody fragments identified from clonal expansion of cells from the same tissue.
  • Exemplary embodiments include the following and refer to numbering of claim-like language through page 71 of the specification: [0174] 1.
  • a method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome or genomic DNA sequence of a sample comprising:
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • the method of claim 1 further comprising a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
  • CDR complementarity determining region
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c); [0186] and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
  • CDR complementarity determining region
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the sample determined, at least in part, by the following equation:
  • Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
  • adenocarcinoma adenocarcinoma
  • lung squamous carcinoma pancreatic adenocarcinoma
  • skin cutaneous carcinoma adenocarcinoma
  • a computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample comprising: in a system comprising at least one processor and a memory, [0196] a. screening, by the at least one processor, the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • the method of claim 13 further comprising a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
  • CDR complementarity determining region
  • nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
  • nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
  • h obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject;
  • steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c);
  • step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
  • CDR complementarity determining region
  • the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
  • step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the sample is determined, at least in part, by the following equation: t ⁇ f a logzjcc)
  • Ci is the clone fraction of rearrangement i and N is the total number of rearrangements; and wherein the sorting of the nucleic acids into the first set of nucleci acid sequences is performed if the score is 0.1 or higher.
  • adenocarcinoma adenocarcinoma
  • lung squamous carcinoma pancreatic adenocarcinoma
  • skin cutaneous carcinoma adenocarcinoma
  • a method of compiling a set of nucleic acid sequences encoding an antibody or antibody fragment from a sample comprising:
  • compositions comprising Antibodies
  • the disclosure relates to one or more pharmaceutical compositions comprising an effective amount of one or more antibodies disclosed herein, antibody fragments disclosed herein, or salts thereof; and one or more pharmaceutically acceptable carriers.
  • the disclosure features antibodies, or antigen-binding fragments thereof, that binds to a tumor tissue.
  • the antibodies, or antigen-binding fragments thereof, of the disclosure are cross-reactive among tissue samples from different cancer types, but do not bind normal tissue.
  • the antibodies, or antigen-binding fragments thereof, of the disclosure selectively bind to one type of tumor tissue.
  • Exemplary cancers include, but are not limited to, Acute Lymphocytic
  • ALL Acute Myeloid Leukemia
  • AML Adrenal Cancer
  • Anal Cancer Basal and Squamous Cell Skin Cancer
  • Bile Duct Cancer Bladder Cancer, Bone Cancer, Brain and Spinal Cord Tumors, Breast Cancer, Cervical Cancer, Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Colorectal Cancer, Endometrial Cancer, Esophagus Cancer, Ewing Family of Tumors, Eye Cancer, Gallbladder Cancer, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumor (GIST), Gestational Trophoblastic Disease, Hodgkin Lymphoma, Kaposi Sarcoma, Kidney Cancer, Laryngeal and Hypopharyngeal Cancer, Leukemia, Liver Cancer, Lung Cancer, Lung Carcinoid Tumor, Lymphoma, Lymphoma of the Skin, Malignant
  • Mesothelioma Melanoma Skin Cancer, Merkel Cell Skin Cancer, Multiple Myeloma, Myelodysplastic Syndromes, Nasal Cavity and Paranasal Sinuses Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cavity and Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Penile Cancer, Pituitary Tumors, Prostate Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Stomach Cancer, Testicular Cancer, Thymus Cancer, Thyroid Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, Wilms Tumor.
  • the disclosure relates to a method comprising validating antibody specificity using immunofluorescence methods known in the art by comparing its binding to cancer and normal tissues.
  • the disclosure relates to a composition of antibody that are broadly reactive to cancer tissues but rarely to normal tissues.
  • the disclosure relates to a composition of the cancer- specific antibodies with amino acid sequence identified in sequence ID 1-9.
  • the disclosure relates to a composition of antibodies that are narrowly specific for tissues from which the antibody sequence were composited based immunoseq data.
  • the disclosure relates to a composition
  • a composition comprising individual cancer- specific antibodies in claim 45 with amino acid sequence identified in sequence ID 10- 18.
  • Immunoseq-derived high abundance antibody sequences comprising CDR1, CDR2 and CDR3 as well as somatically mutated sequences.
  • Immunoseq derived sequences from cancer tissues in claim 48 comprising one of the sequences in sequence ID19.
  • the disclosure relates to use of antibodies constructed from sequences in claims 42-48 for cancer diagnosis, comprising staining of tissues by immunohistochemistry of immunofluorescence.
  • the antibodies are modified for optimal antibody-dependent cellular cytotoxicity or antibody-dependent cellular phagocytosis.
  • the antibody or fragment thereof or salt thereof is used as antibody-drug conjugates.
  • the antibodies are used an component of bi-specific antibodies. In some embodiments, the antibodies are used as key component of chimeric antigen -receptor T cells (CART).
  • CART chimeric antigen -receptor T cells
  • the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2206, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2208, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2210, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2216, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2218, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2220.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2226, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2228, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2230, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2236, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2238, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2240.
  • a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2226
  • a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2228
  • a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2246, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2248, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2250, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2256, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2258, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2260.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2266, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2268, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2270, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2276, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2278, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2280.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2286, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2288, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2290, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2296, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2298, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2300.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2306, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2308, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2310, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2316, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2318, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2320.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2326, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2328, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2330, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2336, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2338, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2340.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2346, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2348, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2350, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2356, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2358, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2360.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2366, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2368, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2370, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2376, a light chain
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2386, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2388, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2390, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2396, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2398, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2400.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2406, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2408, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2410, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2416, a light chain
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2426, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2428, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2430, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2436, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2438, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2440.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2446, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2448, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2450, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2456, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2458, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2460.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2466, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2468, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2470, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2476, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2478, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2480.
  • a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2466
  • a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2468
  • a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2490, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2496, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2498, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2500.
  • a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486
  • a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488
  • a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2506, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2508, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2510, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2516, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2518, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2520.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2526, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2528, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2530, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2536, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2538, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2540.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2546, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2548, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2550, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2556, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2558, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2560.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2566, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2568, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2570, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2576, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2578, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2580.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2586, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2588, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2590, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2596, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2598, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2600.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2606, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2608, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2610, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2616, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2618, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2620.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2626, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2628, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2630, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2636, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2638, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2640.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2646, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2648, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2650, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2656, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2658, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2660.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2666, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2668, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2670, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2676, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2678, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2680.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2686, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2688, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2690, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2696, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2698, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2700.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2706, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2708, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2710, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2716, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2718, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2720.
  • One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an antigen binding protein.
  • An antigen binding protein may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently.
  • the CDRs permit the antigen binding protein to specifically bind to a particular antigen of interest.
  • the present disclosure is directed to an antibody, or an antigen binding fragment thereof, having the antigen binding regions of any of the antibodies described in Table 17.
  • the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2204, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2204, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2214, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2214.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2224, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2224, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2234, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2234.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2244, or a sequence having at least 70%, 80%, 85%, 90%, 91%,
  • SEQ ID NO: 2244 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2244, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2254, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2254.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2264, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2264, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2274, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2274.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2284, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2284, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2294, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2294.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2304, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2304, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2314, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2314.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2324, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2324, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2344, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2344, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2354, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2354.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2364, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2364, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2374, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2374.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2384, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2384, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2394, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2394.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2404, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2404, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2414, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2414.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2424, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2424, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2444, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2444, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2454, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2454.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2464, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2464, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2474, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2474.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2484, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2484, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2494, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2494.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2504, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2504, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2514, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2514.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2524, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2524, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2534, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2534.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2544, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2544, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2554, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2554.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2564, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2564, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2574, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2574.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2584, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2584, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2594, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2594.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2604, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2604, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2614, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2614.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2624, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2624, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2634, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2634.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2644, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2644, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2654, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2654.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2664, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2664, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2674, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2674.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2684, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2684, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2694, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2694.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2704, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2704, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2714, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2714.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2202, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2202, and/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2212, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2212.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2222, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2222, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2232, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2232.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2242, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2242, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2252, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2252.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2262, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2262, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2272, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2272.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2282, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2282, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2292, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2292.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2302, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2302, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2312, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2312.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2322, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2322, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2332, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2332.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2342, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2342, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2352, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2352.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2362, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2362, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2372, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2372.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2382, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2382, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2392, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2392.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2402, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2402, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2412, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2412.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2422, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2422, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2432, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2432.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2442, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2442, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2452, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2452.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2462, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2462, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2472, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2472.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2482, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2482, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2492, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2492.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2502, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2502, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2512, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2512.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2522, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2522, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2532, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2532.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2542, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2542, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2552, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2552.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2562, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2562, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2572, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2572.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2582, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2582, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2592, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2592.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2602, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2602, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2612, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2612.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2622, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2622, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2632, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2632.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2642, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2642, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2652, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2652.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2662, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2662, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2672, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2672.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2682, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2682, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2692, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2692.
  • the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2702, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2702, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2712, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2712.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2202, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2212. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2222, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2232. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2242, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2252. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2262, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2272.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2282, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2292. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2302, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2312. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2322, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2332. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2342, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2352.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2362, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2372. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2382, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2392. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2402, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2412. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2422, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2432.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2442, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2452. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO:
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2472.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2482, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2492.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2502, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2512.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2522, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2532.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2542, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2552. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2562, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2572. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2582, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2592. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2602, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2612.
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2622, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2632. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2642, and the light chain comprises an amino acid sequence set forth in SEQ ID NO:
  • the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2662, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2672. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2682, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2692. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2702, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2712.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2202. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2212. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2222. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2232. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2242. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2252. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2262. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
  • composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2272. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2282. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2292. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2302. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2312. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2322. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2332.
  • composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2342. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2352. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2362. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
  • composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2372. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2382. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2392. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2402. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2412. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2422. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2432.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2442. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2452. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2462. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2482. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2492. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2502.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2512. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2522. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2532. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2542. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2552. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2562. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2572.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2582. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2592. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising 2602. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2612. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2622. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2632. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2642.
  • the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2652. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2662. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2672. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2682. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2692. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2702. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2712.
  • the antibody comprises a heavy chain constant region, such as an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region.
  • the antibody, or antigen-binding fragment is classified as an isotype selected from the group consisting of an IgG, an IgM, an IgD, an IgA, and an IgE.
  • Techniques are known for deriving an antibody of a different subclass or isotype from an antibody of interest, i.e., subclass switching.
  • IgG antibodies may be derived from an IgM antibody, for example, and vice versa.
  • Such techniques allow the preparation of new antibodies that possess the antigen-binding properties of a given antibody (the parent antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody.
  • Recombinant DNA techniques may be employed. Cloned DNA encoding particular antibody polypeptides may be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype (Lantto et al., 2002, Methods Mol. Biol. 178:303-16).
  • the antibody can comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region.
  • the antibody, or antigen-binding fragment is selected from the group consisting of a Fab, a Fab', a F(ab')2, an Fv, a domain antibody, and a single-chain antibody.
  • the disclosure features an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, that competes with the antibody, or antigen- binding fragment thereof, as described in Table 17.
  • the competing antibody, or antigen-binding portion thereof is an antibody, or antigen-binding portion thereof, that competes with any of the antibodies presented herein.
  • the invention provides a competing antibody which can compete with
  • variable domain regions characterized by the amino acid sequences of their variable domain regions.
  • the amino acid sequences can undergo some changes while retaining their high degree of binding to their specific targets. More specifically, many amino acids in the variable domain region can be changed with conservative substitutions and it is predictable that the binding characteristics of the resulting antibody will not differ from the binding characteristics of the wild type antibody sequence.
  • amino acids in an antibody variable domain that do not directly interact with the antigen or impact antigen binding and are not critical for determining antibody structure. For example, a predicted nonessential amino acid residue in any of the disclosed antibodies is preferably replaced with another amino acid residue from the same class.
  • a conservative modification or functional equivalent of a peptide, polypeptide, or protein disclosed in this disclosure refers to a polypeptide derivative of the peptide, polypeptide, or protein, e.g., a protein having one or more point mutations, insertions, deletions, truncations, a fusion protein, or a combination thereof. It retains substantially the activity to of the parent peptide, polypeptide, or protein (such as those disclosed in this disclosure).
  • a conservative modification or functional equivalent is at least 60% (e.g., any number between 60% and 100%, inclusive, e.g., 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) identical to a parent (e.g., one of SEQ ID NOs: 1-53).
  • the substitutions made within a heavy or light chain that is at least 95% identical are conservative amino acid substitutions.
  • a "conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity).
  • R group side chain
  • a conservative amino acid substitution will not substantially change the functional properties of a protein.
  • the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution.
  • the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
  • the percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4: 11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a
  • Blossum 62 matrix or a PAM250 matrix and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the protein sequences of the present disclosure can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences.
  • Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10.
  • Gapped BLAST can be utilized as described in Altschul et al, (1997) Nucleic Acids Res. 25(17):3389-3402.
  • the default parameters of the respective programs ⁇ e.g., XBLAST and NBLAST) can be used. (See www.ncbi.nlm.nih.gov).
  • the antibody can be linked to one of a variety of nonproteinaceous polymers, for example, polyethylene glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol.
  • the antibody also can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules), or in
  • Variant antibodies and salts thereof also are included within the scope of the disclosure.
  • Variants of the sequences recited in the application also are included within the scope of the disclosure.
  • Further variants of the antibody sequences having improved affinity can be obtained using methods known in the art and are included within the scope of the disclosure.
  • amino acid substitutions can be used to obtain antibodies with further improved affinity.
  • codon optimization of the nucleotide sequence can be used to improve the efficiency of translation in expression systems for the production of the antibody.
  • Variants may include non-natural amino acids up to a certain percentage.
  • the antibody comprises a variant amino acid sequence comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more percent of non-natural amino acids.
  • the antibody in cases where the antibody, or antigen binding fragment thereof, are non- human antibodies, the antibody can be "humanized" to reduce immunogenicity to a human recipient.
  • Methods for humanizing non-human antibodies have been described in the art. See, e.g., Jones et al., Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988), and U.S. Pat. No. 4,816,567.
  • residues from the variable domain of a non-human antibody are "imported" into a human immunoglobulin molecule, resulting in antibodies in which some hypervariable region residues and possibly some FR residues of a human antibody are substituted by residues from analogous sites of non-human antibodies. It is important to humanize a non-human antibody while retaining high affinity for the antigen. To this end, three dimensional immunoglobulin models are commonly available and suitable for use in analyzing proposed humanized sequences in comparison to the parental non-human antibodies. Such analysis permits identification of residues likely involved in recognition and binding of the antigen, and therefore rational design of humanized sequences that retain the specificity and affinity for the antigen.
  • humanized antibodies are antibody molecules from non- human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and framework regions from a human immunoglobulin molecule.
  • CDRs complementarity determining regions
  • Known human Ig sequences are disclosed, e.g., www.ncbi.nlm.nih.gov/entrez- /query. fcgi; www.atcc.org/phage/hdb.html;
  • baserv.uci.kun.nl/.about.jraats/linksl.html www.recab.uni-hd.de/immuno.bme.nwu.edu/; www.mrc-cpe.cam.ac.uk/imt-doc/pu- blic/ JJvTTRO.html; www.ibt.unam.mx/vir/V_mice.html; imgt.cnusc.fr:8104/; www.biochem.ucl.ac.uk/.about.martin/abs/index.html;
  • Framework residues in the human framework regions may be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding.
  • These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art.
  • Antibodies can be humanized using a variety of techniques known in the art, such as but not limited to those described in Jones et al., Nature 321:522 (1986); Verhoeyen et al., Science 239: 1534 (1988)), Sims et al., J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992); Presta et al., J. Immunol.
  • One or more hypervariable region residues of an antibody can be substituted to select for variants that have improved biological properties relative to the parent antibody by employing, e.g., affinity maturation using phage or yeast display.
  • the Fab region of an antibody of the disclosure can be mutated at several sites selected based on available structural information to generate all possible amino substitutions at each site.
  • the antibody variants thus generated are displayed in a monovalent fashion from phage particles or on the surface of yeast cells. The displayed variants are then screened for their biological activity (e.g. binding affinity). Modifications to the Fc Region
  • the antibody can be modified to improve certain biological properties of the antibody, e.g., to improve stability, to enhance or reduce effector functions such as antigen- dependent cell-mediated cyotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antibody, improved or decreased internalization and/or recycling, among others.
  • ADCC antigen- dependent cell-mediated cyotoxicity
  • CDC complement dependent cytotoxicity
  • the Fc fragment of some antibodies can be replaced with human IgGl that increases effector function mediated through FcRs (except FcRn). Such modification may improve the stability of the resulting antibody by about 5 fold.
  • the IgGl Fc fragment can be modified to improve the recycling of the antibody via the antibody salvage pathway.
  • Still another type of modification involves alteration of the glycosylation pattern of a parent antibody, including deletions of one or more carbohydrate moieties found in the parent antibody, or addition of one or more carbohydrates (via addition of one or more glycosylation sites) that are not present in the parent antibody.
  • the invention also provides pharmaceutical compositions comprising an antibody, or antigen-binding portion thereof, of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the invention may include a
  • therapeutically effective amount or a “prophylactically effective amount” of an antibody or antibody portion of the invention.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the antibody or antibody portion may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody, or antibody portion, are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • the antibodies and antibody-portions of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject.
  • the pharmaceutical composition comprises an antibody or antibody portion of the invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
  • Various delivery systems are known and can be used to administer one or more antibodies of the invention or the combination of one or more antibodies of the invention and a prophylactic agent or therapeutic agent useful for preventing, managing, treating, or ameliorating a disorder or one or more symptoms thereof, e.g. , encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibody or antibody fragment, receptor-mediated endocytosis (see, e.g. , Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc.
  • a prophylactic agent or therapeutic agent useful for preventing, managing, treating, or ameliorating a disorder or one or more symptoms thereof, e.g. , encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibody or antibody fragment, receptor-mediated endocytosis (
  • Methods of administering a prophylactic or therapeutic agent of the invention include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural administration, intratumoral administration, and mucosal administration (e.g., intranasal and oral routes).
  • parenteral administration e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous
  • epidural administration e.g., intratumoral administration
  • mucosal administration e.g., intranasal and oral routes.
  • pulmonary administration can be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. See, e.g., U.S. Pat. Nos.
  • an antibody of the invention, combination therapy, or a composition of the invention is administered using Alkermes AIR pulmonary drug delivery technology (Alkermes, Inc., Cambridge, Mass.).
  • prophylactic or therapeutic agents of the invention are administered intramuscularly, intravenously, intratumorally, orally, intranasally, pulmonary, or subcutaneously.
  • the prophylactic or therapeutic agents may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
  • compositions of the invention may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion, by injection, or by means of an implant, said implant being of a porous or non-porous material, including membranes and matrices, such as sialastic membranes, polymers, fibrous matrices (e.g., TISSUEL), or collagen matrices.
  • an effective amount of one or more antibodies of the invention antagonists is administered locally to the affected area to a subject to prevent, treat, manage, and/or ameliorate a disorder or a symptom thereof.
  • an effective amount of one or more antibodies of the invention is administered locally to the affected area in combination with an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents) other than an antibody of the invention of a subject to prevent, treat, manage, and/or ameliorate a disorder or one or more symptoms thereof.
  • therapies e.g., one or more prophylactic or therapeutic agents
  • the pharmaceutical compositoins of the invention can be delivered in a controlled release or sustained release system.
  • a pump may be used to achieve controlled or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989, N. Engl. J. Med. 321:574).
  • polymeric materials can be used to achieve controlled or sustained release of the therapies of the invention (see e.g., Medical
  • polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolides (PLG),
  • polyanhydrides poly(N- vinyl pyrrolidone), poly( vinyl alcohol), polyacrylamide,
  • the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable.
  • a controlled or sustained release system can be placed in proximity of the prophylactic or therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • the composition of the invention is a nucleic acid encoding a prophylactic or therapeutic agent
  • the nucleic acid can be administered in vivo to promote expression of its encoded prophylactic or therapeutic agent, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U. S. Pat. No.
  • a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression by homologous recombination.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (e.g., topical), transmucosal, and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
  • compositions of the invention are to be administered topically, the compositions can be formulated in the form of an ointment, cream, transdermal patch, lotion, gel, shampoo, spray, aerosol, solution, emulsion, or other form well-known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences and Introduction to Pharmaceutical Dosage Forms, 19th ed., Mack Pub. Co., Easton, Pa. (1995).
  • viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed.
  • Suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
  • auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts
  • Other suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g. , a gaseous propellant, such as freon) or in a squeeze bottle.
  • a pressurized volatile e.g. , a gaseous propellant, such as freon
  • humectants can also be added to
  • the method of the invention comprises intranasal administration of a composition
  • the composition can be formulated in an aerosol form, spray, mist or in the form of drops.
  • prophylactic or therapeutic agents for use according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g. ,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges (composed of, e.g. , gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions can be formulated orally in the form of tablets, capsules, cachets, gel caps, solutions, suspensions, and the like. Tablets or capsules can be prepared by conventional means with
  • binding agents e.g. , pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose
  • fillers e.g. , lactose, microcrystalline cellulose, or calcium hydrogen phosphate
  • lubricants e.g. , magnesium stearate, talc, or silica
  • disintegrants e.g. , potato starch or sodium starch glycolate
  • wetting agents e.g. , sodium lauryl sulphate.
  • the tablets may be coated by methods well- known in the art.
  • Liquid preparations for oral administration may take the form of, but not limited to, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. , sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g. , lecithin or acacia); non-aqueous vehicles (e.g. , almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g. , methyl or propyl- p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. , sorbitol syrup, cellulose derivatives, or hydrogenated edible fats
  • emulsifying agents e.g. , lecithin or acacia
  • non-aqueous vehicles e.g.
  • the preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated for slow release, controlled release, or sustained release of a prophylactic or therapeutic agent(s).
  • the method of the invention may comprise pulmonary administration, e.g. , by use of an inhaler or nebulizer, of a composition formulated with an aerosolizing agent. See, e.g. , U.S. Pat. Nos. 6,019, 968, 5,985, 320, 5, 985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos.
  • combination therapy, and/or composition of the invention is administered using Alkermes AIR pulmonary drug delivery technology (Alkermes, Inc., Cambridge, Mass.).
  • the method of the invention may comprise administration of a composition formulated for parenteral administration by injection (e.g. , by bolus injection or continuous infusion).
  • Formulations for injection may be presented in unit dosage form (e.g. , in ampoules or in multi-dose containers) with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle (e.g. , sterile pyrogen-free water) before use.
  • compositions formulated as depot preparations may additionally comprise of administration of compositions formulated as depot preparations.
  • long acting formulations may be administered by implantation (e.g. , subcutaneously or intramuscularly) or by intramuscular injection.
  • the compositions may be formulated with suitable polymeric or hydrophobic materials (e.g. , as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g. , as a sparingly soluble salt).
  • compositions formulated as neutral or salt forms include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2- ethylamino ethanol, histidine, procaine, etc.
  • compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • composition can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the invention also provides that one or more of the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity of the agent.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of the agent.
  • one or more of the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted (e.g. , with water or saline) to the appropriate concentration for administration to a subject.
  • one or more of the prophylactic or therapeutic agents or pharmaceutical compositions of the invention is supplied as a dry sterile lyophilized powder in a hermetically sealed container at a unit dosage of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg.
  • the lyophilized prophylactic or therapeutic agents or pharmaceutical compositions of the invention should be stored at between 2° C. and 8° C.
  • the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention should be administered within 1 week, preferably within 5 days, within 72 hours, within 48 hours, within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being reconstituted.
  • one or more of the prophylactic or therapeutic agents or pharmaceutical compositions of the invention is supplied in liquid form in a hermetically sealed container indicating the quantity and concentration of the agent.
  • the liquid form of the administered composition is supplied in a hermetically sealed container at least 0.25 mg/ml, more preferably at least 0.5 mg/ml, at least 1 mg/ml, at least 2.5 mg/ml, at least 5 mg/ml, at least 8 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml, at least 50 mg/ml, at least 75 mg/ml or at least 100 mg/ml.
  • the liquid form should be stored at between 2° C. and 8° C. in its original container.
  • the antibodies and antibody-portions of the invention can be incorporated into a pharmaceutical composition suitable for parenteral administration.
  • the antibody or antibody-portions will be prepared as an injectable solution containing 0.1-250 mg/ml antibody.
  • the injectable solution can be composed of either a liquid or lyophilized dosage form in a flint or amber vial, ampule or pre-filled syringe.
  • the buffer can be L-histidine (1- 50 mM), optimally 5- 10 mM, at pH 5.0 to 7.0 (optimally pH 6.0).
  • Other suitable buffers include but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate.
  • Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0-300 niM (optimally 150 mM for a liquid dosage form).
  • Cryoprotectants can be included for a lyophilized dosage form, principally 0-10% sucrose (optimally 0.5- 1.0%).
  • Other suitable cryoprotectants include trehalose and lactose.
  • Bulking agents can be included for a lyophilized dosage form, principally 1- 10% mannitol (optimally 2-4%).
  • Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1-50 mM L- Methionine (optimally 5- 10 mM).
  • Other suitable bulking agents include glycine, arginine, can be included as 0-0.05% polysorbate-80 (optimally 0.005-0.01%).
  • Additional surfactants include but are not limited to polysorbate 20 and BRIJ surfactants.
  • the pharmaceutical composition comprising the antibodies and antibody-portions of the invention prepared as an injectable solution for parenteral administration, can further comprise an agent useful as an adjuvant, such as those used to increase the absorption, or dispersion of a therapeutic protein (e.g. , antibody).
  • a particularly useful adjuvant is hyaluronidase, such as HYLENEX
  • compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g. , injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g. , injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
  • the preferred mode of administration is parenteral (e.g. , intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the active compound (i.e. , antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including, in the composition, an agent that delays absorption, for example, monostearate salts and gelatin.
  • the antibodies and antibody-portions of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is subcutaneous injection, intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a carrier such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • an antibody or antibody portion of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • To administer a compound of the invention by other than parenteral administration it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • an antibody or antibody portion of the invention may be conjugated to a polymer-based species such that said polymer-based species may confer a sufficient size upon said antibody or antibody portion of the invention such that said antibody or antibody portion of the invention benefits from the enhanced permeability and retention effect (EPR effect) (See also PCT Publication No. WO2006/042146A2 and U.S. Publication Nos. 2004/0028687A1, 2009/0285757A1, and 2011/0217363A1, and U.S. Patent No.
  • EPR effect enhanced permeability and retention effect
  • an antibody or fragment thereof is linked to a half-life extending vehicle known in the art.
  • vehicles include, but are not limited to, the Fc domain, polyethylene glycol, and dextran.
  • Such vehicles are described, e.g., in U.S.
  • nucleic acid sequences comprising nucleotide sequences encoding an antibody of the invention or another prophylactic or therapeutic agent of the invention are administered to treat, prevent, manage, or ameliorate a disorder or one or more symptoms thereof by way of gene therapy.
  • Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid.
  • the nucleic acids produce their encoded antibody or prophylactic or therapeutic agent of the invention that mediates a prophylactic or therapeutic effect.
  • Antibodies of the present invention may be produced by any of a number of techniques known in the art. For example, expression from host cells, wherein expression vector(s) encoding the heavy and light chains is (are) transfected into a host cell by standard techniques.
  • the various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
  • the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells is preferable, and most preferable in mammalian host cells, because such eukaryotic cells (and in particular mammalian cells) are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody.
  • nucleic acids of the invention are shown in Table 17.
  • Exemplary mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P.A. Sharp (1982) Mol. Biol. 159:601-621), NS0 myeloma cells, COS cells and SP2 cells.
  • Chinese Hamster Ovary CHO cells
  • dhfr- CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P.A. Sharp (1982) Mol. Biol. 159:601-621
  • the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Host cells can also be used to produce functional antibody fragments, such as Fab fragments or scFv molecules. It will be understood that variations on the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding functional fragments of either the light chain and/or the heavy chain of an antibody of this invention. Recombinant DNA technology may also be used to remove some, or all, of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to the antigens of interest. The molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention.
  • bifunctional antibodies may be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than the antigens of interest by crosslinking an antibody of the invention to a second antibody by standard chemical crosslinking methods.
  • a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr- CHO cells by calcium phosphate-mediated transfection.
  • the antibody heavy and light chain genes are each operatively linked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription of the genes.
  • the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
  • the selected transformant host cells are cultured to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium.
  • Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the antibody from the culture medium.
  • the invention provides a method of synthesizing a recombinant antibody of the invention by culturing a host cell of the invention in a suitable culture medium until a recombinant antibody of the invention is synthesized. The method can further comprise isolating the recombinant antibody from the culture medium.
  • Another embodiment of the invention provides a glycosylated antibody, or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof comprises one or more carbohydrate residues.
  • Nascent in vivo protein production may undergo further processing, known as post-translational modification.
  • sugar (glycosyl) residues may be added enzymatically, a process known as glycosylation.
  • glycosylation The resulting proteins bearing covalently linked oligosaccharide side chains are known as glycosylated proteins or glycoproteins.
  • Antibodies are glycoproteins with one or more carbohydrate residues in the Fc domain, as well as the variable domain.
  • Carbohydrate residues in the Fc domain have important effect on the effector function of the Fc domain, with minimal effect on antigen binding or half-life of the antibody (R. Jefferis, Biotechnol. Prog. 21 (2005), pp. 11-16).
  • glycosylation of the variable domain may have an effect on the antigen binding activity of the antibody.
  • Glycosylation in the variable domain may have a negative effect on antibody binding affinity, likely due to steric hindrance (Co, M.S., et al., Mol. Immunol. (1993) 30: 1361- 1367), or result in increased affinity for the antigen (Wallick, S.C., et al, Exp. Med.
  • One aspect of the present invention is directed to generating glycosylation site mutants in which the O- or N-linked glycosylation site of the antibody, or an antigen-binding portion thereof, has been mutated.
  • One skilled in the art can generate such mutants using standard well-known technologies.
  • Glycosylation site mutants that retain the biological activity, but have increased or decreased binding activity are another object of the present invention.
  • the glycosylation of the antibody or antigen- binding portion of the invention is modified.
  • an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation).
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen.
  • carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region glycosylation sites to thereby eliminate
  • a modified antibody of the invention can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNAc structures.
  • Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. See, for example, Shields, R. L. et al. (2002) J. Biol. Chem.
  • Protein glycosylation depends on the amino acid sequence of the protein of interest, as well as the host cell in which the protein is expressed. Different organisms may produce different glycosylation enzymes (e.g., glycosyltransferases and glycosidases), and have different substrates (nucleotide sugars) available. Due to such factors, protein glycosylation pattern, and composition of glycosyl residues, may differ depending on the host system in which the particular protein is expressed. Glycosyl residues useful in the invention may include, but are not limited to, glucose, galactose, mannose, fucose, n-acetylglucosamine and sialic acid. Preferably the glycosylated antibody, or an antigen-binding portion thereof, comprises glycosyl residues such that the glycosylation pattern is human.
  • a practitioner may prefer a therapeutic protein with a specific composition and pattern of glycosylation, for example glycosylation composition and pattern identical, or at least similar, to that produced in human cells or in the species-specific cells of the intended subject animal.
  • glycosylated proteins different from that of a host cell may be achieved by genetically modifying the host cell to express heterologous glycosylation enzymes. Using techniques known in the art a practitioner may generate antibodies or antigen-binding portions thereof exhibiting human protein glycosylation. For example, yeast strains have been genetically modified to express non-naturally occurring glycosylation enzymes such that glycosylated proteins (glycoproteins) produced in these yeast strains exhibit protein glycosylation identical to that of animal cells, especially human cells (U.S. patent Publication Nos. 20040018590 and 20020137134 and PCT publication
  • an anti-idiotypic (anti-Id) antibody specific for such antibodies, or antigen binding portions thereof, of the invention.
  • An anti-Id antibody is an antibody, which recognizes unique determinants generally associated with the antigen-binding region of another antibody.
  • the anti-Id can be prepared by immunizing an animal with the antibody, or antigen binding portion thereof, or a CDR containing region thereof. The immunized animal will recognize, and respond to the idiotypic determinants of the immunizing antibody and produce an anti-Id antibody.
  • the anti-Id antibody may also be used as an "immunogen" to induce an immune response in yet another animal, producing a so-called anti-anti-Id antibody.
  • a protein of interest may be expressed using a library of host cells genetically engineered to express various glycosylation enzymes, such that member host cells of the library produce the protein of interest with variant glycosylation patterns.
  • a practitioner may then select and isolate the protein of interest with particular novel glycosylation patterns.
  • the protein having a particularly selected novel glycosylation pattern exhibits improved or altered biological properties.
  • Example 1 Computational framework for estimating and filtering the immunoglobulin sequences based on RNAseq data from TCGA database.
  • the present disclosure describes a computational framework that was developed and successfully tested for antibody discovery, by mining 1945 solid tumor RNA- sequencing-based samples for abundant Ig CDR3 sequences among TCGA database of glioblastoma multiforme (GBM), lower grade glioma (LGG), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), pancreatic adenocarcinoma (PAAD) and skin cutaneous melanoma (SKCM).
  • GBM glioblastoma multiforme
  • LGG lower grade glioma
  • LUAD lung adenocarcinoma
  • LUSC lung squamous carcinoma
  • PAAD pancreatic adenocarcinoma
  • SKCM skin cutaneous melanoma
  • BCR B cell receptor
  • Vh selected predominant variable heavy
  • Vk variable light
  • the analyses described herein have the potential to identify both broadly cross-reactive and highly selective anti-cancer human monoclonal antibodies for cancer diagnosis and treatment.
  • the platform described herein considerably reduces existing barriers in developing human anti-cancer antibodies, and paves the way for cancer treatment using patient-derived tumor-reactive monoclonal antibodies.
  • clonotypes were assembled by the initial assembler and mapper, clustering was then performed and the clonotypes with low abundance were attached to highly similar clonotypes with significantly greater abundance.
  • Figure IB a large number of clonotypes were identified among all six cancer types, although LUSC and LUAD transcriptomes were more enriched for BCR clonotypes. Therefore, the number of aligned Ig heavy chain reads per million RNAseq sequencing reads (IGHPM) and the number of assembled Ig heavy chain clonotypes per million RNAseq sequencing reads (CTPM) were used as the measures of Ig abundance among each samples.
  • IGHPM aligned Ig heavy chain reads per million RNAseq sequencing reads
  • CPM assembled Ig heavy chain clonotypes per million RNAseq sequencing reads
  • the final step was to align clonal sequences to reference V, D, J and C genes to rebuild alignments for clonal sequences and annotated them with information such as amino acid sequence and associated variable (V) and joining (J) genes.
  • V amino acid sequence and associated variable
  • J joining
  • Tables 1-6 show the top 100 heavy and top 100 light chains that were picked from the top three patients from the TCGA database.
  • Tables 7-16 show the top 50 heavy and top 50 light chains that were picked from each tumor sample from the Adaptive Biotechnologies Database.
  • Example 2 Antibody pool of 13 recombinant antibodies generated by random pairing of 3 heavy chains and 6 light chains binds to LUSC and LUAD tissues.
  • H2L7 was characterized for its binding to both normal and different types of cancer tissues. When frozen tissue micro array of normal tissues was performed, H2L7 showed no reactivity to majority of normal tissues tested (Figure 3A). Although some binding to either intracellular components or extracellular matrix were observed in pancreas, spleen, parotid gland, and testis, definitive cell surface staining to any normal tissues was not found.
  • H2L7 was broadly reactive to 9/11 types of cancer tissues tested, including colon adenocarcinoma, esophagus adenocarcinoma, stomach adenocarcinoma, ovary adenocarcinoma, soft tissue giant cell tumor, liver hepatocellular carcinoma, testis seminoma, lung adenocarcinoma, and lung squamous carcinoma (Figure 3B).
  • H2L7 was tested against LUSC TMA containing paired malignant and normal adjacent tissue. Staining results demonstrate the H2L7 binds strongly to 100% of LUSC but only 25% of adjacent benign tissue (Figure 3C & Figure 3D).
  • Example 4 Recombinant antibodies derived from targeted genomic sequence of LUAD (sample 463) and LUSC (sample 427) showed limited cross-reactivities.
  • the VDJ gene usage information presented by BCR sequencing results were validated by the IMGT alignment result. Then, the rearrangement sequences were extended to full-length immunoglobulin sequences by using the germ-line sequence of verified V and J gene.
  • the heavy chains and light chains from the same samples were homogenously paired and expressed in 293T cells through transient transfection. As shown in Figure 4B, all eight combinations resulted in significant levels of antibody production.
  • Antibodies H5L12 and H6L13 were picked and tested against 2 LUSC and 3 LUAD samples, including the sample from which the antibody sequence was assembled. As shown in Figure 4C, H6L13 showed strong and specific binding to the cancer tissue from which it was obtained.
  • H5L12 showed binding to not only the LUAD tissue sample it was obtained from, but it also showed cross-reactivity to the other case of LUAD tested, but not to any of the 3 LUSC samples tested.
  • H5L12 and H6L13 were also tested against multiple normal and malignant tissues used in Figure 3, no cross -reactivity to other cancerous or normal tissues was observed. Therefore, these antibodies represent those that primarily or exclusively reactive to the cancer tissue from which they were isolated.
  • antibodies that are either broadly cross- reactive or highly specific for cancer samples suggests that the platform described herein can allow identification of fully human antibodies for treatment and/or diagnosis of human cancer.
  • these antibodies can be further modified by mutagenesis to further eliminate their cross-reactivity to normal tissues.
  • the antibodies can be further modified to enhance effector functions through Fc optimization (7) , antibody-drug conjugations (8) ,bi-specific antibody (9) and chimeric antigen receptors (10).
  • Examples 1-4 make use of, but are not limited to, the following methods.
  • NCI Genomic Data Commons portal https://portal.gdc.cancer.gov/.
  • First all files were extracted to the fastq files using samtools (11) fastq function with -O settings.
  • the reads were aligned to reference V, D, J and C genes of human B- cell receptors by using MIXCR (12) align function.
  • IgH clonality was defined as 1- Pielou's evenness and was calculated on productive rearrangements by:
  • Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
  • Tthe calculation of IgH clonality was implemented in R software (https://www.r-project.org/) by using the vegan package (14)
  • DNA of these samples was sent for BCR repertoire sequencing by using the IMMUNOSEQ Assay (Adaptive Biotechnologies).
  • the BCR sequencing was performed at survey level and the raw TCR reads were preprocessed with the immunoSEQ Analyzer.
  • HEK293T cells were grown in DMEM (Life Technologies Inc.).
  • Frozen lung tumor samples were purchased from ProteoGenex (Inglewood,
  • Frozen tissues were embedded into the cryomold (Tissue-Tek, 4728) with O.C.T compound (Tissue-Tek, 4583) and sectioned into 5um sections.
  • Frozen multiple tissue microarray (FMC402a), and lung tissue microarray (FLC320) were purchased from US Biomax, Inc (Rockville, MD). Frozen tissue sections and TMAs were thawed at room temperature for 10-20 minutes and washed three times in PBS. The slides were fixed in 4% formaldehyde for 10 minutes at RT. Slides were then washed in PBS three times for five minutes and incubated in blocking solution (5% normal goat serum in PBS) for one hour.
  • Adenocarcinomas an Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence. Cancer Discov. 10, 1088- 1097 (2017).
  • CARGLSSFGGIMNWYDPW CDR3 AACTGGTACGACCCCTGG
  • CAKPGLSGYYYYMDVW CDR3 ATGGACGTCTGG heavy chain TGTGCGAGAGCCCCTACAACTATATCGAACCCGAAA 658

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Abstract

The present disclosure relates to a method of identifying and producing antibody-based cancer therapies. In some embodiments, methods of identifying nucleic acid sequences that encode antibodies or antibody fragments from a transcriptome or genomic DNA sequences of a sample. Another embodiment of the disclosure is a computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample. The present disclosure further provides a composition comprising an antibody or antibody fragment, wherein the antibody or antibody fragment is reactive to cancer tissues. The disclosure also relates to methods of treating a subject diagnosed or suspected of having a hyperproliferative disorder comprising administering any one or combination of the pharmaceutical compositions disclosed herein to the subject.

Description

METHODS OF ANTIBODY DISCOVERY USING TRANSCRIPTOMES AND COMPOSITIONS DERIVED THEREFROM
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional Patent Application
No. 62/575,369, filed October 20, 2017, the contents of which are hereby incorporated by reference in its entirety.
BACKGROUND
[0002] Generation of specific antibodies for cancer therapy is a major endeavor, involving lengthy process of antigen identification, immunization, hybridoma production and in most cases, antibody humanization. There remains a need in the art for methods of identification and generation of antibodies for cancer therapy. SUMMARY OF THE INVENTION
[0003] The present disclosure relates to The present disclosure relates to a method of identifying and producing antibody-based cancer therapies. In some embodiments, methods of identifying nucleic acid sequences that encode antibodies or antibody fragments from a transcriptome or genomic DNA sequences of a sample comprise steps of:
[0004] a. screening the transcriptome or genomic DNA sequence of the sample for enriched nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0005] b. calculating a clonality score of the sample;
[0006] c. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon sequence alignment.
[0007] Optionally, after the sorting step, such methods can further comprise a step of:
(d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences. It should be appreciated that the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences can be repeated one or more times. [0008] In further aspects of the methods disclosed herein, exemplary methods can comprise steps of:
[0009] e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0010] f. calculating a clonality score of the sample;
[0011] g. identifying the most enriched CDR3 sequences from a sample or series of samples; and
[0012] h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject.
[0013] Steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c). Preferably, the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a
transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
[0014] The first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments. Suitable antibody fragments include: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and/or a constant region of the antibody. In further aspects of the first set of abundantly expressed nucleic acid sequences from the subject, such nucleic acid sequences encode variable heavy chain and/or variable light chain portions of the antibody.
[0015] In other embodiments, the screening step comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation:
Figure imgf000004_0001
wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements. Exemplary screening methods include performing FASTQ, MIXCR, and/or VDJtools functions on the transcriptome data.
[0016] It may be advantageous to align amino acid sequences before screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences. One, non- limiting example of a function that aligns clonal sequences comprises performing an immunoSEQ function.
[0017] Samples for use in the disclosed methods are tissue sample from a subject having a hyperproliferative cell disorder. Contemplated samples include, but are not limited to, cancer tissues from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and/or skin cutaneous carcinoma.
[0018] Another embodiment of the disclosure is a computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample, the method comprising: in a system comprising at least one processor and a memory,
[0019] a. screening, by the at least one processor, the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0020] b. calculating, by the at least one processor, a clonality score;
[0021] c. sorting, by the at least one processor, the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
[0022] The at least one processor can be further configured to (d) identify a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting. The processor can repeat the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences one or more times.
[0023] The methods disclosed herein can further comprise steps of:
[0024] e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0025] f. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences;
[0026] g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score; and
[0027] h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject.
[0028] Steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c). The step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
[0029] In other embodiments, the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
[0030] In other embodiments, the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
[0031] In other embodiments, the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the sample is determined, at least in part, by the following equation: i ¾∑f Ci logZjCi)
log2( )
wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements; and wherein the sorting of the nucleic acids into the first set of nucleci acid sequences is performed if the score is 0.1 or higher. [0032] In other embodiments, the screening the transcriptome of a series of samples for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data. Screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences. Alignment of clonal sequences comprises performing an immunoSEQ function.
[0033] Contemplated samples include tissue samples from subjects having
hyperproliferative cell disorders, such as: a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
[0034] In another embodiment, the first set of nucleic acids that encode an antibody or antibody fragment encode an antibody capable of binding one or a plurality of cells from the sample and/or subject.
[0035] The disclosure further describes a method of compiling a set of nucleic acid sequences encoding an antibody or antibody fragment from a sample, the method comprising:
[0036] (a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25; and
[0037] (b) repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample.
[0038] In other embodiments, a method of designing an antibody or antibody fragment capable of binding to an epiptope on a cell from a sample comprises:
[0039] (a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25;
[0040] (b) repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample;
[0041] (c) cloning the one or plurality of nucleic acids in a vector or synthesizing the antibody from solid state chemical synthesis; and
[0042] if the one or plurality of nucleic acid sequences are cloned into a vector, (d) transforming the vector into a host cell and (e) allowing a time period to elapse sufficient for the host cell to recombinantly produce the encoded antibody or antibody fragment. [0043] In other embodiments, a composition comprising an antibody or antibody fragment comprises at least one CDR sequence obtained from performing any of the methods described above.
[0044] In other embodiments, a library of antibodies comprising at least one amino acid sequence obtaining from performing any of the methods described above.
[0045] In other embodiments, a non-transitory computer program product encoded on computer-readbale storage medium comprising instructions for:
[0046] a. screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0047] b. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
[0048] c. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
[0049] Optionally, the non- transitory computer program product of claim 30 further comprises instructions for a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting. Preferably, an instruction is included for repeating the step of identifying a nucleic acid sequence encoding at least one
CDR of a variable chain and compiling a plurality of CDR sequences.
[0050] The inventors contemplate yet further instructions for:
[0051] e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0052] f. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences;
[0053] g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score; and [0054] h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject
[0055] Steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c). The step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
[0056] The first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
[0057] The first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
[0058] The step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation:
,∑f Ci logKCi)
A ~*"
log2(N)
wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
[0059] The screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
[0060] The screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences. The alignment of clonal sequences comprises performing an immunoSEQ function. [0061] The sample is a tissue sample from a subject having a hyperproliferative cell disorder, such as cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
[0062] In other embodiments, the method of validating antibody specificity uses immunofluorescence methods known in the art by comparing its binding to cancer and normal tissues.
[0063] In other embodiments, compositions of antibodies are broadly reactive to cancer tissues but rarely to normal tissues. In preferred embodiments, compositions of the cancer-specific antibodies have amino acid sequence identified in sequence ID 1-9.
[0064] In other embodiments, compositions of antibodies are narrowly specific for tissues from which the antibody sequence were composited based immunoseq data.
[0065] In other embodiments, compositions of individual cancer- specific antibodies in claim 45 with amino acid sequence identified in sequence ID 10- 18.
[0066] In other emodiments, immunoseq-derived high abundance antibody sequences comprise CDR1, CDR2 and CDR3 as well as somatically mutated sequences. For example, immunoseq-derived high abundance antibody sequences comprise one of the sequences in sequence ID 19.
[0067] In other embodiments, use of antibodies constructed from sequences in claims 42-48 for cancer diagnosis, comprising staining of tissues by immunohistochemistry of immunofluorescence. Such uses are contemplated for cancer therapy. The disclosed uses include: antibodies modified for optimal antibody-dependent cellular cytotoxicity or antibody-dependent cellular phagocytosis and/or antibody-drug conjugates. The antibodies are used an component of bi-specific antibodies. The antibodies are used as key component of chimeric antigen-receptor T cells (CART). Other aspects of the disclosure are described in the detailed description.
[0068] In a specific embodiment, the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2206, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2208, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2210, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2216, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2218, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2220. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2226, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2228, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2230, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2236, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2238, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2240. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2246, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2248, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2250, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2256, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2258, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2260. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2266, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2268, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2270, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2276, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2278, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2280. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2286, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2288, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2290, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2296, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2298, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2300. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2306, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2308, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2310, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2316, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2318, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2320. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2326, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2328, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2330, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2336, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2338, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2340. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2346, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2348, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2350, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2356, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2358, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2360. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2366, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2368, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2370, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2376, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2378, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2380. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2386, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2388, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2390, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2396, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2398, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2400. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2406, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2408, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2410, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2416, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2418, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2420. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2426, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2428, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2430, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2436, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2438, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2440. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2446, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2448, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2450, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2456, a light chain
CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2458, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2460. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2466, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2468, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2470, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2476, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2478, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2480. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2490, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2496, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2498, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2500. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2506, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2508, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2510, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2516, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2518, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2520. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2526, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2528, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2530, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2536, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2538, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2540. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2546, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2548, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2550, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2556, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2558, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2560. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2566, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2568, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2570, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2576, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2578, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2580. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2586, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2588, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2590, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2596, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2598, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2600. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2606, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2608, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2610, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2616, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2618, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2620. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2626, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2628, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2630, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2636, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2638, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2640. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2646, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2648, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2650, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2656, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2658, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2660. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2666, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2668, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2670, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2676, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2678, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2680. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2686, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2688, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2690, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2696, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2698, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2700. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2706, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2708, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2710, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2716, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2718, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2720.
[0069] In a specific embodiment, the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2204, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2204, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2214, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2214. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2224, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2224, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2234, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2234. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2244, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2244, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2254, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2254. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2264, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2264, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2274, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2274. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2284, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2284, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2294, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2294. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2304, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2304, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2314, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2314. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2324, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2324, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
2334, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2334. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2344, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2344, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2354, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2354. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2364, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2364, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2374, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2374. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2384, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2384, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2394, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2394. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2404, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2404, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2414, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2414. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2424, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2424, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
2434, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2434. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2444, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2444, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2454, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2454. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2464, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2464, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2474, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2474. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2484, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2484, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2494, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2494. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2504, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2504, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2514, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2514. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2524, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2524, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2534, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2534. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2544, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2544, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2554, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2554. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2564, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2564, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2574, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2574. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2584, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2584, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2594, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2594. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2604, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2604, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2614, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2614. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2624, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2624, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2634, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2634. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2644, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2644, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2654, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2654. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2664, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2664, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2674, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2674. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2684, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2684, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2694, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2694. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2704, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2704, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2714, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2714.
[0070] In a further specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2202, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2202, and/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2212, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2212. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2222, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2222, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2232, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2232. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2242, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2242, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2252, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2252. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2262, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2262, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2272, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2272. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2282, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2282, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2292, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2292. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2302, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2302, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2312, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2312. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2322, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2322, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2332, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2332. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2342, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2342, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2352, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2352. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2362, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2362, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2372, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2372. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2382, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2382, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2392, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2392. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2402, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2402, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2412, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2412. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2422, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2422, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2432, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2432. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2442, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2442, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2452, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2452. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2462, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2462, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2472, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2472. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2482, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2482, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2492, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2492. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2502, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2502, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2512, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2512. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2522, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2522, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2532, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2532. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2542, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2542, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2552, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2552. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2562, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2562, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2572, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2572. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2582, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2582, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2592, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2592. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2602, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2602, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2612, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2612. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2622, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2622, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2632, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2632. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2642, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2642, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2652, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2652. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2662, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2662, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2672, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2672. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2682, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2682, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2692, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2692. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2702, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2702, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2712, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2712.
[0071] In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2202, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2212. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2222, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2232. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2242, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2252. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2262, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2272. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2282, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2292. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2302, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2312. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2322, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2332. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2342, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2352. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2362, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2372. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2382, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2392. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2402, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2412. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2422, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2432. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2442, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2452. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO:
2462, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2472. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2482, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2492. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2502, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2512. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2522, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2532. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2542, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2552. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2562, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2572. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2582, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2592. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2602, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2612. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2622, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2632. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2642, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2652. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2662, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2672. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2682, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2692. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2702, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2712.
[0072] In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2202. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2212. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2222. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2232. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2242. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2252. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2262. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
SEQ ID NO: 2272. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2282. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2292. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2302. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2312. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2322. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2332. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2342. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2352. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2362. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2372. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2382. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2392. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2402. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2412. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2422. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
SEQ ID NO: 2432. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2442. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2452. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2462. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2482. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2492. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2502. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2512. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2522. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2532. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2542. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2552. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2562. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2572. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2582. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2592. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising 2602. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2612. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2622. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2632. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2642. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2652. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2662. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2672. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2682. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2692. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2702. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2712.
[0073] In one embodiment, the antibody or antigen-binding fragment thereof is selected from the group consisting of a Fab, a Fab', a F(ab')2, an Fv, a domain antibody, and a single-chain antibody. In another embodiment, the antibody, or antigen binding portion fragment thereof, is classified as an isotype selected from the group consisting of an IgG, an IgM, an IgD, an IgA, and an IgE.
[0074] In another aspect, the disclosure features an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, that competes with the antibody, or antigen binding portion thereof, of any one of the preceding aspects or embodiments.
[0075] In one embodiment, the antibody, or antigen binding portion thereof, is humanized.
[0076] In one embodiment, the tantibody, or antigen binding fragment thereof, of any one of the aspects or embodiments herein, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition is lyophilized.
[0077] In one embodiment, the disclosure features an isolated nucleic acid encoding an antibody, or antigen-binding fragment thereof, of any one of the aspects and embodiments herein. In one embodiment, a vector comprises the nucleic acid. In another embodiment, a host cell comprises the vector. In another embodiment, the host cell is a prokaryotic cell or a eukaryotic cell. In a further embodiment, the eukaryotic cell is a protist cell, an animal cell, a plant cell, a fungal cell, a yeast cell, a mammalian cell, an avian cell, or an insect cell. In another further embodiment ,the mammalian cell is a CHO cell or a COS cell. BRIEF DESCRIPTION OF THE DRAWINGS
[0078] Figure 1 (A-G) shows a computational framework for estimating and filtering the immunoglobulin sequences based on RNAseq data from TCGA database. Figure 1A is a schematic diagram of rearranged sequences detection and selection from TCGA cohorts and lung cancer frozen tissues for curated extend and experimental validation. Figure IB is a graph that shows the abundance of immunoglobulin aligned reads count (left) and clonotypes count (right) among different tumor samples. Figure 1C is a graph that shows the CDR3 sequences clonality among different tumor types. Figure ID is a graph that shows the distribution of the ratio of aligned immunoglobulin transcripts to total RNAseq reads across all samples from TCGA LUAD cohorts. The sample (TCGA-L9-A444-01A) has the highest abundance of Immunoglobulin transcripts is marked in red and chosen for further study.
Figure IE is a graph that shows the distribution of clone fraction value of all immunoglobulin arrangement clonotypes from the most abundant sample (TCGA-L9-A444-01A). The red dots indicated with arrows depict the clonotypes chosen for proof-of-concept studies based on high abundance and high alignment scores. Figure IF is a table that shows selected sequences with annotated information and gene usage for further extend analysis and experimental validation. Figure 1G is a graph that shows expression of recombinant antibodies based on random pairing from 3 heavy and 6 light chains were expressed with transient transfection.
[0079] Figure 2 (A&B) shows results of immunofluorescence experiments that demonstrate recombinant antibodies reconstructed from CDR3 sequences from an LUAD patient cross-react with unrelated LUSC and LUAD tissues. Figure 2A shows reactivity of CDR3-based antibodies to unrelated LUSC and LUAD tissues. LUSC (sample 427) was recognized by H1L7, H2L5, H2L6, H2L7, H2L8 and H2L9 whereas LUAD (Sample 429) was recognized by H1L5, H1L7, H1L9, H2L5, H2L6, H2L7, H2L8, H2L9, and H3L9. Figure 2B shows H2L5 and H2L7 binds to 2/2 LUAD tissues and 3/3 LUSC tissues. Isotype control of mouse IgG2a k was included.
[0080] Figure 3 (A-D) shows results of immunofluorescence experiments that demonstrate H2L7 binds a broad range of malignant tissues but shows limited binding to normal tissues. Figure 3A shows that H2L7 has limited binding to normal tissues. H2L7 does not react to most normal tissues although some non-cell surface binding was observed against normal parotid gland, normal pancreas tissue, normal testis tissue, normal lymph node tissue, and normal spleen tissue. Figure 3B shows that H2L7 shows broad cross-reactivity against multiple malignant tissues, including colon adenocarcinoma, esophagus adenocarcinoma, stomach adenocarcinoma, ovary adenocarcinoma, Soft tissue giant cell tumor, liver hepatocellular carcinoma, breast invasive ductal carcinoma, skin squamous cell carcinoma, testis seminoma, LUAD and LUSC. Figure 3C shows selective images depicting H2L7 binds to lung squamous cell carcinoma but not its normal adjacent tissue (NAT). Figure 3D is a graph that shows H2L7 binds to 16/16 lung squamous cell carcinoma and 4/16 of NATs. P values in D were calculated by a fisher exact test.
[0081] Figure 4 (A-C) shows recombinant antibodies derived from targeted genomic sequence of LUAD (sample 463) and LUSC (sample 427) showed limited cross-reactivities. Figure 4A is a table that shows selected sequences with annotated information and gene usage for further extend analysis and experimental validation. Figure 4B is a graph that shows recombinant antibodies from heavy and light chains derived from LUAD and LUSC samples were expressed with transient transfection. Figure 4C show results from
immunofluorescence studies, where H5L12 derived from LUAD sample 463 recognizes 2/2 LUAD tissues whereas H6L13, which was derived from LUSC sample 427, shows very specific binding to LUSC tissue of which it was derived from.
[0082] Figure 5 shows antibody pool of 13 recombinant antibodies generated by random pairing of 3 heavy chains and 6 light chains binds to LUSC and LUAD tissues.
Isotype control of mouse IgG2a k was included as a control.
DETAILED DESCRIPTION OF THE INVENTION
[0083] Generation of specific antibodies for cancer therapy is a major endeavor, involving lengthy process of antigen identification, immunization, hybridoma production and in most cases, antibody humanization. Departing from the conventional approach, the present disclosure describes rapid and en masse identification of cancer- specific antibodies directly from human cancer tissues by de novo assembly from transcriptome and genome sequences. The platform described herein considerably reduces a barrier that exists in developing human anti-cancer antibodies, and paves the way for cancer treatment using patient-derived tumor- reactive monoclonal antibodies. [0084] Further areas of applicability of the present disclosure will become apparent from the detailed description provided herein. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the disclosure, are intended for purposes of illustration only and are not intended to limit the scope of the disclosure.
I. Definitions
[0085] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. Also, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.
[0086] Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well known and commonly used in the art. The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well- known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. [0087] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
[0088] That the present disclosure may be more readily understood, select terms are defined below.
[0089] The articles "a" and "an" are used herein to refer to one or to more than one
(i.e. , to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element, e.g. , a plurality of elements.
[0090] The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to" or "including, without limitation."
[0091] The term "or" is used herein to mean, and is used interchangeably with, the term "and/or," unless context clearly indicates otherwise. For example, an amino acid sequence with a modified amino acid is understood to include the options of an amino acid with a modified sidechain, a an amino acid with a modified backbone, and an amino acid with a modified sidechain and a modified backbone.
[0092] The term "about" is used herein to mean within the typical ranges of tolerances in the art. For example, "about" can be understood as about 2 standard deviations from the mean. According to certain embodiments, about means +10%, +9%, +8%, +7%, +6%, +5%, ±4%, +3%, +2%, +1%, +0.9%, +0.8%, +0.7%, +0.6%, +0.5%, 0.4%, 0.3%, +0.2%, +0.1% or +0.05%. According to certain embodiments, about means +5%. When "about" is present before a series of numbers or a range, it is understood that "about" can modify each of the numbers in the series or range.
[0093] The term "at least" prior to a number or series of numbers (e.g. "at least two") is understood to include the number adjacent to the term "at least", and all subsequent numbers or integers that could logically be included, as clear from context. When at least is present before a series of numbers or a range, it is understood that "at least" can modify each of the numbers in the series or range.
[0094] As used herein, "up to" as in "up to 10" is understood as up to and including
10, i.e. , 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[0095] Ranges provided herein are understood to include all individual integer values and all subranges within the ranges. [0096] The term "polypeptide" as used herein, refers to any polymeric chain of amino acids. The terms "peptide" and "protein" are used interchangeably with the term polypeptide and also refer to a polymeric chain of amino acids. The term "polypeptide" encompasses native or artificial proteins, protein fragments and polypeptide analogs of a protein sequence. A polypeptide may be monomeric or polymeric.
[0097] The term "isolated protein" or "isolated polypeptide" is a protein or polypeptide that by virtue of its origin or source of derivation is not associated with naturally associated components that accompany it in its native state; is substantially free of other proteins from the same species; is expressed by a cell from a different species; or does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be "isolated" from its naturally associated components. A protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art. An example of an isolated polypeptide is an isolated antibody, or antigen- binding portion thereof.
[0098] The term "recovering" as used herein, refers to the process of rendering a chemical species such as a polypeptide substantially free of naturally associated components by isolation, e.g., using protein purification techniques well known in the art.
[0099] The terms "specific binding" or "specifically binding", as used herein, in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A" and the antibody, will reduce the amount of labeled A bound to the antibody.
[0100] The term "antibody", as used herein, broadly refers to any immunoglobulin
(Ig) molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivation thereof, which retains the essential epitope binding features of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art. Non-limiting embodiments of which are discussed below. [0101] In a full-length antibody, each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Immunoglobulin molecules can be of any type {e.g., IgG, IgE, IgM, IgD, IgA and IgY), class {e.g., IgG 1, IgG2, IgG 3, IgG4, IgAl and IgA2) or subclass.
[0102] The term "antigen binding portion" or "antigen binding fragment" of an antibody (or simply "antibody portion" or "antibody fragment"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may also be bispecific, dual specific, or multi- specific formats; specifically binding to two or more different antigens. Examples of binding fragments encompassed within the term "antigen -binding portion" or "antigen binding fragment" of an antibody 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; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546, Winter et al, PCT publication WO 90/05144 Al herein incorporated by reference), which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" or "antigen binding fragment" of an antibody. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994) Structure 2: 1121-1123). Such antibody binding portions are known in the art (Kontermann and Dubel eds., Antibody Engineering (2001) Springer- Verlag. New York. 790 pp. (ISBN 3-540-41354-5).
[0103] The term "antibody construct" as used herein refers to a polypeptide comprising one or more the antigen-binding portions of the invention linked to a linker polypeptide or an immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen- binding portions. Such linker polypeptides are well known in the art (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994) Structure 2: 1121-1123). An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences are known in the art and represented below.
Figure imgf000037_0001
[0104] An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities. An isolated antibody may have cross-reactivity to other antigens from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.
[0105] The term "chimeric antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.
[0106] The term "CDR-grafted antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.
[0107] The terms "Kabat numbering", "Kabat definitions and "Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and , Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.
[0108] As used herein, the terms "acceptor" and "acceptor antibody" refer to the antibody or nucleic acid sequence providing or encoding at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or 100% of the amino acid sequences of one or more of the framework regions. In some embodiments, the term "acceptor" refers to the antibody amino acid or nucleic acid sequence providing or encoding the constant region(s). In yet another embodiment, the term "acceptor" refers to the antibody amino acid or nucleic acid sequence providing or encoding one or more of the framework regions and the constant region(s). In a specific embodiment, the term "acceptor" refers to a human antibody amino acid or nucleic acid sequence that provides or encodes at least 80%, preferably, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the framework regions. In accordance with this embodiment, an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues that does (do) not occur at one or more specific positions of a human antibody. An acceptor framework region and/or acceptor constant region(s) may be, e.g., derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well-known in the art, antibodies in development, or antibodies commercially available).
[0109] As used herein, the term "CDR" refers to the complementarity determining region within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term "CDR set" as used herein refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia et al., J. Mol. Biol. 196:901-917 (1987) and Chothia et al , Nature 342:877-883 (1989)) found that certain sub- portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as LI, L2 and L3 or HI, H2 and H3 where the "L" and the "H" designates the light chain and the heavy chains regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (FASEB J. 9: 133-139 (1995)) and
MacCallum ( Mol Biol 262(5) :732-45 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not
significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although preferred embodiments use Kabat or Chothia defined CDRs.
[0110] As used herein, the term "canonical" residue refers to a residue in a CDR or framework that defines a particular canonical CDR structure as defined by Chothia et al. (J. Mol. Biol. 196:901-907 (1987); Chothia et al, J. Mol. Biol. 227:799 (1992), both are incorporated herein by reference). According to Chothia et ah , critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.
[0111] As used herein, the terms "donor" and "donor antibody" refer to an antibody providing one or more CDRs. In a preferred embodiment, the donor antibody is an antibody from a species different from the antibody from which the framework regions are obtained or derived. In the context of a humanized antibody, the term "donor antibody" refers to a non- human antibody providing one or more CDRs.
[0112] As used herein, the term "framework" or "framework sequence" refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of light chain and CDR-H1, CDR-H2, and CDR-H3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four sub- regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred by others, represents the combined FR's within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub- regions, and FRs represents two or more of the four sub- regions constituting a framework region.
[0113] As used herein, the term "fragment" is defined as a physically contiguous portion of the primary structure of a biomolecule. In some embodiments, the biomolecule is an antibody or a polypeptide sequence that binds an antigen recognized by the antibody. In the case of antibodies or polypeptides, a fragment may be defined by a contiguous portion of the amino acid sequence of a protein and may be at least 3-5 amino acids, at least 6-10 amino acids, at least 11-15 amino acids, at least 16-24 amino acids, at least 25-30 amino acids, at least 30-45 amino acids and up to the full length of the protein minus a few amino acids. In the case of polynucleotides, a fragment is defined by a contiguous portion of the nucleic acid sequence of a polynucleotide and may be at least 9-15 nucleotides, at least 15-30 nucleotides, at least 31-45 nucleotides, at least 46-74 nucleotides, at least 75-90 nucleotides, and at least 90-130 nucleotides. In some embodiments, fragments of biomolecules are immunogenic fragments.
[0114] In some embodiments, the term "functional fragment" means any portion of a polypeptide or amino acid sequence that is of a sufficient length to retain at least partial biological function that is similar to or substantially similar to the wild-type polypeptide or amino acid sequence upon which the fragment is based. If the fragment is a functional fragment of an antibody or antibody-like molecule, the fragment can be immunogenic and therefore possess a binding avidity for one or a plurality of antigens. In some embodiments, a functional fragment of a polypeptide associated with the extracellular matrix is a polypeptide that comprises 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity of any polypeptide disclosed in Table 1 and has sufficient length to retain at least partial binding affinity to one or a plurality of ligands that bind to the amino acid sequence in Tables 1 through 17
(including tables 2 through 16). In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Table 1 and has a length of at least about 10, about 20, about 30, about 40, about 50 , about 60, about 70, about 80, about 90, or about 100 contiguous amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 50 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 100 amino acids. In some
embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 150 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 200 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 250 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 300 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 350 amino acids. In some
embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 400 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 450 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 500 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 550 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 600 amino acids. In some
embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 650 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 700 amino acids. In some embodiments, the fragment is a fragment of any polypeptide disclosed in Tables 1 through 17 and has a length of at least about 750 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 800 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 850 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 900 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 950 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 1000 amino acids. In some embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of at least about 1050 amino acids. In some
embodiments, the fragment is a fragment of any amino acid sequence disclosed in Tables 1 through 17 and has a length of no more than the aforementioned alternative number of amino acids in this paragraph. In some embodiments, the composition or pharmaceutical
compositions of the disclosure include any one or more conservative substitutions disclosed in Table A.
[0115] Human heavy chain and light chain acceptor sequences are known in the art.
In one embodiment of the invention the human heavy chain and light chain acceptor sequences are selected from the sequences described in the tables below.
Heavy Chain Acceptor Sequences
Figure imgf000042_0001
Figure imgf000043_0001
Light Chain Acceptor Sequences
Figure imgf000043_0002
[0116] As used herein, the term "germline antibody gene" or "gene fragment" refers to an immunoglobulin sequence encoded by non- lymphoid cells that have not undergone the maturation process that leads to genetic rearrangement and mutation for expression of a particular immunoglobulin. (See, e.g., Shapiro et al., Crit. Rev. Immunol. 22(3): 183-200 (2002); Marchalonis et al., Adv Exp Med Biol. 484: 13-30 (2001)).
[0117] As used herein, the term "hyperproliferative disorder" is meant to refer to those diseases and disorders characterized by hyperproliferation of cells or cells that exhibit a dysfunction in their growth cycle. In some embodiments, the hyperproliferative disease is a dysplasia or cancer. The terms "hyperproliferative disorder" refer to a disorder
characterized by abnormal proliferation, abnormal growth, abnormal senescence, abnormal quiescence, or abnormal removal of cells any or in an organism, and includes include hyperplasias, neoplasias, cancer, fibroproliferative disorders (such as involving connective tissues, as well as other disorders characterized by fibrosis, including for example, rheumatoid arthritis, insulin dependent diabetes mellitus, glomerulonephritis, cirrhosis, and scleroderma), smooth muscle proliferative disorders (such as atherosclerosis and restinosis), chronic inflammation, and epithelial cell proliferative disorders (for example, psoriasis; keratosis; acne; comedogenic lesions; verracous lesions such as verruca plana, plantar warts, verruca acuminata, and other verruciform lesions marked by proliferation of epithelial cells; folliculitis and pseudofolliculitis; keratoacanthoma; callosities; Darier's disease; ichthyosis; lichen planus; molluscous contagiosum; melasma; Fordyce disease; and keloids or hypertrophic scars). In some embodiments, the hyperproliferative disease is a cancer derived from the gastrointestinal tract or urinary system. In some embodiments, a hyperproliferative disease is a cancer of the adrenal gland, bladder, bone, bone marrow, brain, spine, breast, cervix, gall bladder, ganglia, gastrointestinal tract, stomach, colon, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, or uterus. In some embodiments, the term hyperproliferative disease is a cancer chosen from: lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas). In some embodiments,
hyperproliferative disorder is a glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, or skin cutaneous carcinoma. [0118] As used herein, the term "hyperproliferative-associated protein" is meant to refer to proteins that are associated with a hyperproliferative disease. In some embodiments, the hyperproliferative-associated protein is an antigen expressed on the cell that has a dysfunctional growth cycle. In some embodiments, the cell having a dysfunctional growth cycle is cancerous. In some embodiments, the hyperproliferative-associated protein is an antigen that is expressed on a hyperproliferative cell in an abundance that is higher as compared to a normal cell. In some embodiments, the hyperproliferative-associated protein is an antigen that is expressed on a hyperproliferative cell but absent on a normal cell. In some embodiments, the hyperproliferative cell is a cell from a sample from a cancer patient. In some embodiments, the hyperproliferative cell is a cell from a tissue or solid tumor that is cancerous. In some embodiments, the cancer is
[0119] As used herein, the term "key" residues refer to certain residues within the variable region that have more impact on the binding specificity and/or affinity of an antibody, in particular a humanized antibody. A key residue includes, but is not limited to, one or more of the following: a residue that is adjacent to a CDR, a potential glycosylation site (can be either N- or O-glycosylation site), a rare residue, a residue capable of interacting with the antigen, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region, a residue within the Vernier zone, and a residue in the region that overlaps between the Chothia definition of a variable heavy chain CDR1 and the Kabat definition of the first heavy chain framework.
[0120] The term "host cell" as used herein is intended to refer to a cell into which exogenous DNA has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell, but, to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein. Preferably host cells include prokaryotic and eukaryotic cells selected from any of the phyla of living creatures.
Eukaryotic cells include protist, fungal, plant and animal cells. Other embodiments include cells include but are not limited to the prokaryotic cell line E.Coli; mammalian cell lines CHO, HEK 293 and COS; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.
[0121] Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose.
[0122] As used herein, the term "humanized antibody" is an antibody or a variant, derivative, analog or fragment thereof which immunospecifically binds to an antigen of interest, and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementary determining region (CDR) having substantially the amino acid sequence of a non-human antibody. As used herein, the term "substantially" in the context of a CDR refers to a CDR having an amino acid sequence at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to the amino acid sequence of a non-human antibody CDR. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab') 2, FabC, Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. Preferably, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. In some embodiments, a humanized antibody contains both the light chain as well as at least the variable domain of a heavy chain. The antibody also may include the CHI, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, a humanized antibody only contains a humanized light chain. In some embodiments, a humanized antibody only contains a humanized heavy chain. In specific embodiments, a humanized antibody only contains a humanized variable domain of a light chain and/or humanized heavy chain.
[0123] The humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including without limitation IgG 1, IgG2, IgG3 and IgG4. The humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains may be selected to optimize desired effector functions using techniques well- known in the art. [0124] The framework and CDR regions of a humanized antibody need not correspond precisely to the parental sequences, e.g., the donor antibody CDR or the consensus framework may be mutagenized by substitution, insertion and/or deletion of at least one amino acid residue so that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. In a preferred embodiment, such mutations, however, will not be extensive. Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region in the consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (See e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of
immunoglobulins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.
[0125] As used herein, "Vernier" zone refers to a subset of framework residues that may adjust CDR structure and fine-tune the fit to antigen as described by Foote and Winter (1992, J. Mol. Biol. 224:487-499, which is incorporated herein by reference). Vernier zone residues form a layer underlying the CDRs and may impact on the structure of CDRs and the affinity of the antibody.
[0126] The term "epitope" includes any polypeptide determinant capable of specific binding to a an antibody or antigen-binding portion thereof. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics. In various embodiments, an epitope may be a linear or sequential epitope, i.e., a linear sequence of amino acids, of the primary structure of the antigen. Alternatively, in other embodiments, an epitope may be a conformational epitope having a specific three-dimensional shape when the antigen assumes its secondary structure. For example, the conformational epitope may comprise non-linear, i.e., non- sequential, amino acids of the antigen.
[0127] In a particular embodiment, an epitope is a region of an antigen that is bound by an antibody or antigen-binding portion thereof. In certain embodiments, an antibody or antigen-binding portion thereof is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macro molecules.
[0128] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
[0129] The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further in Section II C, below), antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom H.R., (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith W.E., (2002) Clin. Biochem. 35:425-445; Gavilondo J.V., and Larrick J.W. (2002) BioTechniques 29: 128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378 ), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann S-A., and Green L.L. (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[0130] The terms "crystal", and "crystallized" as used herein, refer to an antibody, or antigen-binding portion thereof, that exists in the form of a crystal. Crystals are one form of the solid state of matter, which is distinct from other forms such as the amorphous solid state or the liquid crystalline state. Crystals are composed of regular, repeating, three-dimensional arrays of atoms, ions, molecules (e.g. , proteins such as antibodies), or molecular assemblies (e.g. , antigen/antibody complexes). These three-dimensional arrays are arranged according to specific mathematical relationships that are well-understood in the field. The fundamental unit, or building block, that is repeated in a crystal is called the asymmetric unit. Repetition of the asymmetric unit in an arrangement that conforms to a given, well-defined
crystallographic symmetry provides the "unit cell" of the crystal. Repetition of the unit cell by regular translations in all three dimensions provides the crystal. See Giege, R. and Ducruix, A. Barrett, Crystallization of Nucleic Acids and Proteins, a Practical Approach, 2nd ea., pp. 20 1- 16, Oxford University Press, New York, New York, (1999)."
[0131] The term "polynucleotide" as used herein refers to a polymeric form of two or more nucleotides, either ribonucleotides or deoxvnucleotides or a modified form of either type of nucleotide. The term includes single and double stranded forms of DNA but preferably is double- stranded DNA.
[0132] The term "isolated polynucleotide" as used herein shall mean a polynucleotide
(e.g. , of genomic, cDNA, or synthetic origin, or some combination thereof) that, by virtue of its origin , the "isolated polynucleotide": is not associated with all or a portion of a polynucleotide with which the "isolated polynucleotide" is found in nature; is operably linked to a polynucleotide that it is not linked to in nature; or does not occur in nature as part of a larger sequence.
[0133] The term "vector", as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g. , bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g. , non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g. , replication defective retroviruses, adenoviruses and adeno- associated viruses), which serve equivalent functions.
[0134] The term "operably linked" refers to a juxtaposition wherein the components described are in a relationship permitting them to function in their intended manner. A control sequence "operably linked" to a coding sequence is ligated in such a way that expression of the coding sequence is achieved under conditions compatible with the control sequences. "Operably linked" sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest. The term "expression control sequence" as used herein refers to polynucleotide sequences which are necessary to effect the expression and processing of coding sequences to which they are ligated. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e. , Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences include promoters and transcription termination sequence. The term "control sequences" is intended to include components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. Protein constructs of the present disclosure may be expressed, and purified using expression vectors and host cells known in the art, including expression cassettes, vectors, recombinant host cells and methods for the recombinant expression and proteolytic processing of recombinant polyproteins and pre-proteins from a single open reading frame (e.g. , WO 2007/014162 incorporated herein by reference).
[0135] "Transformation", as defined herein, refers to any process by which exogenous DNA enters a host cell. Transformation may occur under natural or artificial conditions using various methods well known in the art. Transformation may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method is selected based on the host cell being transformed and may include, but is not limited to, viral infection, electroporation, lipofection, and particle bombardment. Such "transformed" cells include stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome. They also include cells which transiently express the inserted DNA or RNA for limited periods of time.
[0136] The term "recombinant host cell" (or simply "host cell"), as used herein, is intended to refer to a cell into which exogenous DNA has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell, but, to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein. Preferably host cells include prokaryotic and eukaryotic cells selected from any of the Kingdoms of life. Preferred eukaryotic cells include protist, fungal, plant and animal cells. Most preferably host cells include but are not limited to the prokaryotic cell line E.Coli; mammalian cell lines CHO, HEK 293 and COS; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.
[0137] Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation {e.g., electroporation, lipofection).
Enzymatic reactions and purification techniques may be performed according to
manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose.
The term "inhibit" and its various grammatical forms is used to refer to a restraining, blocking, or limiting of the range or extent of a certain biological event or effect.
[0138] The term "effective amount," is used herein to include the amount of an agent
{e.g. a multispecific antibody) that, when administered to a patient for treating a subject infection, is sufficient to effect treatment of the disease {e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease or its related
comorbidities). The "effective amount" may vary depending on the agent, how it is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. An effective amount includes an amount that results in a clinically relevant change or stabilization, as appropriate, of an indicator of a disease or condition. "Effective amount" refers to an amount of a compound, material, or composition, as described herein effective to achieve a particular biological result such as, but not limited to, biological results disclosed, described, or exemplified herein. Such results may include, but are not limited to, the effective reduction of symptoms associated with any of the disease states mentioned herein, as determined by any means suitable in the art. The effective amount of the composition may be dependent on any number of variables, including without limitation, the species, breed, size, height, weight, age, overall health of the subject, the type of formulation, the mode or manner or administration, the type and/or severity of the particular condition being treated, or the need to modulate the activity of the molecular pathway induced by association of the analog to its receptor. The appropriate effective amount can be routinely determined by those of skill in the art using routine optimization techniques and the skilled and informed judgment of the practitioner and other factors evident to those skilled in the art. An effective dose of the antibodies or mutants or variants described herein may provide partial or complete biological activity as compared to the biological activity induced by the wild-type or naturally occurring polypeptides upon which the antibodies or mutants or variants are derived. A therapeutically effective dose of the antibodies or mutants or variants described herein may provide a sustained biochemical or biological affect and/or an increased resistance to degradation when placed in solution as compared with the normal affect observed when the naturally occurring and fully processed translated protein is administered to the same subject.
[0139] An "immunoconjugate" is an antibody or multispecific antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
[0140] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
[0141] The term "administer" as used herein means to give or to apply. The term
"administering" as used herein includes in vivo administration.
[0142] The term "linker" refers to a chemical moiety that connects one peptide to another, e.g., one antibody to another. Linkers can also be used to attach antibodies to labels or solid substrates. A linker can include amino acids. Linkers can be straight or branched, saturated or unsaturated carbon chains. They can also include one or more heteroatoms within the chain.
[0143] The term "enriched" or "enrichment" means an increased number or the process of identifying an portion of transcriptome with an increased number of nucleic acid sequences (e.g. RNA sequences). In some embodiments, the term is relative to the number of Ig-like sequences or CDR3 seqeunces (or sequneces honmolgous thereto) in a transcriptome of a sample. In some embodiments, the term is used to modify the number of Ig-like sequences or CDR3 seqeunces (or sequneces honmolgous thereto) in a transcriptome or the genomic deoxyribonucleic acid (DNA) of a sample and corresponds to the abundance of nucleic acid sequences in genomic DNA or a transciptome that encode Ig-like sequences or CDR3 seqeunces.
[0144] The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. A pharmaceutical composition of the present disclosure can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. To administer an antibody according to the disclosure by certain routes of administration, it may be necessary to coat the antibody with, or coadminister the antibody with, a material to prevent its inactivation. For example, the antibody may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
[0145] A "pharmaceutically acceptable carrier" refers to an ingredient in a
pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
Pharmaceutically acceptable carriers includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one preferred embodiment, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g. by injection or infusion).
[0146] The pharmaceutical compositions according to the disclosure may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0147] The term "subject" is used throughout the specification to describe an animal to which one or more compositions comprising the antibody or antibodies disclosed herein. In some embodiment, the animal is a human. For diagnosis of those conditions which are specific for a specific subject, such as a human being, the term "patient" may be
interchangeably used. In some instances in the description of the present disclosure, the term "patient" will refer to human patients suffering from a particular disease or disorder. In some embodiments, the subject may be a human suspected of having or being identified as at risk to develop cancer. In some embodiments, the subject is suspected of having or has been diagnosed with cancer. In some embodiments, the subject may be a human suspected of having or being identified as at risk to develop cancer or a hyperproliferative disorder. In some embodiments, the subject may be a mammal. In some embodiments, the subject may be a non-human animal. The term "mammal" encompasses both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.is used herein to refer to an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g. , a monkey, and a
chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, a horse, and a whale), or a bird (e.g. , a duck or a goose). In an embodiment, the subject is a human, such as a human being treated or assessed for a hyperproliferative disorder; or a human having an HIV infection that would benefit from a multispecific antibody as described herein. In some embodiments, the subject is a subject in need thereof, meaning that the subject is is need of the treatment being administered.
[0148] The term "salt" refers to acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Examples of these acids and bases are well known to those of ordinary skill in the art. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids. In some embodiments, salts of the compositions comprising either an antibody or antibody-like molecule may be formed by reacting the free base, or a salt, enantiomer or racemate thereof, with one or more equivalents of the appropriate acid. In some embodiments, pharmaceutical acceptable salts of the present disclosure refer to derivatives or amino acid sequences comprising at least one basic group or at least one basic radical. In some embodiments, pharmaceutical acceptable salts of the disclosed compositions comprise a free amino group, a free guanidino group, a pyrazinyl radical, or a pyridyl radical that forms acid addition salts. In some embodiments, the pharmaceutical acceptable salts of the present disclosure refer to modified amino acids that are acid addition salts of the subject compounds with (for example) inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4- aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, hetero aromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2- sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin. In some embodiments, the salts may be those that are physiologically tolerated by a patient. Salts according to the present disclsoure may be found in their anhydrous form or as in hydrated crystalline form (i.e., complexed or crystallized with one or more molecules of water). In some embodiments, the compositions or pharmaceutical compositions comprise crystalline forms or lyophilized forms of the antibodies, antibody-like molecules or salts thereof.
[0149] The term "treat" or "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms. The term "treat" or "treating" as used herein further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
[0150] The term "potency" as used herein refers to the neutralization capacity, i.e. the
IC50 or ICgo of the antibody, or fragment thereof.
[0151] Humanization and primatization refer to in cases where the tri-specific fusion antibody or the three antibodies forming the tri-specific fusion antibody are non-human antibodies, the antibody can be "humanized" to reduce immunogenicity to a human recipient. Methods for humanizing non-human antibodies have been described in the art. See, e.g., Jones et al., Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-327 (1988);
Verhoeyen et al., Science 239: 1534- 1536 (1988), and U.S. Pat. No. 4,816,567. Generally, residues from the variable domain of a non-human antibody are "imported" into a human immunoglobulin molecule, resulting in antibodies in which some hypervariable region residues and possibly some FR residues of a human antibody are substituted by residues from analogous sites of non-human antibodies. It is important to humanize a non-human antibody while retaining high affinity for the antigen. To this end, three dimensional immunoglobulin models are commonly available and suitable for use in analyzing proposed humanized sequences in comparison to the parental non-human antibodies. Such analysis permits identification of residues likely involved in recognition and binding of the antigen, and therefore rational design of humanized sequences that retain the specificity and affinity for the antigen.
[0152] In specific embodiments, tri-specific fusion antibodies are formed from aany of the fragments or antibody sequences disclosed herein.
[0153] Similarly, a bi-specific or tri-specific fusion antibody or the three antibodies forming the fusion can be "primatized" to reduce immunogenicity to another primate, non- human recipient, e.g., a rhesus recipient. Residues from the variable domain of a donor antibody (such as a non-primate antibody or an antibody of a primate species different from the recipient primate) are "imported" into a nonhuman primate recipient immunoglobulin molecule, resulting in antibodies in which some hypervariable region residues and possibly some FR residues of a nonhuman primate antibody are substituted by residues from analogous sites of donor antibodies. Alternatively, primatized antibodies can be made for use in a desirable primate species by using a recipient immunoglobulin having non-primate sequences or sequences from a different primate species by introducing the Fc fragment, and/or residues, including particularly framework region residues, from the desirable primate, into the recipient immunoglobulin.
[0154] By "affinity maturation" is meant when one or more hypervariable region residues of an antibody can be substituted to select for variants that have improved biological properties relative to the parent antibody by employing, e.g., affinity maturation using phage or yeast display. For example, the Fab region of an anti-cancer antigen can be mutated at several sites selected based on available structural information to generate all possible amino substitutions at each site. The antibody variants thus generated are displayed in a monovalent fashion from phage particles or on the surface of yeast cells. The displayed variants are then screened for their biological activity (e.g. binding affinity).
[0155] "Operably linked" as used herein when referring to a gene operably linked to a promoter refers to the linkage of the two components such that expression of the gene is under the control of a promoter with which it is spatially connected. A promoter may be positioned 5' (upstream) or 3' (downstream) of a gene under its control. The distance between the promoter and a gene may be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance may be accommodated without loss of promoter function. When referring to a signal peptide operable linked to a protein, the term refers to the protein having the signal peptide incorporated as part of the protein in a manner that it can function as a signal peptide. When referring to coding sequence that encodes a signal peptide operable linked to coding sequence that encodes a protein, the term refers to the coding sequences arranged such that the translation of the coding sequence produces a protein having the signal peptide incorporated as part of the protein in a manner that it can function as a signal peptide.
[0156] As used herein, "conservative" amino acid substitutions may be defined as set out in Tables A, B, or C below. Anitbodies, antibody-like molecules and derivative, mutants, variants ans salts thereof include those amino acid sequence wherein conservative
substitutions have been introduced by solid state chemistry and/or recombinant modification of nucleic acids that encode amino acid sequences disclosed herein. In some embodiments, the compositions and pharmaceutical compositions of the disclosure comprise 1, 2, 3, 4, 5 or more conservative amino acid substitutions. Amino acids can be classified according to physical properties and contribution to secondary and tertiary protein structure. A conservative substitution is recognized in the art as a substitution of one amino acid for another amino acid that has similar properties. Exemplary conservative substitutions are set out in Table A.
Table A— Conservative Substitutions I
Side Chain Characteristics Amino Acid
Aliphatic
Non-polar G A P I L V F
Polar - uncharged C S T M N Q
Polar - charged D E K R
Aromatic H F W Y
Other N Q D E
Alternately, conservative amino acids can be grouped as described in Lehninger,
(Biochemistry, Second Edition; Worth Publishers, Inc. NY, N.Y. (1975), pp. 71-77) as set forth in Table B.
Table B— Conservative Substitutions II
Side Chain Characteristic Amino Acid
Non-polar (hydrophobic)
Aliphatic: A L I V P .
Aromatic: F W Y
Sulfur-containing: M
Borderline: G Y
Uncharged-polar
Hydroxyl: S T Y
Amides: N Q
Sulfhydryl: C
Borderline: G Y
Positively Charged (Basic): K R H
Negatively Charged (Acidic): D E Alternately, exemplary conservative substitutions are set out in Table C.
Table C— Conservative Substitutions III
Original Residue Exemplary Substitution
Ala (A) Val Leu He Met
Arg (R) Lys His Asn (N) Gin
Asp (D) Glu
Cys (C) Ser Thr
Gin (Q) Asn
Glu (E) Asp
Gly (G) Ala Val Leu Pro
His (H) Lys Arg
He (I) Leu Val Met Ala Phe
Leu (L) He Val Met Ala Phe
Lys (K) Arg His
Met (M) Leu He Val Ala
Phe (F) Trp Tyr He
Pro (P) Gly Ala Val Leu He
Ser (S) Thr
Thr (T) Ser
Trp (W) Tyr Phe He
Tyr (Y) Trp Phe Thr Ser
Val (V) He Leu Met Ala
[0157] It should be understood that the amino acids disclosed described herein are intended to include polypeptides bearing one or more insertions, deletions, or substitutions, truncation or any combination of amino acid residues as well as modifications other than insertions, deletions, or substitutions of amino acid residues.
[0158] As used herein, the term "sample" refers to a biological sample obtained or derived from a source of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheo alveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises bodily fluid. In some embodiments, a sample is a "primary sample" obtained directly from a source of interest by any appropriate means. For example embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term "sample" refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semipermeable membrane. Such a "processed sample" may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc. in some embodiments, the methods disclosed herein do not comprise a processed sample. In some embodiments, the methods disclosed herein comprise taking a sample from water or other environmental surface, processing the sample to include a known volume, and exposing the sample to the antibody, antibody fragments, system, or
compositions disclosed herein.
[0159] As used herein the term "transcriptome" means nucleic acid sequences that are transcribed by one or a plurality of cells in a sample. In some embodiments, the sample comprises one or a plurality of hyperproliferative cells.
[0160] As used herein "whole blood" means blood that is taken directly from the subject and unprocessed by filtration or additives prior to manipulation, in some
embodiments, whole blood may comprise anti-coagulants. In some embodiments, whole blood is free of anti-coagulants.
[0161] As used herein, "sequence identity" is determined by using the stand-alone executable BLAST engine program for blasting two sequences (bl2seq), which can be retrieved from the National Center for Biotechnology Information (NCBI) ftp site, using the default parameters (Tatusova and Madden, FEMS Microbiol Lett., 1999, 174, 247-250; which is incorporated herein by reference in its entirety). To use the term "homologus to" is synonymous with a measured "sequence identity." In some embodiments, if an embodiment comprises a nucleic acid sequence or amino acid sequence with a percent sequence identity the term refers to a disclosed nucleic acid sequence or amino acid sequence possessing a homology to a disclosed sequence over its entire length.
[0162] The terms "clonality score" refers to the number solution obtained after solving for the IgH number described corresponding to those nucleci acid sequences from samples or those samples, whether they be cancer tissue, with more extensive clonal expansion of B lymphocytes. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.1 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.15 or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.2 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.25 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.3 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.4 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.5 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.6 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.7 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.8 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.9 or higher.In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 1. or higher. In some embodiments, the clonality score is considered to have a character of more extensive clonal expansion if the value is about 0.35 or higher.
Methods
[0163] The disclosure relates to a method of A method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome or genomic DNA sequence of a sample comprising: a. screening the transcriptome or genomic DNA sequence of the sample for enriched nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; b. calculating a clonality score of the sample; c. sorting at least one nucleic acid sequence into the first set or the second set of nucleic acid sequences based upon sequence alignment between the nucleic acids from the sample that are Ig-like sequence or homolgous to CDR3 as compared to V, J, D sequences in the sample, or as compared to the Ig-like sequence identified in a control set of samples. In some embodiments, the method further comprises a step of: (d) identifying a nucleic acid sequence encoding at least one
complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting. In some embodiments, the method further comprises further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences from the sample. In some embodiments, the method further comprises further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences from the sample based upon one or a combination of: the clonality score, the presence or abundance of CDR3 or Ig-like nucleic acid sequence enrichment in the sample and alignment of the CDR sequence to the CDR3 or Ig-like nucleic acid sequence in the sample. In some embodiments, the method further comprises a step of:screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score of the seris of control samples;
identifying the most enriched CDR3 sequences from a sample or series of samples; and. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject, wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c) corresponding to those subparts in the claims; and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h) corresponding to those steps in the claims disclosed herein.
[0164] In some embodiments, the control set of samples is from a publicly available database of transcriptomes. In some embodiments, the publicly available database comprises transcriptomes from known cancer tissue. In some embodiments, the publicly available database comprises transcriptomes from known cancer tissue that is capable of being sorted based upon cancer type. In some embodiments, the publicly available database comprises transcriptomes from known cancer tissue from one or a combination of cancer tissues identified herein. In some embodiments, the publicly available database comprises transcriptomes from known cancer tissue is the TGCA database.
[0165] The disclosure also relates to a computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample, the method comprising: in a system comprising at least one processor and a memory, a. screening, by the at least one processor, the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; b. calculating, by the at least one processor, a clonality score; and sorting, by the at least one processor, the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score. In some embodiments, the method further comprises a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
[0166] In any of the disclosed methods, in some embodiments, the sample is a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
[0167] A method of designing an antibody or antibody fragment capable of binding to an epiptope on a cell from a sample, the method comprising: (a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25; and repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample; (b) cloning the one or plurality of nucleic acids in a vector or synthesizing the antibody from solid state chemical synthesis; and if the one or plurality of nucleic acid sequences are cloned into a vector, (c) transforming the vector into a host ceil and (d) allowing a time period to elapse sufficient for the host cell to recombinantly produce the encoded antibody or antibody fragment.
[0168] The disclosure also relates to methods of treating a subject diagnosed or suspected of having a hyperproliferative disorder comprising administering any one or combination of the pharmaceutical compositions diclosed herein to the subject. In some embodiments, the pharmaceutical compositoipn comprises an effective amount of antibodies or antibody fargments disclosed herein or salts thereof. In some embodiments, the hyperproliferative disorder is a cancer chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma. Computer-Implemented Methods
[0169] In some embodiments, the disclosure relates to a computer-implemented method of detecting, cataloguing or compiling one or a plurality of nucleic acid sequences encoding one or a plurality of antibodies or antibody fragments from a transcriptome of a sample. In some embodiments the method comprises a device that accesses the internet, the device capable to executing one or more steps of a method comprising: identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome of a subject comprising: screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
[0170] In some embodiments, the disclosure relates to a system comprising a processor that performs a computer-implemented method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome of a subject comprising: screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
[0171] In some embodiments, the disclosure relates to a system comprising a processor that performs a computer-implemented method of detecting exit behavior of a user of a user device that accesses the internet, the method comprising: screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences; calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score; and obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject. In some embodiments, the disclosure relates to a system including at least one processor and a computer readable memory, said computer readable memory having stored thereon program code for detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment from a transcriptome of a sample, and a means for storing data associated with a user of a user device In some embodiments, the disclosure relates to a system that comprises at least one processor, a program storage, such as memory, for storing program code executable on the processor, and one or more input/output devices and/or interfaces, such as data communication and/or peripheral devices and/or interfaces. In some embodiments, the user device and computer system or systems are communicably connected by a data communication network, such as a Local Area Network (LAN), the Internet, or the like, which may also be connected to a number of other client and/or server computer systems. The user device and client and/or server computer systems may further include appropriate operating system software. [0172] In some embodiments, the disclosure relates to a computer-implemented method of identifying sequences from a transcripotome or genomic DNA of a sample that are nucleic acid seqeunces that encode antibodies or antibody fragments that more effectively bind cancer tissue than antibodies or antibody fragments identified from clonal expansion of cells from the same tissue.
[0173] Exemplary embodiments include the following and refer to numbering of claim-like language through page 71 of the specification: [0174] 1. A method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome or genomic DNA sequence of a sample comprising:
[0175] a. screening the transcriptome or genomic DNA sequence of the sample for enriched nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0176] b. calculating a clonality score of the sample;
[0177] c. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon sequence alignment.
[0178] 2. The method of claim 1 further comprising a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
[0179] 3. The method of claim 2 further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences.
[0180] 4. The method of claim 2 further comprising:
[0181] e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0182] f. calculating a clonality score of the sample
[0183] g. identifying the most enriched CDR3 sequences from a sample or series of samples.
[0184] h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject;
[0185] wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c); [0186] and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
[0187] 5. The method of any of claims 1 through 5, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
[0188] 6. The method of any of claims 1 through 5, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
[0189] 7. The method of any of claims 1 through 6, wherein the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the sample determined, at least in part, by the following equation:
Λ . ∑f
I -I Ci log2(Ci)
log2(N)
wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
[0190] 8. The method of any of claims 1 through 7, wherein the screening the transcriptome or genomic DNA of a series of samples for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
[0191] 9. The method of any of claims 1 through 8, wherein the screening the transcriptome or genomic DNA of the sample for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
[0192] 10. The method of claim 9, wherein the alignment of clonal sequences comprises performing an immunoSEQ function. [0193] 11. The method of any of claims 1 through 10, wherein the sample is a tissue sample from a subject having a hyperproliferative cell disorder.
[0194] 12. The method of any of claims 1 through 10, wherein the sample is a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung
adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
[0195] 13. A computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample, the method comprising: in a system comprising at least one processor and a memory, [0196] a. screening, by the at least one processor, the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0197] b. calculating, by the at least one processor, a clonality score;
[0198] c. sorting, by the at least one processor, the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
[0199] 14. The method of claim 13 further comprising a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
[0200] 15. The method of claim 14 further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences.
[0201] 16. The method of claim 14 further comprising:
[0202] e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
[0203] f. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
[0204] g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score. [0205] h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject;
[0206] wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c);
[0207] and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
[0208] 17. The method of any of claims 13 through 16, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
[0209] 18. The method of any of claims 13 through 17, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
[0210] 19. The method of any of claims 13 through 18, wherein the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the sample is determined, at least in part, by the following equation: t∑f a logzjcc)
l.og2(N)
wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements; and wherein the sorting of the nucleic acids into the first set of nucleci acid sequences is performed if the score is 0.1 or higher.
[0211] 20. The method of any of claims 16 through 19, wherein the screening the transcriptome of a series of samples for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
[0212] 21. The method of any of claims 13 through 20, wherein the screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
[0213] 22. The method of claim 21, wherein the alignment of clonal sequences comprises performing an immunoSEQ function.
[0214] 23. The method of any of claims 13 through 22, wherein the sample is a tissue sample from a subject having a hyperproliferative cell disorder.
[0215] 24. The method of any of claims 13 through 23, wherein the sample is a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung
adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
[0216] 25. The method of claims 1 or 13, wherein the first set of nucleic acids that encode an antibody or antibody fragment encode an antibody capable of binding one or a plurality of cells from the sample and/or subject.
[0217] 26. A method of compiling a set of nucleic acid sequences encoding an antibody or antibody fragment from a sample, the method comprising:
[0218] (a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25; and
[0219] (b) repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample.
Compositions Comprising Antibodies
[0220] The disclosure relates to one or more pharmaceutical compositions comprising an effective amount of one or more antibodies disclosed herein, antibody fragments disclosed herein, or salts thereof; and one or more pharmaceutically acceptable carriers.
[0221] The disclosure features antibodies, or antigen-binding fragments thereof, that binds to a tumor tissue. In certain embodiments, the antibodies, or antigen-binding fragments thereof, of the disclosure are cross-reactive among tissue samples from different cancer types, but do not bind normal tissue. In other embodiments, the antibodies, or antigen-binding fragments thereof, of the disclosure, selectively bind to one type of tumor tissue. [0222] Exemplary cancers include, but are not limited to, Acute Lymphocytic
Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenal Cancer, Anal Cancer, Basal and Squamous Cell Skin Cancer, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain and Spinal Cord Tumors, Breast Cancer, Cervical Cancer, Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Colorectal Cancer, Endometrial Cancer, Esophagus Cancer, Ewing Family of Tumors, Eye Cancer, Gallbladder Cancer, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumor (GIST), Gestational Trophoblastic Disease, Hodgkin Lymphoma, Kaposi Sarcoma, Kidney Cancer, Laryngeal and Hypopharyngeal Cancer, Leukemia, Liver Cancer, Lung Cancer, Lung Carcinoid Tumor, Lymphoma, Lymphoma of the Skin, Malignant
Mesothelioma, Melanoma Skin Cancer, Merkel Cell Skin Cancer, Multiple Myeloma, Myelodysplastic Syndromes, Nasal Cavity and Paranasal Sinuses Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cavity and Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Penile Cancer, Pituitary Tumors, Prostate Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Stomach Cancer, Testicular Cancer, Thymus Cancer, Thyroid Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, Wilms Tumor.
[0223] In some embodiments, the disclosure relates to a method comprising validating antibody specificity using immunofluorescence methods known in the art by comparing its binding to cancer and normal tissues.
[0224] In some embodiments, the disclosure relates to a composition of antibody that are broadly reactive to cancer tissues but rarely to normal tissues.
[0225] In some embodiments, the disclosure relates to a composition of the cancer- specific antibodies with amino acid sequence identified in sequence ID 1-9.
[0226] In some embodiments, the disclosure relates to a composition of antibodies that are narrowly specific for tissues from which the antibody sequence were composited based immunoseq data.
[0227] In some embodiments, the disclosure relates to a composition comprising individual cancer- specific antibodies in claim 45 with amino acid sequence identified in sequence ID 10- 18.
[0228] In some embodiments, Immunoseq-derived high abundance antibody sequences comprising CDR1, CDR2 and CDR3 as well as somatically mutated sequences. [0229] In some embodiments, Immunoseq derived sequences from cancer tissues in claim 48, comprising one of the sequences in sequence ID19.
[0230] In some embodiments, the disclosure relates to use of antibodies constructed from sequences in claims 42-48 for cancer diagnosis, comprising staining of tissues by immunohistochemistry of immunofluorescence.
[0231] In some embodiments, the antibodies are modified for optimal antibody- dependent cellular cytotoxicity or antibody-dependent cellular phagocytosis.
[0232] In some embodiments, the antibody or fragment thereof or salt thereof is used as antibody-drug conjugates.
[0233] In some embodiments, the antibodies are used an component of bi-specific antibodies. In some embodiments, the antibodies are used as key component of chimeric antigen -receptor T cells (CART).
[0234] In a specific embodiment, the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2206, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2208, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2210, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2216, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2218, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2220. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2226, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2228, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2230, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2236, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2238, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2240. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2246, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2248, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2250, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2256, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2258, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2260. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2266, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2268, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2270, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2276, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2278, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2280. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2286, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2288, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2290, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2296, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2298, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2300. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2306, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2308, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2310, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2316, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2318, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2320. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2326, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2328, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2330, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2336, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2338, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2340. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2346, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2348, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2350, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2356, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2358, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2360. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2366, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2368, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2370, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2376, a light chain
CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2378, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2380. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2386, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2388, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2390, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2396, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2398, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2400. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2406, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2408, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2410, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2416, a light chain
CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2418, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2420. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2426, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2428, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2430, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2436, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2438, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2440. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2446, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2448, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2450, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2456, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2458, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2460. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2466, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2468, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2470, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2476, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2478, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2480. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2490, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2496, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2498, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2500. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2506, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2508, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2510, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2516, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2518, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2520. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2526, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2528, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2530, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2536, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2538, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2540. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2546, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2548, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2550, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2556, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2558, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2560. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2566, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2568, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2570, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2576, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2578, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2580. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2586, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2588, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2590, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2596, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2598, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2600. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2606, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2608, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2610, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2616, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2618, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2620. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2626, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2628, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2630, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2636, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2638, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2640. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2646, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2648, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2650, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2656, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2658, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2660. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2666, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2668, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2670, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2676, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2678, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2680. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2686, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2688, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2690, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2696, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2698, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2700. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2706, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2708, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2710, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2716, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2718, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2720.
[0235] One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an antigen binding protein.
[0236] An antigen binding protein may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently. The CDRs permit the antigen binding protein to specifically bind to a particular antigen of interest.
[0237] In one embodiment, the present disclosure is directed to an antibody, or an antigen binding fragment thereof, having the antigen binding regions of any of the antibodies described in Table 17.
[0238] In a specific embodiment, the disclosure relates to an antibody, or antigen- binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2204, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2204, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2214, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2214. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2224, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2224, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2234, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2234. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2244, or a sequence having at least 70%, 80%, 85%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2244, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2254, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2254. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2264, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2264, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2274, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2274. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2284, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2284, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2294, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2294. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2304, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2304, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2314, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2314. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2324, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2324, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
2334, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2334. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2344, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2344, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2354, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2354. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2364, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2364, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2374, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2374. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2384, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2384, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2394, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2394. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2404, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2404, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2414, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2414. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2424, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2424, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO:
2434, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2434. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2444, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2444, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2454, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2454. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2464, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2464, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2474, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2474. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2484, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2484, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2494, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2494. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2504, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2504, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2514, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2514. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2524, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2524, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2534, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2534. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2544, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2544, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2554, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2554. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2564, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2564, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2574, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2574. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2584, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2584, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2594, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2594. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2604, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2604, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2614, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2614. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2624, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2624, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2634, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2634. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2644, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2644, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2654, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2654. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2664, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2664, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2674, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2674. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2684, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2684, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2694, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2694. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2704, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2704, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2714, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2714.
[0239] In a further specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2202, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2202, and/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2212, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2212. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2222, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2222, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2232, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2232. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2242, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2242, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2252, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2252. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2262, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2262, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2272, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2272. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2282, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2282, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2292, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2292. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2302, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2302, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2312, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2312. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2322, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2322, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2332, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2332. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2342, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2342, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2352, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2352. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2362, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2362, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2372, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2372. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2382, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2382, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2392, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2392. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2402, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2402, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2412, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2412. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2422, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2422, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2432, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2432. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2442, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2442, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2452, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2452. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2462, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2462, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2472, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2472. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2482, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2482, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2492, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2492. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2502, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2502, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2512, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2512. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2522, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2522, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2532, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2532. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2542, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2542, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2552, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2552. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2562, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2562, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2572, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2572. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2582, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2582, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2592, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2592. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2602, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2602, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2612, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2612. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2622, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2622, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2632, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2632. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2642, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2642, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2652, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2652. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2662, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2662, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2672, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2672. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2682, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2682, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2692, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2692. In a specific embodiment, the disclosure relates to an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2702, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2702, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2712, or a sequence having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2712.
[0240] In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2202, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2212. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2222, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2232. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2242, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2252. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2262, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2272. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2282, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2292. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2302, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2312. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2322, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2332. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2342, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2352. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2362, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2372. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2382, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2392. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2402, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2412. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2422, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2432. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2442, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2452. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO:
2462, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2472. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2482, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2492. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2502, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2512. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2522, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2532. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2542, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2552. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2562, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2572. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2582, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2592. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2602, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2612. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2622, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2632. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2642, and the light chain comprises an amino acid sequence set forth in SEQ ID NO:
2652. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2662, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2672. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2682, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2692. In certain embodiments, the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2702, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2712.
[0241] In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2202. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2212. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2222. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2232. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2242. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2252. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2262. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
SEQ ID NO: 2272. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2282. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2292. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2302. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2312. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2322. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2332. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2342. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2352. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2362. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising
SEQ ID NO: 2372. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2382. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2392. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2402. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2412. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2422. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2432. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2442. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2452. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2462. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2482. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2492. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2502. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2512. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2522. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2532. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2542. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2552. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2562. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2572. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2582. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2592. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising 2602. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2612. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2622. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2632. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2642. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2652. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2662. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2672. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2682. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2692. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2702. In some embodiments, the composition or pharmaceutical composition is free of an amino acid sequence comprising SEQ ID NO: 2712.
[0242] In certain embodiments, the antibody comprises a heavy chain constant region, such as an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. In certain embodiments of the disclosure, the antibody, or antigen-binding fragment is classified as an isotype selected from the group consisting of an IgG, an IgM, an IgD, an IgA, and an IgE. Techniques are known for deriving an antibody of a different subclass or isotype from an antibody of interest, i.e., subclass switching. Thus, IgG antibodies may be derived from an IgM antibody, for example, and vice versa. Such techniques allow the preparation of new antibodies that possess the antigen-binding properties of a given antibody (the parent antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody. Recombinant DNA techniques may be employed. Cloned DNA encoding particular antibody polypeptides may be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype (Lantto et al., 2002, Methods Mol. Biol. 178:303-16).
[0243] Furthermore, the antibody can comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region.
[0244] In certain embodiments of the disclosure, the antibody, or antigen-binding fragment is selected from the group consisting of a Fab, a Fab', a F(ab')2, an Fv, a domain antibody, and a single-chain antibody.
[0245] In other embodiments, the disclosure features an antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, that competes with the antibody, or antigen- binding fragment thereof, as described in Table 17. In particular embodiments, the competing antibody, or antigen-binding portion thereof, is an antibody, or antigen-binding portion thereof, that competes with any of the antibodies presented herein. In one
embodiment, the invention provides a competing antibody which can compete with
antibodies described herein.
[0246] The present disclosure provides a number of antibodies structurally
characterized by the amino acid sequences of their variable domain regions. However, the amino acid sequences can undergo some changes while retaining their high degree of binding to their specific targets. More specifically, many amino acids in the variable domain region can be changed with conservative substitutions and it is predictable that the binding characteristics of the resulting antibody will not differ from the binding characteristics of the wild type antibody sequence. There are many amino acids in an antibody variable domain that do not directly interact with the antigen or impact antigen binding and are not critical for determining antibody structure. For example, a predicted nonessential amino acid residue in any of the disclosed antibodies is preferably replaced with another amino acid residue from the same class. Methods of identifying amino acid conservative substitutions which do not eliminate antigen binding are well- known in the art (see, e.g., Brummell et al., Biochem. 32: 1180-1187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:412-417 (1997), all of which are incorporated by reference in their entireties herein). Near et al. Mol. Immunol. 30:369-377, 1993 explains how to impact or not impact binding through site-directed mutagenesis. Near et al. only mutated residues that they thought had a high probability of changing antigen binding. Most had a modest or negative effect on binding affinity (Near et al. Table 3) and binding to different forms of digoxin (Near et al. Table 2).
[0247] A conservative modification or functional equivalent of a peptide, polypeptide, or protein disclosed in this disclosure (e.g., the hinge region or a heavy chain having the hinge region) refers to a polypeptide derivative of the peptide, polypeptide, or protein, e.g., a protein having one or more point mutations, insertions, deletions, truncations, a fusion protein, or a combination thereof. It retains substantially the activity to of the parent peptide, polypeptide, or protein (such as those disclosed in this disclosure). In general, a conservative modification or functional equivalent is at least 60% (e.g., any number between 60% and 100%, inclusive, e.g., 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) identical to a parent (e.g., one of SEQ ID NOs: 1-53).
[0248] In one embodiment, the substitutions made within a heavy or light chain that is at least 95% identical (or at least 96% identical, or at least 97% identical, or at least 98% identical, or at least 99% identical) are conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331, herein incorporated by reference. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine.
[0249] As used herein, the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology=# of identical positions/total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
[0250] The percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4: 11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a
Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
[0251] Additionally or alternatively, the protein sequences of the present disclosure can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the molecules of the disclosure. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al, (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs {e.g., XBLAST and NBLAST) can be used. (See www.ncbi.nlm.nih.gov).
[0252] Other modifications of the antibody are contemplated herein. For example, the antibody can be linked to one of a variety of nonproteinaceous polymers, for example, polyethylene glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol. The antibody also can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules), or in
macroemulsions. Such techniques are disclosed in, for example, Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980).
[0253] Variant antibodies and salts thereof also are included within the scope of the disclosure. Variants of the sequences recited in the application also are included within the scope of the disclosure. Further variants of the antibody sequences having improved affinity can be obtained using methods known in the art and are included within the scope of the disclosure. For example, amino acid substitutions can be used to obtain antibodies with further improved affinity. Alternatively, codon optimization of the nucleotide sequence can be used to improve the efficiency of translation in expression systems for the production of the antibody. Variants may include non-natural amino acids up to a certain percentage. In some embodiments, the antibody comprises a variant amino acid sequence comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more percent of non-natural amino acids. Antibody Modifications
Humanization
[0254] In cases where the antibody, or antigen binding fragment thereof, are non- human antibodies, the antibody can be "humanized" to reduce immunogenicity to a human recipient. Methods for humanizing non-human antibodies have been described in the art. See, e.g., Jones et al., Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988), and U.S. Pat. No. 4,816,567. Generally, residues from the variable domain of a non-human antibody are "imported" into a human immunoglobulin molecule, resulting in antibodies in which some hypervariable region residues and possibly some FR residues of a human antibody are substituted by residues from analogous sites of non-human antibodies. It is important to humanize a non-human antibody while retaining high affinity for the antigen. To this end, three dimensional immunoglobulin models are commonly available and suitable for use in analyzing proposed humanized sequences in comparison to the parental non-human antibodies. Such analysis permits identification of residues likely involved in recognition and binding of the antigen, and therefore rational design of humanized sequences that retain the specificity and affinity for the antigen.
[0255] As described above, humanized antibodies are antibody molecules from non- human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and framework regions from a human immunoglobulin molecule. Known human Ig sequences are disclosed, e.g., www.ncbi.nlm.nih.gov/entrez- /query. fcgi; www.atcc.org/phage/hdb.html;
www.sciquest.com/; www.abcam.com/; www.antibodyresource.com/onlinecomp.html;
www .public. iastate.edu/.about.pedro/research_tools.html; www.mgen.uni- heidelberg . de/S D/IT/IT .html ; w w w . whfreeman . com/immunology/CH- 05/kuby05.htm ;
www .library . thinkquest . org/ 12429/Immune/ Antibody .html ;
www.hhmi.org/grants/lectures/1996/vlab/; www.path.cam.ac. uk/.about.mrc7/m- ikeimages.html; www.antibodyresource.com/; mcb.harvard.edu/BioLinks/Immuno- logy.html.www.immunologylink.com/; pathbox.wustl.edu/.about.hcenter/index.- html;
www.biotech.ufl.edu/.about.hcl/; www.pebio.com/pa/340913/340913.html- ;
www.nal.usda.gov/awic/pubs/antibody/; www.m.ehime-u.acjp/.about.yasuhito- /Elisa.html; www.biodesign.com/table.asp; www.icnet.uk/axp/facs/davies/lin- ks.html;
www.biotech.ufl.edu/.about.fccl/protocol.html; www.isac-net.org/sites_geo.html;
aximtl.imt.uni-marburg.de/.about.rek/AEP- Start.html;
baserv.uci.kun.nl/.about.jraats/linksl.html; www.recab.uni-hd.de/immuno.bme.nwu.edu/; www.mrc-cpe.cam.ac.uk/imt-doc/pu- blic/ JJvTTRO.html; www.ibt.unam.mx/vir/V_mice.html; imgt.cnusc.fr:8104/; www.biochem.ucl.ac.uk/.about.martin/abs/index.html;
antibody.bath.ac.uk/; abgen.cvm.tamu.edu/lab/wwwabgen.html; www.unizh.ch/.about.honegger/AHOsem- inar/SlideOl .html;
www.cryst.bbk.ac.uk/.about.ubcg07s/; www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.htm;
www .path. cam.ac.uk/.about.mrc7/h- umanisation/T AHHP.html;
www.ibt.unam.mx/vir/structure/stat_aim.html; www.biosci.missouri.edu/smithgp/index.html; www.cryst.bioc. cam.ac.uk/.abo- ut.fmolina/Web-pages/Pept/spottech.html; www.jerini.de/fr roducts.htm; www.patents.ibm.com/ibm.html.Kabat et al., Sequences of Proteins of
Immunological Interest, U.S. Dept. Health (1983), each entirely incorporated herein by reference. Such imported sequences can be used to reduce immunogenicity or reduce, enhance or modify binding, affinity, on-rate, off-rate, avidity, specificity, half-life, or any other suitable characteristic, as known in the art.
[0256] Framework residues in the human framework regions may be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Antibodies can be humanized using a variety of techniques known in the art, such as but not limited to those described in Jones et al., Nature 321:522 (1986); Verhoeyen et al., Science 239: 1534 (1988)), Sims et al., J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al. , PNAS 91:969-973 (1994); PCT publication WO 91/09967, PCT/: US98/16280, US96/18978, US91/09630, US91/05939, US94/01234, GB89/01334, GB91/01134, GB92/01755; WO90/14443, WO90/14424, WO90/14430, EP 229246, EP 592,106; EP 519,596, EP 239,400, U.S. Pat. Nos. 5,565,332, 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5814476, 5763192, 5723323, 5,766886, 5,714,352, 6,204,023, 6,180,370,
5,693,762, 5,530,101, 5,585,089, 5,225,539; 4,816,567, each entirely incorporated herein by reference, included references cited therein.
Affinity Maturation
[0257] One or more hypervariable region residues of an antibody can be substituted to select for variants that have improved biological properties relative to the parent antibody by employing, e.g., affinity maturation using phage or yeast display. For example, the Fab region of an antibody of the disclosure can be mutated at several sites selected based on available structural information to generate all possible amino substitutions at each site. The antibody variants thus generated are displayed in a monovalent fashion from phage particles or on the surface of yeast cells. The displayed variants are then screened for their biological activity (e.g. binding affinity). Modifications to the Fc Region
[0258] The antibody can be modified to improve certain biological properties of the antibody, e.g., to improve stability, to enhance or reduce effector functions such as antigen- dependent cell-mediated cyotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antibody, improved or decreased internalization and/or recycling, among others.
[0259] For example, the Fc fragment of some antibodies (derived from human Ig4) can be replaced with human IgGl that increases effector function mediated through FcRs (except FcRn). Such modification may improve the stability of the resulting antibody by about 5 fold. In another example, the IgGl Fc fragment can be modified to improve the recycling of the antibody via the antibody salvage pathway.
[0260] Still another type of modification involves alteration of the glycosylation pattern of a parent antibody, including deletions of one or more carbohydrate moieties found in the parent antibody, or addition of one or more carbohydrates (via addition of one or more glycosylation sites) that are not present in the parent antibody.
Pharmaceutical Compositions
[0261] The invention also provides pharmaceutical compositions comprising an antibody, or antigen-binding portion thereof, of the invention and a pharmaceutically acceptable carrier. [0262] The pharmaceutical compositions of the invention may include a
"therapeutically effective amount" or a "prophylactically effective amount" of an antibody or antibody portion of the invention. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the antibody or antibody portion may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody, or antibody portion, are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
[0263] The antibodies and antibody-portions of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject. Typically, the pharmaceutical composition comprises an antibody or antibody portion of the invention and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
[0264] Various delivery systems are known and can be used to administer one or more antibodies of the invention or the combination of one or more antibodies of the invention and a prophylactic agent or therapeutic agent useful for preventing, managing, treating, or ameliorating a disorder or one or more symptoms thereof, e.g. , encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibody or antibody fragment, receptor-mediated endocytosis (see, e.g. , Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of administering a prophylactic or therapeutic agent of the invention include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural administration, intratumoral administration, and mucosal administration (e.g., intranasal and oral routes). In addition, pulmonary administration can be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. See, e.g., U.S. Pat. Nos. 6,019,968, 5,985, 320, 5,985,309, 5,934, 272, 5,874,064, 5,855,913, 5,290, 540, and 4,880,078; and PCT Publication Nos. WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, each of which is incorporated herein by reference their entireties. In one embodiment, an antibody of the invention, combination therapy, or a composition of the invention is administered using Alkermes AIR pulmonary drug delivery technology (Alkermes, Inc., Cambridge, Mass.). In a specific embodiment, prophylactic or therapeutic agents of the invention are administered intramuscularly, intravenously, intratumorally, orally, intranasally, pulmonary, or subcutaneously. The prophylactic or therapeutic agents may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
[0265] In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion, by injection, or by means of an implant, said implant being of a porous or non-porous material, including membranes and matrices, such as sialastic membranes, polymers, fibrous matrices (e.g., TISSUEL), or collagen matrices. In one embodiment, an effective amount of one or more antibodies of the invention antagonists is administered locally to the affected area to a subject to prevent, treat, manage, and/or ameliorate a disorder or a symptom thereof. In another embodiment, an effective amount of one or more antibodies of the invention is administered locally to the affected area in combination with an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents) other than an antibody of the invention of a subject to prevent, treat, manage, and/or ameliorate a disorder or one or more symptoms thereof.
[0266] In another embodiment, the pharmaceutical compositoins of the invention can be delivered in a controlled release or sustained release system. In one embodiment, a pump may be used to achieve controlled or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989, N. Engl. J. Med. 321:574). In another embodiment, polymeric materials can be used to achieve controlled or sustained release of the therapies of the invention (see e.g., Medical
Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J., Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al, 1985, Science 228: 190; During et al, 1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 7 1: 105); U.S. Pat. No. 5,679,377; U.S. Pat. No. 5, 916,597; U. S. Pat. No. 5,912,015; U.S. Pat. No. 5,989,463; U.S. Pat. No. 5,128,326; PCT Publication No. WO 99/15154; and PCT Publication No. WO 99/20253. Examples of polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolides (PLG),
polyanhydrides, poly(N- vinyl pyrrolidone), poly( vinyl alcohol), polyacrylamide,
poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides) (PLGA), and polyorthoesters. In a preferred embodiment, the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable. In yet another embodiment, a controlled or sustained release system can be placed in proximity of the prophylactic or therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
[0267] Controlled release systems are discussed in the review by Langer (1990,
Science 249: 1527-1533). Any technique known to one of skill in the art can be used to produce sustained release formulations comprising one or more therapeutic agents of the invention. See, e.g., U. S. Pat. No. 4,526, 938, PCT publication WO 91/05548, PCT publication WO 96/20698, Ning et al., 1996, "Intratumoral Radioimmunotheraphy of a
Human Colon Cancer Xenograft Using a Sustained-Release Gel," Radiotherapy & Oncology 39: 179-189, Song et al, 1995, "Antibody Mediated Lung Targeting of Long- Circulating Emulsions," PDA Journal of Pharmaceutical Science & Technology 50:372-397, Cleek et al., 1997 ', "Biodegradable Polymeric Carriers for a bFGF Antibody for Cardiovascular
Application," Pro. Int'l. Symp. Control. Rel. Bioact. Mater. 24:853-854, and Lam et al, 1997, "Microencapsulation of Recombinant Humanized Monoclonal Antibody for Local Delivery," Proc. Int'l. Symp. Control Rel. Bioact. Mater. 24:759- 760, each of which is incorporated herein by reference in their entireties. [0268] In a specific embodiment, where the composition of the invention is a nucleic acid encoding a prophylactic or therapeutic agent, the nucleic acid can be administered in vivo to promote expression of its encoded prophylactic or therapeutic agent, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U. S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see, e.g., Joliot et al, 1991, Proc. Natl. Acad. Sci. USA 88: 1864-1868). Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression by homologous recombination.
[0269] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (e.g., topical), transmucosal, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
[0270] If the compositions of the invention are to be administered topically, the compositions can be formulated in the form of an ointment, cream, transdermal patch, lotion, gel, shampoo, spray, aerosol, solution, emulsion, or other form well-known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences and Introduction to Pharmaceutical Dosage Forms, 19th ed., Mack Pub. Co., Easton, Pa. (1995). For non-sprayable topical dosage forms, viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed. Suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure. Other suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g. , a gaseous propellant, such as freon) or in a squeeze bottle. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art.
[0271] If the method of the invention comprises intranasal administration of a composition, the composition can be formulated in an aerosol form, spray, mist or in the form of drops. In particular, prophylactic or therapeutic agents for use according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g. ,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges (composed of, e.g. , gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0272] If the method of the invention comprises oral administration, compositions can be formulated orally in the form of tablets, capsules, cachets, gel caps, solutions, suspensions, and the like. Tablets or capsules can be prepared by conventional means with
pharmaceutically acceptable excipients such as binding agents (e.g. , pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g. , lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g. , magnesium stearate, talc, or silica); disintegrants (e.g. , potato starch or sodium starch glycolate) ; or wetting agents (e.g. , sodium lauryl sulphate). The tablets may be coated by methods well- known in the art. Liquid preparations for oral administration may take the form of, but not limited to, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. , sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g. , lecithin or acacia); non-aqueous vehicles (e.g. , almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g. , methyl or propyl- p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated for slow release, controlled release, or sustained release of a prophylactic or therapeutic agent(s). [0273] The method of the invention may comprise pulmonary administration, e.g. , by use of an inhaler or nebulizer, of a composition formulated with an aerosolizing agent. See, e.g. , U.S. Pat. Nos. 6,019, 968, 5,985, 320, 5, 985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos. WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, each of which is incorporated herein by reference their entireties. In a specific embodiment, an antibody of the invention,
combination therapy, and/or composition of the invention is administered using Alkermes AIR pulmonary drug delivery technology (Alkermes, Inc., Cambridge, Mass.).
[0274] The method of the invention may comprise administration of a composition formulated for parenteral administration by injection (e.g. , by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage form (e.g. , in ampoules or in multi-dose containers) with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g. , sterile pyrogen-free water) before use.
[0275] The methods of the invention may additionally comprise of administration of compositions formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. , subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compositions may be formulated with suitable polymeric or hydrophobic materials (e.g. , as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g. , as a sparingly soluble salt).
[0276] The methods of the invention encompass administration of compositions formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2- ethylamino ethanol, histidine, procaine, etc.
[0277] Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the mode of administration is infusion, composition can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the mode of administration is by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
[0278] In particular, the invention also provides that one or more of the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity of the agent. In one embodiment, one or more of the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted (e.g. , with water or saline) to the appropriate concentration for administration to a subject. Preferably, one or more of the prophylactic or therapeutic agents or pharmaceutical compositions of the invention is supplied as a dry sterile lyophilized powder in a hermetically sealed container at a unit dosage of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. The lyophilized prophylactic or therapeutic agents or pharmaceutical compositions of the invention should be stored at between 2° C. and 8° C. in its original container and the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention should be administered within 1 week, preferably within 5 days, within 72 hours, within 48 hours, within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being reconstituted. In an alternative embodiment, one or more of the prophylactic or therapeutic agents or pharmaceutical compositions of the invention is supplied in liquid form in a hermetically sealed container indicating the quantity and concentration of the agent. Preferably, the liquid form of the administered composition is supplied in a hermetically sealed container at least 0.25 mg/ml, more preferably at least 0.5 mg/ml, at least 1 mg/ml, at least 2.5 mg/ml, at least 5 mg/ml, at least 8 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml, at least 50 mg/ml, at least 75 mg/ml or at least 100 mg/ml. The liquid form should be stored at between 2° C. and 8° C. in its original container.
[0279] The antibodies and antibody-portions of the invention can be incorporated into a pharmaceutical composition suitable for parenteral administration. Preferably, the antibody or antibody-portions will be prepared as an injectable solution containing 0.1-250 mg/ml antibody. The injectable solution can be composed of either a liquid or lyophilized dosage form in a flint or amber vial, ampule or pre-filled syringe. The buffer can be L-histidine (1- 50 mM), optimally 5- 10 mM, at pH 5.0 to 7.0 (optimally pH 6.0). Other suitable buffers include but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate. Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0-300 niM (optimally 150 mM for a liquid dosage form). Cryoprotectants can be included for a lyophilized dosage form, principally 0-10% sucrose (optimally 0.5- 1.0%). Other suitable cryoprotectants include trehalose and lactose. Bulking agents can be included for a lyophilized dosage form, principally 1- 10% mannitol (optimally 2-4%).
Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1-50 mM L- Methionine (optimally 5- 10 mM). Other suitable bulking agents include glycine, arginine, can be included as 0-0.05% polysorbate-80 (optimally 0.005-0.01%). Additional surfactants include but are not limited to polysorbate 20 and BRIJ surfactants. The pharmaceutical composition comprising the antibodies and antibody-portions of the invention prepared as an injectable solution for parenteral administration, can further comprise an agent useful as an adjuvant, such as those used to increase the absorption, or dispersion of a therapeutic protein (e.g. , antibody). A particularly useful adjuvant is hyaluronidase, such as HYLENEX
(recombinant human hyaluronidase). Addition of hyaluronidase in the injectable solution improves human bioavailability following parenteral administration, particularly
subcutaneous administration. It also allows for greater injection site volumes (i.e. greater than 1 ml) with less pain and discomfort, and minimum incidence of injection site reactions, (see WO2004078140, US2006104968 incorporated herein by reference).
[0280] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g. , injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies. The preferred mode of administration is parenteral (e.g. , intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In another preferred embodiment, the antibody is administered by intramuscular or subcutaneous injection.
[0281] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e. , antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile, lyophilized powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including, in the composition, an agent that delays absorption, for example, monostearate salts and gelatin.
[0282] The antibodies and antibody-portions of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is subcutaneous injection, intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In certain embodiments, the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
[0283] In certain embodiments, an antibody or antibody portion of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier. The compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer a compound of the invention by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
[0284] In other embodiments, an antibody or antibody portion of the invention may be conjugated to a polymer-based species such that said polymer-based species may confer a sufficient size upon said antibody or antibody portion of the invention such that said antibody or antibody portion of the invention benefits from the enhanced permeability and retention effect (EPR effect) (See also PCT Publication No. WO2006/042146A2 and U.S. Publication Nos. 2004/0028687A1, 2009/0285757A1, and 2011/0217363A1, and U.S. Patent No.
7,695,719 (each of which is incorporated by reference herein in its entirety and for all purposes).
[0285] In certain embodiments, an antibody or fragment thereof is linked to a half-life extending vehicle known in the art. Such vehicles include, but are not limited to, the Fc domain, polyethylene glycol, and dextran. Such vehicles are described, e.g., in U.S.
Application Serial No. 09/428,082 and published PCT Application No. WO 99/25044, which are hereby incorporated by reference for any purpose.
[0286] In a specific embodiment, nucleic acid sequences comprising nucleotide sequences encoding an antibody of the invention or another prophylactic or therapeutic agent of the invention are administered to treat, prevent, manage, or ameliorate a disorder or one or more symptoms thereof by way of gene therapy. Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. In this
embodiment of the invention, the nucleic acids produce their encoded antibody or prophylactic or therapeutic agent of the invention that mediates a prophylactic or therapeutic effect.
[0287] Any of the methods for gene therapy available in the art can be used according to the present invention. For general reviews of the methods of gene therapy, see Goldspiel et al, 1993, Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy 3:87-95;
Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, Science 260:926- 932 (1993); and Morgan and Anderson, 1993, Ann. Rev. Biochem. 62: 191-217; May, 1993, TIBTECH 11(5): 155-215. Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley &Sons, NY (1993); and Kriegler, Gene Transfer and
Expression, A Laboratory Manual, Stockton Press, NY (1990). Detailed description of various methods of gene therapy is provided in US20050042664 Al which is incorporated herein by reference. Antibody Production
[0288] Antibodies of the present invention may be produced by any of a number of techniques known in the art. For example, expression from host cells, wherein expression vector(s) encoding the heavy and light chains is (are) transfected into a host cell by standard techniques. The various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like. Although it is possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells is preferable, and most preferable in mammalian host cells, because such eukaryotic cells (and in particular mammalian cells) are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody.
[0289] Exemplary nucleic acids of the invention are shown in Table 17.
[0290] Exemplary mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P.A. Sharp (1982) Mol. Biol. 159:601-621), NS0 myeloma cells, COS cells and SP2 cells. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
[0291] Host cells can also be used to produce functional antibody fragments, such as Fab fragments or scFv molecules. It will be understood that variations on the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding functional fragments of either the light chain and/or the heavy chain of an antibody of this invention. Recombinant DNA technology may also be used to remove some, or all, of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to the antigens of interest. The molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention. In addition, bifunctional antibodies may be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than the antigens of interest by crosslinking an antibody of the invention to a second antibody by standard chemical crosslinking methods.
[0292] In a preferred system for recombinant expression of an antibody, or antigen- binding portion thereof, of the invention, a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr- CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the antibody heavy and light chain genes are each operatively linked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription of the genes. The recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification. The selected transformant host cells are cultured to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the antibody from the culture medium. Still further the invention provides a method of synthesizing a recombinant antibody of the invention by culturing a host cell of the invention in a suitable culture medium until a recombinant antibody of the invention is synthesized. The method can further comprise isolating the recombinant antibody from the culture medium.
[0293] Another embodiment of the invention provides a glycosylated antibody, or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof comprises one or more carbohydrate residues. Nascent in vivo protein production may undergo further processing, known as post-translational modification. In particular, sugar (glycosyl) residues may be added enzymatically, a process known as glycosylation. The resulting proteins bearing covalently linked oligosaccharide side chains are known as glycosylated proteins or glycoproteins. Antibodies are glycoproteins with one or more carbohydrate residues in the Fc domain, as well as the variable domain. Carbohydrate residues in the Fc domain have important effect on the effector function of the Fc domain, with minimal effect on antigen binding or half-life of the antibody (R. Jefferis, Biotechnol. Prog. 21 (2005), pp. 11-16). In contrast, glycosylation of the variable domain may have an effect on the antigen binding activity of the antibody. Glycosylation in the variable domain may have a negative effect on antibody binding affinity, likely due to steric hindrance (Co, M.S., et al., Mol. Immunol. (1993) 30: 1361- 1367), or result in increased affinity for the antigen (Wallick, S.C., et al, Exp. Med. (1988) 168: 1099-1109; Wright, A., et al, EMBO J. (1991) 10:2717-2723). [0294] One aspect of the present invention is directed to generating glycosylation site mutants in which the O- or N-linked glycosylation site of the antibody, or an antigen-binding portion thereof, has been mutated. One skilled in the art can generate such mutants using standard well-known technologies. Glycosylation site mutants that retain the biological activity, but have increased or decreased binding activity, are another object of the present invention.
[0295] In still another embodiment, the glycosylation of the antibody or antigen- binding portion of the invention is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region glycosylation sites to thereby eliminate
glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in further detail in PCT Publication
WO2003016466A2, and U.S. Pat. Nos. 5,714,350 and 6,350,861, each of which is incorporated herein by reference in its entirety.
[0296] Additionally or alternatively, a modified antibody of the invention can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNAc structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. See, for example, Shields, R. L. et al. (2002) J. Biol. Chem. 277:26733- 26740; Umana et al. (1999) Nat. Biotech. 17: 176-1, as well as, European Patent No: EP 1,176,195; PCT Publications WO 03/035835; WO 99/54342 80, each of which is
incorporated herein by reference in its entirety.
[0297] Protein glycosylation depends on the amino acid sequence of the protein of interest, as well as the host cell in which the protein is expressed. Different organisms may produce different glycosylation enzymes (e.g., glycosyltransferases and glycosidases), and have different substrates (nucleotide sugars) available. Due to such factors, protein glycosylation pattern, and composition of glycosyl residues, may differ depending on the host system in which the particular protein is expressed. Glycosyl residues useful in the invention may include, but are not limited to, glucose, galactose, mannose, fucose, n-acetylglucosamine and sialic acid. Preferably the glycosylated antibody, or an antigen-binding portion thereof, comprises glycosyl residues such that the glycosylation pattern is human.
[0298] It is known to those skilled in the art that differing protein glycosylation may result in differing protein characteristics. For instance, the efficacy of a therapeutic protein produced in a microorganism host, such as yeast, and glycosylated utilizing the yeast endogenous pathway may be reduced compared to that of the same protein expressed in a mammalian cell, such as a CHO cell line. Such glycoproteins may also be immunogenic in humans and show reduced half-life in vivo after administration. Specific receptors in humans and other animals may recognize specific glycosyl residues and promote the rapid clearance of the protein from the bloodstream. Other adverse effects may include changes in protein folding, solubility, susceptibility to proteases, trafficking, transport, compartmentalization, secretion, recognition by other proteins or factors, antigenicity, or allergenicity. Accordingly, a practitioner may prefer a therapeutic protein with a specific composition and pattern of glycosylation, for example glycosylation composition and pattern identical, or at least similar, to that produced in human cells or in the species-specific cells of the intended subject animal.
[0299] Expressing glycosylated proteins different from that of a host cell may be achieved by genetically modifying the host cell to express heterologous glycosylation enzymes. Using techniques known in the art a practitioner may generate antibodies or antigen-binding portions thereof exhibiting human protein glycosylation. For example, yeast strains have been genetically modified to express non-naturally occurring glycosylation enzymes such that glycosylated proteins (glycoproteins) produced in these yeast strains exhibit protein glycosylation identical to that of animal cells, especially human cells (U.S. patent Publication Nos. 20040018590 and 20020137134 and PCT publication
WO2005100584 A2).
[0300] In addition to the antibodies, or antigen binding portions thereof, the present invention is also directed to an anti-idiotypic (anti-Id) antibody specific for such antibodies, or antigen binding portions thereof, of the invention. An anti-Id antibody is an antibody, which recognizes unique determinants generally associated with the antigen-binding region of another antibody. The anti-Id can be prepared by immunizing an animal with the antibody, or antigen binding portion thereof, or a CDR containing region thereof. The immunized animal will recognize, and respond to the idiotypic determinants of the immunizing antibody and produce an anti-Id antibody. The anti-Id antibody may also be used as an "immunogen" to induce an immune response in yet another animal, producing a so-called anti-anti-Id antibody.
[0301] Further, it will be appreciated by one skilled in the art that a protein of interest may be expressed using a library of host cells genetically engineered to express various glycosylation enzymes, such that member host cells of the library produce the protein of interest with variant glycosylation patterns. A practitioner may then select and isolate the protein of interest with particular novel glycosylation patterns. Preferably, the protein having a particularly selected novel glycosylation pattern exhibits improved or altered biological properties.
[0302] It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the invention described herein are obvious and may be made using suitable equivalents without departing from the scope of the invention or the embodiments disclosed herein. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting of the invention.
[0303] Any and all journal articles, patent applications, issued patents, or other cited references
[0304] disclosed herein are incorporated by reference in their respective entireties.
EXAMPLES
Example 1. Computational framework for estimating and filtering the immunoglobulin sequences based on RNAseq data from TCGA database.
[0305] The present disclosure describes a computational framework that was developed and successfully tested for antibody discovery, by mining 1945 solid tumor RNA- sequencing-based samples for abundant Ig CDR3 sequences among TCGA database of glioblastoma multiforme (GBM), lower grade glioma (LGG), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), pancreatic adenocarcinoma (PAAD) and skin cutaneous melanoma (SKCM). Surprisingly, synthetic antibodies based on selected high-abundance CDR3 sequences from LUAD patients bound multiple lung cancer samples and were cross- reactive to other cancer types but, importantly, rarely to normal tissues. In addition, targeted DNA sequencing of the B cell receptor (BCR) from 5 lung tumor tissues allowed the identification of variable region sequences with multiple somatic mutations. Antibodies based on selected predominant variable heavy (Vh) and variable light (Vk) sequences showed specific binding to lung cancer samples from which the sequences were identified, but rarely to other cancer samples. The analyses described herein have the potential to identify both broadly cross-reactive and highly selective anti-cancer human monoclonal antibodies for cancer diagnosis and treatment. The platform described herein considerably reduces existing barriers in developing human anti-cancer antibodies, and paves the way for cancer treatment using patient-derived tumor-reactive monoclonal antibodies.
[0306] Recent studies from us and others have demonstrated that TCGA RNAseq database captures signatures of intratumorial T cell repertoire (3). However, similar analysis on antibody repertoire has not been performed. To fill in this major gap, a platform was developed that not only allows the description of the landscape of antibody response, but also to identify specific sequences potentially for cancer therapy and diagnosis, as shown in
Figure 1A.
[0307] First, reads were aligned to reference V, D, J and C genes of B cell receptors, and gene feature sequences were extracted from aligned reads (called clonal sequences). As shown in Figure IB, an abundance of Ig transcripts were identified in all six cancer types that were analyzed. Among them, LUSC and LUAD transcriptomes comprise significantly more abundant Ig transcriptomes. Next, the clonotypes were assembled with respect to the clonal sequence (based on the CDR3 region). After the core clonotypes were built, mapping was performed, which processes records deferred on the previous step and was aimed at rescuing quantitative information from low quality reads. As clonotypes were assembled by the initial assembler and mapper, clustering was then performed and the clonotypes with low abundance were attached to highly similar clonotypes with significantly greater abundance. As shown in Figure IB, a large number of clonotypes were identified among all six cancer types, although LUSC and LUAD transcriptomes were more enriched for BCR clonotypes. Therefore, the number of aligned Ig heavy chain reads per million RNAseq sequencing reads (IGHPM) and the number of assembled Ig heavy chain clonotypes per million RNAseq sequencing reads (CTPM) were used as the measures of Ig abundance among each samples.
[0308] Since local clonal expansion of cancer- specific B cells results in uneven distribution of BCR clones, clonality, a metric of B cell expansion, was analyzed as a parameter to describe local antibody responses. As developed by others to describe T cell response in cancer (3), clonality values approaching 0 indicate a very even distribution of clone frequencies, whereas values of 1 indicate a monoclonal B cell expansion. Analysis of B cell clonality revealed the substantial differences in B cell clonalities across different patients among different tumor cohorts (Figure 1C) and thus provide a valuable guide for identification of patient samples with highly expanded BCR clones. The final step was to align clonal sequences to reference V, D, J and C genes to rebuild alignments for clonal sequences and annotated them with information such as amino acid sequence and associated variable (V) and joining (J) genes. Considering the predominant abundance observed in BCR density and clonality of TCGA LUAD cohorts, the sample ranked 1st in abundance of immunogloblin transcripts to total RNAseq reads was selected for experimental validation of the framework (Figure ID). 1675 IgH, 2999 Igk and 1959 IgL CDR3s were assembled from this sample alone, which has the potential to provide a large number of antibodies for further characterization. Based on the abundance, alignment score and BCR gene usage of assembled CDR3 sequences of this sample, 3 IgH and 6 IgL chain sequences were chosen for proof-of- concept studies (Figure IE). Sequence information and gene usage of CDR3 is shown in Figure IF.
[0309] Co-enrichment of CDR3 of H and L chain suggests that they are likely paired, as suggested by parallel studies in T cells (4). However, it is not possible to determine pairing by frequency alone (5). Nevertheless, since a goal is to identify cancer-reactive antibodies rather than describing endogenous antibody responses, the 3 H-chains and 6 L-chains were combined at random in a pairwise fashion, and tested to determine if immunoglobulins were expressed from these pairings. These antibodies were linked to mouse IgG2a heavy chain and k light chain to facilitate future studies of human tissues that may have endogenous human IgG. As shown in Figure 1G, out of 18 combinations, 13 combinations resulted in significant levels of antibodies in transient transfection, thus providing valuable tools to evaluate antibody specificity.
[0310] Tables 1-6 show the top 100 heavy and top 100 light chains that were picked from the top three patients from the TCGA database.
[0311] Tables 7-16 show the top 50 heavy and top 50 light chains that were picked from each tumor sample from the Adaptive Biotechnologies Database.
Example 2. Antibody pool of 13 recombinant antibodies generated by random pairing of 3 heavy chains and 6 light chains binds to LUSC and LUAD tissues.
[0312] To determine if the antibodies that assembled de novo bind cancer tissues, the 13 antibodies were paired and immunofluorescence was performed using frozen tissues of LUSC and LUAD. The assembled antibodies were detected using goat anti-mouse secondary step-reagents. As shown in Figure 5, the antibody pools showed strong binding to both LUSC and LUAD. When the antibodies were tested individually, 9/13 showed clear binding to LUAD. Among them, 6 also reacted to LUSC. (Figure 2A). H2L7 was selected for further testing because of its unique staining pattern and its broad cross-reactivity to all five lung cancer samples tested, including two LUAD tumor tissues and 3 LUSC tumor tissues in frozen sections. Example 3. H2L7 binds a broad range of malignant tissues but shows limited binding to normal tissues.
[0313] H2L7 was characterized for its binding to both normal and different types of cancer tissues. When frozen tissue micro array of normal tissues was performed, H2L7 showed no reactivity to majority of normal tissues tested (Figure 3A). Although some binding to either intracellular components or extracellular matrix were observed in pancreas, spleen, parotid gland, and testis, definitive cell surface staining to any normal tissues was not found. In contrast, H2L7 was broadly reactive to 9/11 types of cancer tissues tested, including colon adenocarcinoma, esophagus adenocarcinoma, stomach adenocarcinoma, ovary adenocarcinoma, soft tissue giant cell tumor, liver hepatocellular carcinoma, testis seminoma, lung adenocarcinoma, and lung squamous carcinoma (Figure 3B). Furthermore, H2L7 was tested against LUSC TMA containing paired malignant and normal adjacent tissue. Staining results demonstrate the H2L7 binds strongly to 100% of LUSC but only 25% of adjacent benign tissue (Figure 3C & Figure 3D).
Example 4. Recombinant antibodies derived from targeted genomic sequence of LUAD (sample 463) and LUSC (sample 427) showed limited cross-reactivities.
[0314] As an alternative approach, the genomic DNA from frozen tissues of lung cancer samples was extracted and sent for BCR sequencing (Adaptive Biotechnologies, Seattle, WA) using their propitiatory sequencing and analysis methods (IMMUNOSEQ Assay). This method identified 3548 rearrangement sequences of BCR heavy chains and 5913 rearrangement sequences of light chains from sample No. 463, and 5901 heavy chain and 10679 light chain sequences from sample 427. In each case, the two most abundant clones of heavy and light chains were selected (Figure 4A) and aligned to the IMGT BCR reference sequences by using the V-QUEST tool . The alignment with the highest score (S) was reported. For each rearrangement sequence, the VDJ gene usage information presented by BCR sequencing results were validated by the IMGT alignment result. Then, the rearrangement sequences were extended to full-length immunoglobulin sequences by using the germ-line sequence of verified V and J gene. [0315] The heavy chains and light chains from the same samples were homogenously paired and expressed in 293T cells through transient transfection. As shown in Figure 4B, all eight combinations resulted in significant levels of antibody production. Antibodies H5L12 and H6L13 were picked and tested against 2 LUSC and 3 LUAD samples, including the sample from which the antibody sequence was assembled. As shown in Figure 4C, H6L13 showed strong and specific binding to the cancer tissue from which it was obtained.
Interestingly, H5L12 showed binding to not only the LUAD tissue sample it was obtained from, but it also showed cross-reactivity to the other case of LUAD tested, but not to any of the 3 LUSC samples tested. Importantly, when H5L12 and H6L13 were also tested against multiple normal and malignant tissues used in Figure 3, no cross -reactivity to other cancerous or normal tissues was observed. Therefore, these antibodies represent those that primarily or exclusively reactive to the cancer tissue from which they were isolated.
[0316] The data presented herein demonstrates that it is possible to identify en masse immunoglobulin sequences based on de novo assembly of either transcriptomes and targeted sequencing of genomic DNA isolated from clinical samples and that selected examples show both exclusive specificity and broad cross -reactivity against cancer tissues. Several issues deserve consideration.
[0317] First, since the antibodies were assembled based on both somatic and germline sequence, and since the pairing of heavy and light chains is based on random combinations, it is likely that the antibodies identified do not represent endogenous antibody responses to cancer. As such, it may be preferable to use the method described herein for antibody discovery rather than for description of endogenous antibody responses. Recent studies suggest that a single cell-based sequence may allow the description of antibody responses (6). [0318] Second, while this approach allowed bypassing the step of identification of tumor antigens prior to antibody isolation, it can be difficult to identify antigen recognized by the antibodies. An attempt at high throughput antigen screening for H2L7 among most known cell surface proteins has been unsuccessful. One potential explanation is that the antigenic epitope was modified in cancer cells in a way the defy recapitulation in transient transfection. However, it should be noted that while knowing the antigens would be helpful for clinical development, biological effector function of a given antibodies can be similarly evaluated regardless of the antigens involved. [0319] Third, it should be noted that while the depth and length of the RNAseq data in the TCGA database do not allow the assembly of full length Ig sequence, such sequences can be obtained when the lengths and depth can be increased, as are the cases for some more recent databases. It is of note that sequences reconstructed from CDR3 appear to lead to broadly reactive antibodies while those reconstructed from targeted sequencing data include some somatic mutations and are thus highly specific. These data raised the intriguing possibility that somatic mutations that increase antibody affinities may also reduce cross- reactivity. If this hypothesis can be substantiated by further studies, antibody sequences reconstructed from CDR3 only may be intrinsically valuable for cancer diagnosis.
[0320] Taken together, the ability to generate antibodies that are either broadly cross- reactive or highly specific for cancer samples suggests that the platform described herein can allow identification of fully human antibodies for treatment and/or diagnosis of human cancer. For diagnosis, these antibodies can be further modified by mutagenesis to further eliminate their cross-reactivity to normal tissues. For therapeutic development, the antibodies can be further modified to enhance effector functions through Fc optimization (7) , antibody-drug conjugations (8) ,bi-specific antibody (9) and chimeric antigen receptors (10).
Example 5. Methods
[0321] Examples 1-4 make use of, but are not limited to, the following methods.
Access and analysis of TCGA datasets
[0322] Primary solid tumor RNA sequencing data in BAM format for 6 cancer types
(glioblastoma multiforme, N=154; lower grade glioma, N=512; lung adenocarcinoma, N=525; lung squamous carcinoma, N=474; pancreatic adenocarcinoma, N=177; skin cutaneous melanoma, N=103) were obtained from NCI Genomic Data Commons portal (https://portal.gdc.cancer.gov/). First all files were extracted to the fastq files using samtools (11) fastq function with -O settings. The reads were aligned to reference V, D, J and C genes of human B- cell receptors by using MIXCR (12) align function. Then the two rounds of contig assembly were performed using MIXCR rescue function in RNAseq mode. Based on the aligned contigs, BCR CDR3 clones were assembled by using MIXCR function. Further segment usage analysis and correlation analysis of BCR repertoires was performed using VDJtools (13) software and R software (https://www.r-project.org/).
IgH Clonality Calculation
[0323] IgH clonality was defined as 1- Pielou's evenness and was calculated on productive rearrangements by:
, ,∑f iog2(q)
Figure imgf000119_0001
where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements. Tthe calculation of IgH clonality was implemented in R software (https://www.r-project.org/) by using the vegan package (14)
Genomic DNA extraction and BCR repertoire sequencing
[0324] Two cases of LUAD cancer samples (sample-463 and sample-429) and three cases of LUSC cancer samples (sample-427, sample-840,sample-350) of were selected for DNA extraction, which was performed using TRIZOL Reagent (15596026, lot 86105, ThermoFisher Scientific) according to the manufacturer's guidelines. Then the extracted
DNA of these samples was sent for BCR repertoire sequencing by using the IMMUNOSEQ Assay (Adaptive Biotechnologies). The BCR sequencing was performed at survey level and the raw TCR reads were preprocessed with the immunoSEQ Analyzer.
Recombinant antibody production
[0325] Each heavy chain was co-transfected with each light chain into HEK293T
(CRL- 11268, ATCC) at 1 to 1 ratio using POLYFECT Transfection Reagent (Qiagen, 1015586, lot 154044326) or Lipofectamine 3000 (Invitrogen, L3000-015, lotl811506) following manufacturer's instructions. HEK293T cells were grown in DMEM (Life
Technologies, 11965-092) supplemented with 10% fetal calf serum (GE Healthcare Life Sciences, SH30910.03) and lOug/ml penicillin/streptomycin (GE Healthcare Life Sciences, 15140-122). Three days post transfection, supernatants were collected and the concentrations of expressed recombinant antibodies were estimated by sandwiched ELISA with
known standards.
Tissues, tissue microarrays and immunofluorescence
[0326] Frozen lung tumor samples were purchased from ProteoGenex (Inglewood,
CA). Frozen tissues were embedded into the cryomold (Tissue-Tek, 4728) with O.C.T compound (Tissue-Tek, 4583) and sectioned into 5um sections. Frozen multiple tissue microarray (FMC402a), and lung tissue microarray (FLC320) were purchased from US Biomax, Inc (Rockville, MD). Frozen tissue sections and TMAs were thawed at room temperature for 10-20 minutes and washed three times in PBS. The slides were fixed in 4% formaldehyde for 10 minutes at RT. Slides were then washed in PBS three times for five minutes and incubated in blocking solution (5% normal goat serum in PBS) for one hour. Slides were incubated with each recombinant antibody in complete DMEM for 2 hours at room temperature or at 4°C overnight. Tissues were washed three times in PBS as above and incubated with donkey anti-mouse conjugated to Alexa Fluor 488 (ThermoFisher Scientific, A-21202) in blocking solution for 1 hour in a humid chamber at RT. Cells were washed as above and mounted with ProLong Gold Antifade with DAPI (ThermoFisher Scientific, P36931)
Biostatistics
[0327] The specific tests used to analyze each set of experiments are indicated in the figure legends. Data were analyzed using a Fisher exact test for contingency table. Statistical calculations were performed using GraphPad Prism software (GraphPad Software, San Diego, California).
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3. Li, B. et al. Landscape of tumor- infiltrating T cell repertoire of human cancers. Nat. Genet. 48, 725-732 (2016).
4. Linnemann, C. et al. Technical Reports High-throughput identification of antigen- specific TCRs by TCR gene capture. Nat. Med. 19, 1534-1541 (2013). 5. Dekosky, B. J. et al. High-throughput sequencing of the paired human
immunoglobulin heavy and light chain repertoire. Nat. Biotechnol. 31, 166-199 (2013).
6. Georgiou, G. et al. The promise and challenge of high-throughput sequencing of the antibody repertoire. Nat. Biotechnol. 32, 158-168 (2014).
7. Umana, P., Jean-Mairet, J., Moudry, R., Amstutz, H. & Bailey, J. E. Engineered glycoforms of an antineuroblastoma IgGl with optimized antibody-dependent cellular cytotoxic activity. Nat. Biotechnol. 17, 176- 80 (1999).
8. Hurwitz, E., Arnon, R., Sahar, E. & Danon, Y. a Conjugate of Adriamycin and Monoclonal Antibodies To ThyEl Antigen Inhibits Human Neuroblastoma Cells in Vitro. Ann. N. Y. Acad. Sci. 417, 125- 136 (1983). 9. Merchant, A. M. et al. An efficient route to human bispecific IgG. Nat. Biotechnol. 16, 677-681 (1998).
10. Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the
immunoglobulin and T-cell receptors. Proc. Natl. Acad. Sci. 90, 720-724 (1993).
11. Li, H. et al. The Sequence Alignment / Map format and SAMtools. Bioinformatics 25, 2078-2079 (2009). 12. Bolotin, D. A. et al. MiXCR : software for comprehensive adaptive immunity profiling. Nat. Methods 12, 380-381 (2015).
13. Shugay, M. et al. VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires. PLoS Comput. Biol. 11, 1-16 (2015). 14. Reuben, A. et al. TCR Repertoire Intratumor Heterogeneity in Localized Lung
Adenocarcinomas: an Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence. Cancer Discov. 10, 1088- 1097 (2017).
Table 1- Top 100 Heavy Chain CDR3 from Patient 1
Figure imgf000123_0001
heavy chain TGTGCGAAAGATCGGGGGTCACACTACTACTACTAC 628
CAKDRGSHYYYYGMDVW CDR3 GGTATGGACGTCTGG
heavy chain TGTGGGAGAGACTACGGTGACGCACACTACCACATG 629
CGRDYGDAHYHMDVW CDR3 GACGTCTGG
heavy chain TGTGCGAGAAATTCCATTGATATAATTATACTGGGT 630
CARNS IDI I I LGDTLDIW CDR3 GATACTCTTGATATCTGG
heavy chain TGTGCGAGAAGAAGGGGTAGCCACAGCTTTGATTAC 631
CARRRGSHSFDYW CDR3 TGG
heavy chain TGTGCGAGAGGGACGTCTATTTTAGTGGTGGTGTAT 632
CARGTSILWVYAIYDYW CDR3 GCTATATACGACTACTGG
heavy chain TGTACGAAAGGCCCCCCGGGCGACGGACACTACTTG 633
CTKGPPGDGHYLDYW CDR3 GACTACTGG
heavy chain TGTGCAAAAAGTGGGGGCGGCTTAACGGGGGGTTTC 634
CAKSGGGLTGGFRSWYFDLW CDR3 CGATCCTGGTACTTCGATCTCTGG
heavy chain TGTGCTCGATACGGTGACGAGGCCTATGCTTTTGAT 635
CARYGDEAYAFDIW CDR3 ATCTGG
heavy chain TGTGCGAGAGCCCCTACAACTATATCGAACCCGAAA 636
CARAPTTISNPKNFDIW CDR3 AATTTTGAIATCTGG
heavy chain TGTGCGAGACCAAGGGACTCGCACCTGTTTGATGAT 637
CARPRDSHLFDDAFDVW CDR3 GCTTTTGATGTCTGG
heavy chain TGTGCGAGAGATGTGGCCGAGGGGTGGTTCGACCCC 638
CARDVAEGWFDPW CDR3 TGG
heavy chain 639
TGTGCGAGAGATCTCACCTGGGCCTTTGACTACTGG CARDLTWAFDYW CDR3
heavy chain TGTGCGAGAGGCCTCTCGTCATTTGGGGGCATTATG 640
CARGLSSFGGIMNWYDPW CDR3 AACTGGTACGACCCCTGG
heavy chain TGTGTGAAGAGATCGACAATAGTGACCACGGCGGAC 641
CVKRSTIVTTADSW CDR3 TCCTGG
heavy chain 642
TGTGCGAGAGATCCAGCTGCTTGGGACCACTGG CARDPAAWDHW CDR3
heavy chain TGTGCGAAGTCGTCCATGACTACGAGGATTACGATT 643
CAKS SMTTRI TIDYW CDR3 GACTACTGG
heavy chain TGTGCGAGGGGGGGCGTGGCTGCGATCTTGGACTAC 644
CARGGVAAI LDYW CDR3 TGG
heavy chain TGTGCGAGACAGGGACCAGAGCGCAGGACTTTTGAT 645
CARQGPERRTFDIW CDR3 ATCTGG
heavy chain TGTGCGAAAGATCAGGGGTCACATTACTACTACTAC 646
CAKDQGSHYYYYGMDVW CDR3 GGTATGGACGTCTGG
heavy chain TGTGCGAGAGGTCCCGGCAGACGGGAGTGGGAGTTA 647
CARGPGRREWELLPRDYW
CDR3 CTTCCACGTGACTACTGG
heavy chain TGTGCGAAAGTTCGGGATTACTATGATAGGAGTGGT 648
CAKVRDYYDRSGLDYW CDR3 CTTGACTACTGG
heavy chain TGTGCGAAACTGCCTTTGGGCCGTGTTTTTGATAGC 649
CAKLPLGRVFDSW CDR3 TGG
heavy chain TGTGCGAGAGATGAATTTGGCGGGGACCGTTTCTTC 650
CARDEFGGDRFFYYGMDVW CDR3 TACTACGGTATGGACGTCTGG
heavy chain TGTGCGAGAGGCAGTCGCTCGGTCGCGCTTGACCAC 651
CARGSRSVALDHW CDR3 TGG
heavy chain TGTGCGAGAGCCCCTACAACTATATCGAACCCGAAA 652
CARAPTTI SNPKHFDVW CDR3 CATTTTGATGTCTGG
heavy chain TGTGCAAGAGTAGGTGGGAACTACTACTATAGTGCT 653
CARVGGNYYYSAFDIW CDR3 TTTGATATCTGG
heavy chain TGTGCGAAAGATAAGTCCGGGAATTAC ACTAC AC 654
CAKDKSGNYYYYGLDVW CDR3 GGTTTGGACGTCTGG
heavy chain TGTGCGAGAATGCGGGCGTGGTCCGACGGAAATGAT 655
CARMRAWSDGNDAFDIW CDR3 GCTTTTGATATCTGG
heavy chain 656
TGTACGAGAGCGTCCGCCATGGACGTCTGG CTRASAMDVW CDR3
heavy chain TGTGCGAAACCGGGTTTGTCGGGCTACTACTACTAC 657
CAKPGLSGYYYYMDVW CDR3 ATGGACGTCTGG heavy chain TGTGCGAGAGCCCCTACAACTATATCGAACCCGAAA 658
CARAPTTISNPKHFDIW CDR3 CATTTTGATATCTGG
heavy chain TGTACGAAACTTATGGGGCTAGGGTGGTATTTCGAC 659
CTKLMGLGWYFDVW CDR3 GTCTGG
heavy chain TGTGCGAGAGAAAACTCCTATACTAACTCGACCCGC 660 CARENSYTNSTRSRLYNYYYMD CDR3 TCGCGCCTATATAACTACTATTACATGGACGTCTGG VW
heavy chain 661
TGTGGCCGGGGCAACTCCGCTTTTGACATCTGG CGRGNSAFDI CDR3
heavy chain TGTGCGAGAGATCCCGGCGCGATAICCCCTCTACAC 662
CARDPGAISPLHNWFDPW CDR3 AACTGGTTCGACCCCTGG
heavy chain TGTACGAAAGATCAGAGGGGTTATAACTACTACTAC 663
CTKDQRGYNYYYGMGVW CDR3 GGTATGGGCGTCTGG
heavy chain 664
TGTGCGAGAGAGGCCACCCGGGAGGGCTACTGG CAREATREGYW CDR3
heavy chain TGCGCGAGGGGGGAGAGTACTGGCTGTACTGACTAC 665
CARGESTGCTDYW CDR3 TGG
heavy chain 666
TGTGCGAGTCCGTGGAATTACATGGACATCTGG CASPWNYMDIW CDR3
heavy chain TGTGCGAGAGATTCCCGCCCCGACIACTTTGATAAT 667
CARDSRPDYFDNYCFDLW CDR3 TACTGCTTTGACCTCTGG
heavy chain TGTGCCAGAGTTTGGGGATACAGCTATGTTTTGAGG 668
CARVWGYSYVLRHFDVW CDR3 CACTTCGATGTCTGG
heavy chain TGTGCCAGAGATCTCGGTTCCTACAAAGCCTACATG 669
CARDLGSYKAYMDVW CDR3 GACGTCTGG
heavy chain TGTGCGAGAGAAGTCAGCTTGGACIGGTTAGGTGGT 670
CAREVSLDWLGGMDVW CDR3 ATGGACGTCTGG
heavy chain TGTACCACATTAGAGGGAGTGGTGGCTGCTACGGGA 671
CTTLEGWAATGGSW CDR3 GGCTCCTGG
heavy chain 672
TGTGCGAGATACGATTTTTGGAGTGGTATCCACTGG CARYDFWSGIHW CDR3
heavy chain TGTGCGAGAGATTCAGCTTTTTGGAGCGGTTATTCC 673
CARDSAFWSGYSSVFDYW CDR3 TCCGTGTTTGACTACTGG
heavy chain TGTGCAAAAGATCGATATATGAACCTTTATGTTTTT 674
CAKDRYMNLYVFDIW CDR3 GATATTTGG
heavy chain TGTGCGAGAGTGTTGACTACAATAACTACTCAGGCG 675
CARVLTTITTQADW CDR3 GACTGG
heavy chain 676
TGTGCGAGAGATAACAATGGCTACGGTATATCCTGG CARDNNGYGI SW CDR3
heavy chain TGTGCGAGATCCCCCCTTTCGCTTATGATACCGACC 677
CARSPLSLMIPTTWFDPW
CDR3 ACCTGGTTCGACCCCTGG
heavy chain TGTGTAAGAGGAGGGATGAAAGTGAGTGGCCTTGAC 678
CVRGGMKVSGLDAFDIW CDR3 GCTTTTGATATCTGG
heavy chain TGTGCAAGAGACACAAATTTCTCCCACATGGACGTC 679
CARDTNFSHMDVW CDR3 TGG
heavy chain 680
TGTGCGTGGGTGGGCAACTGG CAWVGNW CDR3
heavy chain TGTGCGAGAGGCCTAGCAGTGGCCCTGGGCGATTGG 681
CARGLAVALGDWYFYYGMDVW CDR3 TACTTCTACTACGGTATGGACGTCTGG
heavy chain TGTGCGAGAGATGGGGGGATAGCTGCTAACTACTTT 682
CARDGGIAANYFDFW CDR3 GACTTCTGG
heavy chain TGTGCGAGAGATACTATTACGGGAAGGCGCTTTGAC 683
CARDTITGRRFDYW CDR3 TACTGG
heavy chain 684
TGTGCGAGAGGCGGAGTTTGG CARGGVW CDR3
heavy chain 685
TGTGCGAAAGCGGTGCGTCTGGACGTCTGG CAKAVRLDVW CDR3
heavy chain TGTGCGAGGGGGGGTTCGTGGGTCATTGTAGTAGTA 686
CARGGSWVIVWPTATEFDPW CDR3 CCAACTGCTACCGAGTTCGACCCCTGG
heavy chain TGTGCGAGAGGGCACTATCTGCGACCCTTCGACCCC 687
CARGHYLRPFDPW CDR3 TGG 88 heavy chain 688
TGTGTCCACGGTGAGACCCGGGGGTTTGAGTACTGG CVHGETRGFEYW CDR3
89 heavy chain TGTGCGAGAGGGACTTTCGGTGGTGTCATCTTTGAA 689
CARGTFGGVIFEHW CDR3 CACTGG
90 heavy chain TGTGCGAGACTAAGGATGACTTCAGTAGCTGCTTTT 690
CARLRMISVAAFDVW CDR3 GATGTCTGG
91 heavy chain 691
TGTGCGAGAGACAGAGAATTGGGGCTTGACTACTGG CARDRELGLDYW CDR3
92 heavy chain TGTGCGAAAGGCCGATCTAGTGTAGCGTCTCGCCGA 692
CAKGRSSVASRRAPGYFDLW CDR3 GCCCCCGGGTACTTCGATCTCTGG
93 heavy chain 693
TGTGCGAGAAATTTCCCTACCCTTGACTACTGG CARNFPTLDYW CDR3
94 heavy chain TGTGCGAGAGGCCTGTGGGGCCCGAGAGGAAATGAT 694
CARGLWGPRGNDAFDIW CDR3 GCTTTTGATATCTGG
95 heavy chain 695
TGTGCAACCTCCGGGGATCAACCCTGG CATSGDQPW CDR3
96 heavy chain TGTGCGAGAGTGACTTGGGGACTCTTGGCCTACAGG 696
CARVTWGLLAYRPQYFDYW CDR3 CCCCAGTACTTTGACTACTGG
97 heavy chain TGTGCGAAAGATAATAGTGGCGCCGATCCCTACTAC 697
CAKD SGADPYYYYYMD W CDR3 TACTACTACATGGACGCCTGG
98 heavy chain TGTGCGAGAGGGAAGACGTACTATGGCGCAGGGGAT 698
CARGKTYYGAGDGFFDYW CDR3 GGTTTTTTTGACTACTGG
99 heavy chain TGTGCGCAAGATGGGGGGGGTGATCATGCTTCGGGA 699
CAQDGGGDHASGSYFNW CDR3 AGTTATTTCAACTGG
100 heavy chain TGTGCGAAATCTGGAAGAACAGTATTCTCCTTTGAC 700
CAKSGRTVFSFDSW CDR3 TCCTGG
Table 2- Top 100 Light Chain CDR3 from Patient 1
SEQ Description Nucleic Acid Sequence SEQ Amino Acid Sequence
ID ID
NO NO
101 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCACCGGGTA 701
CQVWDSSSDHRVF CDR3 TTC
102 light chain 702
CDR3 TGTCAGCTGCGTAGCAGCTGGCCTCCGGCGTTC CQLRSSWPPAF
103 light chain 703
CDR3 TGTCAACAGACTAACAGTTTCCCCCTCACTTTC CQQTNSFPLTF
104 light chain 704
TGTCAAAAGTATAACAGTGCCCCCCTCACTTTC CQKYNSAPLTF CDR3
105 light chain 705
TGTCAACAGAGTTATATTACCCCCTGGACGTTC CQQSYITPWTF CDR3
106 light chain TGTCAGGTGTGGGATAGTATTGGTGATCATGTGCTC 706
CQVWDSIGDHVLL CDR3 CTC
107 light chain 707
TGTCAACAGAGTTATATTGTCCCCTGGACGTTC CQQSYIVPWTF CDR3
108 light chain 708
TGTCAACAGGCTAACAGTTTCCCCCTCTCTTTC CQQANSFPLSF CDR3
109 light chain TGTCAATCAGCAGACAGCAGTGGTACTTATGTGGTA 709
CQSADSSGTYWL CDR3 CTC
110 light chain 710
TGTCAGCAGTATAATAGCTGGCCTCCTCTCACTTTC CQQYNSWPPLTF CDR3
111 light chain 711
TGTCAGCAGTATGATACCTGGCCTCCGAGAACGTTC CQQYDTWPPRTF CDR3
112 light chain 712
TGCCAACAGTATAATGTTCTGCTCACTTTC CQQYNVLLTF CDR3
113 light chain 713
TGTCAGGCGTGGGACAGCAGCACTGTGGTATTC CQAWDSSTWF CDR3 114 light chain TGTGCAACATGGGATGACAGCCTGAATGGTTGGGTG 714
CATWDDSLNGWVF CDR3 TTC
115 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCATTCTTGG 715
CQVWDSSSDHSWVF CDR3 GTGTTC
116 light chain TGTCAGGTGTGGGATAGTAGTAGTGATAACCGGGTA 716
CQVWDSSSDNRVF CDR3 TTT
117 light chain 717
TGCCAACAGTATAATCGTTATCCCGGGACGTTC CQQYNRYPGTF CDR3
118 light chain TGTCAGGTGTGGGATAGTGGTAGTGATCATTGGGTG 718
CQVWDSGSDHWVF CDR3 TTC
119 light chain 719
TGTCAGCAATATTATAGTACTCCTCGGACTTTT CQQYYSTPRTF CDR3
120 light chain 720
TGTTACTCTGCGGCTGACAACAATGTGGTATTC CYSAADNNWF CDR3
121 light chain 721
TGTCAGCAATATTATAGTAATCCTCGAACGTTC CQQYYSNPRTF CDR3
122 light chain 722
TGCATGCAAGTTCTACAAATTCCTCCGTCTTTC CMQVLQIPPSF CDR3
123 light chain 723
TGTTACTCTGCGGCTGACAACAATCTAGTATTC CYSAADNNLVF CDR3
124 light chain 724
TGTCAGCAGTATGGTAGCTCACCGGAGACGTTC CQQYGSSPETF CDR3
125 light chain 725
TGCATGCAAGTTCTACAAACTCCTCTCAGTTTC CMQVLQTPLSF CDR3
126 light chain TGTGCAGCTTGGGATGACAGCCTGGATGGTTGGGTG 726
CAAWDDSLDGWVF CDR3 TTC
127 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCATTGGGTG 727
CQVWDSSSDHWVF CDR3 TTC
128 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCATGTGGTT 728
CQVWDSSSDHWF CDR3 TTC
129 light chain 729
TGCATGCAAGGTACACACTTGTGGACGTTC CMQGTHLWTF CDR3
130 light chain 730
TGTCAACAGAGTTATATTATCCCCTGGACGTTC CQQSYIIPWTF CDR3
131 light chain 731
TGTCAGCAGAGTTACAGCTTGCTCACTTTC CQQSYSLLTF CDR3
132 light chain 732
TGCATGCAAGCTCTACAAACTCCTCACACTTTT CMQALQTPHTF CDR3
133 light chain TGCATGCAAGGTACACACTGGCCTCCGGCGCTCACT 733
CMQGTHWPPALTF
CDR3 TTC
134 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCAGCGGGTA 734
CQVWDSSSDQRVF CDR3 TTC
135 light chain 735
TGTCAACAACTTAATACTTACCCTCGTACTTTT CQQLNTYPRTF CDR3
136 light chain 736
TGTCAACAGGCTAACAGTTTCCCCCTCACTTTC CQQANSFPLTF CDR3
137 light chain 737
TGTCAACAATATCATGATACTCCGACGTTC CQQYHDTPTF CDR3
138 light chain TGTCAGGTGTGGGAGACTAGTAGTAGTGATCATCCG 738
CQVWETSSSDHPHWF CDR3 CATGTGGTATTC
139 light chain TGTCAGGTGTGGGATAGTATTCGTGATCATGTGCTC 739
CQVWDSIRDHVLL CDR3 CTC
140 light chain TGTCAGCAGTTTGGTAGCTCACCTCCGGAGTACGCT 740
CQQFGSSPPEYAF CDR3 TTT
141 light chain 741
TGCCAACAGTATAATGCTCTGCTCACTTTC CQQYNALLTF CDR3
142 light chain 742
TGTCAACAGTTTGATAGTTCTCCCTCATTCACTTTC CQQFDSSPSFTF CDR3
143 light chain TGTGCAGCATGGGATGACAGCCTGAATGGTTGGGTG 743
CAAWDDSLNGWVF CDR3 TTC 144 light chain 744
TGCATGCAAGCTCTACAAACTTTCACGTGGACGTTC CMQALQTFTWTF CDR3
145 light chain 745
TGTATGCAGGTTCTACAAACTCCTCTCAGTTTC CMQVLQTPLSF CDR3
146 light chain TGTCAGGTGTGGGATAGTGGTAGTGATCAGCGGGTA 746
CQVWDSGSDQRVF CDR3 TTC
147 light chain 747
TGTCAGCAGTATGGTAGCTCGCGGACGTTC CQQYGSSRTF CDR3
148 light chain TGTGCAGCATGGGATGACAGCCTGAGAGGCGGGGTG 748
CAAWDDSLRGGVF CDR3 TTC
149 light chain 749
TGTCAGTCTTATGATACCAACAATTGGGTGTTC CQSYDTNNWVF CDR3
150 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCCTTATGTC 750
CQVWDSSSDPYVF CDR3 TTC
151 light chain 751
TGTCAAAAGCATAACAGTGCGCCATTCACTTTC CQKHNSAPFTF CDR3
152 light chain 752
TGTCAGCAGTATGCTAGCTCTGTCACTTTC CQQYASSVTF CDR3
153 light chain TGTGCAGCATGGGATGACAGCCTGAATGGTGTGGTA 753
CAAWDDSLNGWF CDR3 TTC
154 light chain 754
TGTCAACAGAGTTACAGTACCCCATTCACTTTC CQQSYSTPFTF CDR3
155 light chain 755
TGTCTACAAGATCACCATTACCTCTGGACGTTC CLQDHHYLWTF CDR3
156 light chain 756
TGTCAGCAGGCTAACAGTTTCCCTCTCACTTTC CQQANSFPLTF CDR3
157 light chain 757
TGTCAGCAGTATAATAATTGGCCTCGGACGTTC CQQYNNWPRTF CDR3
158 light chain 758
TGTCTCCAGCATCATTCTTACCCGTGGACGTTC CLQHHSYPWTF CDR3
159 light chain 759
TGTCAGCAGTATGGTAGCTCACCGTTCACTTTT CQQYGSSPFTF CDR3
160 light chain TGTCAGGTGTGGGATAGTAGTAGTGGTCATCCTAAT 760
CQVWDSSSGHPNWVF CDR3 TGGGTGTTC
161 light chain 761
TGTATGCAACGTATAGAGTTTCCTTCGACGTTC CMQRIEFPSTF CDR3
162 light chain 762
TGTCAGTCTTATGATAGCAGCAATCATTGGGTCTTC CQSYDSSNHWVF CDR3
163 light chain 763
TGTCTACAACATAATACTTTCCCATTCTCTTTC CLQHNTFPFSF CDR3
164 light chain 764
TGTCAGCAATATTATAGTAGTCCTTTCACTTTC CQQYYSSPFTF CDR3
165 light chain 765
TGTCACCAATATTACAATACTCCTCTCACTTTC CHQYYNTPLTF CDR3
166 light chain 766
TGTCAGCAGTATGGTAGCTCACCACTCACTTTC CQQYGSSPLTF CDR3
167 light chain 767
TGCTGCTCACCTGCAGGCGGTTACTCTTGGGTGTTC CCSPAGGYSWVF CDR3
168 light chain 768
TGTCTGCAGCATAATAGTTACCCCCTCACTTTC CLQHNSYPLTF CDR3
169 light chain 769
TGTCAACAGGCTAACAGTTTCCCTCTCACTTTC CQQANSFPLTF CDR3
170 light chain TGCTGCTCATATGCTGGCAGCTACACTTTTGTCCTT 770
CCSYAGSYTFVLF CDR3 TTC
171 light chain 771
TGTCAACAATATCATAGTTCTCCGACGTTC CQQYHSSPTF CDR3
172 light chain 772
TGCATGCAAGCTCTACAAACCCCTCGCTTC CMQALQTPRF CDR3
173 light chain 773
TGCATGCAAGTTCTACAAACTCCGCTCAGTTTC CMQVLQTPLSF CDR3 174 light chain 774
TGTCAGCAGCGTAGCAACTGGCCGGGGCTCACTTTC CQQRSNWPGLTF CDR3
175 light chain 775
TGTCAGCAGTATATTAACTGGCCTATATTCACTTTC CQQYINWP IFTF CDR3
176 light chain 776
TGCCAACAGTATAAAACTTATTCGTGGACGTTC CQQYKTYSWTF CDR3
177 light chain TGTGTAGTTTGGGATGACAGCCTGAGTGATCCTTGG 777
CWWDDSLSDPWVF CDR3 GTGTTC
178 light chain 778
TGCATGCAAGGAATACAGAAGTGGACGTTC CMQGIQKWTF CDR3
179 light chain 779
TGTCAGCAGTATGGTAGGTCACCGGAGACGTTC CQQYGRSPETF CDR3
180 light chain 780
TGTCAACAGAGTTACAGTTTCCCCAGGACCTTC CQQSYSFPRTF CDR3
181 light chain 781
TGCCAACAATATGATACTTATACGIGGACGTTC CQQYDTYTWTF CDR3
182 light chain 782
TGCATGCAAGCTCTACAAACCGCGCTCACTTTC CMQALQTALTF CDR3
183 light chain 783
TGCATGCAAGGTACATACTGGCCGTGGACGTTC CMQGTYWPWTF CDR3
184 light chain 784
TGTCAACAATATCATAGTACTCCGACGTTC CQQYHSTPTF CDR3
185 light chain TGTCAGCAGCGTACCAGCTGGCCTTTTTCTTTCAAC 785
CQQRTSWPFSFNF CDR3 TTC
186 light chain 786
TGCCAACAGTATGATAGTTATCCGTACACTTTT CQQYDSYPYTF CDR3
187 light chain TGTTCCTCAACAGACGCCAGTGGTCCTTATAGGGGG 787
CSSTDASGPYRGVF CDR3 GTCTTC
188 light chain 788
TGTCAGCAATATTTTAATAGTCCGACCACGTTC CQQYFNSPTTF CDR3
189 light chain 789
TGTCAGCAATATTATAGTACTCCTTTCACTTTC CQQYYSTPFTF CDR3
190 light chain TGTCAGGTGTGGGATAGTGATACTGATCACCGGGTT 790
CQVWDSDTDHRVF CDR3 TTC
191 light chain 791
TGCTGCTCATATGCAGATACTAGTACCTTGGTGTTC CCSYADTSTLVF CDR3
192 light chain 792
TGTCAGCAATATCATAGTACTCCGACGTTC CQQYHSTPTF CDR3
193 light chain 793
CDR3 TGTCAACAGTCTAACAGTTTCCCACTTACTTTC CQQSNSFPLTF
194 light chain TGCCAGTCCTATGACAGCAGACTGAGGGCTTATGTC 794
CQSYDSRLRAYVF CDR3 TTC
195 light chain 795
TGTCAACAACGTAGCAACTCGCGCACTTTC CQQRSNSRTF CDR3
196 light chain 796
TGTCAGCAGCGTAGCATCTGGCCGCTCAGTTTC CQQRSIWPLSF CDR3
197 light chain 797
TGCCAACAATATAATACTTATCCGTGGACGTTC CQQYNTYPWTF CDR3
198 light chain 798
TGTCAGCACCATGGTGGCTCAACTCCGTGGACGTTC CQHHGGSTPWTF CDR3
199 light chain TGTCAGGTGTGGGATAATAGTAGTGATCATTGGGTG 799
CQVWDNSSDHWVF CDR3 TTC
200 light chain 800
TGCACCTCATATACAAGCAGCAGCACTCTGGTATTC CTSYTSSSTLVF CDR3 Table 3- Top 100 Heavy Chain CDR3 from Patient 2
SEQ Description Nucleic Acid Sequence SEQ Amino Acid Sequence
ID ID
NO NO
201 heavy chain TGTGCCAGAACAATGGTGGTCGCTGCATACTTTGAC 801
CARTMWAAYFDYW CDR3 TACTGG
202 heavy chain 802
CDR3 TGTGCAAGGGATCCGGCCGGTCTGGACGTCTGG CARDPAGLDVW
203 heavy chain TGTGCGAGAGATTGGTATAAGGTGCGGTTCGACCCC 803
CARDWYKVRFDPW CDR3 TGG
204 heavy chain TGTGCCAGAGATGAAGGGGGGGCCACTCCGGACTAC 804
CARDEGGATPDYW CDR3 TGG
205 heavy chain TGTGTGAAAGATCGCGTCTTTCGGGGAGATGTCGAC 805
CVKDRVFRGDVDW CDR3 TGG
206 heavy chain TGTGCGAGAGTCGCACGGGGTGGTGAAAACACTCGC 806
CARVARGGENTRRGFFDNW CDR3 CGGGGCTTCTTTGACAACTGG
207 heavy chain TGTACTAGAGTTGGTGTGACCACGAGCGGTATGGAC 807
CDR3 CTRVGVTTSGMDVW
GTCTGG
208 heavy chain TGTGCAAAAGGTCTAGCACCAGTTGGAACGGCGGTG 808
CAKGLAPVGTAVGGYGMDVW CDR3 GGTGGCTACGGAATGGACGTCTGG
209 heavy chain TGTGCGAGAGTCCGTCTAGAGGGAACTACTAACTCC 809
CARVRLEGTTNSAMDVW
CDR3 GCTATGGACGTCTGG
210 heavy chain TGTGCGAGAGATTTTGACGCTATTGGGGGTCTGGAC 810
CARDFDAIGGLDVW CDR3 GTCTGG
211 heavy chain TGTGCGGGCCGGGGCTCGTCCCGGGACTATGATCCT 811
CAGRGSSRDYDPFGFW CDR3 TTTGGTTTTTGG
212 heavy chain TGTGCGAAAGACGTTTCGAGAGGTGGATCGCAAGAC 812
CAKDVSRGGSQDFR CDR3 TTCCGG
213 heavy chain TGTGCAACAGATGTGAGGCACGGCTTCTATGCTTTT 813
CATDVRHGFYAFNVW CDR3 AATGTCTGG
214 heavy chain TGTGCCAGAGTCGGAGTTCCCCCAACGGTGTTTGAC 814
CARVGVPPTVFDFW CDR3 TTCTGG
215 heavy chain TGTACAAGAGGGGGAGCCGATTACAGCTTTGACGTG 815
CTRGGADYSFDVW CDR3 TGG
216 heavy chain TGTGTGAGAGGCCTCTTATATCCAGGCGACTTCCAC 816
CVRGLLYPGDFHGMDVW CDR3 GGTATGGACGTCTGG
217 heavy chain TGTGCGGGCCGGGGCTCGTCTCGGGACTATGATCCT 817
CAGRGSSRDYDPFGFW CDR3 TTTGGTTTTTGG
218 heavy chain TGTGCGAGACGGGGCACTGTGAATGATTTCCTAATG 818
CARRGTVNDFLMFDPW CDR3 TTTGACCCCTGG
219 heavy chain TGTGCGACAGGGGGCCTTCCGGCGTCGATTGAAACA 819
CATGGLPAS IETLVGWFDDW CDR3 CTCGTGGGCTGGTTTGACGACTGG
220 heavy chain TGTGCACACAGATGGGGCAGTTCGTCCGGAAACTTT 820
CAHRWGSSSGNFDFW CDR3 GACTTCTGG
221 heavy chain 821
CDR3 TGTGCTAGGGATCCGGCCGGTCTGGACGTCTGG CARDPAGLDVW
222 heavy chain 822
TGTGCGAGAGAAGTCGAGGCCTACGACGTCTGG CAREVEAYDVW CDR3
223 heavy chain TGTGCAACAGATCTGAGGCACGGCTTCTATGCTTTT 823
CATDLRHGFYAFNVW CDR3 AATGTCTGG
224 heavy chain TGTGTGAGATCCTTTTGGGGGAGTTTTCGGCCGGAC 824
CVRSFWGSFRPDLHWFDLW CDR3 CTCCACTGGTTCGACCTCTGG
225 heavy chain TGTGCGAGGGGGAAGCAGTGGCTGGGACCCTTTGAC 825
CARGKQWLGPFDFW CDR3 TTCTGG
226 heavy chain TGTGCGACGGATAGGCCGATAATGGGTATCGACGTC 826
CATDRPIMGIDVW CDR3 TGG
227 heavy chain TGTGCACACAGGGTGATTTATTATGATAGGAGTGAA 827 CAHRVIYYDRSEFYFDNW CDR3 TTTTACTTIGACAACTGG
228 heavy chain TGTGCGAGATTAGATGGTAGTGGTICTTACTTGGGT 828
CARLDGSGSYLGAAFDV CDR3 GCTGCTTTTGATGTCTGG
229 heavy chain TGTGCGAGAGGGGGGGTGGTAGGAGCCCCACTTGAC 829
CARGGWGAPLDYW CDR3 TACTGG
230 heavy chain TGTGCGAGACATGCTCGGTTCGGCIACTACTTTGAC 830
CARHARFGYYFDSW CDR3 TCCTGG
231 heavy chain 831
TGTGCGAACGGACTGTGGGGTCCGTTTGACTACTGG CANGLWGPFDYW CDR3
232 heavy chain TGTGCGAGAGATTGGTATAAGGTGCGGTTGGACCCC 832
CARDWYKVRLDPW CDR3 TGG
233 heavy chain 833
TGTATCACAATGGCCAAGTACTGG CITMAKYW CDR3
234 heavy chain TGTGCAGTCGGATATGAGCCCTATGGCCCGGATGCT 834
CAVGYEPYGPDAFDIW CDR3 TTTGATATCTGG
235 heavy chain TGTGCCAGAGTCGGAGTTCCCCCAACGGGGTTTGAC 835
CARVGVPPTGFDFW CDR3 TTCTGG
236 heavy chain TGTGCAAGAGACCTGCCGTTGTTAIGGATCGGGGAC 836
CARDLPLLWI GDNGLDV CDR3 AACGGTTTGGACGTCTGG
237 heavy chain TGTGTGAGAGACTCTTATGTTGGGGCCTACTATGCC 837
CVRDSYVGAYYAYW CDR3 TATTGG
238 heavy chain TGTGCGAGAGATGATTACGTTATTAGTGCTTTGGAT 838
CARDDYVI SALDVW CDR3 GTCTGG
239 heavy chain 839
TGTGCCAGAGGCCCATATTTTGACTCGTGG CARGPYFDSW CDR3
240 heavy chain 840
TGTGCGAGAATCGGAACTAGTGGACACTTCTGG CARIGTSGHFW CDR3
241 heavy chain TGTGCGAGGCTTGCTCGGTTCGCATACTACTTTGAC 841
CARLARFAYYFDYW CDR3 TATTGG
242 heavy chain TGTGCGAGACGGGGACACAGCCTTGGCTCATACGAC 842
CARRGHSLGSYDFALW CDR3 TTTGCTTTATGG
243 heavy chain TGTGCGCAGAATGTCCTGACCTCGAATACATTTGGC 843
CAQNVLTSNTFGTLYFDYW CDR3 ACCTTGTACTTTGACTACTGG
244 heavy chain TGTGCGAGAGATCCTGGCCAATACGCCTCGGATCAA 844
CARDPGQYASDQEYFPHW CDR3 GAGTACTTCCCGCACTGG
245 heavy chain TGTGCGTTGATCGCTTACGGAATCGGGCAGTTCGTT 845
CALIAYGIGQFVDYW CDR3 GACTACTGG
246 heavy chain 846
TGTGCGAAATGGGACTACGGAATGGACGTCTGG CAKWDYGMDVW CDR3
247 heavy chain TGTGCGAGAGATTTCCGACTGTCGGCCGATGACCAG 847
CARDFRLSADDQEYFPHW CDR3 GAATACTTCCCACACTGG
248 heavy chain TGTGCGAGAGACCTGGGGGCCCTAACATATTACTTT 848
CARDLGALTYYFDT IGPDYW CDR3 GATACTATTGGTCCTGACTACTGG
249 heavy chain TGTGCTAGAGACTTTAGCAGAAAGTTCTCCTTTAGT 849
CARDFSRKFSFSDW CDR3 GACTGG
250 heavy chain TGTGCGAGACACATGGGAACTACCGACGTTGACTAC 850
CARHMGTTDVDYW CDR3 TGG
251 heavy chain TGTGCGGCTAAAAGGGGATTCGATACTAGTGGTTTT 851
CAAKRGFDTSGFHNGWLDPW CDR3 CACAACGGGTGGCTCGACCCCTGG
252 heavy chain TGTGCGAGACTGAAGTGGCTGGTGCCAGATGCTTTT 852
CARLKWLVPDAFDMW CDR3 GATATGTGG
253 heavy chain TGTGCGAGTTCAAGGGACGTAATTACTAGTACCGAC 853
CASSRDVITSTDYW CDR3 TACTGG
254 heavy chain 854
TGTGCGAAGTCGACATCTACTTGG CAKSTSTW CDR3
255 heavy chain TGTGCAACAGATGTGAGGCACGGCTTCTATGCCTTT 855
CATDVRHGFYAFNVW CDR3 AATGTCTGG
256 heavy chain TGTGCGAGAGACAGGGGGAGCAGCAGACCGATTGAG 856
CARDRGSSRP IEHW CDR3 CACTGG
257 heavy chain TGTGCGAGAGATCCCGGGCGAAGACTCGACCCTTGG 857 CARDPGRRLDP CDR3
258 heavy chain TGTGCGAGAGATCCTGCCCAATACGCCTCGGATCAA 858
CARDPAQYASDQDYFPHW CDR3 GATTACTTCCCGCACTGG
259 heavy chain TGTGCGAGAGATGCAAATCTTGTCCCTGGTCACGAC 859
CARDANLVPGHDVW CDR3 GTCTGG
260 heavy chain TGTGCAAAAGACGTGAGACTCACCAACCCCGGGGGT 860
CAKDVRLTNPGGLDVW CDR3 TTGGACGTCTGG
261 heavy chain 861
TGTGCGAGAGGGGATATCGGTTGGTTCGACCCCTGG CARGDIGWFDPW CDR3
262 heavy chain TGTGCGGGCCGGGGCTCGTCCCGGGACTATGATCCT 862
CAGRGSSRDYDPFDFW CDR3 TTTGATTTTTGG
263 heavy chain TGTGCGAGAGAACCCGACAGTGGCTTCCGCGGTATG 863
CAREPDSGFRG DLW CDR3 GACCTTTGG
264 heavy chain TGTGCGAGAGGAACTCTGTTTAGCAGTGGATGGGAA 864
CARGTLFS SG EAFEVW CDR3 GCATTCGAGGTCTGG
265 heavy chain TGTGCGAGAGATATCGGCGACCCTGATATTAATGGT 865
CARD I GDPD INGYPTYW CDR3 TATCCCACGTATTGG
266 heavy chain 866
TGTGCGGTCCTCAAGTTAGCACTGACTGACAACTGG CAVLKLALTDNW CDR3
267 heavy chain TGTGCGAGGTTGTCTTTCGATGTTTTGACTGGTTAT 867
CARLSFDVLTGYYDSFDIW CDR3 TATGATTCTTTTGATATTTGG
268 heavy chain TGTGCGAGATTACCCCGTTTAGCAGCAGAAAGTCTC 868
CARLPRLAAESLW CDR3 TGG
269 heavy chain TGTGCGAGACCGAATCGCCGCGAATTCGTTTGGGGG 869
CARPNRREFV GSYAYW CDR3 AGTTATGCCTACTGG
270 heavy chain TGTGCCAGAGTCGGAATTCCCCCAACGGCGTTTGAT 870
CARVGIPPTAFDFW CDR3 TTCTGG
271 heavy chain TGTGCAAGAGGAGGAGCCGATTACAGCTTTGACGTG 871
CARGGADYSFDVW CDR3 TGG
272 heavy chain 872
TGTGTGAGAGGAATAGGACGTCTTGAATCCTGG CVRGIGRLES CDR3
273 heavy chain 873
TGTACCACTAACAACTGGTTCCCTGAGTGG CTTNNWFPEW CDR3
274 heavy chain TGTGCGACAGTCGCACGGGGTGGTGAAAACACTCGC 874
CATVARGGENTRRGFFDNW CDR3 CGGGGCTTCTTTGACAACTGG
275 heavy chain TGTGCGAGAGATAATGGATTCACCTATGGATACACT 875
CARDNGFTYGYTHYFDYW CDR3 CATTACTTTGACTATTGG
276 heavy chain TGTGCGAGACATCGAGGGGTTCTTGGAGAATACTAC 876
CARHRGVLGEYYGMDVW CDR3 GGTATGGACGTCTGG
277 heavy chain TGTGCCAGAGTCGGAATTCCCCCAACGGTTTTTGAC 877
CARVGIPPTVFDFW CDR3 TTCTGG
278 heavy chain TGTGCGACGGATAGGCCGATAATGGGTATGGACGTC 878
CATDRP IMGMDVW CDR3 TGG
279 heavy chain 879
TGTGCGAGAACGGAGTCTGACAATTCAGAATATTGG CARTESDNSEYW CDR3
280 heavy chain TGCGCGAGACGGGCGAGAGACGGCCCTACGCACGGG 880
CARRARDGPTHGAFDIW CDR3 GCTTTTGATATCTGG
281 heavy chain TGTGGGGGATCCCCTGGGGGTTATTACGGGATAGAC 881
CGGSPGGYYGIDVW CDR3 GTCTGG
282 heavy chain 882
TGTGCGAGAACGGAGAATGACAACTCGGAATTCTGG CARTENDNSEFW CDR3
283 heavy chain TGTGCCAGAGGAAAAACTTCGGTGTACACGGGCTGG 883
CARGKTSVYTGWFDPW CDR3 TTCGACCCCTGG
284 heavy chain TGTGCGAGAAGCCCTGACTACGGCGAGACCTTTGAC 884
CARSPDYGETFDFW CDR3 TTCTGG
285 heavy chain TGTGCGAGATTGCCCCGCTTAGCGTCAGAAAGTGCC 885
CARLPRLASESAW CDR3 TGG
286 heavy chain TGTGCGAAGGCCCAAGGTCTACGATCGGACCAATAT 886
CAKAQGLRSDQYYYTLDVC CDR3 TACTACACTTTGGACGTCTGC
287 heavy chain TGTACGAGAGGTGGATACAGTTATAGTCCGAACTAT 887 CTRGGYSYSPNYYGMDV CDR3 TACGGTATGGACGTCTGG
288 heavy chain TGTGCGAGAGCCTCTCCCTATAGTGGGATGAGCTAT 888
CARASPYSGMSYASDYW CDR3 GCCTCTGACTACTGG
289 heavy chain TGTGCGAGACCAAACGAGGGACAGCTTTGGGGCGGT 889
CARPNEGQLWGGLLYW CDR3 TTGCTCTACTGG
290 heavy chain TGTGCACGGAGCATTACAGCTATGGGCTTAAAGTAC 890
CARS I TAMGLKYYGMDV CDR3 TACGGTATGGACGTCTGG
291 heavy chain TGTGCGAGAGGGGACGAGGACCTTCTGGGGGCCGCC 891
CARGDEDLLGAAYFYYGMDVW CDR3 TACTTTTACTACGGTATGGACGTCTGG
292 heavy chain TGTGTGAGACAGGGAGGATTTGCCTCGTCCCCCCCC 892
CVRQGGFAS SPPFFFGMDVW CDR3 TTCTTCTTCGGTATGGACGTCTGG
293 heavy chain TGTGCGAGAGGCTTTCATTATTCTGGTTCGGGGGTC 893
CARGFHYSGSGVTT GMDVW CDR3 ACAACAATGGGTATGGACGTCTGG
294 heavy chain TGTGCGAGAGGGGAGACTACTTTAGGCCGCTTCTTT 894
CARGETTLGRFFYGLDV CDR3 TACGGTTTGGACGTCTGG
295 heavy chain TGTGCACGACGGGGATATTATCACTACGCTGTGGAC 895
CARRGYYHYAVDLW CDR3 CTCTGG
296 heavy chain 896
TGTGTGAGAGACACCACCGACGGTATGGACGTCTGG CVRDTTDGMDV CDR3
297 heavy chain TGTGCGAGCGTCGTGGACTACATAAGGACGGGACTC 897
CASWDYIRTGLYYFDNW CDR3 TACTACTTTGACAACTGG
298 heavy chain TGTGCGAAAGACGTTGCGAGAGGTGGATCGCAAGAC 898
CAKDVARGGSQDFR CDR3 TTCCGG
299 heavy chain TGTGCGACAGAAAAGCGGAGTGGGACCTTTGGCTAT 899
CATEKRSGTFGYGYFYGMDVW CDR3 GGGTACTTTTACGGTATGGACGTCTGG
300 heavy chain TGTGCAACAGATCTGAGTCACGGCTTCTATGCTTTT 900
CATDLSHGFYAFNVW CDR3 AATGTCTGG
Table 4- Top 100 Light Chain CDR3 from Patient 2
SEQ Description Nucleic Acid Sequence SEQ Amino Acid Sequence
ID ID
NO NO
301 light chain 901
CDR3 TGTCAGCAGTATGGTAGCTCGCCGTACACTTTT CQQYGSSPYTF
302 light chain 902
TGCCAACAGTATAATAGTTATTGGATGTTC CQQYNSYWMF CDR3
303 light chain TGCAGCTCATTTATAAGCAGCATCAGTCTCTATGTC 903
CSSFISSISLYVIF CDR3 ATTTTC
304 light chain 904
TGTCAATCAGCAGACAGCTATTTC CQSADSYF CDR3
305 light chain 905
TGCCAACAGTATAATACTTACCCGTACACTTTT CQQYNTYPYTF CDR3
306 light chain TGTTACTCAATAGACAATAGTGGAAATCATCAGGGG 906
CYS IDNSGNHQGVF CDR3 GTATTC
307 light chain 907
TGTCAGCAGTATTATGTTACTCCTATCACTTTC CQQYYVTPITF CDR3
308 light chain 908
TGTCAGCAGTATAATGACTGGCCTCGGACGTTC CQQYNDWPRTF CDR3
309 light chain 909
TGCTGCTCATATGCAGGTAGTAGTTCTGCAGTGTTC CCSYAGSSSAVF CDR3
310 light chain 910
TGTCAACAGCTTCATGGTTACCCTTTCACTTTC CQQLHGYPFTF CDR3
311 light chain 911
TGCTGCTCATATGCAGGTAGTAACACTTACATTTTC CCSYAGSNTYIF CDR3
312 light chain TGCCAGTCGTTTGATACCAGCCTGAGTGGTTCGGTG 912
CQSFDTSLSGSVF CDR3 TTC
313 light chain TGTCAGCAGTATAATGGTGGGCCTCGGACGTTC 913 CQQYNGGPRTF CDR3
314 light chain 914
TGTCAACAGAGTTACAGTACCCCCCCCCTTTTC CQQSYSTPPLF CDR3
315 light chain TGCTGCTCATATGCAGGCAGTGACACTTTTTGGGTC 915
CCSYAGSDTF VF CDR3 TTC
316 light chain 916
TGCCAACAGAGTTACAGTTCATTCACTTTC CQQSYSSFTF CDR3
317 light chain TGTCAACAGTATAAGACCTGGCCTCCGGAGCTCACT 917
CQQYKTWPPELTF CDR3 TTT
318 light chain 918
TGTCAGCAACATGGTAACTCAGTTCTAACTTTC CQQHGNSVLTF CDR3
319 light chain 919
TGTCAACAGGCTAACAGTATCCCCTATACTTTC CQQA S IPYTF CDR3
320 light chain 920
TGCAGCTCATATACAAGCAGCACC1CTGTGGTTTTT CSSYTSSTSWF CDR3
321 light chain 921
TGCTGCTCATATGCAGGTCGGAGTATTGTGCTTTTC CCSYAGRSIVLF CDR3
322 light chain 922
TGCATGCAAGGCACACACTGGCCGGACACTTTT CMQGTHWPDTF CDR3
323 light chain 923
TGTCAGCAGTATGGTAGTTCACCT1TCACCTTC CQQYGSSPFTF CDR3
324 light chain 924
1G1CAGCAG1ATGGGAGC1CACTCIGGACGTTC CQQYGSSLWTF CDR3
325 light chain 925
TGTCAGCACCGGAGTAACGGGTACACTTTT CQHRSNGYTF CDR3
326 light chain 926
TGCATGCAAGCTCTACAAACTTGGACGTTC CMQALQTWTF CDR3
327 light chain TGTGCATCATGGGATGACAGCCTGCATGTCTGGGCG 927
CASWDDSLHV AF CDR3 TTC
328 light chain 928
TGCCTACAGCACAGTTCTTACCCCATCACTTTC CLQHSSYPITF CDR3
329 light chain TGTTACTCAACAGACAGCAGTGGTAGTCTATGGGTG 929
CYSTDSSGSLWVF CDR3 TTC
330 light chain 930
TGCCAACAGTATTTAACTCACCCTGTCACCTTC CQQYLTHPVTF CDR3
331 light chain TGCCAGTCGTTTGACGGGAGACTGAGCCATGTGGTT 931
CQSFDGRLSHWF CDR3 TTC
332 light chain 932
TGTCAGCAGTATTATAATACTCCTCCGACGTTC CQQYYNTPPTF CDR3
333 light chain TGTGCAGCCTGGGATGACAGCCTGGGTGGTCCGGTG 933
CAAWDDSLGGPVF CDR3 TTC
334 light chain 934
TGCTGCTCATATGCAGGTAGTAGTACTTGGGTGTTC CCSYAGSSTWVF CDR3
335 light chain 935
TGTCAGCAGTCTGGTGGCTCACCGATCACCTTC CQQSGGSPITF CDR3
336 light chain 936
TGTCAACAGAGTTACAGTCCCCCTCCGGTCACTTTC CQQSYSPPPVTF CDR3
337 light chain TGCAGTTCATATGCAGGCGGCAACAATTTGAGGGTC 937
CSSYAGGNNLRVF CDR3 TTC
338 light chain 938
TGCATGCAAGATCTACAAAGTACCATCACATTC CMQDLQSTITF CDR3
339 light chain 939
TGTCAGCAGTATGGTACCTCACTCTGGACGTTC CQQYGTSLWTF CDR3
340 light chain 940
TGTCAGGCGTGGGACATCAGCGTACTTTTC CQAWDISVLF CDR3
341 light chain 941
CDR3 TGCTGCTCATATACAAGCAGCAGCACTCTGATGTTC CCSYTSSSTL F
342 light chain TGTCAGCAGCGTCTCAACTGGCCTCCCCGATTCGCT 942
CQQRLNWPPRFAF CDR3 TTC 343 light chain 943
TGTCAGCAGTATTATAGTTCGTGGACGTTC CQQYYSSWTF CDR3
344 light chain 944
TGTCAGCAGTATGGTAGCTCACCTCCGTGGACGTTC CQQYGSSPPWTF CDR3
345 light chain 945
TGTCAGCAGTATGGTACCTCGCCTCGGACGTTC CQQYGTSPRTF CDR3
346 light chain TGTGCAGTATGGGATGACAGACTGAATGGTCCGGTA 946
CAVWDDRLNGPVF CDR3 TTC
347 light chain 947
TGTCAGCAGTATGGTAGCTCACAGACGTTC CQQYGSSQTF CDR3
348 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCATTGGGAA 948
CQVWDSSSDHWEF CDR3 TTT
349 light chain 949
TGCTGCGCATATGCAGGTGGTAGTATTTGGGTGTTC CCAYAGGSIWVF CDR3
350 light chain 950
TGTCAGCAATATAATAACTGGCCTCTCACTTTC CQQYNNWPLTF CDR3
351 light chain 951
TGTCAACAGGCTGCCAGTTTCCCGCTCACTTTC CQQAASFPLTF CDR3
352 light chain 952
TGTCAGCAGTATGATACCTCCCCGCTCACTTTC CQQYDTSPLTF CDR3
353 light chain 953
TGCCAATCAGTAGACGAGGTTGGAACTTACATCTTC CQSVDEVGTYIF CDR3
354 light chain TGCAGTTCTTATACAGGCAACGACAATTTCCTCTAT 954
CDR3 CSSYTGNDNFLYVF
GTCTTC
355 light chain 955
TGTCAACAGTATGGTAGCTCACCGCACACTTTT CQQYGSSPHTF CDR3
356 light chain 956
TGTCAACAGAGTTTCGGCCTCCGTIACACTTTT CQQSFGLRYTF CDR3
357 light chain 957
TGCCAACAGTATAATAGTTATCCGIGGACGTTC CQQYNSYPWTF CDR3
358 light chain 958
TGTCATCAGAGTAGTAGTTTCCCTATCACCTTC CHQSSSFPITF CDR3
359 light chain 959
TGCAAACAAAGTGTACAGCTCCCGATCACCTTC CKQSVQLPITF CDR3
360 light chain 960
TGTCAACAGTATAATAGTTACTCGTACACTTTT CQQYNSYSYTF CDR3
361 light chain 961
TGTCAGCAGTATGGAACCTCGCCTCGGACGTTC CQQYGTSPRTF CDR3
362 light chain TGTCAACAATATAAGACCTGGCCTCCGGAGCTCACT 962
CQQYKTWPPELTF CDR3 TTT
363 light chain 963
TGCTCCTCATATACAAGCAGCACCTCTGTGGTTTTT CSSYTSSTSWF CDR3
364 light chain 964
TGCTGCTCATATGCAGGTCGGAGTACTGTGCTTTTC CCSYAGRSTVLF CDR3
365 light chain 965
TGTCAAAAGTATAACAGTGCCCCTCTCACTTTC CQKYNSAPLTF CDR3
366 light chain 966
TGCCAAGTTTATAATAGTGATCGGACGTTC CQVYNSDRTF CDR3
367 light chain 967
TGTCAACAATATGATAGTCTCCCTCTCACCTTC CQQYDSLPLTF CDR3
368 light chain 968
TGCCAACAGTATCATACTTACCCTCTCACTTTC CQQYHTYPLTF CDR3
369 light chain 969
TGTCTACAAGATTACGAATACCCGTACACTTTT CLQDYEYPYTF CDR3
370 light chain TGCCAGTCTTTTGACAGCAGGCTTAATGTATATGTC 970
CQSFDSRLNVYVF CDR3 TTC
371 light chain 971
TGCCAACAATATGATAGTTATTCCTACACTTTT CQQYDSYSYTF CDR3
372 light chain TGCAGTTCATATACAGGCACAAGCACTCGACTCTTC 972 CSSYTGTSTRLF CDR3
373 light chain TGCCAGTCGTTTGACGGGAGACTGAGCCATGTGATT 973
CQSFDGRLSHVIF CDR3 TTC
374 light chain 974
TGTCAGCAGTATCATAGAGCAATTACTTTC CQQYHRAITF CDR3
375 light chain TGTGCAGCATGGGATGACAGCCTGGGAGGCCATGTG 975
CAAWDDSLGGHWF CDR3 GTTTTC
376 light chain 976
TGTCAGCAATATTATGGCCGTCCCACTTTC CQQYYGRPTF CDR3
377 light chain 977
TGCATGCAAGCTTTCCAAGGGGGGACGTTC CMQAFQGGTF CDR3
378 light chain 978
TGTGACTCCCAGGTCAGCAGTGGCGAATGGGTGTTC CDSQVSSGEWVF CDR3
379 light chain 979
TGTCTCCACTATAATGACTGGCCTGCGTGGACGTTC CLHYNDWPAWTF CDR3
380 light chain 980
TGTCAGCAGTATAATAACTGGTACACTTTT CQQYNNWYTF CDR3
381 light chain 981
TGTCAGCAGTATAATAACTGGTATACTTTT CQQYNNWYTF CDR3
382 light chain 982
TGCCAACAATATCATAGTTACTTTTGGACGTTC CQQYHSYFWTF CDR3
383 light chain 983
TGTCIACAAGATCACAGTTTCCCACTCACTTTC CLQDHSFPLTF CDR3
384 light chain 984
TGTCAACAGTATGGTAGCTCACCACTCACTTTC CQQYGSSPLTF CDR3
385 light chain 985
TGTAGTTCATATACAGGCACCAGCACTCGGCTATTC CSSYTGTSTRLF CDR3
386 light chain TGTGCAACATGGGATGACAGTCTGAATGGCTGGATG 986
CATWDDSLNG MF CDR3 TTC
387 light chain 987
TGTCAGGAATATAGTAACTGGCCCATGTACACTTTT CQEYSNWPMYTF CDR3
388 light chain TGCCAGTCGTTTGATAGCAGCCTGAGTGGTTCGGTG 988
CQSFDSSLSGSVF CDR3 TTC
389 light chain 989
TGCATGCAAGCTCTACAAACATTCACTTTC CMQALQTFTF CDR3
390 light chain 990
TGTCAACAGTTTAATAACTGGCCCCCGTGGACGTTC CQQFNNWPPWTF CDR3
391 light chain 991
TGTCAACAGTATGATAATGTCCCGCTCACTTTC CQQYDNVPLTF CDR3
392 light chain TGCAGCTCATATACAGACATCAGTTATCAATGGGTG 992
CSSYTDISYQ VF CDR3 TTC
393 light chain 993
TGCATGCAATCTCTAGAGACTCCTCGGACGTTC CMQSLETPRTF CDR3
394 light chain 994
TGCATGCAAGCTCGACAAACTCTTCTCTTC CMQARQTLLF CDR3
395 light chain 995
TGTCAACAGTCTGATAATCTCCCCCTCACCTTC CQQSDNLPLTF CDR3
396 light chain 996
TGCAGCTCATATACAAGCTCCAACACTCTGATTTTC CSSYTSSNTLIF CDR3
397 light chain 997
TGTCAACAGAGTCACACCACCGCGACGTTC CQQSHTTATF CDR3
398 light chain 998
TGTCAGCAATATCACAGTCTTCCGCTCACTTTC CQQYHSLPLTF CDR3
399 light chain 999
TGCTGCTCATATGCAGGCAGCTACACTTGGGTGTTC CCSYAGSYTWVF CDR3
400 light chain 1000
TGTCAGCAGTATAATTACTGGCCTCCGACGTTC CQQYNYWPPTF CDR3 Table 5- Top 100 Heavy Chain CDR3 from Patient 3
SEQ Description Nucleic Acid Sequence SEQ Amino Acid Sequence
ID ID
NO NO
401 heavy chain 1001
TGTGAGAGGAATATGGACGTCTGG CERNMDVW CDR3
402 heavy chain TGTGTGAAAGCCAAAACTGGAACGACGACCTTAGGG 1002
CVKAKTGTTTLGFDYW CDR3 TTTGACTACTGG
403 heavy chain TGTGCAAAAGCCAAAACTGGAACGACGACCTTAGGC 1003
CAKAKTGTTTLGFDYW CDR3 TTTGACTACTGG
404 heavy chain 1004
TGTACCACAGATCCCGTCTACTGG CTTDPVYW CDR3
405 heavy chain TGTGCGAAAGATACTATGATAGTAGTGGTTATTTAC 1005
CAKD MIVWIYLDYW
CDR3 TTGGACTACTGG
406 heavy chain 1006
TGTGCAAGTAGGTTCATCTGG CASRFIW CDR3
407 heavy chain TGTGCAAAAGCCAAAACTGGAACGACGACCTTAGGG 1007
CAKAKTGTTTLGFDYW CDR3 TTTGACTACTGG
408 heavy chain TGTGCGAGATCCCTCTCCCGGGGTCGAAGTGACTAC 1008
CARSLSRGRSDYW CDR3 TGG
409 heavy chain TGTGCGAGGTGGTACAGTAATGAATATTACAACGGT 1009
CARWYSNEYYNGMDVW CDR3 ATGGACGTCTGG
410 heavy chain 1000
TGTGCGAGAGGCAACGGTGACTTCGACTACTGG CARGNGDFDYW CDR3
411 heavy chain 1011
TGTACGCGAGGGTACGGTATGGACGTCTGG CTRGYGMDVW CDR3
412 heavy chain 1012
TGTACCACCGTGGTCCACTACTGG CTTWHYW CDR3
413 heavy chain TGTGCGAAAGATGCGAGAAGAGCAGTTGGTACCCTG 1013
CAKDARRAVGTLSDLW CDR3 TCCGATCTCTGG
414 heavy chain TGTGCGAAAGCCAAAACTGGAACGACGACCTTAGGG 1014
CAKAKTGTTTLGFDYW CDR3 TTTGACTACTGG
415 heavy chain 1015
TGTGTAGGAGGGAGTGTCTACTGG CVGGSVYW CDR3
416 heavy chain 1016
TGTGCGAGAGGGCTACTCGGTATGGACGTCTGG CARGLLGMDVW CDR3
417 heavy chain TGTGCGAGGTGGTACAGTAATCAATACTATCACGGT 1017
CARWYSNQYYHGMDVW CDR3 ATGGACGTCTGG
418 heavy chain 1018
TGTGCGACTTCGAGGCGGATAGTCCTTGACCACTGG CATSRRIVLDHW CDR3
419 heavy chain TGTGCGAGACATGGGGCCGGGTGGGGGGCCATTGGA 1019
CARHGAGWGAIGEPPDYW CDR3 GAACCCCCTGACTACTGG
420 heavy chain TGCGCACACAGACGGTTCGGTGACCGCACTCCCCTC 1020
CAHRRFGDRTPLDPW CDR3 GACCCCTGG
421 heavy chain TGTGCAGGGCGGTTAGTCTTAGTCACAAGTGGGCAG 1021
CDR3 CAGRLVLVTSGQIDYW
ATTGACTACTGG
422 heavy chain TGTGCGAGGGGTCAAGCTGGAACTACGGGACTTGAC 1022
CARGQAGTTGLDYW CDR3 TACTGG
423 heavy chain TGTGCTACTGTAATAATATCAGCTGCCCTAGACGGG 1023
CATVI I SAALDGWFDPW CDR3 TGGTTCGACCCCTGG
424 heavy chain TGTGCGAAAGAACAAGGAAATCCATCCCATTCCTTT 1024
CAKEQGNP SHSFDYW CDR3 GACTACTGG
425 heavy chain TGTGTGAAAGGACTACTGAAAGCCCCGCTTGACTAC 1025
CVKGLLKAPLDYW CDR3 TGG
426 heavy chain 1026
TGTACCACAGATCCCGTCCACTGG CTTDPVHW CDR3
427 heavy chain TGTGTAGCCGATGGCTTCAATGAGGCCCGGGTTGAC 1027
CVADGFNEARVDYW CDR3 TACTGG 428 heavy chain TGTGCTAGAGGCTTAATGGGTTATAGCAGCTCGTAI 1028
CARGLMGYS S SYPEMDVW CDR3 CCTGAGATGGACGTCTGG
429 heavy chain TGTGCAAGAGATTTGTGTACTACTACCATCTGCTAT 1029
CARDLCTTT I CYTRPFDYW CDR3 ACTCGGCCTTTTGACTACTGG
430 heavy chain 1030
TGTGCCCGTACGAGGTACTACTTTGACTACTGG CARTRYYFDYW CDR3
431 heavy chain TGTGCGAGAGAGTCGTCGCTACGACTCCGTTTATTT 1031
CARES SLRLRLFDHW CDR3 GACCACTGG
432 heavy chain TGTGCGATAGGGGGCATACCAGTGGCGGGCAGGAGG 1032
CAIGGIPVAGRRFDPW CDR3 TTCGACCCCTGG
433 heavy chain TGTGCGAGAGGAGGGGGGAAGTGGTATGCTTTTGAT 1033
CARGGGKWYAFDIW CDR3 ATCTGG
434 heavy chain 1034
TGTACTACGGCAGGGGGAGTTGACTACTGG CTTAGGVDYW CDR3
435 heavy chain 1035
TGTCTATCGCCGGGCGGGCTCTGG CLSPGGLW CDR3
436 heavy chain TGTGCGAAAGATGGGAGAGCAGCAGCTGGTACCCTG 1036
CAKDGRAAAGTLADLW CDR3 GCCGATCTCTGG
437 heavy chain TGTGCAGGGCGGTTATTCTTAGTCACAAGTGGGCAG 1037
CAGRLFLVTSGQIDYW CDR3 ATTGACTACTGG
438 heavy chain TGTGCGAAAGATACTATGATAGTAGTGATTCTTTAC 1038
CAKDTMIWI LYLDFW CDR3 TTGGACTTCTGG
439 heavy chain TGTGCGAGAGATGCGTGGCTGGTACTTCCTGACTTC 1039
CARDAWLVLPDFW CDR3 TGG
440 heavy chain TGTGCGAAAGCCCCAAGCTCGGTCAACGTGGATTTA 1040
CAKAP SSVNVDLVATRYW CDR3 GTGGCTACGCGCTACTGG
441 heavy chain TGTGCGAAAGATGGGAGAGCAGCAGCTGGAACCCTG 1041
CAKDGRAAAGTLSDLW CDR3 TCCGATCTCTGG
442 heavy chain TGTGCGAGGGAGGCATCTACGATGCAAAGACCCCCC 1042
CAREASTMQRPPYYFDYW CDR3 TACTACTTTGACTACTGG
443 heavy chain TGTGCGAGAATTTCGGTTAGTATGAGTCAGGGAGTT 1043
CARISVSMSQGVPNYSGLDVW CDR3 CCCAACTACTCCGGTCTGGACGTCTGG
444 heavy chain TGTGCGAGCGTGCAGACCTATAGAAATGGCTACTAC 1044
CASVQTYRNGYYGLLSW CDR3 GGTTTGTTGAGCTGG
445 heavy chain TGTGCGAAGGATTGGCGGTGGGAGCGGCTGTGTTAC 1045
CAKDWRWERLCYGMNIW CDR3 GGTATGAACATCTGG
446 heavy chain TGTGCGAGATTCGAGGCATATGACTACGGTGAATAT 1046
CARFEAYDYGEYQNAYW CDR3 CAAAACGCCTACTGG
447 heavy chain 1047
TGTGCGAGAGGGCATTTTGCIGTGGACGTCTGG CARGHFAVDVW
CDR3
448 heavy chain TGTGCGAGAATAGCAGTGGCTGGTACTAGGAGACCT 1048
CARIAVAGTRRPDYW CDR3 GACTACTGG
449 heavy chain TGTGCGAGAGATGTAATTGGCAGCAGCTGGTACAGT 1049
CARDVIGSSWYSHW CDR3 CACTGG
450 heavy chain TGTGCAAAAGGCCTAGGCCGGCAGCTGGTACAGAGG 1050
CAKGLGRQLVQRFDYW CDR3 TTTGACTACTGG
451 heavy chain TGTGCGAAAAAAGTCGGGTTAAGCAGTGGCTGGGAG 1051
CAKKVGLSSG ENYW CDR3 AACTACTGG
452 heavy chain TGTGCGACAGCGGCGGCCCTGGAAAGTAATGGTTAT 1052
CATAAALESNGYAGLNYW CDR3 GCCGGCCTAAACTACTGG
453 heavy chain 1053
TGTACCACCGTGGTCCACTTCTGG CTTWHFW CDR3
454 heavy chain 1054
TGTGCGAGAGACCGCTACTACCTGGGCGTCTGG CARDRYYLGVW CDR3
455 heavy chain TGTGCGAGACACGGATCCAACTCGCCGGATGTTCCA 1055
CARHGSNSPDVPNFDYW CDR3 AACTITGACTACTGG
456 heavy chain TGTGCAAAAGATTGGCGGGGCAGTGGCTGGTACGGT 1056
CAKDWRGSGWYGAFDIW CDR3 GCTTTTGATATCTGG
457 heavy chain TGTGCGAGAGGTGGAAGCCACTACTCATCTCCTTTT 1057
CARGGSHYSSPFYIW CDR3 TATATATGG 458 heavy chain 1058
TGTGCGAGAGGTGGCTTCATAGACTACTGG CARGGFIDYW CDR3
459 heavy chain TGTGCGAGAAGTACTGTAAGTGTGAGGTACCACGGC 1059
CARSTVSVRYHGLGFDSW CDR3 CTTGGATTTGACTCCTGG
460 heavy chain TGTGCGAAAGATGGTGGAAATGGGGACTGCTTTGAC 1060
CAKDGGNGDCFDYW CDR3 TACTGG
461 heavy chain TGTACTACAGATAGAATTACGCTTTTTGGAATAGGT 1061
CTTDRITLFGIGDFW CDR3 GACTTCTGG
462 heavy chain TGTGCGAGAAGCACGGGGAGCTACCCCACCTTTGAC 1062
CARSTGSYPTFDYW CDR3 TACTGG
463 heavy chain TGTGCGAGAGATGGGGCACATGGGAGTTACTTCTAC 1063
CARDGAHGSYFYW CDR3 TGG
464 heavy chain 1064
TGTGCGAAAGTAGTTGACGGCTACTTTGACTACTGG CAKWDGYFDYW CDR3
465 heavy chain 1065
TGTGCGAGAGGACTCGGGGACCTTAAGTACTGG CARGLGDLKYW CDR3
466 heavy chain TGTGCGAGAGTGAGTGGCAGTACACGCCTTTTCGGT 1066
CARVSGSTRLFGMDVW CDR3 ATGGACGTCTGG
467 heavy chain TGTGCAAAAGGCAAAACTGGAACGACGACCTTAGGG 1067
CAKGKTGTTTLGFDYW CDR3 TTTGACTACTGG
468 heavy chain TGTGCGAAAGATGTGGCCGTCGCAGCAGCTGCCGCC 1068
CAKDVAVAAAAAYNYYGMDVW CDR3 TACAATTACTACGGTATGGACGTCTGG
469 heavy chain TGTGCACACAGACGGGGGGCGCCGGGATACTTTGAC 1069
CAHRRGAPGYFDYW CDR3 TACTGG
470 heavy chain TGTGCGAGAGAGATCGGGTTCT CGATAGCAGG CG 1070
CAREIGFFDSRSGIWIFDYW CDR3 GGGATC GGA CTTTGACTACTGG
471 heavy chain TGTGCGAAAGAACAAGGAAATCCATCCCACTCCTTT 1071
CAKEQGNP SHSFDYW CDR3 GACTACTGG
472 heavy chain TGTACCACAGATGTGATCTGGTCCGATATGATAGAA 1072
CTTDVIWSDMIELW CDR3 CTCTGG
473 heavy chain TGTGCGAGAGATAGTGTTTTGGTGGCTGCCAATGAA 1073 CARDSVLVAANERDYYYYDMDV CDR3 AGGGACTACTACTACTACGATATGGACGTCTGG
474 heavy chain TGTACAAAAGATTGGCGGGGCAGTGGCTGGTACGGT 1074
CTKDWRGSGWYGAFDIW CDR3 GCTTTTGATATCTGG
475 heavy chain TGTGCACACAGACGGAATGGTGACCGCACTCCCCTC 1075
CAHRRNGDRTPLDPW CDR3 GACCCCTGG
476 heavy chain TGTGCGAAACGGGGGAAGATGGCCGCAGAGCGGGAG 1076
CAKRGKMAAERELDHW CDR3 CTTGACCACTGG
477 heavy chain TGTGCGAGAATAGCAGTGGCTGGTACTCGGAGACCT 1077
CARIAVAGTRRPDYW CDR3 GACTACTGG
478 heavy chain TGTGCGAAAGGTTCAAGAGGGGGAGCTACTCCCTAC 1078
CAKGSRGGATPYYYYGMDVW CDR3 TACTACTACGGTATGGACGTCTGG
479 heavy chain TGTGCGAGAGCTAATTGTAGTAGTACCAGCTGCTAT 1079
CARANCSSTSCYAPGGDYW CDR3 GCCCCCGGGGGTGACTACTGG
480 heavy chain TGTGCGAGAGATCTAATTGACTACAGAAAAAGCGAC 1080
CARDL IDYRKSDYYGMDVW CDR3 TACTACGGTATGGACGTCTGG
481 heavy chain TGTACTAGACCAGTGGCACAACTGGGGGAGTCAAAC 1081
CTRPVAQLGESNWYFDLW CDR3 TGGTACTTCGATCTCTGG
482 heavy chain TGTGCGAAATTGCATTTGGGCAACCCCGATGGTTTT 1082
CAKLHLGNPDGFDIW CDR3 GATATCTGG
483 heavy chain 1083
TGTGCGACCTCGAGGCGGATAGTCCTTGACCACTGG CATSRRIVLDHW CDR3
484 heavy chain 1084
TGTACCACAGATCCGGTCTACTGG CTTDPVYW CDR3
485 heavy chain TGTGCGAGGGAGGGATCTACGATGCAAAGACCCCCC 1085
CAREGSTMQRPPYYFDYW CDR3 TACTACTTTGACTACTGG
486 heavy chain TGTGTGAAGGGAAATCCCGATTCAATTGTTGACTAT 1086
CVKGNPDS IVDYGMAVW CDR3 GGCATGGCCGTCTGG
487 heavy chain TGTGCGAGGTGGTACAGTAATCAATACTACTACGGT 1087 CARWYSNQYYYGMDVW CDR3 ATGGACGTCTGG
488 heavy chain TGTGCGAGAGAATTCCAGCATGGTICGGGGAGTTAT 1088
CAREFQHGSGSYPDYW CDR3 CCTGACTACTGG
489 heavy chain TGTGCGAGAGATCTACCCTATGGTTCGGGGAGTTAC 1089
CARDLPYGSGSYW CDR3 TGG
490 heavy chain 1090
TGTGCGAGAGGCAACGGTGACTTCGACTATTGG CARGNGDFDYW CDR3
491 heavy chain 1091
TGTGCCACAGATCCCGTCTACTGG CATDPVYW CDR3
492 heavy chain TGTGCCCTTCCGTATAGCAGTGGCTGGGAATCCAGT 1092
CALPYSSGWESSYYFDYW CDR3 TATTACTTTGACTACTGG
493 heavy chain TGTGCGAAAGCCAAAACTGGAACGACGACCTTAGGG 1093
CAKAKTGTTTLGFDYC CDR3 TTTGACTACTGC
494 heavy chain TGTGCGAGACTACTTCGAGGGAGTGGTTATTACTTT 1094
CARLLRGSGYYFDYW CDR3 GACTACTGG
495 heavy chain TGTGCACACAGGCGAAACGGTGACCGCACTCCCCTC 1095
CAHRRNGDRTPLDPW CDR3 GACCCCTGG
496 heavy chain TGTGCACACAGACGAAATGGTGACCACACTCCCCTC 1096
CAHRRNGDHTPLDPW CDR3 GACCCCTGG
497 heavy chain TGTGCGAAATGGGTGGGAGCCCCCGGCAGGTTCTTT 1097
CAKWVGAPGRFFDYW CDR3 GACTACTGG
498 heavy chain TGTGCGAGGGAATACGGTGCCCCTAACAGGTTCGAC 1098
CAREYGAPNRFDPW CDR3 CCCTGG
499 heavy chain TGTGCGAGAAGCACGGAGAGCTACCCCACCTTTGAC 1099
CARSTESYPTFDYW CDR3 TACTGG
500 heavy chain TGTGCAAAAGTGGGGGGGGGGCTGGTACCCTTTCAC 1100
CAKVGGGLVPFHFYGMDVW CDR3 TTCTACGGCATGGACGTCTGG
Table 6- Top 100 Light Chain CDR3 from Patient 3
SEQ Description Nucleic Acid Sequence SEQ Amino Acid Sequence
ID ID
NO NO
501 light chain 1101
TGTCAACAGGCTAACAGTTTCCCTCTCACTTTC CQQANSFPLTF CDR3
502 light chain TGTGCAACATGGGATGACAGCCTGGATGGTGGGGTG 1102
CATWDDSLDGGVF CDR3 TTC
503 light chain 1103
TGTCAACAGTATGATAATCTCCGGGCTTTC CQQYDNLRAF CDR3
504 light chain 1104
TGCAGCTCATATGCAGGCAGCACTGTGCTATTC CSSYAGSTVLF CDR3
505 light chain 1105
TGTCAACAGGCCAACATTTACCCTCTCACTTTC CQQANIYPLTF CDR3
506 light chain TGTTACTCAACAGACAGCAGTGGTAATCAGGGGGTA 1106
CYSTDSSGNQGVF CDR3 TTC
507 light chain 1107
TGCATGCAGGCTCTACAAACTCCTCCGATCACCTTC CMQALQTPPITF CDR3
508 light chain 1108
CDR3 TGCATGCAAGCTCTACAAACTCCTCCGATCACCTTC CMQALQTPPITF
509 light chain 1109
TGCCAACAGTATAATAGTTACCCGTATATTTTT CQQYNSYPYIF CDR3
510 light chain 1100
TGTCAACAGTATGATAGTCTCCCTCCCACTTTT CQQYDSLPPTF CDR3
511 light chain 1111
TGTCAGCACTATGGTAGCTCACCGTACACTTTT CQHYGSSPYTF CDR3
512 light chain 1112
TGTCAACAGTATGATAATCTCCCGTGGACGTTC CQQYDNLPWTF CDR3
513 light chain TGCTGCTCATATGCAGGTAGTAGCACTTGGGTGTTC 1113 CCSYAGSST F CDR3
514 light chain 1114
TGTCAACAGTATGATACTCTCCCTCCCACTTTT CQQYDTLPPTF CDR3
515 light chain 1115
TGTCAGCAGTATTATAGTATTCCTAACACTTTT CQQYYSIPNTF CDR3
516 light chain TGTAACTCCCGGGACAGCAGTGGTAACCATGTGGTT 1116
CNSRDSSGNHWF CDR3 TTC
517 light chain 1117
TGTCAACAGAGTTACCGTTTGTGGACGTTC CQQSYRLWTF CDR3
518 light chain 1118
TGCCAACAGTATAATAGTTACCCCATCACCTTC CQQYNSYPITF CDR3
519 light chain 1119
TGCCAACAGTATAATACTTATCTCTCGTGGACGTTC CQQYNTYLSWTF CDR3
520 light chain TGTCAATCAGCAGACAGCAGTGGTACTTATCAGGTA 1120
CQSADSSGTYQVF CDR3 TTC
521 light chain TGCGGAACATGGGATAGCAGCCTGAGTGTTGTGGTA 1121
CGTWDSSLSVWF CDR3 TTC
522 light chain 1122
TGTCAGCAATATTATAGTACTCCGATCACCTTC CQQYYSTPITF CDR3
523 light chain 1123
TGTCAACAGTTTAATACTTACCCATTCACTTTC CQQFNTYPFTF CDR3
524 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCATGTGGTA 1124
CQVWDSSSDHWF CDR3 TTC
525 light chain TGTTATTCAACAGACAGCAGTGGTGATCATAGGGTA 1125
CYSTDSSGDHRVF CDR3 TTC
526 light chain 1126
TGTCAACAGAGTTACAGTACCACGTGGACGTTC CQQSYSTTWTF CDR3
527 light chain 1127
TGTCAGCAATATTATAATACTCCTCCTACTTTT CQQYYNTPPTF CDR3
528 light chain 1128
TGTCAGTCTTATGATAGCAGCAATCAGGGGGTATTC CQSYDSSNQGVF CDR3
529 light chain TGTCAATCAGCAGACAGCAGTGGTACTTATGTGGTA 1129
CQSADSSGTYWF CDR3 TTC
530 light chain TGTGCAACATGGGATGACAGCCTGAATGGTGGGGTG 1130
CATWDDSLNGGVF CDR3 TTC
531 light chain 1131
TGCATGCAAGCTCTACAAACTCTCACTTTC CMQALQTLTF CDR3
532 light chain 1132
TGTCAACAGAGTTACAGTACCCCTCAGACGTTC CQQSYSTPQTF CDR3
533 light chain 1133
TGTCAACAGAGTTACCGTACGTGGACGTTC CQQSYRTWTF CDR3
534 light chain 1134
TGCTGCTCATATGCAGGTAGTAGTGTTTGGGTGTTC CCSYAGSSVWVF CDR3
535 light chain 1135
TGTCAGTCTTATGATAGCAGCAATCATGCGGTATTC CQSYDSSNHAVF CDR3
536 light chain 1136
TGTCAACAGGCTAACAATTTCCTCGGGTACACTTTT CQQANNFLGYTF CDR3
537 light chain 1137
TGTCATCAGAGTAGTAGTTTACCGGTCACTTTC CHQSSSLPVTF CDR3
538 light chain TGCAGCTCATATACAAGCAGCAGCACCCCTGTGGTA 1138
CSSYTSSSTPWF CDR3 TTC
539 light chain 1139
TGCTGCTCATATGCAGGTACTAGACTATTC CCSYAGTRLF CDR3
540 light chain 1140
TGTCAACAGCTTAATAGTTACCCGATCACCTTC CQQLNSYPITF CDR3
541 light chain 1141
TGTCAGCAGTATAATAACTGGCCTCGAACTTTC CQQYNNWPRTF CDR3
542 light chain TGCATGCAAGCTACACACTGGCCTCCGGAATACACT 1142
CMQATHWPPEYTF CDR3 TTT
543 light chain TGCCAACAGTATAATAGTTACTCCTACACTTTT 1143 CQQYNSYSYTF CDR3
544 light chain 1144
TGTCAACAACTTAATAGTTACCCTCTCACTTTC CQQLNSYPLTF CDR3
545 light chain 1145
TGCCTACAGTATAATAGTTATTGGACGTTC CLQYNSYWTF CDR3
546 light chain 1146
TGTCAGCAGTATAATAACTGGCCTCCGTACACTTTT CQQYNNWPPYTF CDR3
547 light chain 1147
TGTCAGCAGCGTAGCAACTGGCCTCTCACTTTC CQQRSNWPLTF CDR3
548 light chain 1148
TGTCAGCAATATAATAACTGGCCTCCGTACACTTTT CQQYNNWPPYTF CDR3
549 light chain 1149
TGTCTATCACCAGACAGTAGTTTTGTTTATGTCTTC CLSPDSSFVYVF CDR3
550 light chain 1150
TGCAGCTCATATGCAGGTTAIGTGGTATTC CSSYAGYWF CDR3
551 light chain TGCATGCAAGGTACACACTGGCCTCCGGAATACACT 1151
CMQGTHWPPEYTF CDR3 TTT
552 light chain 1152
TGTCAACAGAGTTACCGTATGTGGACGTTC CQQSYRMWTF CDR3
553 light chain 1153
TGTCAACATCTTAATAGTTACCCATTCACTTTC CQHLNSYPFTF CDR3
554 light chain 1154
CDR3 TGTATGATTTGGCCAAGCAATGCTTGGGTGTTC CMIWPSNAWVF
555 light chain TGTTACTCAACAGACAGCAGTGGTAATCATGGGGTA 1155
CYSTDSSGNHGVF CDR3 TTC
556 light chain 1156
TGTAACTCCCGGGACAGCAGTGGTCACCGGGTGTTC CNSRDSSGHRVF CDR3
557 light chain 1157
TGTCAACAGTATGATAATCTCCCTAACACCTTC CQQYDNLPNTF CDR3
558 light chain 1158
TGTCAGCAGTATAATAACTGGCCTCAGCTCACTTTC CQQYNNWPQLTF CDR3
559 light chain 1159
TGTCAACAGAGTTATCGTAGGTGGACGTTC CQQSYRRWTF CDR3
560 light chain 1160
TGCATGCAAGCTCTACAAACTCCTCTCACTTTC CMQALQTPLTF CDR3
561 light chain 1161
TGCCAGTCCTATGACAGCAGCCTGAGTGTGGTATTC CQSYDSSLSWF CDR3
562 light chain TGTCAATCAGCAGACAGCAGTGGTGCTTATGTGGTA 1162
CQSADSSGAYWF CDR3 TTC
563 light chain 1163
TGTCAGCAGTATGGTAGTTCACCCATGTATACTTTT CQQYGSSPMYTF CDR3
564 light chain 1164
TGTCAACAGAGTTACAGTACCCCGTGGACGTTC CQQSYSTPWTF CDR3
565 light chain 1165
TGCAGTTCAAAAACAAGCAGCAACACTCAGTTGTTC CSSKTSSNTQLF CDR3
566 light chain 1166
TGCCAACAGTATAATAGTTACCCGTACACTTTT CQQYNSYPYTF CDR3
567 light chain 1167
TGTCAACAGCTTAATAGTGACCCTCAGACTTTT CQQLNSDPQTF CDR3
568 light chain TGTGCAGCATGGGATGACAGTCTGAGTGGTTGGGTG 1168
CAAWDDSLSGWVF CDR3 TTC
569 light chain 1169
TGCATGCAAGGTACACACTGGCCCACGTGGACGTTC CMQGTHWPTWTF CDR3
570 light chain TGTCAGGTGTGGGATAGTAGTAGTGATCCCCGGGTA 1170
CQVWDSSSDPRVF CDR3 TTC
571 light chain 1171
TGTCAACAATATTATAGTAGTTCCGTCACTTTT CQQYYSSSVTF CDR3
572 light chain 1172
TGCATGGAAGTTCTACAAACTTCGATCACCTTC CMEVLQTS I TF CDR3 573 light chain TGTCAGGTGTGGGACAGTGCTTCTGATCATGTGGTG 1173
CQVWDSASDHWF CDR3 TTC
574 light chain 1174
TGCCAACAGTATAATACTTATCTCACGTGGACGTTC CQQYNTYLTWTF CDR3
575 light chain 1175
TGTCAACAGGCTAACAGTTTCCCGTACACTTTT CQQANSFPYTF CDR3
576 light chain 1176
TGTCAGCAGTATGGTAGCTCACCGTACACTTTT CQQYGSSPYTF CDR3
577 light chain 1177
TGCCAACAGTATAATAGTTACCCGTATAGTTTT CQQYNSYPYSF CDR3
578 light chain TGTCAATCAGCAGACAGCAGTTCTACTTTTTGGGTG 1178
CQSADSSSTFWVF CDR3 TTC
579 light chain 1179
TGTCTACAAGATTACAATTACCCTTGGACGTTC CLQDYNYPWTF CDR3
580 light chain 1180
TGTCAGCAGTATTACAGTATTCCTAACACTTTT CQQYYSIPNTF CDR3
581 light chain 1181
TGTCAGCAATATTATAGTATTCCTCGCACTTTT CQQYYSIPRTF CDR3
582 light chain 1182
TGTCAGGCGTGGGACAGCAGCACTCTTTATGTCTTC CQAWDSSTLYVF CDR3
583 light chain 1183
TGTCTACAGGCTAACACTTTCCCTCTCACTTTC CLQANTFPLTF CDR3
584 light chain 1184
TGTCAACAGGCTAACAGTTTCCTCGGGTACACTTTT CQQANSFLGYTF CDR3
585 light chain TGTGCCTCCCGGGACACCGGCAATGACCATCTGGTA 1185
CASRDTGNDHLVF CDR3 TTC
586 light chain 1186
TGTCTACAGCATTATAGTTACCCTCGGACGTTC CLQHYSYPRTF CDR3
587 light chain 1187
TGCAGCTCATATACAAGCAGCACTCTCGTGGTATTC CSSYTSSTLWF CDR3
588 light chain 1188
TGTCAACAGAGTTACAGTACCCCATTCACTTTC CQQSYSTPFTF CDR3
589 light chain TGTCAGCAGCGTAGCAACTGGCCTCCGGTATTCACT 1189
CQQRSNWPPVFTF CDR3 TTC
590 light chain 1190
TGCCAACAGTATAATAGTTATTCGTGGACGTTC CQQYNSYSWTF CDR3
591 light chain 1191
TGTCAACAGGCTAACAGTTTCCCTCCGTGGACGTTC CQQANSFPPWTF CDR3
592 light chain 1192
TGTCAGCAGTATGGTAGCTCTCCGTACACTTTT CQQYGSSPYTF
CDR3
593 light chain 1193
TGTCAACAGCTTAATAGTTACCCCTTCACTTTC CQQLNSYPFTF CDR3
594 light chain 1194
TGTCAGTCTTATGATAGCAGCAATGTGGTATTC CQSYDSSNWF CDR3
595 light chain 1195
TGTCAACAGAGTTACAGTACCCCACTCACTTTC CQQSYSTPLTF CDR3
596 light chain 1196
TGTCAGTCTTATGATAGCAGCAATCATGTGGTATTC CQSYDSSNHWF CDR3
597 light chain 1197
TGCCAACAGTATAATAGTTATCCGATCACCTTC CQQYNSYPITF CDR3
598 light chain 1198
GCTCATATACAAGCAGCAGCGTGGTATTC CSSYTSSSWF CDR3 TGCA
599 light chain 1199
TGTCAACAGGCTAACAGTTTCCTCGGGTGCACTTTT CQQANSFLGCTF CDR3
600 light chain 1200
TGTCAACAGTATGATAATCTCCCTCCCACTTTT CQQYDNLPPTF CDR3 Table 7- sample 350 (heavy)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1201 CARVNCSDGN 1251 GGACCTGAGGAGCCTGAGATCCGACGACACGGCCGTTTACTACTGT CYSPGVLYHYY GCGAGAGTGAATTGTAGTGATGGAAACTGCTATTCCCCCGGGGTCC GMDIW TATACCACTACTACGGTATGGACATCTGGGGCCAAGGG
1202 1252 GGACGAATCCACGAGCACAGCCTACCTGGACTTGGCCAGCCTGACA
CARLPRVISYPN
TCTGAGGACACGGCCGTGTATTACTGTGCGAGACTCCCCCGAGTTAT AMDVW
TTCGTACCCTAACGCTATGGACGTCTGGGGCCAAGGG
1203 1253 CACCATATCACTAGACACGTCCACGAACCAGTTCTTTCTGAGGCTGA
CARFDLVTATD
CCTCTGTGACCGCCGCAGACACGGCCGTCTATTACTGTGCGAGGTT KW
CGATTTAGTCACAGCCACGGATAAGTGGGGCCAGGGA
1204 1254 TGATGTAAAAAAGACGCTGTATCTGCAGATGAATAGCCTGAAAACCG
CTASITGTTYFY
AGGACACAGCCGTGTATTATTGTACCGCATCGATAACTGGAACTACT YGIDVW
TACTTCTATTACGGTATCGACGTCTGGGGCCAGGGG
1205 CARVNCSGGN 1255 GGACCTGAGGAGCCTGAGATCCGACGACACGGCCGTTTACTACTGT CYSPGVLYYYY GCGAGAGTGAATTGTAGTGGTGGAAACTGCTATTCCCCCGGGGTCC GMDVW TATACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1206 1256 TTCCAAGAACACGCTGTATCTGCAAATGAGCAGCCTGAGAGTCGAG
CARGSYGGNFP
GACACGGCTGTGTATTACTGTGCGAGAGGGTCCTACGGTGGTAACT LDHGMDVW
TCCCCTTGGACCACGGTATGGACGTCTGGGGCCTAGGG
1207 1257 CAACGCCAAGAATTCACTGTATTTGCAAATGAACAGCCTGAGAGCCG
CAREFYDSGYY
AGGACACGGCTGTTTATTATTGTGCGAGAGAGTTCTATGACTCTGGA YSGMDVW
TATTACTACTCCGGTATGGACGTCTGGGGCCAAGGG
1208 1258 CTCAAGAGATGATTCAAGAAACACAGTGTATCTGCAAATGAACAGCC
CTTSWGYYDF
TGAAAACCGAGGACACAGCCGTCTATTATTGTACTACCTCCTGGGGA WFDPW
TATTACGATTTCTGGTTCGACCCCTGGGGCCAGGGA
1209 1259 AGACAACTCCAAGAACACGCTATATCTGGAAATGAACAGCCTGAGA
CAKDRSGPGIT
GTCGAGGACACGGCCGTTTATTACTGTGCGAAGGATAGGAGCGGGC NWLDFW
CAGGTATAACTAACTGGCTCGACTTCTGGGGCCAGGGA
1210 1260 CGCAGACACGTCCAAGAACCAGTTCTCCCTGCACCTGGACTCTGTGA
CASGQIGVAAY
CTCCCGAGGACACGGCTGTCTATTACTGTGCGAGCGGGCAAATAGG AFDIW
AGTGGCTGCCTATGCTTTTGATATTTGGGGCCAGGGG
1211 1261 AGTCACCATGACCAGAGACACGTCCACGAGCACAGTCTACATGGAC
CGREALGATDV
CTCAGTAGCCTGAAATCTGAGGACACGGCCATGTATTACTGTGGGA W
GAGAGGCATTGGGAGCTACGGACGTCTGGGGCCAAGGG
1212 1262 CACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGA
CARVPYFYGM
GCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGT DVW
CCCGTATTTCTACGGTATGGACGTCTGGGGCCAAGGG
1213 CAKDSGSGEYS 1263 GTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTAT GYDYYYYYGM TACTGTGCGAAAGATTCGGGGAGTGGTGAATATAGTGGCTACGATT DVW ACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1214 1264 CGACAAGTCCATCAGCACCGCCCACCTGCAGTGGAGTAGCCTGAGG
CARALRAGKG
GCCTCGGACACCGCCACTTATTACTGTGCGAGGGCGCTGCGGGCGG DHGMDVW
GGAAAGGCGACCACGGTATGGACGTCTGGGGCCAAGGG
1215 1265 CTCAAGAGATGATTCCGAAGGCACCGTCTATCTGCAAATGAATAGTC
CTREYMVRGSS
TGAAAGTCGAAGACACAGGCGTATATTATTGTACTAGAGAATATATG FGPW
GTTCGAGGATCTTCGTTCGGCCCCTGGGGCCAGGGA
1216 1266 AAGAGATAATTCCAGAGGCATCGCCTATCTGCAAATGGATAGCCTGA
CTRRHNDWFR
AAACCGAGGACTCAGCCCTGTATTATTGTACTAGAAGACACAATGAC GGLDVW
TGGTTTCGAGGCGGTTTGGACGTCTGGGGCCAAGGG
1217 CARATGCRDTA 1267 CCTGCGGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATATATTAC CSSDYYYFHD TGTGCGAGAGCGACGGGATGTCGTGATACAGCTTGTTCTAGTGATT MDVW ATTACTACTTCCACGACATGGACGTCTGGGGCCCAGGG
1218 1268 AAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGA
CGYSYGVRAY
AAACCGAGGACACAGCCGTGTATTACTGCGGATACAGCTATGGAGT YGVDVW
AAGGGCCTACTACGGTGTGGACGTCTGGGGCCAAGGG
1219 CATSYAANGM 1269 CATCATGACCGCGGACACAGCAACAGAGACAGCCTACATGGAATTG DVW AACAGCCTGAAATCTGAGGACACGGCCAAATATTATTGTGCAACAAG
TTACGCAGCGAACGGTATGGACGTCTGGGGCCAAGGG
1220 CTTDPGTYNGF 1270 GTATCTGCAAATGAACAGTCTGAGAATCGAAGACACAGCCGTCTATT WSRYYAGDWP ATTGCACGACAGATCCCGGAACTTATAATGGCTTCTGGAGTAGGTAT DPW TATGCCGGGGACTGGCCCGACCCCTGGGGCCAGGGA
1221 1271 TGACGAGTCCATCAGCACTGCCTACCTGCAGTGGAGCAGCCTGAAG
CAGGSQDLYY
GCCTCGGACAGCGCCATGTATTACTGTGCGGGAGGGTCACAAGACC YYMMKVW
TATACTACTACTACATGATGAAAGTCTGGGGCCAAGGG
1222 1272 CAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAATAGCCTGA
CARMRGYSYG
GAGCCGAGGACACGGCTGTTTATTATTGTGCGAGAATGCGTGGATA YYLDYW
TAGTTACGGTTACTACTTGGACTACTGGGGCCAGGGA
1223 1273 CCGATTCACCATCTCCAGAGACAACGCCGAGAACACGCTGTCTCTGC
CVRGGVSGWN
AAATGAACAGTCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGT W
AAGAGGGGGTGTCAGTGGCTGGAACTGGGGCCAGGGA
1224 1274 TATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACA
CTGRMFGPYG
GCCTGGAAACCGAGGACACTGCCGTGTACTTTTGCACTGGAAGAAT MDVW
GTTTGGACCTTACGGTATGGACGTCTGGGGCCAAGGG
1225 CVKVGYYDSS 1275 GAACACGCTGTATCTTCAAATGAGCAGTCTGAGAGCTGAGGACACG GYYLYWFFDL GCTGTGTATTACTGTGTGAAAGTGGGTTACTATGATAGTAGTGGTTA W TTACCTCTACTGGTTCTTCGATCTCTGGGGCCGTGGC
1226 1276 GGACAACGCCAAGAACACATTGTTTCTGCAAATGAACAGCCTTAGAG
CARSLTPYSYY
TCGAAGACACCGCCATATATTACTGTGCGAGATCTTTAACGCCTTAC YGLDVW
TCCTATTACTACGGTTTGGACGTCTGGGGCCAAGGG
1227 1277 TGACAAGTCCACCAGCACTGCCTACCTGCAGTGGAGCAGCCTGAAG
CAGGAQGLYY
GCCTCGGACACCGCCATTTATTACTGTGCGGGAGGGGCGCAGGGCC YYAMSVW
TCTATTACTACTACGCAATGAGCGTCTGGGGCCAAGGG
1228 1278 ATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAA
CTLGDDVGYY
TGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTACCCTT YW
GGGGATGATGTTGGTTATTACTACTGGGGCCAGGGA
1229 1279 CGTCAGCACCGCCTACTTGCAGTGGCGCAGCCTGAAGGCCTCGGAC
CARARALGTPA
TCCGCCATTTATTACTGTGCGAGAGCGCGCGCTTTGGGAACGCCTG PHRHGLDVW
CCCCCCACCGCCACGGTTTGGACGTCTGGGGCCAAGGG
1230 CARAADYYGS 1280 GAGGACAGCCTACATGGAGGTGAGCAGCCTGAGATATGAAGACACG GQFYFHGMDD GCTGTTTATTACTGTGCGAGAGCGGCAGATTACTATGGTTCGGGACA W ATTCTATTTCCACGGCATGGACGACTGGGGCCAAGGG
1231 1281 GTCCATCAGCACCGCCTATCTGGTATGGAGCAGCCTGAAGGCCTCG
CARLLGGHYY
GACACCGCCATGTATTACTGTGCGAGACTCCTCGGTGGTCACTATTA YSYYSLDVW
CTACTCCTACTACAGTTTGGACGTCTGGGGCCAAGGG
1232 1282 CATGACCATGGACACCTCCATAAGCACAGCCTACATGGACCTGAGC
CARQRFGNYG
AGCCTGAAATCTGAGGACACGGCCGTGTATTACTGTGCGAGACAGC MDVW
GATTCGGGAATTACGGCATGGACGTCTGGGGCCAAGGG
1233 1283 TATCGACCCAGACAGATCCAAGAACCAGTTCTCCCTCAAGTTGAAAT
CARRGDSSGW
CTGTGATTCCCGAGGACACGGGTGTATATTTCTGTGCAAGACGGGG YDTW
GGACAGCAGTGGCTGGTACGACACCTGGGGCCAGGGA
1234 1284 CAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGC
CLRGTGTFDY
AAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTTTA W
AGGGGTACAGGGACCTTTGACTACTGGGGCCAGGGA
1235 CATDLPPMKAI 1285 ATATCTGCAAATGAACAGCCTGAAAATCGAGGACACAGCCCTGTATT LTAEDYVDWF ACTGTGCCACAGATCTCCCGCCGATGAAGGCGATTCTTACAGCTGAA DPW GATTATGTGGACTGGTTCGACCCCTGGGGCCAGGGA
1236 1286 CACATCCAAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCG
CARNIAGTDTW
AGGACACGGCTGTGTATTACTGTGCAAGAAATATAGCAGGAACTGA LLPFDYW
TACATGGCTCCTACCCTTTGACTACTGGGGCCAGGGA
1237 1287 CAGCATGTCAGTGGACACGTCCAAGAGCCAGTTCTCCCTGGAACTG
CARESTPNGMD
vw AGTTCAGTGACCACTGCGGACACGGCCGTGTATTACTGTGCGAGGG
AAAGCACCCCAAACGGAATGGACGTCTGGGGCCAAGGG
1238 1288 GCAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAACACGCTGT
CTIVWHGYW ATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTCTATTAC TGTACCATAGTATGGCATGGCTACTGGGGCCAGGGA 1239 1289 CACAAGAGATGATTTAAACAACACACTTTTTCTGCAAATGAACAGCC
CCSLDPYSGYD TGAAGAGCGCGGACACAGCCGTATATTACTGTTGTTCTCTCGACCCA PSYW TACAGTGGCTACGACCCTAGTTACTGGGGCCAGGGA
1240 1290 CTCCAAAAACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGG
CARAVDTAMV ACACAGCCACGTATTACTGTGCACGGGCGGTGGATACAGCTATGGT SYYYGMDVW GTCCTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1241 1291 CATCTCCAGAGACAATTCGAAGAACACCCTGTATCTGCAAATGAACA
C AKDLHFLS AM ACCTGAGAGCCGAGGACACGGCCCTATATTACTGTGCGAAAGATTT DVW ACATTTCCTTTCCGCTATGGACGTCTGGGGCCAAGGG
1242 CAKDQIGVDF 1292 GCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGT WSGYRPRLDY GCGAAAGATCAAATAGGTGTGGATTTTTGGAGTGGTTATCGACCCA YGMDVW GGCTCGACTACTACGGTATGGACGTCTGGGGCCAAGGG
1243 1293 GAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACG
CARRDKGDVPT ALLGYGMDVW GCCGTGTATTACTGTGCGAGAAGGGACAAAGGGGACGTCCCAACTG CTTTATTAGGCTACGGTATGGACGTCTGGGGCCAAGGG
1244 CAKATPGVGQ 1294 CAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGCC YYDDSSGYYY ACACCTGGGGTGGGTCAGTATTATGATGATAGTAGTGGTTATTACTA YYYYGMDVW CTACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1245 CARSKRDCSDT 1295 GTTCTCCCTGGAACTGACCTCTGTGACCGCCGCAGACACGGCCGTC GCYGYYYAMD TACTACTGTGCGAGATCAAAGCGGGACTGTAGTGATACCGGCTGCT
vw ACGGCTACTACTACGCTATGGACGTCTGGGGTCAAGGG
1246 1296 ATTCACCATCTCAAGAGATGATTCAAAGAACTCACTGTATCTGCAGA
CARGRSGGMD TGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTACTGTGCTAG VW AGGTCGAAGCGGCGGTATGGACGTCTGGGGCCAAGGG
1247 1297 CATGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCG
CARGEDFGSGT CGGACACGGCCGTGTATTACTGTGCGAGAGGAGAAGACTTTGGTTC YHWFDPW GGGGACTTATCATTGGTTCGACCCCTGGGGCCAGGGA
1248 CARDPGTRMG 1298 GAACACGCTGTATCTGCAAATGAGCAACCTGAGAGTTGAAGACACG RRVPNFSVDV GCTGTTTTTTACTGTGCGAGAGACCCAGGCACTAGGATGGGTCGAA W GAGTGCCGAATTTCAGTGTGGACGTCTGGGGCCAAGGG
1249 1299 CTCCAGAGACATTTCTAAGAACACGCTGTATCTTCAAATGAACAGCC
CARFGYGDTGE TGAGAGTCGAGGACACGGCCGTGTATTACTGTGCGAGGTTCGGCTA GDVW CGGTGACACCGGGGAAGGGGACGTCTGGGGCCAAGGG
1250 1300 CACCATCTCAAGAGATGATTCCAAAAACATCGCCTATCTGCAAGTGA
CLREGPYGDGD FW ATAGCCTGAAAGTCGAGGACACAGCCGTTTATTACTGTCTTAGAGAG GGGCCCTACGGTGACGGGGACTTCTGGGGCCAGGGA
Table 8- sample 350 (light)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1301 1351 CGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTT
MQALQTPTF ACACTGAAAATCAGCAAAGTGGAGGCTGAGGATGTTGGGGTTTATT ACTGCATGCAAGCTCTACAAACTCCCACTTTCGGCGGA
1302 1352
QVWDSSSDHV TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTAGTAGTGATCATGTGGTATTCGGCGGA
1303 1353 TTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYTRSRTVVF CGATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAG CTCATATACAAGGAGCAGGACTGTGGTATTCGGCGGA
1304 1354 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGV VF TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC ATGGGATGACAGCCTGAATGGTGTGGTATTCGGCGGA
1305 1355 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCTCCCTGGCCA
AAWDDSLNGV TCAGTGGGCTCCGGTCCGAGGATGAAGGTGATTATTACTGTGCAGC
VF ATGGGATGACAGCCTGAATGGTGTTGTGTTCGGAGGA
1306 1356 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSTSDHV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTACTAGTGATCATGTGGTATTCGGCGGA 1307 1357 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
ATWDDSLSGLV TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTATTGTGCAAC F ATGGGATGACAGCCTGAGTGGTCTGGTGTTCGGCGGA
1308 1358 TCGATTTTCTGGCTCCAGGTCTGGCACCTCAGCCTCCCTGGTCATCA
AAWDDSLNGR GTGGGCTCCAGTCAGAAGATGAGGGTGATTACCACTGTGCTGCATG VVF GGATGACAGCCTGAATGGTCGGGTGGTCTTCGGCGGA
1309 1359 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
ATWDDSLNGVI TCAGTGGGCTGCAGTCTGAGGATGAGGCTGATTATTACTGTGCAAC F CTGGGATGACAGCCTGAATGGTGTTATATTCGGCGGA
1310 1360 CCGCTTCTCTGGCTCCAGGTCTGGCACCTCAGCCTCCCTGGCCATCA
ATWDDSLSGR GTGGTCTCCGGTCCGACGATGAGGCTGATTATTACTGTGCAACATG VVF GGATGACAGCCTGAGTGGTCGAGTGGTTTTCGGCGGA
1311 1361 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QSYDSSNAVF TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGT CAGTCTTATGATAGCAGCAATGCTGTGTTCGGAGGA
1312 1362 GATCCCTGAGCGATTCTCTGGCTCCAACTCGGGGAACACGGCCACC
QVWDSSTVVF CTGACCATCAGCAGAGCCCAAGCCGGACATGAGGCTGACTATTACT GTCAGGTGTGGGACAGCAGCACTGTGGTATTCGGCGGA
1313 1363 CCCTGATCGATTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCT
QSYDTTWVF CCCTCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTA CTGTCAGTCTTATGATACCACCTGGGTGTTCGGCGGA
1314 1364 AGACCGCTTCTCTGGCTCCAGCTCAGGAAGCACAGCTTCCTTGACCA
NSRDSSGKHW TCACTGGGGCTCAGGCGGCAGATGAGGCTGACTATTACTGTAACTC VF CCGGGACAGCAGTGGTAAGCATTGGGTGTTCGGCGGA
1315 1365 AGTCCCATCAAGATTCAGCGGCAGTGGGTCTGGGACAACTTTCACTC
QQYFNIPVTF TGACCATCAGTGGCCTGCAGTCCGAAGATGTTGCAATTTATTTCTGT CAACAATACTTCAATATTCCCGTGACATTCGGCCCG
1316 1366 TTCTAATCGCTTCTCTGGCTCCAAATCTGGCAACACGGCCTCCCTGA
TSYTSGYTYVF CCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAC CTCATATACAAGCGGCTACACTTATGTCTTCGGAACT
1317 1367 TGAACGATTCTCTGGCTCCGCCTCTGGGAACACGGCCACCCTGACC
QVWDAPTNQA ATCAGCGGGGTCGAGGTCGGGGATGAGGCCGACTACTATTGTCAGG VF TGTGGGATGCTCCTACTAATCAGGCGGTGTTCGGCGGA
1318 1368 TCGATTCTCTGGTTCCATCGACACGTCCTCCAATTCTGCCTCCCTCA
QSYIGGSPVVF CCATCTCTGGACTGAAGACGGAGGACGAGGCTGACTACTACTGTCA GTCTTATATTGGAGGCAGTCCTGTGGTTTTCGGCGGA
1319 1369 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWDRSTARF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTATTG TCAGGCGTGGGACAGAAGTACTGCCCGATTCGGCGGA
1320 1370 GATCCCTGACCGATTCTCTGGCTCCAACTCGGGGAACACGGCCACC
QVWDTSTEIF CTGACCATCAGCAGAGCCCAAGCCGGGGATGAGGCTGACTATTACT GTCAGGTGTGGGACACCAGCACTGAGATATTCGGCGGA
1321 1371 TGAGCGATTCTCTGGCTCCAACTCTGGGGACACGGCCACCCTGACC
QVWDSISDHVV ATCAGCAGGGTCGAAGACGGGGATGAGGCCGAATATTACTGTCAGG F TGTGGGACAGTATTAGTGATCATGTTGTTTTCGGCGGA
1322 1372 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCTGCCTCCCTGGCCA
ASWDDSLSGV TCAGTGGACTCCGGTCCGAGGATGAGGCTGATTATTTTTGTGCATCA VF TGGGATGACAGCCTGAGTGGTGTGGTTTTCGGCGGA
1323 1373 TTCTAATCGCTTCTCTGGCTCCAGGTCTGGCAACACGGCCTCCCTGA
CSYAGSGTLVF CAATCTCTGGGCTCCAGGCTGAGGACGAGTCTGATTATTACTGCTGT TCATATGCAGGTAGTGGCACTTTGGTATTCGGCGAG
1324 1374 TGACCGATTCTCTGGTTCCAAGTCTGGCACCTCAGCCTCCCTGGGCA
ATWDDDLNGW TCAGTGGACTCCAGTCTGAGGATGAGGCTACTTATTTCTGTGCAACA VF TGGGATGACGACTTGAATGGTTGGGTGTTCGGCGGA
1325 1375 TGAGCGATTCTCTGGCTCCAATTCTGGGAACACGGCCACCCTGACCA
QVWDSSSDHPD TCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGT
F GTGGGATAGTAGTAGTGATCATCCAGACTTCGGAAGT
1326 NSRDSSGNHHV 1376 CCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCA
VF CTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCG GGACAGCAGTGGTAACCATCATGTGGTATTCGGCGGA
1327 1377 TGACCGATTCTCTATGTTCAAATCTGGCACCTCAGCCTCCCTGGTCA
AVWDDSLSAV
TCAGTGGGCTCCGGTCCGGGGATGAGGCTGATTATCACTGTGCAGT VF
ATGGGATGACAGCCTGAGTGCTGTGGTCTTCGGCGGA
1328 1378 CGACAGCTCCTCAAACTCTGCCTCCCTCACCATCTCTGGACTGAAGC
QSDDTRSYDST
CTGAGGACGAGGCTGACTACTACTGTCAGTCTGATGATACTCGCTCT PAQAVF
TATGATAGTACCCCTGCACAAGCGGTGTTCGGCGGA
1329 1379 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QSYDNNYEVF TCACCATCTCTGGACTGCAGACTGACGACGAGGCTGACTACTACTGT CAGTCTTATGATAACAACTACGAGGTGTTCGGCGGA
1330 1380 GTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCACCA
QSYDSGNPGVV
TCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCAGTCT
TATGATAGCGGCAATCCAGGGGTGGTATTCGGCGGA
1331 1381 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSGW
TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC VF
ATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGA
1332 1382 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGC
GTWDSSLSAVV
ATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAA
CATGGGATAGCAGCCTGAGTGCTGTGGTATTCGGCGGA
1333 1383 CCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSFAGSNNLLF CCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAG CTCATTTGCAGGCAGCAACAATTTGCTATTCGGCGGA
1334 1384 CTTCTCTGGCTCCATCGACAGCTCCTCCAATTCTGCCTCCCTCACCA
QS YD AS NPH V V
TCTCTGGGCTGAAGCCTGAGGACGAGGCTGACTACTACTGTCAGTC
TTATGATGCCAGCAATCCCCATGTGGTATTCGGCGGA
1335 1385 AGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCA
NSRDSSGNPVV
TCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTC
CCGGGACAGCAGTGGTAACCCCGTGGTATTCGGCGGA
1336 1386 CCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYAGSNNLVF CCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAG CTCATATGCAGGCAGCAACAATTTGGTATTCGGCGGA
1337 1387 TGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACC
QSADSSGTYW
ATCAGTGGAGTCCAGGCAGAAGACGAGGCTGACTATTACTGTCAAT VF
CAGCAGACAGCAGTGGTACTTATTGGGTGTTCGGCGGA
1338 1388 CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCA
AAWDDSLNGH
GTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATG VVF
GGATGACAGCCTGAATGGTCATGTGGTATTCGGCGGA
1339 1389 CTTCTCAGTCTTGGGCTCAGGCCTGAATCGGTACCTGACCATCAAGA
GADHGSGSNFA
ACATCCAGGAAGAGGATGAGAGTGACTACCACTGTGGGGCAGACCA VVF
TGGCAGTGGGAGCAACTTCGCGGTGGTATTCGGCGGA
1340 1390 CCCTGATCGCTTCTCTGGCTCCAAGTTTGACAACACGGCCTCCCTGA
CSFAGSYTWVF CCATCTCTGGGCTCCAGGCTGACGATGAGGCTGATTATTACTGCTGC TCATTTGCAGGCAGCTACACTTGGGTGTTCGGCGGA
1341 1391 CCGATTCTCTGGCTCCGAGTCTGGCACCTCAGCCTCCCTGGCCATCA
AAWDDSLGGS
GTGGGCTCCGGTCCGAGGATGAGGCTGATTATTTCTGTGCAGCATG YLF
GGATGACAGCCTGGGTGGCTCTTATCTATTCGGAAGT
1342 1392 GGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCC
NSYAGSNVVF TGACCGTCTCTGGGCTCCAGCCTGAGGATGAGGCTGATTATTACTGC AACTCATATGCAGGCAGCAACGTGGTCTTCGGCGGA
1343 1393 TCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCA
QSYDSSNHVVF CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA GTCTTATGATAGCAGCAATCATGTGGTATTCGGCGGA
1344 1394 TGACCGATTCTCTGGCTCCAAGTCTGGCAACTCAGCCTCCCTGGCCA
ATWDDSLNGV
TCAGTGGACTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAACA VF
TGGGATGACAGCCTGAATGGCGTGGTTTTCGGCGGA
1345 1395 TCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCT
SSCASDYPANV
CTGGGCTCCAGGCTGAGGACGAGGCCGATTATTACTGCAGCTCATG VF
TGCAAGCGACTACCCTGCCAATGTGGTATTCGGCGGA
1346 QSYDSSNVVF 1396 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGT
CAGTCTTATGATAGCAGCAATGTGGTATTCGGCGGA
1347 1397 CCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYAGSNNFVF CCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAG CTCATATGCAGGCAGCAACAATTTTGTCTTCGGAACT
1348 1398 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGACA
VTWDSSLSEVV TCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGTAAC F ATGGGATAGCAGCCTGAGTGAAGTGGTATTCGGCGGA
1349 1399 GCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCA
QVCDGNSDHK GCAGGGTCGAAGCCGGGGATGAGGCCGACTGTTACTGTCAGGTGTG DVC CGATGGTAATAGTGATCATAAGGATGTGTGCGCAACT
1350 1400 GGTTGAGAGATTCTCAGCCTCCACCTCAGGGACAATGGTCACCTTGA
YSADSDNHRLF CTATCAGTGGGGCCCAGGTGGAGGATGAAGCTGACTACTATTGTTA CTCAGCAGACAGTGATAATCATAGGCTTTTCGGCGGA
Table 9- sample 427 (heavy)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1401 1451 CAGAGATGATTCAAAGAACACGGCGTATCTGCAAATGAACAGCCTG
CSSPQATMTSV
AAAACCGAGGACACGGCCGTGTATTACTGTTCTAGCCCCCAGGCGA GMDPW
CGATGACTTCGGTGGGGATGGACCCCTGGGGCCAGGGA
1402 1452 TACCGCAGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGC
CARDLGSGSYY
CTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATCTGG FFYW
GTAGTGGGAGTTACTATTTTTTCTACTGGGGCCAGGGA
1403 1453 CACCATCTCCAGAGACAACGCCAAGAGCTCACTGTATCTGCAAATGA
CATQAVAGPR
ACAGTCTGAGAGCCGAGGACGCGGCTGTGTATTACTGTGCGACCCA GDW
AGCAGTGGCTGGCCCCCGCGGAGACTGGGGCCAGGGA
1404 1454 CAGAGACAACGCCGAGAACTCACTGTATCTGCAAATGAACAGCCTG
CTREGPYSSSW
AGAGCCGAGGACACGGCTGTATATTACTGTACGAGAGAAGGGCCGT YFLHW
ACAGTAGTAGCTGGTACTTCCTTCACTGGGGCCAGGGC
1405 1455 TACCGCAGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGC
CARDLGTGSYY
CTGAGATCTGAGGACACGGCCGTCTATTATTGTGCGAGAGATCTGG FFYW
GTACTGGGAGTTACTATTTTTTCTACTGGGGCCAGGGA
1406 1456 AGATGATTCAAAAACCACTCTGTATCTACAAATGAACACCCTGAAAA
CTTHMIFGIVN
GCGAGGACACAGCCGTCTATTACTGTACCACCCATATGATTTTTGGA DAFDIW
ATAGTTAATGATGCTTTTGATATCTGGGGCCAAGGG
1407 1457 TACCAGGGACATGTCCACAAGCACAGCCTACATGGAGCTGAGCAGC
CAAFNYYDSSG
CTGAGATCCGAGGACACGGCCGTGTATTACTGTGCGGCCTTTAATTA FPAW
CTATGATAGTAGTGGTTTCCCTGCCTGGGGCCAGGGA
1408 1458 ATCTCTAGACACGTCCAAGAAACAGTTCTCCCTGAACCTGAGCTCTG
CASGGHDFPK
TGACCGCTGCGGACACGGCCGTATATTACTGTGCGAGTGGGGGACA WFDPW
TGACTTCCCTAAGTGGTTCGACCCCTGGGGCCAGGGA
1409 1459 AGACAACGCCAAGAACTCCCTGTATTTGGAAATGAACAGTCTGAGA
CAKDIRRSGWF
GCTGAGGACACGGCCTTGTACTACTGTGCAAAAGATATTAGGCGCA GTIDYW
GTGGCTGGTTCGGGACGATTGACTATTGGGGCCAGGGA
1410 1460 CAACGCCGAGAACTCAGTGTATCTGCGAATGAACAGCCTGAGAGTC
CVRDRDVTANP
GAGGACACGGCTGTGTATTACTGTGTGAGAGATCGTGACGTGACTG HDASDIW
CAAATCCACATGATGCTTCTGATATCTGGGGCCAAGGG
1411 CARGDRRFSYY 1461 GAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTTCTGT GSGNSDYFYDV GCGAGAGGGGATCGGCGGTTCAGCTACTATGGTTCGGGCAACTCAG LDVW ACTACTTCTACGACGTTCTGGACGTCTGGGGCCTAGGG
1412 1462 CGCGGACACATCCACGGACACAGCCTACATGGAGTTGAGCAGCCTG
CARVWGEGSD
ACATCTGACGACACGGCCGTATATTACTGTGCGAGAGTGTGGGGGG SYFYYW
AGGGTAGTGACAGCTACTTCTACTACTGGGGCCAGGGA
1413 CARWYNYYGS 1463 AGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGA
GRSYDYW GTCGCGGACACGGCTGTCTATTATTGTGCGAGATGGTACAATTACTA TGGTTCGGGGAGGTCCTATGACTACTGGGGCCAGGGA
1414 1464 AATAAGCGTCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCAAC
CARDGGHNCD
TGCGCTCTGTGACTCCCGAGGACGCGGCTGTGTACTATTGTGCAAG SW
AGATGGTGGTCACAATTGCGACTCCTGGGGCCGGGGA
1415 1465 GGAGAAGTCACTGTATCTGCAAATGAACAGCCTGAGAGTCGAGGAC
CARANSGGGD
ACGGCTATCTATTACTGTGCGAGAGCGAATTCGGGGGGGGGTGATG ATYYRSFDSW
CGACCTACTATCGCTCATTTGACTCCTGGGGCCAGGGA
1416 1466 AACCATCAGGCCAGACACATCCAAGAACCAGTTCTCCCTGCAGCTGA
CARDGDSGWN
AGTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGA DYW
CGGGGACAGTGGCTGGAACGACTACTGGGGCCAGGGA
1417 1467 TTCTAAGAACTCGCTGTATTTGCAAATGAACAGCCTGAGAGTCGAGG
CAKDRRDTSGY
ACACGGCCGTCTATTACTGTGCGAAAGACCGTCGTGATACTAGTGGT SCCSFDSW
TATTCCTGTTGCAGCTTTGACTCCTGGGGCCAGGGA
1418 1468 CGCCAAGAACACGCTGTATCTGCAAATGAACAGTCTGAGAGTCGAG
CAREYRSGWY
GACACGGCTATGTATTACTGTGCAAGAGAATATAGGAGTGGCTGGT GYYYGMDVW
ACGGCTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1419 1469 CATCTCAGCCGACAAGTCCATCAGCACCACCTACCTGCAGTGGAGC
CARHVSDNRRL
AGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGACATG DYW
TCTCGGATAACAGAAGGCTTGACTACTGGGGCCAGGGA
1420 1470 AGACAATTCCAAGAACACTCTATATCTACAAATGAACAGGCTGAGAG
CAKGGAPPVW
CCGAAGACACGGCCGTTTACTACTGTGCGAAAGGGGGGGCACCTCC DFGMDVW
TGTCTGGGACTTCGGCATGGACGTCTGGGGCCAAGGG
1421 1471 CAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTG
CARGVVGTVA
AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGGGTAGTCG GKVDYW
GAACAGTGGCTGGAAAGGTCGACTACTGGGGCCAGGGA
1422 1472 CGCCAAGAACTCAGTGTATCTGCAAATGAACAGCCTGAGAGCCGAG
CARDQGYDFW
GACACGGCCCTGTATTACTGTGCGAGAGATCAGGGATACGATTTTTG SAKGTFDIW
GAGTGCCAAGGGTACTTTTGATATCTGGGGCCGAGGG
1423 1473 CAATTCCAAGAACACGGTGTATCTGCAGATGAACAGCCTGAGAGCC
CARAMTGTYF
GAGGACACGGCTGTTTATTACTGTGCGAGAGCTATGACTGGGACCT GMGVFDYW
ACTTCGGGATGGGTGTTTTTGACTACTGGGGCCAGGGA
1424 1474 CAGAGACATCTTCAAGAACTCCCTGTCTCTGCAAATGAACAGTCTGA
CAKDLGSGELL
GAAGTGAGGACACGGCCGTGTATTATTGTGCAAAAGATTTGGGTTC GLDYW
GGGGGAGTTATTGGGGCTGGACTACTGGGGCCAGGGA
1425 1475 CAAGAACTCACTGTTTCTGCAAATGAACAGCCTGAGAGCCGAGGAC
CARDAFCSGGR
ACGGCCGTCTATTACTGTGCGAGAGATGCGTTCTGTAGTGGTGGTC CSFFGMDVW
GTTGTTCCTTCTTCGGTATGGACGTCTGGGGACAAGGG
1426 1476 CAGAGACAATTCCAAGAACACGCTGTATCTGCAGATGAACAGCCTG
CARDWSSVGG
CGAGCCGAAGACACGGCTGTGTATTACTGTGCGAGAGATTGGTCCA WYLSWW
GCGTTGGTGGCTGGTACTTGTCCTGGTGGGGCCAGGGA
1427 1477 CGCGGACGAATCCACGACCACAGCCTACATGGAGCTGAGCAGCCTG
CAREGYGDRN
AGATCTGAGGACACGGCCGTGTACTACTGTGCGAGAGAAGGGTACG NPYDHW
GTGACCGTAACAACCCTTATGACCACTGGGGCCAGGGA
1428 1478 AGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTG
CARDRGLVLLP
CCGCGGACACGGCCGTGTATTACTGTGCGAGAGACCGGGGCTTAGT GWFDPW
ACTCCTCCCGGGGTGGTTCGACCCCTGGGGCCAGGGA
1429 1479 AGATGATTCAAAAAACGCACTGTATCTGCAAATGAACAGCCTGAGAA
CTTDRRSPDIG
CCGAGGACACAGCCATGTACTATTGTACTACAGACCGTCGTAGCCCC AQFDYW
GATATAGGAGCCCAGTTTGACTACTGGGGCCAGGGA
1430 CAKGRAIVVRG 1480 TCTGCAAATGAACAGTCTGAGAGTTGAGGACACGGCCCTGTATTACT ILKTRYDYYGM GTGCAAAAGGTCGGGCTATTGTGGTCCGGGGAATTCTTAAGACTCG DVW ATACGACTACTACGGTATGGACGTCTGGGGCCAAGGG
1431 CARESSGGSQS 1481 CACGCTGTATCTGCAAATGAACAACCTGAGAGCTGAGGACACGTCT YTYYYYAMDV GTGTACTACTGTGCGAGAGAGTCCAGTGGTGGTAGCCAGTCTTATA W CGTACTACTACTACGCTATGGACGTCTGGGGCCAAGGG
1432 CARMWCYDFW 1482 AAACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACA SGSYYYGMDV GCCACGTATTACTGTGCACGGATGTGGTGTTACGATTTTTGGAGTGG W TTCCTATTACTACGGTATGGACGTCTGGGGCCAAGGG
1433 CARLNYHDRG 1483 CAACGCCAAGAACTCGCTGTATCTGGAAATGAACAGCCTGAGAGTC HYYPEANW GACGACACGGCTGTGTATTACTGTGCGAGGCTCAATTACCATGATCG
TGGTCATTATTACCCCGAGGCCAACTGGGGCCGGGGA
1434 1484 GACGACAGACACATCCACGGGCACAGCCTACATGGAGCTGAGGAGC
CARDVNNWSH
CTAACATCTGACGACACAGCCGTGTATTTCTGTGCGAGAGACGTCAA YFEYW
CAACTGGTCGCACTACTTTGAGTATTGGGGCCAGGGA
1435 1485 AGCCATCATCCCAGACACATTCAAGAACCAGTTCTCCCTGCAGCTGA
CARDGGSGWID
ACTCTGTGACTCCCGAGGACACGGCTGTCTATTACTGTGCAAGGGA PW
CGGTGGGTCGGGCTGGATCGACCCCTGGGGCCAGGGA
1436 1486 CATCTCCAGAGACAACGCCAAGAACTCACTGTACCTGCAAATGAACA
CATAPISPPHFD
GCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGACAGCACC HW
CATTAGTCCCCCCCACTTTGACCACTGGGGCCAGGGA
1437 1487 CACGTCCATCAGCACAGCCTACATGGAGGTGACCGGACTGACATCT
CARERSMVGRP
GACGACACGGCCGTGTATTACTGTGCGAGAGAACGGAGTATGGTAG ESWFDPW
GTCGTCCGGAGTCCTGGTTCGACCCCTGGGGCCAGGGA
1438 1488 CCAGAACTCCCTCTATCTGCACATGAACGGTCTGAGGCCTGAAGACA
CARDSSGTFVY
CGGCCTTCTATTACTGTGCAAGAGATTCGAGCGGTACCTTCGTCTAT EEYGGFDSW
GAAGAATATGGTGGTTTTGACTCCTGGGGCCACGGA
1439 1489 CTCCAGAGACAATTCCAAGAACACGTTGTATCTGCACATGAACAGCC
CARDLVARHD
TGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCTAGT CFDLW
AGCTCGGCACGATTGTTTTGATCTCTGGGGCCAAGGG
1440 1490 TACCGCGGACGAATCCACGACCACAGCCTACATGGAGCTGAGCAGC
CARDLGSGSYY
CTGAGATCTGAGGACGCGGCCGTGTATTACTGTGCGAGAGATCTGG FFYW
GTAGTGGGAGCTACTATTTTTTCTACTGGGGCCAGGGA
1441 CAGAPDCGNG 1491 ACTGTATCTGCAAATGAACAGTCTGAGAGCCGAGGACACGGGTGTG VCSGFHYYGM TATTACTGTGCAGGAGCGCCGGATTGTGGTAATGGTGTGTGTTCTG DVW GTTTTCACTACTACGGTATGGACGTCTGGGCCCAAGGG
1442 1492 CAAGAACTCATTGTTTCTGCAAATGAACAGCCTGAGAGCCGAGGAC
CARDAYCSGGS
ACGGCCGTGTATTACTGTGCGAGAGATGCGTATTGTAGTGGGGGTA CSFYGMDAW
GCTGCTCCTTCTACGGTATGGACGCCTGGGGCCAAGGG
1443 1493 CTCAAGAGATGATTCAAAAAATATGTTGTATCTGGAAATGAACAGCC
CTTVRYDRSNY
TGAAAACCGAGGACACAGCCTTTTATTACTGTACCACAGTCCGCTAT PDYW
GATAGGAGTAACTATCCAGACTACTGGGGCCAGGGA
1444 1494 CGCGGACGAATCCACGAGCACTGCCTACATGGAGCTGAGTAGTCTG
CARRQQLPKYS
AAATCTGAGGACACGGCCATATATTTCTGTGCGAGAAGGCAGCAGC GLDVW
TGCCCAAGTATTCCGGCTTGGACGTCTGGGGCCAAGGG
1445 1495 CGCGGACAAATCCACGAGCACAGCCTACATGGAGGTGAGCAGCCTG
CARGTGDSSGY
AGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGGAACTGGTG YYFYW
ATAGTAGTGGTTATTACTACTTTTACTGGGGCCAGGGA
1446 1496 CAGAGATGATTCAAAGAACACGACGTATCTGCAAATGAACAGCCTG
CSSPQSTMTSV
AAAACCGAGGACACGGCCGTGTATTACTGTTCTAGCCCCCAGTCGA GMDPW
CGATGACTTCGGTGGGGATGGACCCCTGGGGCCAGGGA
1447 1497 CAAGAACACGTTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGAC
CARGHYDTTFY
ACGGCCGTGTATTACTGTGCGAGAGGTCACTATGATACTACTTTTTA HHSEFFQQW
TCATCACTCTGAATTCTTCCAGCAGTGGGGCCAGGGC
1448 1498 CATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACA
CVRVASSRMG
GCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGTGAGAGTGGC MDVW
CAGCTCGCGAATGGGTATGGACGTCTGGGGCCAAGGG
1449 1499 AATAACCATCAATCCAGACACATCCAAGAACCAATTCTCCCTGCAGC
CARGFGGYVDS
TGAACTCTGTGACCCCCGAGGACACGGCTGTGTATTACTGTGCAAG W
AGGGTTTGGTGGCTACGTTGACTCCTGGGGCCAGGGA
1450 1500 CTCCAGAGACAATTCCAAGAACATATTGTATCTCCAAATGAACAGCC
CAKEVAVAAQ
TGAGAGGTGAGGACACGGCTGTGTATTACTGTGCGAAAGAGGTCGC YVDLW
AGTGGCTGCCCAGTACGTGGACCTCTGGGGCCAGGGA Table 10- sample 427 (light)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1501 1551 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACCGACTTCACT
QQYGSSPYTF CTCACCATCAGCAGACTGGAGCCTGAGGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCGTACACTTTTGGCCAG
1502 1552 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPRTF CTCACCATCAGCAGCCTGCGGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCGGACGTTCGGCCAA
1503 1553 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDS LNGW TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTGCTGTGCAGC VF ATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGT
1504 1554 TGGGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTAGTAGTGATCATGTGGTGTTCGGCGGA
1505 1555 TCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGA
QAWDSSTPYVF CCGTCAGCGGGACCCTGTCTATGGATGAGGCTGACTATTACTGTCA GGCGTGGGACAGCAGCACTCCATATGTCTTCGGAACT
1506 1556 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHY ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTAGTAGTGATCATTATGTCTTCGGAACT
1507 1557 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLKGP TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC
VF ATGGGATGACAGTTTGAAGGGTCCGGTGTTCGGCGGA
1508 1558 TGACCGATTCTCTGGCACCACGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDNLNGP TCAGTGGGCTCCAGTCTGAGGACGAGGCTGATTATTACTGTGCAGC VF ATGGGATGACAACCTGAATGGTCCGGTATTCGGCGGA
1509 1559 GGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTC
QKYNSAPWTF TCACCATCAGCAGCCTGCAGCCTGAAGATGCTGCAACTTATTACTGT CAAAAGTATAACAGTGCCCCCTGGACGTTCGGCCAA
1510 1560 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHW ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTAGTAGTGATCATTGGGTGTTCGGCGGA
1511 1561 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGGCTTCACT
QQYGSSPYTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCGTACACTTTTGGCCAG
1512 1562 TGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDS LSGP TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCGGC VF ATGGGATGACAGCCTGAGTGGTCCGGTATTCGGCGGA
1513 1563 TTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYTSSSTVVF CCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAG CTCATATACAAGCAGCAGCACTGTGGTATTCGGCGGA
1514 1564 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
QSYDRSLAGYV TCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTC F CTATGACAGGAGCCTGGCTGGTTATGTCTTCGGAACT
1515 1565 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPLTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCGCTCACTTTCGGCGGA
1516 1566 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPLTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCGCTCACTTTCGGCGGA
1517 1567 GGTCCCATCAAAGTTCAGCGGCAGTGGATCTGGGACAGATTTCACT
QQYNSYPLTF CTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTG CCAACAGTATAATAGTTACCCTCTCACTTTCGGCGGA
1518 1568 AGACACTGGGGTCCCAGCCAGGTTCAGCGGCAGTGGGTCTGGGACC
LHSATSG GATTTCACCCTCACAATTAATCCTGTGGAAGCTAATGATACTGCAAA TTATTACTGTCTGCACTCTGCGACTAGTGGCAGCCCA
1519 QQYGSSPFTF 1569 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG
TCAGCAGTATGGTAGCTCACCATTCACTTTCGGCCCT
1520 1570 TGAGCGCTTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDGSSDHVI ATCAGCAGGGTCGAAGTCGGGGATGAGGCCGACTATTACTGTCAGG F TGTGGGATGGTAGTAGTGATCATGTGATATTCGGCGGC
1521 1571 GGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACA
MQNLQAPYTF CTGGAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACT GCATGCAGAATCTACAAGCCCCGTACACTTTTGGCCAG
1522 1572 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPYTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCGTACACTTTTGGCCAG
1523 1573 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGACA
GAWDSSVTVW TCACCGGACTCCAGACTGGGGACGAGGGCGATTATTTTTGCGGAGC VF ATGGGATAGCAGTGTGACCGTTTGGGTGTTCGGCGGA
1524 1574 TAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCA
SSYTTSSTLDVF TCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTC ATATACAACCAGCAGCACTCTCGATGTCTTCGGAACT
1525 1575 TCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCA
QSYDTSAHVVF CCATCTCTGGACTGACGACTGATGACGAGGGTGACTATTACTGTCAG TCTTATGATACCAGTGCCCATGTAGTCTTCGGCGGA
1526 1576 TTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSHTTSSTLVF CCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAG CTCACATACAACCAGCAGCACTCTGGTGTTCGGCGGA
1527 1577 TGAGCGATTCTCTGGCTCCAATTCTGGGAACACGGCCACCCTGACCA
QVWDSTTAHV TCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGT LF GTGGGATAGTACTACTGCTCATGTACTATTCGGCGGA
1528 1578 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPWTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCGTGGACGTTCGGCCAA
1529 1579 TTCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
CSYAGGSTLVF CAATCTCTGGGCTCCGGGCTGAGGACGAGGCTGATTATTACTGCTG CTCATATGCAGGTGGTAGCACTTTGGTGTTCGGCGGA
1530 1580 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPYTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCTCCGTACACTTTTGGCCAG
1531 1581 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDS LNGW TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC VF ATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGA
1532 1582 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPLTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCTCACTTTCGGCGGA
1533 1583 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYDNPLTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCGGTTTATTTCTG TCAGCAATATTATGATAACCCGCTCACTTTCGGCGGA
1534 1584 CCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGA
QAWDSSTYVV CCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTGTCA F GGCGTGGGACAGCAGCACTTATGTGGTATTCGGCGGA
1535 1585 CATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPWTF CTCACCATCAGCAGACTGGAGCCTGATGATTTTGCAGTGTATTGCTG TCAGCAGTATGGTAGCTCACCGTGGACGTTCGGCCAA
1536 1586 TATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACT
QQYNNWPRTF CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTG TCAGCAGTATAATAACTGGCCTCGGACGTTCGGCCAA
1537 1587 GATCCCTCATCGCTTCTCAGGCTCCAGCTCTGGGGCTGAGCGCTACC
QTWDSGIVVF TCATCATCTCCAGCCTCCAGTCTGAGGATGAGGCTGAGTATCACTGT CAGACCTGGGACTCTGGCATTGTGGTTTTCGGCGGA
1538 1588 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPYTF CTCACCATCAGTAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCCCCGTACACTTTTGGCCAG 1539 1589 GGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACA
MQSLQIPPTF CTGAAAATCAGTAGAGTGGAGGCTGAAGATGTTGGGGTTTATTACT GCATGCAATCTCTACAAATTCCTCCCACCTTCGGCCAA
1540 1590 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSASDHV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTGCTAGTGATCATGTGGTGTTCGGCGGA
1541 1591 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHPV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCATCCTGTCTTCGGAACT
1542 1592 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWDSSTVVF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTG TCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGA
1543 1593 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSYHV ATCACCAGGGTCGCAGCCGGGGATGAGGCCGACTATTACTGTCAGG
VF TGTGGGATAGTAGTAGTTATCATGTGGTCTTCGGCGGA
1544 1594 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPLTF CTCACCATCAACAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCGCTCACTTTCGGCGGG
1545 1595 GGTCCCAGACAGATTCAGTGGCAGTGGGGCAGGGACAGATTTCACA
MQATHFPWTF CTGAAAATCAGCAGGGTGGAAGCTGAGGATGTCGGAGTTTATTACT GCATGCAAGCGACACACTTTCCGTGGACGTTCGGCCAA
1546 1596 AGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCA
NSRDSSGNHLV TCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTC F CCGGGACAGCAGTGGTAACCATCTGGTATTCGGCGGA
1547 1597 TGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTC
QQRSNWPSF ACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTA CTGTCAGCAGCGTTCCAACTGGCCTTCTTTCGGCCCT
1548 1598 GGTCCCTGACCGGTTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYNTPQTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAATACTCCTCAAACTTTTGGCCAG
1549 1599 CCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTC
QHYNNWPPWT ACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCA F GCACTATAATAACTGGCCTCCGTGGACGTTCGGCCAA
1550 1600 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QHYSTYPRTF CTCACCATCAGCGACCTGCAGGCTGAAGATGCGGCAGTTTATTACTG TCAGCACTATTCTACGTATCCCCGGACGTTCGGCCAA
Table 11- sample 429 (heavy)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1601 1651 CAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGA
CAKGSGYDIFAN GAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGTAGTGGCTA FDYW CGATATTTTTGCCAACTTTGACTACTGGGGCCAGGGA
1602 1652 CCGATTCACCATCTCCAGAGACAACGCCAAGAACACGGTGTATCTGC
CASSSGWYQGW AAATGAACAGTCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGC CTCTAGCAGTGGCTGGTACCAGGGCTGGGGCCAGGGA
1603 1653 GGGCCGATTCACCATCTCCAGAGACAATGCCAAGAATACAGTGTATC
CAGFSDYAYW TCCAAATGAACAGCCTGAGAGAAGAGGACACGGCTGTGTATTACTG TGCGGGCTTCAGTGACTACGCCTACTGGGGCCAGGGG
1604 1654 CACAGCCTACATGGAGCTGAGCAGCCTGACATCCGAGGACACGGCC
CARDHNGIQRTS GTGTATTACTGTGCGAGAGATCATAACGGGATACAGAGAACCTCCG DFHFYGMDVW ACTTCCACTTCTACGGTATGGACGTCTGGGGCCAAGGG
1605 1655 GAATCAGTTTTCCCTGAGGATGAACGCCGTTACCGCCGCAGACACG
CARRVDSSALV GCCGTGTATTACTGTGCGAGACGGGTCGACTCTAGTGCGCTTGTTG GSYQNWLDPW GGAGTTACCAAAACTGGCTCGATCCCTGGGGCCAGGGA
1606 CARESRSVLHYY 1656 AGACACTTCCAAGAACACACTGTATCTGCAACTGAACAGCCTGAGAG GMDVW CTGAGGACACGGCTGTGTTTTACTGTGCGAGAGAAAGTCGGAGTGT
TCTCCACTACTACGGTATGGACGTCTGGGGCCAGGGG
1607 1657 CTCCAAAAAGCAGGTGGTCCTTACAATGACGAACGTGGATCCGGTG
CARLRYGFRDSS
GACACAGCCACCTATTATTGTGCACGTCTACGGTATGGTTTTCGTGA DYLMDVW
CAGTAGTGATTATTTGATGGACGTCTGGGGCCAAGGG
1608 1658 CGATTCAAAGAACACGCTGTTTTTGCAAATGAACAGCCTGAAGACCG
CSTLSMNWNYY
AGGACACAGCCGTGTATTATTGTTCCACCCTCTCTATGAACTGGAAT SYAMDVW
TACTACTCCTACGCCATGGACGTCTGGGGCCAGGGG
1609 1659 CTCCAGAGACAATTCCAGGAACACCCTCTATCTGCAAATGCACAGCC
CTNGLNDNNTPF
TGAGACCTGAGGACGCGGCTGTGTATTACTGTACAAACGGCCTTAAT HYW
GACAACAACACTCCCTTTCACTACTGGGGCCAGGGA
1610 CVANGLYGSGS 1660 GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTA YANYYYYGMD TATTACTGTGTCGCAAACGGGCTGTATGGTTCGGGGAGTTATGCGA VW ACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1611 CARRGICSSGSC 1661 GCAAATGGACAGCCTGAGAGCCGAGGACACGGCCGTGTATTATTGT VGNDMDVWGG GCGAGAAGGGGGATTTGTAGTAGTGGAAGTTGTGTAGGCAACGATA MDVW TGGACGTCTGGGGCGGTATGGACGTCTGGGGCCAAGGG
1612 1662 CTCCAGAGACAACGCCAAGAACTCACTTTATCTGCAAATGAACAGCC
CARVGCSGGTC
TGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGTGGGTTG VNYW
CAGTGGTGGTACCTGCGTTAACTACTGGGGCCAGGGA
1613 1663 AGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGA
CAKGGYCSSTSC
GCTGAGGACACGGCCTTGTATTACTGTGCAAAAGGGGGATATTGTA YFDYW
GTAGTACCAGCTGCTATTTTGACTACTGGGGCCAGGGA
1614 1664 CACCATCTCCAGAGACAACAGCAAAAATTCCCTGTATCTGCAAATGA
CGKGGLDYYFD
ACAGTCTGAGAGCTGAGGACACCGCCTTGTATTACTGTGGAAAAGG YW
GGGGCTAGACTACTACTTTGACTACTGGGGCCAGGGA
1615 1665 CAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGA
CADGGKSGYYY
GACCTGAGGACACGGCTGTGTATTACTGCGCCGACGGTGGTAAGTC GMDVW
CGGCTACTACTATGGTATGGACGTCTGGGGCCAAGGG
1616 1666 CATCTCCAGAGATGATTCAAAGAATACGGCATATCTGCAAATGAACA
CTRPRPEYSGMD
GCCTGAAAACCGAGGACACGGCCCTGTATTACTGTACTAGACCCCG VW
CCCAGAGTATTCGGGTATGGACGTCTGGGGCCAGGGG
1617 1667 CTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGACCAAGA
CARMEDSTYYY
TGGACCCTGTGGACACAGCCACGTATTACTGTGCACGGATGGAGGA FDYW
CAGCACCTATTACTACTTTGACTACTGGGGCCAGGGA
1618 1668 CAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGGT
CARDPQAAAAY
GAGGACACGGCTGTGTATTACTGTGCGAGAGATCCACAAGCAGCTG IQGMDVW
CCGCTTACATACAGGGTATGGACGTCTGGGGCCAAGGG
1619 CAKDQKRGFWS 1669 CACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCT DYYSRHGMDV GTGTATTACTGTGCGAAAGATCAGAAACGGGGTTTTTGGAGTGATTA W TTATTCTCGTCACGGTATGGACGTCTGGGGCCAAGGG
1620 1670 CAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGA
CARATTYYYYN
GAGCCGAGGACACGGCCTTGTATCACTGTGCGAGAGCGACTACTTA GMDVW
CTACTATTATAACGGTATGGACGTCTGGGGCCAAGGG
1621 1671 CATATCAGTAGACACGTCCAAGAACCAGATCTCCCTGAGGCTGAGG
CARDYGASYYF
TCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGACT DYW
ACGGTGCCTCGTACTACTTTGACTACTGGGGCCAGGGA
1622 1672 GAACTCACTCTTTCTACAAATGTACAGACTGAGAGTCGAGGACACGG
CVRWGGTMVR
CTGTTTACTATTGTGTCAGATGGGGTGGGACTATGGTTCGGGGACTC GLAIVHGMDVW
GCAATAGTCCACGGTATGGACGTCTGGGGCCAAGGG
1623 1673 CGACAAGTCCATCAACACCGCTTACCTGCAATGGAGCGGCCTGAAG
CARMGSIGALIN
GCCTCGGACAGCGGCATATATTATTGCGCGCGAATGGGGAGTATAG YFDPW
GTGCTCTTATTAATTACTTCGATCCTTGGGGCCAGGGA
1624 1674 AGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGA
CARESRSVLHYY
GCTGAGGACACGGCTGTGTATTACTGTGCGAGAGAAAGTCGGAGTG GMDVW
TTCTCCATTACTACGGTATGGACGTCTGGGGCCAAGGG
1625 1675 CATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCT
CARDYGSDSFFD
CTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGATTA YW
TGGTTCGGACAGTTTCTTTGACTACTGGGGCCAGGGA 1626 1676 GACCAGGGCCACGTGGACGAGCACCTTCTACATGGAGTTGGGAAGC
CAREYTGYDNF
CTGACATCTGAGGACACGGCCGTGTATTATTGTGCGAGGGAATATA FDSW
CTGGCTATGATAACTTCTTTGACTCCTGGGGTCAGGGA
1627 1677 AGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGA
CARVGCSGGGG
GCCGAGGACACGGCTGTGTATTACTGTGCGAGAGTGGGTTGTAGTG TCFNYW
GTGGTGGTGGTACCTGCTTTAACTACTGGGGCCAGGGA
1628 1678 GACCCAGTTCTCCCTGAAACTGATCTCTGTGACTGCCGCGGACACG
CARGGDGSGDS
GCCGTCTACTACTGTGCGAGAGGTGGAGATGGCAGCGGTGACTCCA RNYYYGLDLW
GGAACTACTACTACGGTTTGGACCTCTGGGGCCGAGGG
1629 1679 AGATGATTCAAAGAACACGGCGTATCTGCAAATGAACAGCCTGAAA
CSRPTPGGDGDP
ACCGAGGACACGGCCGTGTATTACTGTTCCAGACCAACGCCGGGGG FVDYW
GGGACGGGGACCCTTTCGTTGACTACTGGGGCCAGGGA
1630 1680 CAATTCCAAGAACACGCTGTCTCTGCAAATGAACAGCCTGAGAGCTG
CAREEDTAMVV
AGGACACGGCTGTGTATTACTGTGCGAGAGAGGAGGATACAGCTAT YYGMDVW
GGTTGTCTACTACGGTATGGACGTCTGGGGCCAAGGG
1631 1681 CATAGACACGTCCAAGAACCAGTTCTCCCTGAGGCTGAGCTCTGTGA
CARQQASYGDY
CCGCCGCAGACACGGCTGTCTATTACTGTGCGAGACAACAGGCCTC YFDYW
CTACGGTGACTACTACTTTGACTACTGGGGCCAGGGA
1632 1682 CAGAGATGATTCAAAGAACACGGCGTATCTGCAAATGAACAGCCTG
CSRHIEPSGSSLV
AAAACCGAGGACACGGCCGTGTATTACTGTTCTAGACATATTGAGCC DYW
TAGTGGGAGCTCACTGGTCGACTACTGGGGCCAGGGA
1633 CAKDEKAGFWN 1683 CACCTTGTTTTTGCAAATGAACGGTCTGAGAGAAGAGGACACGGCT EYYSRHGMDV GTGTATTACTGTGCGAAAGATGAAAAAGCGGGTTTTTGGAATGAATA W TTATTCTCGTCACGGAATGGACGTCTGGGGCCAAGGG
1634 1684 GGGCCGATTCACCGTCTCCAGAGACAATGCCCAGAATACACTGTATC
CAGYADYAYW TGGAAATGACCAGCCTGAGAGAAGAGGACACGGCTGTGTATTACTG TGCGGGCTACGCTGACTACGCCTACTGGGGCCAGGGA
1635 1685 CTCCAGAGACAGTTCCAAGAACACGGTGTTTCTGCAAATGAGCAGTC
CANGLSGNYVA
TGAGAAGTGAGGACACGGCTGTGTATTACTGTGCAAACGGCCTCAG FASW
TGGGAACTACGTTGCCTTTGCCTCCTGGGGCCAGGGA
1636 1686 CTCCAGAGACAACGCCAAGAACTCACTGTATCTTCAAATGGACAGCC
CARQQWLESYF
TGAGAGCCGAGGATACGGCTGTCTATTACTGTGCGAGACAACAGTG FDYW
GCTGGAAAGTTACTTCTTTGACTACTGGGGCCAGGGA
1637 1687 GCTGAAAGGCAGGTTCACCATCTCCAGAGATGATTCAAAGAACACG
CTRQGVDW GCGTATCTGCAAATGAACAGACTGAAAACCGAGGACACGGCCGTCT ATTACTGTACTAGACAGGGCGTTGACTGGGGCCAGGGA
1638 1688 AGACAACGCCAAGAACTCACTGTATCTGCAAATGGACAGCCTGAGA
CARVGCSGGGG
GCCGAGGACACGGCTGTCTATTACTGTGCGAGAGTCGGTTGTAGTG TCFNYW
GTGGTGGTGGTACCTGCTTTAACTACTGGGGCCAGGGA
1639 1689 AAAGAACACGGCGTATCTGCAAATGAACAGCCTGAAAACCGAGGAC
CTLVVPVDISSD
ACGGCCGTGTATTATTGTACATTAGTAGTACCAGTTGATATTTCGTC YYYGMDVW
CGACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1640 1690 AGATGATTCCAACAGCCTCGCCTATCTGCAAATGAACAGTCTGAACA
CSRDFLYFHGRP
GCGAGGACACAGCCGTGTATTACTGTTCTAGAGACTTCCTATACTTC PFDYW
CATGGCCGGCCACCCTTTGACTACTGGGGACCGGGA
1641 1691 GAACATGGCGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACG
CTSPTPLEYIDSP
GCCGTGTATTACTGTACTAGTCCGACCCCACTCGAATATATCGACTC KINTMDVW
GCCCAAAATTAACACTATGGACGTCTGGGGCCGAGGG
1642 1692 AGGACTGGTTCACTGTCGCCAGAGACACACACAAGAAAACGCTTTTC
PRLFYVKGVW TGCAGATGATCAGCCTGAGAGGCGAGGACACGGGTGTTTTTAGGCC CAGATTGTTCTACGTTAAGGGCGTCTGGGGCCAGGGG
1643 1693 TGATTCAAAGAACACGGCGTATCTGCAAATGAACAGCCTGAAAACC
CSSPQSRADYGD
GAGGACACGGCCGTGTATTACTGTTCTAGTCCCCAAAGTCGGGCCG KSVDYW
ACTACGGTGATAAATCCGTTGACTACTGGGGCCAGGGA
1644 1694 TCGAATTACCATATCAGTAGACACGTCTAAGAACGAGTTCTCCCTGA
CARYYYALDIW ACCTGAGGTCTGTGACTGCCGCGGACACGGCCGTCTATTACTGTGC GCGTTATTACTACGCTTTGGACATCTGGGGCCAAGGG
1645 DIVLMVYALIDY 1695 CACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGA
W ACAGCCTGAGAGCTGAGGACACGGCTTGGTCCTAGGATATTGTACT AATGGTGTATGCTCTCATTGACTACTGGGGCCAGGGA
1646 1696 CTCCAGAGACAACGCCAAGAACTCTCTGAATCTGCAACTGAACAGCC
CASLCSSTSCGID TGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGCCTTTGTAG PW TAGTACCAGCTGCGGGATCGACCCCTGGGGCCAGGGA
1647 1697 AAAGAACACGGCGTATCTGCAAATGAACAGCCTGAAATCCGAGGAC
CTLVVPVDISSD ACGGCCGTGTATTATTGTACATTAGTAGTACCAGTTGATATTTCGTC LNSGMDVW CGACCTCAACTCCGGTATGGACGTCTGGGGCCAAGGG
1648 1698 AACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCC
CARDHNGIQRTS GTGTATTACTGTGCGAGAGATCATAACGGGATACAGAGAACCTCCG DLYYYGMDVW ACCTCTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1649 CARGACGDDCY 1699 CCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCT NTYYYYGMDV GTGTATTACTGTGCGAGAGGGGCCTGTGGTGATGATTGCTACAACA W CTTACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1650 1700 CAACTCCAAAAACACTCTGTATCTACAAATGGACAGCCTGAGAGATG
CAKDDRIEADLV ACGACACGGCTGTGTATTTTTGTGCGAAAGACGACCGCATAGAGGC GGLDIW AGACCTAGTGGGTGGCCTTGATATCTGGGGCCAAGGG
Table 12- sample 429 (light)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1701 1751 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACC
QQYCSTPSTF CTCACCATCAATAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATACTGTAGTACTCCGTCCACTTTTGGCCAG
1702 1752 GCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGC
LVRVIF ACCTCAGCCTCCCTGGGCGTCAGTGGGCTCCAGTCTGAGGATGAGT CTGGTTATTTTTGACTGGTCCGAGTGATATTCGGCGGA
1703 1753 GGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACA
MQALQTPFTF CTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACT GCATGCAAGCTCTACAAACTCCATTCACTTTCGGCCCT
1704 1754 TGAGCGATTCTCTGGCTCCATCTCTGGGAACACGGCCACCCTGACCA
QVWDSSSDHVV TCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGT
F GTGGGATAGTAGTAGTGATCACGTGGTATTCGGCGGA
1705 1755 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVFDSSSDQVLF ATCAGCAGGGTCGAAGCCGGTGATGAGGCCGAGTATTCCTGTCAGG TGTTCGATAGTAGTAGTGATCAAGTACTTTTCGGCGGA
1706 1756 TGATCGGTTCTCTGGCTCCATCGACGGCTCCTCCAACTCTGCCTCCC
QSYDSTYQVF TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGT CAGTCTTATGACAGTACCTATCAGGTGTTCGGCGGG
1707 1757 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLTGLV TCAGTGGGCTCCAGTCTGACGATGAGGCTGACTATTTTTGTGCAGCA
F TGGGATGACAGCCTGACTGGCCTGGTGTTCGGCGGA
1708 1758 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHVV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCATGTGGTATTCGGCGGA
1709 1759 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYSRTPRTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTCTAGGACTCCTCGAACGTTCGGCCAA
1710 1760 TGAGCGATTCTCTGGGTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDQVV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCAAGTGGTATTCGGCGGA
1711 1761 TGAGCGATTCTCTGGCTTCAACTCTGGGAACACGGCCACCCTGACCA
QVWDRSSDHVV TCAGCAGGGTCGAGGCCGGGGATGAGGCCGACTATTACTGTCAGGT
F GTGGGATAGAAGTAGTGATCATGTGGTATTCGGCGGA
1712 1762 TGACCGATTCTCTGGCTCCAAGTCTGCCACCTCAGCCTCCCTGGCCA
AAWDDRMNGM TCAGTGGGCTCCGGTCCGGCGATGAGGGCATGTATTACTGCGCAGC AF ATGGGATGACAGGATGAATGGTATGGCATTCGGCGGA 1713 1763 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPYTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCGTACACTTTTGGCCAG
1714 1764 GCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCA
QVWDSSSDHPG GCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTG VF GGATAGTAGTAGTGATCATCCGGGGGTATTCGGCGGA
1715 1765 TGAGCGATTCTCTGGCTCCAACTCTGGAAACACGGCCACCCTGACCA
QLWDSVSDHVV TCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGTT
F GTGGGATAGTGTTAGTGATCATGTGGTATTCGGCGGA
1716 1766 TGACCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCA
QVWDSSSDEVV TCAGCAGGGTCGAAGCCGGGGATGAGGCCGAGTATTACTGTCAGGT
F GTGGGATAGTAGTAGTGATGAAGTGGTTTTCGGCGGA
1717 1767 CATTCCAGGTAGGTTCAGTGCCAGTGGGTCTGGGACAGACTTCACT
QQRHAWPLTF CTCACCATCAGCAGCCTAGAACCTGAAGACTTTGCAGTTTATTTCTG TCAGCAGCGTCATGCCTGGCCGCTCACTTTCGGCGGG
1718 1768 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSAPLTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTGCTCCTCTCACTTTCGGCGGA
1719 1769 TTCTGATCGCTTCTCTGGCTCCAAGTCTGACAACACGGCCTCCCTGA
SSYTSSSTYVF CCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAG CTCATATACAAGCAGCAGCACTTATGTCTTCGGAAGT
1720 1770 CCCTGATCGCTTCTCTGCCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYAGSNTYVF CCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAG CTCATATGCAGGCAGCAACACCTATGTCTTCGGAAGT
1721 1771 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPRTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCGAACGTTCGGCCAA
1722 1772 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDTSSDHVV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATACTAGTAGTGATCATGTGGTATTCGGCGGA
1723 1773 TGACCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCA
QVWDSSSDQVV TCAGCAGGGTCGAAGCCGGGGATGAGGCCGAGTATTACTGTCAGGT
F GTGGGATAGTAGTAGTGATCAAGTGGTTTTCGGCGGA
1724 1774 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGC
GTWDSSLSAVV ATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAA
F CATGGGATAGCAGCCTGAGTGCTGTGGTATTCGGCGGA
1725 1775 CCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYAGENTYVF CCGTCTCTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGCAGC TCATATGCAGGCGAGAACACCTATGTCTTCGGAAGT
1726 1776 TGAGCGATTCTCTGGCTCCAACTTTGGGCATACGGCCACCCTCACCA
QVWDNTSGEGV TCACCGGAGTCGAAGTCGGGGATGAGGCCGACTATTATTGTCAGGT
F GTGGGATAATACTAGCGGTGAGGGGGTATTCGGCGGC
1727 1777 CCGATTCTCTGGCTCCAGCTCTGGGAACACGGCCACCCTGACCATCA
QVWDSGRDHPG CCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAAGTTTG VF GGACAGTGGTAGAGATCATCCTGGGGTCTTCGGAGCT
1728 1778 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGVV TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAATGGTGTGGTATTCGGCGGA
1729 1779 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGPV TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAATGGTCCGGTATTCGGCGGA
1730 1780 TGACCGATTCTCTGGCTCCAGGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGVV TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATCACTGTGCAGC
F ATGGGATGACAGCCTGAACGGTGTGGTGTTCGGCGGA
1731 1781 TGCCCGCTTCTCTGGCTCCAAGTCTGGCACCTCTGCCTCCCTGGCCA
SVRDDSLNALVF TCAGTGGGCTCCGGTCTGAGGATGAAGCTGACTATTATTGTTCAGTA AGAGATGACAGTCTGAATGCTCTGGTCTTCGGCGGA
1732 AAWDDILRAYV 1782 TGACCGGTTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
F TCAGTGGGCTCCGGTCCGAGGATGAGGCTCATTATTACTGTGCTGC ATGGGATGACATTCTGAGAGCTTATGTCTTCGGAATT
1733 1783 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPLTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCTCACTTTCGGCGGA
1734 1784 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWDNNSGVF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTG TCAGGCGTGGGACAACAATAGTGGGGTATTCGGCGGA
1735 1785 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQSKRTPHTF CTCACCATCAGCAGACTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATCTAAGCGTACTCCTCACACTTTTGGCCAG
1736 1786 TGACCGATTCTCTGGCTCCAAGTCTGGCTCCTCAGCCTCCCTGGCCA
AAWDDSLSGVV TCAGTGGACTCCGGTCCGAGGATGAGGCTGATTATCACTGTGCAGC
F ATGGGATGACAGTCTGAGTGGCGTGGTGTTCGGCGGA
1737 1787 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSAVV TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAGTGCCGTGGTATTCGGCGGA
1738 1788 TGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTC
QQRNYLYTF ACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTA TTGTCAGCAGCGTAACTACCTGTACACTTTTGGCCAG
1739 1789 TGATCGTTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QSYDGDNLVF TCACCATCTCTGGCCTGAAGACTGAGGACGAGGCCGACTACTACTG TCAGTCCTATGATGGCGACAACCTGGTATTTGGCGGA
1740 1790 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGC
GTWDSSLSAGV ATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAA
F CATGGGATAGCAGCCTGAGTGCTGGGGTATTCGGCGGA
1741 1791 GATCCCTGAGCGATTCTCTGGCTCCAACTCGGGGAACACGGCCACC
QVWDSSTVVF CTGACCATCAGCAGAGCCCAAGCCGGGGATGAGGCTGACTATTACT GTCAGGTGTGGGACAGCAGCACTGTGGTATTCGGCGGT
1742 1792 GGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCC
CSYAGSTGVF TGACCATCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGC TGCTCATATGCAGGCAGCACGGGGGTATTCGGCGGA
1743 1793 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSGRV TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAGTGGTCGGGTGTTCGGCGGA
1744 1794 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWDSSTVVF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTG TCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGA
1745 1795 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPQTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCAAACTTTTGGCCAG
1746 1796 GGTCCCTGATCGATTTAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSAPLTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTGCTCCTCTCACTTTCGGCGGA
1747 1797 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGW TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC VF ATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGA
1748 1798 GACACCTGCCCGATTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCC
LVSYSGARVF CTGACCCTTTCGGGTGCGCAGCCTGAGGATGAGGCTGAGTATTACT GCTTGGTCTCCTATAGTGGTGCTCGGGTGTTCGGCGGA
1749 1799 GGTTTCTAATCGCTTCTCTGGCTCCAAGTTTGAAAACACGGCCTCCC
SSYTSTGHIF TGACCATCTCTAACCTCCAGGCTGAGGACGAGGCTGTTTATTACTGC AGCTCATATACAAGCACCGGACACATATTCGGCGGA
1750 1800 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGW TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAATGGCGTGGTTTTCGGCGGA Table 13- sample 463 (heavy)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1801 1851 AGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTG
CASWEVGPSYY
CCGCGGACACGGCCGTGTATTTCTGTGCGAGTTGGGAAGTGGGCCC YGMDVW
CTCCTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1802 1852 CAGCGCCAAGCGGTCAGTCTTTCTGCAAATGAAGAACTTGAGAGTC
CAREAPVGSYPD
GACGACACGGCCATCTTTTACTGCGCGAGAGAGGCTCCTGTTGGGA NWFDLW
GCTACCCCGACAACTGGTTCGACCTCTGGGGCCAGGGA
1803 1853 AGACAACGCCAAGAACTCATTGTTTCTGCAGATGAACAGCCTGAGA
CVRDRIIDNGRI
GCCGAGGACACGGCTGTTTATTACTGTGTGAGAGATCGGATCATTG WFDPW
ACAATGGTCGCATCTGGTTCGACCCCTGGGGCCAGGGA
1804 1854 CAGAGACAACTCCAAGAACACGTTGTTTCTGCAAATGAACAGCCTGA
CAKAPHSLVAD
CAGCCGAGGACACGGCCATTTATTACTGTGCGAAAGCTCCTCACTCT
ALEMW
CTCGTCGCGGATGCTCTTGAGATGTGGGGCCAAGGG
1805 1855 AAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGA
CTTLYCGGDCY
AAACCGAGGACACAGCCGTGTATTACTGTACCACCCTCTATTGTGGT PLDYW
GGTGACTGCTATCCCCTTGACTACTGGGGCCAGGGA
1806 1856 CACCATCTCCAGAGACAATGCCAAGAACTCACTTTATCTGGAAATGA
CARRSPHYAFDI
ACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAG W
GAGCCCGCATTATGCCTTCGATATCTGGGGCCAAGGG
1807 1857 AGACACATCCAAGAACCAGTTCTCCCTACACCTAAACTCTGTCACTC
CARDLTLYSSSS
CCGAAGACACGGCTATGTATTACTGTGCAAGGGATCTGACCCTTTAT YFDYW
AGCAGCAGCTCCTACTTTGACTACTGGGGCCAGGGA
1808 1858 CAGAGACAACGTCAAGAACACACTGTATCTGCAAATGAACAATCTGA
CARDQVRTGTT
GAGCCGAGGACACGGCTATTTATTATTGTGCAAGAGATCAGGTGAG PIDYW
GACGGGGACTACACCGATTGACTACTGGGGCCAGGGA
1809 1859 AGACAACGCCAAGAACTCACTTTATCTGCAAATGAACAGCCTGAGAG
CARAPDNFYYY
GCGAGGACACGGCTGTCTATTACTGTGCGAGAGCACCTGACAATTT NGMGVW
CTACTACTACAATGGCATGGGCGTCTGGGGCCAAGGG
1810 1860 CAGAGACAACGCCAAGAATTCACTGTATCTGCAAATGAACAGCCTGA
CGGGYNYGDYY
GAATCGAGGACACGGCTCTGTATTACTGTGGGGGTGGATATAATTAT GMDVW
GGTGACTATTACGGTATGGACGTCTGGGGCCAAGGG
1811 1861 AGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACC
CASAHPGGGSY
GCTGCGGACACGGCCGTCTATTACTGTGCGAGCGCCCACCCCGGTG YYLQHW
GAGGGAGTTATTACTACTTGCAGCACTGGGGCCAGGGC
1812 1862 CACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGGAAATGA
CARRSPHYAFDI
ACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAG W
GAGTCCGCATTATGCTTTCGATATCTGGGGCCAGGGG
1813 1863 CATCTCCAGAGACAATTCCAAGAACACACTGTATTTGCAAATGAACA
CAKELRPINYFD
GCCTGAGAGCCGAGGACACGGCCATGTATTACTGTGCGAAAGAACT PW
ACGACCAATCAACTACTTCGACCCCTGGGGCCAGGGA
1814 1864 CAGAGACACTTCCAAGAACATGGTGTATCTGCAGATGAACAGCCTG
CAKTRGSYSAQ
AGAGCCGAGGACACGGCCATATATTACTGTGCGAAGACCCGAGGGA YFQDW
GTTACTCCGCTCAATACTTCCAGGACTGGGGCCAGGGC
1815 CARLPYRSCKN 1865 TCTGCAAATGAATAGTCTGAGAGCCGAGGACACGGCCTTGTATTACT KGGTCNSYSYM GTGCGAGGTTGCCATATAGATCTTGTAAGAATAAGGGTGGTACCTG DVW CAACTCTTACTCGTACATGGACGTCTGGGGCAAGGGG
1816 1866 CATCTCCAGAGACACTTCCAAGAGCATCCTGTATCTGCAAATGAACA
CATPTGTGRPFD
GCCTGAGCGTCGACGACACGGCCATATATTACTGTGCGACCCCCAC YW
TGGGACTGGTAGACCATTTGACTACTGGGGCCAGGGG
1817 CARLPYKSCKK 1867 TCTGCAAATGAGCAGTCTGAGAGCCGAGGACACGGCCGTGTATTTC KGGWCYSYSYM TGTGCGAGGTTACCGTATAAAAGTTGTAAGAAAAAGGGTGGTTGGT DVW GCTACTCTTATTCCTACATGGACGTCTGGGGCAAGGGG
1818 1868 CAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTG
CAKDGGGPLSL
AGGACACGGCTGTGTATTACTGTGCGAAAGATGGGGGTGGTCCCCT GGAFDIW
TTCCTTAGGTGGCGCTTTTGATATCTGGGGCCGAGGG
1819 CARSYTSGWYG 1869 TTCCAGACACAATTCCAAGAACACCCTCTATCTTCAAATGGACAGCC VIYW TGAGACCTGACGACACGGCCGTGTATTATTGTGCGAGATCGTATACC
AGTGGCTGGTATGGGGTAATCTACTGGGGCCAGGGA
1820 1870 CTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAA
CAKTPAAARESF
GACACGGCTGTGTATCACTGTGCGAAAACGCCGGCAGCAGCTCGTG YFYMDVW
AAAGTTTCTACTTCTACATGGACGTCTGGGGCACAGGG
1821 1871 CAAGAACCAGTTCTCCCTGAGGTTGACCTCCGTGACCGCCGCGGAC
CARPLGPNSSSL
ACGGCCGTGTATTATTGTGCGAGACCCTTAGGGCCAAATAGCAGCT SHPWFDPW
CGTTGAGCCACCCTTGGTTCGACCCCTGGGGCCAGGGA
1822 1872 CAGAGACAATTCCGAGAACACATTGTATCTGCAAATGAACGGCCTGA
CATDHYTAGWP
GAGCCGAGGACTCGGCCGTATATTACTGTGCGACTGACCACTATAC TFDYW
CGCTGGCTGGCCCACTTTTGACTACTGGGGCCAGGGA
1823 1873 GAGTCGAGTTACCATATCACTAAGCACGTCTAAGAATCAGTTCTCCC
CARGLQWKYW TGAGGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTG TGCGAGAGGGCTACAGTGGAAATACTGGGGCCAGGGA
1824 1874 CGTCATCGCCAGAGACAATTCCAGGAACACACTGTTTCTGCATATGA
CATYGVYEPGD
GCAGCCTGAGAGTCGAGGACACGGCCCTATATTACTGTGCGACTTA YW
TGGTGTCTACGAGCCGGGTGATTACTGGGGCCAGGGA
1825 1875 CACGTCCAAGAACCAGTTCTCCCTGAAGTTGAGTTCTGTGACCGCTG
CARVGYREGYH
CGGACACGGCCGTGTATTACTGTGCGAGAGTGGGATATAGGGAAGG YYGMDVW
TTACCACTATTACGGTATGGACGTCTGGGGCCAAGGG
1826 1876 CTCCAGAGACAATTCCAAGAACACGATGTCAATGCAAATGATCAGCC
CAKQGMTTVRP
TGAGAGCCGAAGACACGGCCGTATATTACTGTGCGAAACAGGGCAT VDNW
GACTACAGTTAGACCCGTTGACAACTGGGGCCAGGGA
1827 1877 CATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACA
CARESRNSGSYN
GCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGA GAGA GAG YW
CCGCAATAGTGGGAGCTATAACTACTGGGGCCAGGGA
1828 1878 TGACACATCTAAGAACCAGTTGACCCTGCAGCTGAATTCTGTGACTC
CAGGRGNIDLPS
CCGAGGACACGGCTGTATATTACTGTGCCGGAGGGAGGGGAAATAT YFDFW
CGATCTACCCTCATACTTTGACTTCTGGAGCCAGGGC
1829 1879 CATTTCAATAGACACGTCCAAGAGCCAGTTCTCCCTGAACATGAACT
CARGRETFRCFD
CTGTGACCGCCGCGGACACGGCTATGTATTACTGTGCGAGAGGGCG PW
GGAGACCTTTAGATGTTTCGACCCCTGGGGCCAGGGA
1830 1880 CGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAG
CAREYDSSGYY
GACACGGCTGTGTATTACTGTGCGAGAGAATATGATAGTAGTGGCT LVAAFDIW
ATTACTTGGTGGCTGCTTTTGATATCTGGGGCCAAGGG
1831 1881 CATATCAGTAGACACGTCCAAGAAGCAGTTCTCCCTGAACCTGAGTT
CARVGHFHSYM
CTGTGACCGCCGCGGACACGGCTGTCTATTACTGTGCGAGAGTTGG DVW
GCACTTCCACTCCTACATGGACGTTTGGGGCAAAGGG
1832 1882 CAGAGACATTGCCAAGAACTCAGTTTCTCTACAAATGAAGAGCCTGA
CARINFYVYNY
GAGTCGAGGACACGGCTGTTTATTACTGTGCGAGAATAAATTTTTAT GMDVW
GTCTACAATTATGGCATGGACGTCTGGGGCCAGGGG
1833 1883 AGGGAGATTTACCATTTCAAGAGATGATACCGAAAACATTCTCTATC
CGKANRLEHW TGCAAATGGATGGCCTAAAAGACGAGGACACAGCCGTCTATTACTG TGGTAAAGCCAATCGTTTGGAACACTGGGGCCACGGA
1834 1884 CACGAATACACTTTATCTTCAAATGAATAGTTTGCAGCCTGCGGACA
CAREEGRGYGG
CGGCTGTCTATTATTGTGCCAGAGAAGAAGGGCGTGGATATGGGGG YDFRFFDPW
CTACGACTTTCGCTTCTTCGACCCCTGGGGCCAGGGA
1835 1885 CATCTCCAGAGACAACGCCAAGAACACACTATATTTACACATGAACA
CTRVFSTGTHKD
GTCTGAGAGACGAGGACACGGCTATATACTATTGCACAAGAGTCTTT YW
TCCACTGGAACGCACAAAGACTACTGGGGCCAGGGA
1836 1886 CAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGA
CARNEYISGYSL
GAGTTGAAGACACGGCTTTTTATTACTGCGCGAGAAATGAATACATC CDYW
TCTGGTTATTCCCTCTGTGACTACTGGGGCCAGGGA
1837 1887 CATCTCAGTTGACAAGTCCATCAACTCTGCCTTCCTGCAGTGGAGCA
CARQTPAVGTS
GCCTGAAGGCCTCGGACACCGCCATGTATTTCTGTGCGAGACAGAC GHW
GCCGGCAGTTGGTACATCGGGACACTGGGGCCAGGGA
1838 1888 AGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTG
CATANWNYPTE
CCGCGGACACGGCCGTTTATTACTGTGCGACTGCTAACTGGAACTAC GGMDVW
CCCACCGAGGGGGGTATGGACGTCTGGGGCCAAGGG 1839 1889 AAGAGATGATTCCAAAAGCATCGCCTATTTGCAAATGAACAGCCTGA
CTREYYGDYNY AAACCGAGGACACAGCCATGTATTTCTGTACTAGAGAATACTACGGT GMDVW GACTACAATTACGGTATGGACGTCTGGGGCCAAGGG
1840 1890 AGACAATTTCAAGAACGAGGTCTATCTGCAGATGAGTAGCCTGATAA
CARDARAATGD CTGAGGACACGGCTCTATATTACTGTGCGAGAGATGCCCGGGCAGC PHFDYW AACTGGTGATCCGCACTTTGACTACTGGGGCCAGGGA
1841 1891 GGACGGGTCTTTGATAGTCTACATGGAGCTGAGCAGCCTGAGATCT
CARSPLNGDQES GAGGACACAGCCATGTATTACTGTGCAAGATCGCCTCTAAATGGGG RTFDTW ATCAAGAAAGTCGTACTTTTGATACGTGGGGCCAAGGG
1842 1892 TGACAGGTCCAAGAACCACTTCTCCCTGAACCTGGCCTCTGTGACCG
CAKAKFREPLY CCGCGGACACGGCCGTCTATTTCTGTGCCAAAGCCAAATTTCGCGAA YYMDVW CCCCTCTACTACTACATGGACGTCTGGGGCCAAGGG
1843 CARGVVDDYGD 1893 CCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT YYYYYYGMDV GTGTATTACTGTGCAAGAGGGGTGGTGGATGACTACGGTGACTATT W ACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
1844 1894 CTCCAAAAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGGG
CAKDTVVKDLY GACACGGCTGTGTATTATTGTGCGAAAGATACGGTGGTAAAGGACC YYYGMDVW TCTACTACTACTACGGAATGGACGTTTGGGGCCAAGGG
1845 1895 CATCTCAAGAGATGATGCAAAAGACACACTGTATCTGCAAATGAACA
CTTSSVGGKDR GCCTGAAAACCGACGACACAGCCGTATATTACTGTACCACATCATCC DFW GTGGGAGGTAAAGACAGGGACTTCTGGGGCCAGGGA
1846 1896 CACATCCAGGAGCCGCTTCTCCCTGAGGCTGAGCTCTGTGACCGCC
CVRDRALYRKD GCAGACGCGGCCATTTATTACTGTGTGAGAGATCGGGCCCTTTATCG YYHMDVW AAAGGACTACTATCACATGGACGTCTGGGGCAACGGG
1847 1897 AGACAACTCCAAGAACTCACTGTCTCTGCGGATGAACAGCCTGAGA
CARIEEVGNLYL GCCGAGGACACGGCCGTGTACTATTGTGCGAGGATTGAAGAGGTGG REDYW GCAATCTGTATTTACGTGAGGACTACTGGGGCCTGGGA
1848 1898
CARIYDNYVRYF CTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAATATACGA DLW TAACTACGTCAGGTACTTCGATCTCTGGGGCCGTGGC
1849 1899 AGACAACTCCAAGAACAAGTTGTATCTGCAAATGAACAGCCTAAGAG
CAKVMLGLRGR CCGAGGACACGGCCCGATATTACTGTGCAAAAGTGATGCTTGGACT KYFDAW CCGGGGGAGGAAGTACTTTGACGCCTGGGGCCAGGGA
1850 1900 CACCATTTCAGCAGACACGTCCAAGAATCAGTTCTCCCTGAAGTTGA
CARVPFANGLD VW GCTCTGTGACCGCCGCGGACACGGGTCTATATTACTGTGCGAGAGT TCCGTTCGCAAACGGTTTGGACGTCTGGGGCCAGGGG
Table 14- sample 463 (light)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
1901 1951 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHWV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCATTGGGTGTTCGGCGGA
1902 1952 CCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCA
QQLNTYPPWTF CCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAA CAGCTTAATACTTACCCTCCGTGGACGTTCGGCCAA
1903 1953 TGACCGATTCTCTGACTCCACCTCTGGCACCTCAGCCTCCCTGGCCA
QSYDSSLSAWVF TCACTGGGCTCCAGGCTGAGGATGAGGCTCATTATTACTGCCAGTCC TATGACAGCAGCCTGAGTGCTTGGGTGTTCGGCGGA
1904 1954 GGTACCAGCAGCGCCCGGGCAGTGTCCCCACCACTACTCTGCCTCC
QSYDGSNQVF CTCACCATCTCTGGACTGAAGACTGAAGACGAGGCCGACTACTACT GTCAGTCTTATGATGGCAGCAATCAAGTGTTCGGCAGT
1905 1955 TGAGCGATTCTCTGGCTCCAACTCTGGCAACCCGGCAACTCTGACCA
QVWDKTLNLVV TCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGT
F GTGGGATAAGACTCTTAATCTTGTGGTATTCGGCGGA
1906 AAWDDRLDGW 1956 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA VF TCAGTGGGCTCCAGTCTGATGATGAAGGTGATTATTACTGTGCAGCA
TGGGATGACAGGCTGGATGGTTGGGTGTTCGGCGGA
1907 1957 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGDSPWTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATATTATTG TCAGCAGTATGGTGACTCACCGTGGACGTTCGGCCAG
1908 1958 CGTCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGTSPFTF CTCACCATCAGCAGACTGGAGCCTGAAGATCTTGCAATATATTACTG TCAGCAGTATGGTACCTCACCTTTCACTTTCGGCCCT
1909 1959 GGCGCTGATCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAA
MQDTHWPRMY ATCAGCAGGGTGGAGGCTGAGGATGTAGGGTTTTATTACCGCATGC TF AAGATACACACTGGCCTCGAATGTACACTTTTGGCCAG
1910 1960 TCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCA
QSYDSSNQGVF CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA GTCTTATGATAGCAGCAATCAGGGGGTATTCGGCGGA
1911 1961 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSGWV TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGA
1912 1962 GGTCCCATCAAGGTTCAGTGGAAGTGGATCTAGGACAGACTTTACTT
QQYDSLPWTF TCACCATCAACAGCCTGCAGCCTGAAGACATTGCAACATATTACTGT CAACAGTATGATAGTCTCCCGTGGACGTTCGGCCAA
1913 1963 CTTCTCAGTCCTGGGCTCAGGCCTGACTCGGTCCCTGACCATCAAGA
ATDHGS ENTFL ACATCCAGGAGGAGGATGAGAGTGACTACCACTGTGCGACAGACCA WVF TGGCAGTGAGAACACCTTCCTTTGGGTGTTCGGCGGG
1914 1964 TGGGCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACA
CSYAGTNTYVLF ATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCTGCTC ATATGCAGGTACTAACACTTATGTACTATTCGGCGGA
1915 1965 CCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCA
AAWDDSLNGHV GTGGGCTCCAGTCAGAGGATGAGGCTGATTATTACTGTGCAGCATG LF GGATGACAGCCTGAATGGTCATGTGTTATTCGGCGGA
1916 1966 GGTCCCATCCAGGTTCAGTGGCAGTCGATCGGGGACGGATTACACT
QQYYATPPTF CTCACCATCAGTGGCCTGCAGCCTGAAGATTTTGCAACTTATTACTG TCAACAGTATTATGCTACCCCTCCAACGTTCGGCCAA
1917 1967 GATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCT
NSRDSSGNLF TGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTG TAACTCCCGGGACAGCAGTGGTAACCTCTTCGGCGGA
1918 1968 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWDSSTVVF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTG TCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGA
1919 1969 TGACAGGTTTAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA
MQALQTPRALT TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCA
F AGCTCTACAAACTCCTCGGGCGCTCACTTTCGGCGGA
1920 1970 GGTCCCAGACAGATTCAGCGGCAGTGGGTCAGACACTGATTTCACG
MQGTHWPPAF CTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACT GCATGCAAGGTACACACTGGCCTCCAGCTTTCGGCCCT
1921 1971 GATCCCTGAGCGATTCTCTGGCTCCAACTCGGGGAACACGGCCACC
QVWDSSTEVF CTGACCATCAGCAGAGCCCAAGCCGGGGATGAGGCTGACTATTACT GTCAGGTGTGGGACAGCAGCACTGAGGTGTTCGGCGGA
1922 1972 GCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCA
QVWDSTSDHLW GCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTG MF GGATAGTACTAGTGATCATCTTTGGATGTTCGGCGGA
1923 1973 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSGVV TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAGTGGTGTGGTATTCGGCGGA
1924 1974 AGTGCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACA
MQDAQDLWTF CTGAAAATCAGCCGGGTGGAGGCTGAGGATTTTGGAGTTTATTACT GCATGCAAGATGCACAAGACCTGTGGACGTTCGGCCAA
1925 1975 CCCTGAGCGGTTGTCTGGCTCCAACTCTGGGAACACGGCCACCCTG
QVWDTSDHPVF ACCGTCAGCGGGGTCGAAGCCGGGGATGAGGCCGACTATTTCTGTC AGGTGTGGGATACTAGTGATCATCCAGTTTTCGGCGGA 1926 1976 TCGGTTCTCTGGCTCCATCGACACCTCCTCCAACTCTGCCTCCCTCA
QSSDRNLLWVF CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA GTCTTCTGATAGGAACCTTCTTTGGGTGTTCGGCGGA
1927 1977 GATCCCATCAAGGTTCAGCGGCGATGGATCTGGGACAACTTTCACTC
QQYYISPFTF TCACCATCAGCCGCCTGCAGTCTGAAGATTTTGCAACTTATTATTGT CAACAATATTATATTTCCCCTTTCACTTTCGGCCCT
1928 1978 TGATCGGTTCTCTGGCTCCATCGACAGGTCCTCCAACTCTGCCTCCC
QSYDDDNWVF TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGT CAGTCTTATGATGACGACAATTGGGTGTTCGGCGGA
1929 1979 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPWTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCGTGGACGTTCGGCCAA
1930 1980 GCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACACTG
MQDAQDPLFTF AAAATCAGCCGGGTGGAGGCTGAGGATTTTGGAGTTTATTACTGCAT GCAAGATGCACAAGATCCCCTATTCACTTTCGGCCCT
1931 1981 AGTGCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACA
MQDAQDPLTF CTGAAAATCAGCCGGGTGGAGGCTGAGGATTTTGGAGTTTATTACT GCATGCAAGATGCACAAGATCCTCTCACTTTCGGCGGA
1932 1982 CATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQRSNWPLTF CTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTG TCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGA
1933 1983 CCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCA
NSRDSSGNHPVV CTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCG
F GGACAGCAGTGGTAACCATCCTGTGGTATTCGGCGGA
1934 1984 GGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACT
QQYITYPLTF CTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTTCTG CCAACAGTACATTACTTACCCGCTCACTTTCGGCGGA
1935 1985 GGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACA
MQALQTLFTF CTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACT GCATGCAAGCTCTACAAACCCTTTTCACTTTCGGCCCT
1936 1986 GATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCT
NSRDSSGNLE TGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTG TAACTCCCGGGACAGCAGTGGTAACCTTGAAGGCGGA
1937 1987 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPRTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCGGACGTTCGGCCAA
1938 1988 TGAGCGATTCTCTGGCTCCAGCGCAGGGACAATAGTCACGTTGACC
QSMNISGTHWV ATCAGTGGAGTCCAGGAAGAGGACGAGGCTGACTATTATTGTCAAT
F CAATGAACATCAGTGGGACTCATTGGGTGTTCGGCGGA
1939 1989 TCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCA
QSYDSSNLGVF CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA GTCTTATGATAGCAGCAATCTCGGGGTGTTCGGCGGA
1940 1990 AGTCCCTGTAAGATTCCGTGGCAGTGGCTCTGGGACAGACTTCACTC
QQSFSGPLTF TCACCATCAGCAATCTACAACCTGAAGATTTTGCAACTTACTACTGT CAACAGAGTTTCAGTGGTCCGCTCACTTTCGGCGGA
1941 1991 GCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACACTG
MQGIHLPPEAF AAAATCAGCCGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCA TGCAAGGTATACACCTTCCTCCGGAGGCTTTCGGCCCT
1942 1992 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLNGW TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC VF ATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGA
1943 1993 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QTYDSSIWVF TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTATTGT CAGACCTATGATAGCAGCATCTGGGTGTTCGGCGGA
1944 1994 CCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTC
QQYNNWPPWTF ACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCA GCAGTATAATAACTGGCCTCCGTGGACGTTCGGCCAA
1945 AAWDDSLSGQV 1995 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
F TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC ATGGGATGACAGCCTGAGTGGTCAAGTCTTCGGAACT
1946 1996 CTTCTCAGGCTCGGGCTCAGGCCTGAATCGATATCTGACCATCAAGG
GADHGTKSNFA ACATCCACGAAGAGGATGAGAGTGACTACCACTGTGGGGCAGATCA FVF TGGCACTAAGAGCAATTTCGCGTTCGTCTTCGGGCCT
1947 1997 CCCAGCCAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC
QHRTNWPPYSF ACCATCAGTAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCA GCACCGTACCAATTGGCCTCCGTACAGTTTTGGCCGG
1948 1998 GTTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCC
SSYTTSITLF TGACCATCTCTGGGCTCCAGGCTGAAGACGAGGCTGATTATTACTGC AGCTCATATACAACCAGCATCACTCTCTTCGGAACT
1949 1999 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPYTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCGTACACTTTTGGCCAG
1950 2000 CGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTT
MQALQTLTF ACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATT ACTGCATGCAAGCTCTACAAACTCTCACTTTCGGCCCT
Table 15- sample 840 (heavy)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
2001 2051 CAATTCCAAGAGCACGCTGTTCCTGCAAATGGACAGCCTGAGAGCC
CAKVTFVLSNY GAAGACACGGCCGTATATTACTGTGCGAAAGTGACGTTTGTTCTCTC YYYMDVW CAACTACTACTACTACATGGACGTCTGGGGCAAAGGG
2002 2052 CAAGAACTCACTGTTTCTGCACATGAACCGCCTGAGAGCCGAGGAC
CARAPKLLSDYL ACGGCCGTGTATTACTGTGCGAGAGCCCCGAAGCTGCTATCCGATT YYHGLDVW ACCTCTATTATCACGGTCTGGACGTCTGGGGCCAAGGG
2003 CARDQLKLQNY 2053 ACTGTATCTGCAAATGAACAGCCTGAGAGCCGGGGACACGGCCGTC ESSGYPYYFDY TATTACTGTGCGAGAGATCAGCTTAAGCTCCAGAACTATGAGAGTAG W TGGTTATCCCTACTACTTTGACTACTGGGGCCAGGGA
2004 2054 AGACACGTCCAAGAGCCAGTTCTCCCTGAAGCTGAACTCTGTGACC
CARGDVGEWYS GCCGCAGACACGGCTGTCTATTACTGTGCGAGGGGGGACGTTGGAG ASLRLW AGTGGTATAGCGCCAGTTTACGACTCTGGGGCCAGGGA
2005 CARDQLTLQNY 2055 CCTGTATCTGCAAATGAACAGCCTGAGAGCCGGGGACACGGCCGTC ETSGYPYYFDY TATTACTGTGCGAGAGATCAACTTACGCTCCAGAACTATGAGACTAG W TGGTTACCCCTATTACTTTGACTACTGGGGCCAGGGA
2006 2056 GTCCAAGAGCCAGTTCTCCCTGAGGCTGACCTCTATGACCGCCGCA
CARHGIRGKHSS GACACGGCTATATATTACTGTGCGAGACATGGGATTCGGGGGAAGC PNPFDIW ATAGCAGCCCCAATCCTTTTGATATCTGGGGCCAAGGG
2007 2057 GTCCAGGGACACCTCCAAAAGTACAGCCTACATGGAGTTGAGCGAC
CASYFYDSSGYF CTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGTTATTTCTA DHW TGATAGCAGTGGTTATTTCGACCACTGGGGCCAGGGA
2008 2058 ATCTGCAGACAGGTCCAAGACCCAGTTCTCCCTGAAGCTGGCCTCTA
CARGGTFLAYA TGACCGCCGCGGACACGGCCGTCTATTACTGTGCCAGAGGGGGTAC FDLW ATTCCTTGCTTATGCTTTTGATCTCTGGGGCCAAGGG
2009 2059 CTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCC
CARGKWELRGY TGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGGGAAGTG FDYW GGAGCTACGGGGGTACTTTGACTACTGGGGCCAGGGA
2010 CAKDGQFSSSW 2060 TCTGCAAATGAGCAGTCTGAGACCTGAGGACACGGCCGTGTATTAC YPRPNYYHHGM TGTGCAAAAGACGGCCAGTTTAGTAGCAGTTGGTACCCGCGCCCGA DVW ACTACTATCACCACGGTATGGACGTCTGGGGCCAAGGG
2011 2061 CTCCATAAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAA
CARGKGIEWFG GACACGGCCGTCTATTACTGTGCGAGAGGAAAGGGGATCGAATGGT ELLPFDYW TCGGGGAGTTATTACCCTTTGACTACTGGGGCCAGGGA
2012 2062 CAACGCCAAGATCTCATTGTATCTGCAAATGAACAGCCTGAGACCCG
CARAHSGTWVS AGGACACGGCCGTGTATTTCTGTGCGAGAGCCCATTCTGGCACCTG DGSADYW GGTCTCCGATGGTTCGGCTGATTACTGGGGCCAGGGA 2013 2063 AGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAA
CARGDRKALGV TTGAGGATCCTAAATTCTGACGACACGGCCGTATATTACTGTGCGAG W AGGGGATAGGAAAGCTTTGGGCGTCTGGGGCCAAGGG
2014 2064 CACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTACAAATGA
CTTEGASGSCWS ACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTACCACAGA W GGGGGCGAGTGGTAGCTGCTGGAGCTGGGGCCAGGGA
2015 2065 CCGATTCACCATCTCCAGAGACAGTTCCAAGAACACGCTGTATCTTC
CASFYGDYPYW AAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGC GAGCTTCTACGGTGACTACCCCTACTGGGGCCAGGGA
2016 2066 CAGAGACAATTCCAAGAACACGCTGTTTCTGCAAATGAACAGCCTGA
CARERAGVGRG GAATTGACGACACGGCTATGTATTATTGTGCGAGAGAACGGGCCGG AFDIW GGTGGGGCGTGGTGCATTTGATATCTGGGGCCAAGGA
2017 2067 AGACACGTCCAAGAATCAATTCTCTCTGAAAATGAATTCTGTGACCG
CSRGRGRSTTAD CCGCGGACACGGCTATTTATTACTGTTCAAGAGGCAGAGGGCGCTC LYAVW TACAACTGCGGATCTCTACGCCGTCTGGGGCCTGGGA
2018 2068 GGACACGTCCAAGACCCAGTTCTCCCTGACGCTGAGTTCTATGACCG
CAGTKLTTPEGI CCGCAGACACGGCTGTATATTACTGTGCGGGGACCAAACTGACTAC WFDPW CCCTGAAGGGATCTGGTTCGACCCCTGGGGCCAGGGA
2019 2069 CCCAGACACATCGAAGAACCAGTTCTCCTTGCAACTGAACTCTGTGA
CARDLVGAGQD CTCCCGAGGACACGGCTGTCTATTACTGTGCAAGGGATCTAGTGGG YFDFW CGCGGGGCAGGACTACTTTGACTTCTGGGGCCAGGGA
2020 2070 CTCCAGAGACAATGCCAAGAATTCAGTGTCCCTGCTATTGAACAGCC
CARGDIWSSWV TGAGAGTCGACGACACGGCTGTGTATTATTGTGCGAGAGGGGACAT LDYW CTGGAGCAGTTGGGTCCTTGACTACTGGGGCCAGGGA
2021 CVKDLAVTLQD 2071 TCTGCAAATGAACAGTCTGAGAGTTGAGGACACGGCCTTGTATCACT YESSGPWSGVL GTGTAAAAGATCTCGCCGTTACGTTGCAAGACTATGAAAGTAGTGGC DIW CCCTGGTCGGGGGTTCTTGACATCTGGGGCCAAGGG
2022 CARLFARGEFT 2072 GCAGTGGAGCAGCCTAAAGGCCTCGGACACCGCCATGTATTATTGT MFGVPDAYYYY GCGAGACTCTTTGCGAGGGGGGAGTTTACGATGTTTGGAGTCCCAG MDVW ACGCCTACTACTACTACATGGACGTCTGGGGCAAAGGG
2023 2073 ACTCACCGTCACCAAGGACACTGTTAAAAGTCAGGTGGTCTTGACAA
CAKTIKGLFDD TGACCAACTTGGATCCTGTGGACACAGCCACATATTTCTGTGCAAAG W ACTATAAAAGGCCTCTTTGACGACTGGGGCCAGGGA
2024 2074 AGTCCTGTATCTACAGATGGACGGCCTGAGAGCCGACGACACGGCT
CVREPNDVVLM GTCTATTTTTGTGTGCGAGAGCCTAACGATGTTGTACTGATGGCATA AYGKGPHFDHW TGGCAAGGGGCCACACTTTGACCACTGGGGCCGGGGA
2025 2075 ATCCACAAGCACAGCCTACATGGAACTGCGCAGCCTGAGATCTGAC
CSGTIAAAGEVP GACACGGCTGTATATTATTGCTCGGGGACTATAGCAGCAGCTGGTG GRGDEYW AGGTGCCTGGGAGGGGGGATGAGTACTGGGGCCAGGGA
2026 2076 GTCCAAGAACCAGTTCTCCCTGAAGCTGGCCTCTGTGACCGCCGCG
CARLGLFTVTTP GACACGGCCATTTATTACTGTGCGAGATTGGGACTGTTTACAGTAAC DAGMDVW TACACCGGACGCGGGTATGGACGTCTGGGGCCAAGGG
2027 2077 AGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACACTGTATC
CAPGDGYNPW TACAAATGAACAGCCTGAGAAGCGAGGACACAGCCATATATTACTGT GCCCCAGGGGATGGCTACAACCCCTGGGGCCAGGGA
2028 2078 CTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCC
CARSVGSVAGH TGAGACCTGAGGACACGGCTGTGTATTACTGTGCGAGATCGGTGGG FDSW TTCAGTGGCTGGTCACTTTGACTCCTGGGGCCAGGGA
2029 2079 GGACAAATCCACAAGCACATCTTACATGGAGTTGACTAGGTTGACAT
C ARD YQQS MEG CTGATGACACGGCCGTCTATTATTGTGCGAGAGATTACCAACAGTCG LGFDPW ATGGAAGGATTGGGGTTCGACCCCTGGGGCCAGGGA
2030 2080 GTCTAAGAACCAATTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGG
CARVLGVTAAD ACACGGCCGTGTATTACTGTGCGAGAGTCCTGGGTGTAACAGCGGC YYYYMDVW TGACTACTACTACTACATGGACGTCTGGGGCCAAGGG
2031 2081 AGTCACGATTACCGCGGTCGAATCCACGAGTATAGTCTACATGGAG
CARGMGTIHSL CTGAGCAGCCTGAAATCTGAGGACACGGCCGTCTATTTCTGTGCGC W GAGGCATGGGCACAATTCACAGCCTCTGGGGCCAGGGG
2032 CARGPLTGVLW 2082 AGCCGACAAGTCCATCAACACCGCCTACCTGCAGTGGAGCAGCCTG
YFDYW AAGGCCTCGGACACCGCCATGTATTACTGTGCGAGAGGGCCTCTAA CTGGGGTCCTTTGGTATTTTGACTACTGGGGCCAGGGA
2033 2083 CATTTCAATGGACACGTCTGCAAACCAACTCTCCCTGCAACTGACGT
CAKTRWHVAW
CTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAAGACCAG LDPW
GTGGCACGTTGCCTGGCTCGACCCCTGGGGCCAGGGA
2034 2084 CCGATTCACCATCTCCAGGGACAACGCCAAGACCTCACTGTATCTGC
CAMNGDFFDFW AAATGAACAGCCTGAGAGTCGAGGACACGGCCGTCTATTTCTGTGC GATGAATGGTGATTTCTTTGACTTCTGGGGCCAGGGA
2035 2085 AGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGGGCTCTGTGACC
CARYLIMGGFN
GCCGCTGACACGGCCGTTTATTATTGTGCGAGATATCTGATAATGGG YGYDYW
TGGGTTCAACTATGGCTATGACTACTGGGGCCAAGGA
2036 2086 CACCATCTCCAGAGACAACGCCAAGAACTCAGTGTATCTACAAATGA
CARLYNYYYMD
ACAGCCTGAGAGCCGACGACACGGCCGTGTATTACTGTGCGAGACT
vw
CTACAACTACTACTACATGGACGTCTGGGGCAAAGGG
2037 2087 AGTCACCATGACCAGGAACACCTCCATAAGCACAGCCTACATGGAG
CARDYYYGMD
CTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGA VW
GAGACTACTACTACGGTATGGACGTCTGGGGCCAAGGG
2038 2088 GCTCACCGTCACCAAGGACACTTCCAGAAGCCAGGTGGTCCTTACA
CAQTTRGLFDF
GTGACCAGTTTGGACCCTGTGGACACAGCCACATATTTCTGTGCACA W
GACCACAAGGGGCCTCTTTGACTTCTGGGGCCAGGGA
2039 2089 AAGAGATGATTCAAAAAACACGCTGTATCTGCTAATGAACAGCCTGA
CTSESVANWGS
CAACCGAGGACACAGCCGTCTATCACTGTACCTCAGAGTCGGTGGC NIDYW
TAACTGGGGATCGAATATTGACTACTGGGGCCAGGGA
2040 2090 AGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGA
CAKGAAGGWG
GCTGAGGACACGGCCTTGTATTACTGTGCAAAGGGCGCAGCTGGGG GWNFDYW
GCTGGGGCGGGTGGAACTTTGACTACTGGGGCCAGGGA
2041 2091 CACCATCTCCAGAGACAACGCCAAGAGCACGCTGTATCTGCAAATG
CTRGPTVEGYD
AACAGTCTGAGAGTCGAAGACACGGCTGTTTATTTTTGTACACGCGG YW
TCCAACAGTGGAGGGATACGACTACTGGGGCCAGGGA
2042 2092 TAAAGACTCCCTGTATCTCCATATGAACCGTCGGAGAATTGAGGACA
QMWAREATFDY
CCGCCTTGTAGTATCAAATGTGGGCAAGAGAAGCGACCTTTGATTAC HFCYVMAVW
CACTTCTGCTACGTCATGGCCGTCTGGGGCAAAGGG
2043 2093 CACCTCCGGAAACCAGGTGGTCCTTAAAATGACCAACATGGACCCT
CAHSTSWFGEPP
GGGGACTCAGCCACGTATTACTGTGCACACAGTACCAGTTGGTTTG YAMDVW
GGGAGCCTCCCTACGCTATGGACGTCTGGGGCCGAGGG
2044 2094 CAGAGACAACGCCAAGAACTCAATGTTTCTGCAAATGAACAGCCTGA
CARGGAAGGVD
GGGCCGACGACACGGCTGTGTATTTCTGTGCGAGAGGGGGAGCAGC ALDIW
AGGTGGCGTGGATGCTCTTGATATCTGGGGCCAAGGG
2045 2095 AGACACGTCCAAAAACCAGTTCTCCCTGAAGCTGGGCTCTGTGACC
CARYLIMGGFN
GCCGCTGACACGGCCGTTTATTATTGTGCGAGATATCTGATAATGGG YGYDYW
TGGGTTCAACTATGGCTATGACTACTGGGGCCAAGGA
2046 2096 CACTTTCAAAAACCAGGTGGTCCTTACAATGACCAACATGGACCCTG
CTHTESWFGKS
TGGACACAGCCACATATTACTGTACACACACAGAGTCGTGGTTCGG KYGMDVW
GAAGTCAAAGTATGGCATGGACGTCTGGGGCCAAGGG
2047 2097 GGGCCGCTTCACCATCTCCAGAGACAACGCCAAGAATTTCCTATATA
CVRDDSGDYW TACAGATGAACAGTCTGAGAGCCGAGGACACGGGCTTCTATTACTG TGTGAGAGATGACTCTGGGGACTACTGGGGCCAGGGA
2048 2098 CGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAG
CAKDSRSDFWS
GACACGGCCTTGTATTACTGTGCAAAAGACTCACGGTCCGATTTTTG GYDAFDIW
GAGTGGATATGATGCTTTTGATATCTGGGGCCAAGGG
2049 2099 CACAGCCTACATGGAACTGATCAGCCTGATATCTGACGACACGGCC
CARGLGSCSGG
GTGTATTACTGTGCGAGGGGGCTGGGATCTTGCAGTGGAGGTGGTT GCFEYFGMDIW
GCTTCGAGTATTTCGGTATGGACATCTGGGGCCAAGGG
2050 2100 AGACGATTCCAAGAGAACAGTGTATCTGCAGATGAACAGCCTGAGA
CVKDHRARDGL
GCCGAGGACGCGGCCGTGTATTACTGTGTGAAAGATCACCGCGCGC WGMDVW
GCGATGGCCTCTGGGGAATGGACGTCTGGGGCCAAGGG Table 16- sample 840 (light)
SEQ Amino Acid SEQ ID Nucleotide Sequence Rearrangement containing CDR3
ID NO Sequence CDR3 NO
2101 2151 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWDSSTVVF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTG TCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGA
2102 2152 GGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAATACGGCCTCCA
CSYTSSAYVF TGACCATCTCTGGACTTCAGGCTGAGGACGAGGCTGATTATTAGTGC TGCTCATATACAAGCAGTGCTTATGTCTTCGGAAGT
2103 2153 TGAGCGACTGTCTGGCTCCAATTCTGGGAACACGGCCACCCTGGCC
QVWDRSRDHVV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATCGTAGTCGTGATCATGTGGTATTCGGCGGA
2104 2154 TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGC
GTWDSSLSAVV ATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAA
F CATGGGATAGCAGCCTGAGTGCTGTGGTATTCGGCGGA
2105 2155 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHVV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCATGTGGTATTCGGCGGA
2106 2156 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSGRV TCAGTGGGGTCCGGTCCGAGGATGAGTCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAGTGGGAGGGTGTTCGGCGGA
2107 2157 TCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCA
QSYDSSNHVVF CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA GTCTTATGATAGCAGCAATCATGTGGTATTCGGCGGA
2108 2158 TGAGCGATTCTCTGGCTCCAATTCTGGGAACACGGCCACCCTGACCA
QVWDSSSHHVL TCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGT
F GTGGGATAGTAGTAGTCATCATGTGCTGTTCGGCGGA
2109 2159 CCCATCTCGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCA
QKYNSAPPYTF CCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAA AAGTATAACAGTGCCCCTCCGTACACTTTTGGCCAG
2110 2160 TGAGAGATTCTCTGGCTCCAGCTCAGGGACAATGGCCACCTTGACTA
YSTDSSGNHYVF TCAGTGGGGCCCAGGTGGAGGATGAAGCTGACTACTACTGTTACTC AACAGACAGCAGTGGTAATCATTATGTCTTCGGAACT
2111 2161 ATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTG
QSSDSSLSGPYV GGCTCCAGGCTGAAGATGAGGCTGATTATTACTGCCAGTCCTCTGAC LF AGCAGCCTGAGTGGACCTTATGTGTTATTCGGCGGA
2112 2162 GGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACT
QQYNSYSPTF CTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTG CCAACAATATAATAGTTATTCTCCGACATTCGGCCAA
2113 2163 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPYTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCGTACACTTTTGGCCAG
2114 2164 AGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCA
NSRDSSGNHVVF TCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTC CCGGGACAGCAGTGGTAACCATGTGGTATTCGGCGGA
2115 2165 AGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCC
QAWDSGVVF ACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATT ACTGTCAGGCGTGGGACAGCGGCGTGGTATTCGGCGGA
2116 2166 TTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYTSSSTVVF CCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAG CTCATATACAAGCAGCAGCACTGTGGTATTCGGCGGA
2117 2167 TGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTC
QQDYNLPTF ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAGTTTATTA CTGTCAGCAGGATTATAACTTACCGACTTTCGGCGGA
2118 2168 TGAGCGATTCTCTGGCTCCAGGTCAGGGACAATAGTCACATTGACCA
LSADSSGTYRVF TCAGTGGAGTCCAGGCAGAAGACGAGGCTGACTATTACTGTCTATC AGCAGACAGCAGTGGTACTTATCGAGTATTCGGCGGA
2119 QSYDSSNRWVF 2169 TCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCA CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA
GTCTTATGATAGCAGCAATCGTTGGGTGTTCGGCGGA
2120 2170 TGAGCGATTCTCTGGCTCCAACTCTGGCAACACGGCCACCCTGACCA
QVWDSRSDHW TCAGCAGGGTCGAAGCCGGGGATGACGCCGACTATTACTGTCAGGT VF GTGGGATAGTAGAAGTGATCATTGGGTGTTCGGCGGA
2121 2171 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPYTF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCGTACACTTTTGGCCAG
2122 2172 TGAGCGATTCTCTGGCTCCAAGTCTGCCACTACGGCCACCCTGACCA
HVWDSSRDHVV TCAGCACGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCACGT
F GTGGGACAGTAGTAGGGATCATGTGGTCTTCGGCGGA
2123 2173 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDLRV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCTCCGGGTATTCGGCGGA
2124 2174 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGCGACAGATTTCACT
QQYYSIPPTF CTCACTATCAGCAGTCTGCAGGCTGAAGATGTGGCAGTCTATTACTG TCAGCAATATTATAGTATTCCTCCGACGTTCGGCCAA
2125 2175 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QSYDSSNVVF TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGT CAGTCTTATGATAGCAGCAATGTGGTATTCGGCGGA
2126 2176 CATCCCAGACAGGTTCAGTGGCGGTGGGTCTGGGACAGACTTCACT
QQYGDSPRTF CTCACCATCAGCAGACTGGAGCCTGAAGACTTTGCAGTGTATTACTG TCAGCAGTATGGTGACTCACCTCGCACTTTTGGCCAG
2127 2177 CCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTG
QVWDTSDQGVF ACCATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTC AGGTGTGGGATACTAGTGATCAAGGGGTATTCGGCGGA
2128 2178 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QSYDRNSQVF TCACCATCTCTGGACTGAAGATTGAGGACGAGGCTGACTACTATTGT CAGTCTTATGATAGGAACAGTCAGGTATTCGGCGGA
2129 2179 TGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA
AAWDDSLSGVV TCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAGTGGTGTGGTATTCGGCGGA
2130 2180 GGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACT
QQYYSTPRTF CTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTG TCAGCAATATTATAGTACTCCTCGGACGTTCGGCCAA
2131 2181 ATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCA
QQSYSTPPMYTF TCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAGCAG AGTTACAGTACCCCCCCTATGTACACTTTTGGCCAG
2132 2182 CCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTC
QQYYSTPCGAF ACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCA GCAATATTATAGTACTCCTTGTGGGGCGTTCGGCCAA
2133 2183 GATCCCTGGGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTC
QAWGSSPVVF TGACCATCAGCGGGACCCAGGCTTTGGATGAGGCTGACTATTATTGT CAGGCGTGGGGCAGCAGCCCCGTGGTTTTCGGCGGA
2134 2184 GGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACA
MQGTHWPLTF CTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACT GCATGCAAGGTACACACTGGCCGCTCACTTTCGGCGGA
2135 2185 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWDSSSDHWV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGGATAGTAGTAGTGATCATTGGGTGTTCGGCGGA
2136 2186 CCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTG
QVWDSSSRGVF ACCATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTC AGGTGTGGGATAGTAGTAGTCGGGGAGTATTCGGCGGA
2137 2187 GATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACAAAGCCACTC
QAWDSSTVVF TGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTG TCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGA
2138 2188 TTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGA
SSYTSSSTLVF CCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAG CTCATATACAAGCAGCAGCACTCTGGTATTCGGCGGA 2139 2189 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAATTCTGCCTCCC
QSYDNTNVVF TCACCATCTCTGGACTGAGGACTGAGGACGAGGCTGACTACTACTG TCAGTCTTATGATAACACCAATGTGGTATTCGGCGGC
2140 2190 CCCTGAGCGATTCTCTGGCTCCAACTCTGGGAGCACGGCCACCCTG
QVWDSSSDYVF ACCATCATCAGGGTCGAAGCCGGGGATGAGGCCGACTATTATTGTC AGGTGTGGGATAGTAGTAGTGATTATGTCTTCGGAAGT
2141 2191 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVLDGTNDHYV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTTGGATGGTACTAATGATCACTATGTCTTCGGAACT
2142 2192 TCGGTTCTCTGGCTCCATCGACACCTCCTCCAACTCTGCCTCCCTCA
QSYDSDNQGVF CCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCA GTCTTATGATAGCGACAATCAGGGGGTCTTCGGAACT
2143 2193 TGACCGATTCTCTGGCTCCAAGTTTGGCACCTCAGCCTCCCTGGCCA
ASWDDSLNAYV TCAGTGGGCTTCAATCTGAGGATGAGGCTGATTATTACTGTGCATCA F TGGGATGACAGCCTGAATGCTTATGTCTTCGGGACT
2144 2194 TGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACC
QVWYSSSDHVV ATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGG
F TGTGGTATAGTAGTAGTGATCATGTGGTATTCGGCGGA
2145 2195 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT
QQYGSSPITF CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG TCAGCAGTATGGTAGCTCACCCATCACCTTCGGCCAA
2146 2196 CCCTCATCGCTTCTCTGGCTCCATCCTTGGGAACAAAGCTGCCCTCA
VLYMGSGISLF CCATCACGGGGGCCCAGGCAGATGATGAATCTGATTATTACTGTGT GCTATATATGGGTAGTGGCATTTCGCTCTTCGGCGGA
2147 2197 TGGTCGCTTCTCTGGCTCCAAGTCTGGCAACTCGGCCTCCCTGACCA
SSYTSNNTLVVF TCTCTGGACTCCAGACTGACGACGAGGCTGATTATTACTGCAGCTCA TACACAAGCAACAACACTCTCGTGGTTTTCGGCGGA
2148 2198 TGATCGGTTCTCTGGCTCCATCGACAGCTCCTCCAACTCTGCCTCCC
QSYDISNVVF TCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGT CAGTCTTATGATATCAGCAATGTGGTATTCGGCGGA
2149 2199 TGACCGATTCTCTGGCTCCAAGTCTGGCCCCTCAGCCTCCCTGGCCA
AAWDDSLNGPV TCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGC
F ATGGGATGACAGCCTGAATGGTCCGGTATTCGGCGGA
2150 2200 GGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACT
QQSYSTPYTF CTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTG TCAACAGAGTTACAGTACCCCGTACACTTTTGGCCAG
Table 17. Antibody Sequences
SEQ Description Sequence
ID NO
2201 H1L4 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag nucleic acid ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctg gcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttg ggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt tgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcac ctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgate tccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagat cagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattaca acagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggag ttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaa agggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaac aggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaac aacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttactt catgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcag tggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2202 H1L4 QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY
Heavy chain AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVS SRA full length STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG amino acid LYSLSSWIV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCPRGPTIKP CPPCKCPAPN
LLGGPSVFIF PPKIKDVLMI SLSPIVTCW VDVSEDDPDV QISWFVNNVE VHTAQTQTHR
EDYNSTLRW SALPIQHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP
PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE
KKNWVERNSY SCSWHEGLH NHHTTKSFSR TPGK*
2203 H1L4 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag region ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag nucleic acid atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctaga
2204 H1L4 QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY
Heavy chain AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVS SR variable
region amino
acid
2205 H1L4 gga tac acc ttc acc ggc tac tat
Heavy chain
CDR1 nucleic
acid
2206 H1L4 GYTFTGYY
Heavy chain
CDR1 amino
acid
2207 H1L4 ate aac cct aac agt ggt ggc aca
Heavy chain
CDR2 nucleic
acid
2208 H1L4 INPNSGGT
Heavy chain
CDR2 amino
acid
2209 H1L4 gcg agg ggg gga gtg get gcg ate ttg gac tac
Heavy chain
CDR3 nucleic
acid
2210 H1L4 ARGGVAAI LDY
Heavy chain
CDR3 amino acid
2211 H1L4 gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggcaagagccaccctctc
Light chain ctgcagggccagtcagagtattagttacttcttagcctggtaccaacagaaacctggccaggctc full length ccagactcctcatctatgatgcctccagtagggccactggcatcccagccaggttcagtggcagt nucleic acid gggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattc ctgtcagctgcgtagcagctggcctccggcgttcggccaagggaccaaggtggaaatcaaatcta gaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact gcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtgga taacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacct acagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgc gaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2212 H1L4 EIVLTQSPAT LSLSPGARAT LSCRASQSIS YFLAWYQQKP GQAPRLLIYD ASSRATGIPA
Light chain RFSGSGSGTD FTLTISSLEP EDFAVYSCQL RSSWPPAFGQ GTKVEIKSRT VAAPSVFIFP full length PSDEQLKSGT ASWCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLS STL amino acid TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC *
2213 H1L4 gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggcaagagccaccctctc
Light chain ctgcagggccagtcagagtattagttacttcttagcctggtaccaacagaaacctggccaggctc variable ccagactcctcatctatgatgcctccagtagggccactggcatcccagccaggttcagtggcagt region gggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattc nucleic acid ctgtcagctgcgtagcagctggcctccggcgttcggccaagggaccaaggtggaaatcaaatcta ga
2214 H1L4 EIVLTQSPAT LSLSPGARAT LSCRASQSIS YFLAWYQQKP GQAPRLLIYD ASSRATGIPA
Light chain RFSGSGSGTD FTLTISSLEP EDFAVYSCQL RSSWPPAFGQ GTKVEIKSR
variable
region amino
acid
2215 H1L4 cag agt att agt tac ttc
Light chain
CDR1 nucleic
acid
2216 H1L4
Light chain
CDR1 amino
acid QSISYF
2217 H1L4
Light chain
gat gcc tec
CDR2 nucleic
acid
2218 H1L4
Light chain
CDR2 amino
acid DAS
2219 H1L4
Light chain
cag ctg cgt age age tgg cct ccg gcg
CDR3 nucleic
acid
2220 H1L4
Light chain
CDR3 amino
acid QLRSSWPPA
2221 H1L5 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag nucleic acid ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctg gcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttg ggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt tgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcac ctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgate tccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagat cagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattaca acagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggag ttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaa agggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaac aggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaac aacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttactt catgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcag tggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2222 H1L5 QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY
Heavy chain AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GILVTVS SRA full length STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG amino acid LYSLSSWTV PSSSLGTQTY ICNV HKPSN TKVDKKVEPK SCPRGPTIKP CPPCKCPAPN
LLGGPSVFIF PPKIKDVLMI SLSPIVTCW VDVSEDDPDV QISWFVNNVE VHTAQTQTHR EDYNSTLRW SALPIQHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE KKNWVERNSY SCSWHEGLH NHHTTKSFSR TPGK*
2223 H1L5 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag region ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag nucleic acid atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctaga
2224 H1L5
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY acid AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAALLDYWGQ GTLVTVSSR
2225 H1L5
Heavy chain
gga tac acc ttc acc ggc tac tat
CDR1 nucleic
acid
2226 H1L5
Heavy chain
CDR1 amino
acid GYTFTGYY
2227 H1L5
Heavy charn
CDR2 nucleic
acid ate aac cct aac agt ggt ggc aca
2228 H1L5
Heavy charn
CDR2 amino
acid INPNSGGT
2229 H1L5
Heavy chain
CDR3 nucleic
acid gcg agg ggg gga gtg get gcg ate ttg gac tac
2230 H1L5
Heavy chain
CDR3 amino
acid ARGGVAAI LDY
2231 H1L5 gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcaccatcac
Light chain ttgtcgggcgagtcaggatataagtagctggttagtctggtatcagcagaaaccagggagagccc full length ctatactcctgatcaacactgcatccagtctgcaaagtggcgtcccatcaaggttcagcggcagt nucleic acid ggatctgggacacttttcactctcaccatcaccaccctgcagcctgaagattttgcaacttacta ttgtcaacagactaacagtttccccctcactttcggcggagggaccaaggtggagatcaaatcta gaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact gcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtgga taacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacct acagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgc gaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2232 H1L5 DIQMTQSPSS VSASVGDRVT ITCRASQDIS SWLVWYQQKP GRAPILLINT ASSLQSGVPS
Light chain RFSGSGSGTL FTLTITTLQP EDFATYYCQQ TNSFPLTFGG GTKVEIKSRT VAAPSVFIFP full length PSDEQLKSGT ASWCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLS STL amino acid TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC *
2233 H1L5 gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcaccatcac
Light chain ttgtcgggcgagtcaggatataagtagctggttagtctggtatcagcagaaaccagggagagccc variable ctatactcctgatcaacactgcatccagtctgcaaagtggcgtcccatcaaggttcagcggcagt region ggatctgggacacttttcactctcaccatcaccaccctgcagcctgaagattttgcaacttacta nucleic acid ttgtcaacagactaacagtttccccctcactttcggcggagggaccaaggtggagatcaaatcta ga
2234 H1L5
Light chain
variable
region amino DIQMTQSPSS VSASVGDRVT ITCRASQDIS SWLVWYQQKP GRAPILLINT ASSLQSGVPS acid RFSGSGSGTL FTLTITTLQP EDFATYYCQQ TNSFPLTFGG GTKVEIKSR
2235 H1L5
Light chain
cag gat ata agt age tgg
CDR1 nucleic
acid
2236 H1L5
Light chain
CDR1 amino
acid QDISSW
2237 H1L5
Light chain
act gca tec
CDR2 nucleic
acid
2238 H1L5
Light chain
CDR2 amino
acid TAS
2239 H1L5
Light chain
caa cag act aac agt ttc ccc etc act
CDR3 nucleic
acid
2240 H1L5
Light chain
CDR3 amino
acid QQTNSFPLT
2241 H1L6 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag nucleic acid ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctg gcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttg ggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt tgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcac ctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgate tccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagat cagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattaca acagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggag ttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaa agggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaac aggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaac aacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttactt catgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcag tggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2242 H1L6
Heavy chain QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMG INPNSGGTKY full length AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVS SRA amino acid STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSWTV PSSSLGTQTY ICNV HKPSN TKVDKKVEPK SCPRGPTIKP CPPCKCPAPN LLGGPSVFIF PPKIKDVLMI SLSPIVTCW VDVSEDDPDV QISWFVNNVE VHTAQTQTHR EDYNSTLRW SALPIQHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE KKNWVERNSY SCSWHEGLH NHHTTKSFSR TPGK*
2243 H1L6 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag region ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag nucleic acid atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctaga
2244 H1L6
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY acid AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVS SR
2245 H1L6
Heavy chain
gga tac acc ttc acc ggc tac tat
CDR1 nucleic
acid
2246 H1L6
Heavy chain
CDR1 amino
acid GYTFTGYY
2247 H1L6
Heavy chain
CDR2 nucleic
acid ate aac cct aac agt ggt ggc aca
2248 H1L6
Heavy chain
CDR2 amino
acid INPNSGGT
2249 H1L6
Heavy chain
CDR3 nucleic
acid gcg agg ggg gga gtg get gcg ate ttg gac tac
2250 H1L6
Heavy chain
CDR3 amino
acid ARGGVAAILDY
2251 H1L6 tcctatgtgctgactcagccaccctcggtgtcagtggccccaggacagacggccataattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgttggtcgtctatgatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagtggggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcaccgggtattcggcggagggaccaagctgaccgtcctat ctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2252 H1L6 SYVLTQPPSV SVAPGQTAII TCGGNNIGSK SVHWYQQKPG QAPVLWYDD SDRPSGIPER
Light chain FSGSNSGNTA TLTISGVEAG DEADYYCQVW DSSSDHRVFG GGTKLTVLSR TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2253 H1L6 tcctatgtgc gactcagccaccctcggtgtcagtggccccaggacagacggccataattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgttggtcgtctatgatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagtggggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcaccgggtattcggcggagggaccaagctgaccgtcctat ctaga
2254 H1L6
Light chain
variable
region amino SYVLTQPPSV SVAPGQTAII TCGGNNIGSK SVHWYQQKPG QAPVLWYDD SDRPSGIPER acid FSGSNSGNTA TLTISGVEAG DEADYYCQVW DSSSDHRVFG GGTKLTVLSR
2255 H1L6
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2256 H1L6
Light chain
CDR1 amino
acid NIGSKS
2257 H1L6
Light chain
gat gat age
CDR2 nucleic
acid
2258 H1L6
Light chain
CDR2 amino
acid DDS
2259 H1L6
Light chain
cag gtg tgg gat agt agt agt gat cac egg gta
CDR3 nucleic
acid
2260 H1L6
Light chain
CDR3 amino
acid QVWDSSSDHRV
2261 H1L7 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag nucleic acid ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctg gcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttg ggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt tgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcac ctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgate tccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagat cagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattaca acagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggag ttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaa agggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaac aggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaac aacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttactt catgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcag tggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2262 H1L7 QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY
Heavy chain AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAA1LDYWGQ GTLVTVS SRA full length STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG amino acid LYSLSSWTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCPRGPTIKP CPPCKCPAPN
LLGGPSVFLF PPKIKDVLMI SLSPIVTCW VDVSEDDPDV QISWFVNNVE VHTAQTQTHR EDYNSTLRW SALP1QHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE KKNWVERNSY SCSWHEGLH NHHTTKSFSR TPGK*
2263 H1L7 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag region ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag nucleic acid atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctaga
2264 H1L7
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY acid AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAALLDYWGQ GTLVTVS SR
2265 H1L7
Heavy chain
gga tac acc ttc acc ggc tac tat
CDR1 nucleic
acid
2266 H1L7
Heavy chain
CDR1 amino
acid GYTFTGYY
2267 H1L7
Heavy chain
CDR2 nucleic
acid ate aac cct aac agt ggt ggc aca
2268 H1L7
Heavy chain
CDR2 amino
acid INPNSGGT
2269 H1L7
Heavy chain
CDR3 nucleic
acid gcg agg ggg gga gtg get gcg ate ttg gac tac
2270 H1L7
Heavy chain
CDR3 amino
acid ARGGVAAI LDY
2271 H1L7 tcctatgagctgactcagccaccctcagtgtccgtgtccccgggacagacagccagcatcacctg
Light chain ctctggagataaattgggggataaatttgcttgctggtatcagcagaagccaggccagtcccctg full length tgctggtcatctatcaagatactaagcggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacagccactctgaccatcagcgggacccaggctatggatgaggctgactattactg tcaggcgtgggacagcagcactgtggtattcggcggagggaccaagctgaccgtcctatctagaA cggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcc tctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataa cgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctaca gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaa gtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2272 H1L7 SYELTQPPSV SVSPGQTASI TCSGDKLGDK FAC YQQKPG QSPVLVIYQD TKRPSGIPER
Light chain FSGSNSGNTA TLT I SGTQAM DEADYYCQAW DSSTWFGGG TKLTVLSRTV AAPSVFIFPP full length SDEQLKSGTA SWCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT amino acid LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC*
2273 H1L7 tcctatgagctgactcagccaccctcagtgtccgtgtccccgggacagacagccagcatcacctg Light chain ctctggagataaattgggggataaatttgcttgctggtatcagcagaagccaggccagtcccctg variable tgctggtcatctatcaagatactaagcggccctcagggatccctgagcgattctctggctccaac region tctgggaacacagccactctgaccatcagcgggacccaggctatggatgaggctgactattactg nucleic acid tcaggcgtgggacagcagcactgtggtattcggcggagggaccaagctgaccgtcctatctaga
2274 H1L7
Light chain
variable
region amino SYELTQPPSV SVSPGQTASI TCSGDKLGDK FAC YQQKPG QSPVLVIYQD TKRPSGIPER acid FSGSNSGNTA TLT I SGTQAM DEADYYCQAW DSSTWFGGG TKLTVLSR
2275 H1L7
Light chain
aaa ttg ggg gat aaa ttt
CDR1 nucleic
acid
2276 H1L7
Light chain
CDR1 amino
acid KLGDKF
2277 H1L7
Light chain
caa gat act
CDR2 nucleic
acid
2278 H1L7
Light chain
CDR2 amino
acid QDT
2279 H1L7
Lrght chain
cag gcg tgg gac age age act gtg gta
CDR3 nucleic
acid
2280 H1L7
Light chain
CDR3 amino
acid QAWDSSTW
2281 H1L8 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag nucleic acid ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctg gcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttg ggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt tgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcac ctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgate tccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagat cagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattaca acagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggag ttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaa agggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaac aggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaac aacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttactt catgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcag tggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2282 H1L8 QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY
Heavy chain AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDY GQ GTLVTVS SRA full length STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG amino acid LYSLSSWTV PSSSLGTQTY ICNV HKPSN TKVDKKVEPK SCPRGPTIKP CPPCKCPAPN
LLGGPSVFIF PPKIKDVLMI SLSPIVTCW VDVSEDDPDV QISWFVNNVE VHTAQTQTHR EDYNSTLRW SALPIQHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP
PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE KKNWVERNSY SCSWHEGLH NHHTTKSFSR TPGK*
2283 H1L8 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag region ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag nucleic acid atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctaga
2284 H1L8
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMG INPNSGGTKY acid AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVSSR
2285 H1L8
Heavy chain
gga tac acc ttc acc ggc tac tat
CDR1 nucleic
acid
2286 H1L8
Heavy chain
CDR1 amino
acid GYTFTGYY
2287 H1L8
Heavy chain
CDR2 nucleic
acid ate aac cct aac agt ggt ggc aca
2288 H1L8
Heavy chain
CDR2 amino
acid INPNSGGT
2289 H1L8
Heavy chain
CDR3 nucleic
acid gcg agg ggg gga gtg get gcg ate ttg gac tac
2290 H1L8
Heavy chain
CDR3 amino
acid ARGGVAAILDY
2291 H1L8 tcctatgagctgatgcagccaccctcggtgtcagtgtccccaggacagacggccaggatcacctg
Light chain ctctggagatgcattgccaaagcaatatgcttattggtaccagcagaagccaggccaggcccctg full length tgctggtgatatataaagacagtgagaggccctcagggatccctgagcgattctctggctccagc nucleic acid tcagggacaacagtcacgttgaccatcagtggagtccaggcagaagatgaggctgactattactg tcaatcagcagacagcagtggtacttatgtggtactcggcggagggaccaagctgaccgtcctat ctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2292 H1L8 SYELMQPPSV SVSPGQTARI TCSGDALPKQ YAYWYQQKPG QAPVLVIYKD SERPSGIPER
Light chain FSGSSSGTTV TLTISGVQAE DEADYYCQSA DSSGTYWLG GGTKLTVLSR TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2293 H1L8 tcctatgagctgatgcagccaccctcggtgtcagtgtccccaggacagacggccaggatcacctg
Light chain ctctggagatgcattgccaaagcaatatgcttattggtaccagcagaagccaggccaggcccctg variable tgctggtgatatataaagacagtgagaggccctcagggatccctgagcgattctctggctccagc region tcagggacaacagtcacgttgaccatcagtggagtccaggcagaagatgaggctgactattactg nucleic acid tcaatcagcagacagcagtggtacttatgtggtactcggcggagggaccaagctgaccgtcctat ctaga
2294 H1L8 SYELMQPPSV SVSPGQTARI TCSGDALPKQ YAYWYQQKPG QAPVLVIYKD SERPSGIPER Light chain FSGSSSGTTV TLTISGVQAE DEADYYCQSA DSSGTYWLG GGTKLTVLSR variable
region amino
acid
2295 H1L8
Light chain
gca ttg cca aag caa tat
CDR1 nucleic
acid
2296 H1L8
Light chain
CDR1 amino
acid ALPKQY
2297 H1L8
Lrght chain
aaa gac agt
CDR2 nucleic
acid
2298 H1L8
Light chain
CDR2 amino
acid KDS
2299 H1L8
Light chain
cag tea gca gac age agt ggt act tat gtg gta
CDR3 nucleic
acid
2300 H1L8
Light chain
CDR3 amino
acid QSADSSGTYW
2301 H1L9 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag nucleic acid ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctg gcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactactt ccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttg ggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt tgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcac ctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgate tccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagat cagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattaca acagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggag ttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaa agggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaac aggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaac aacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttactt catgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcag tggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2302 H1L9 QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY
Heavy chain AQKFQGRVSM TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVS SRA full length STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG amino acid LYSLSSWTV PSSSLGTQTY ICNV HKPSN TKVDKKVEPK SCPRGPTIKP CPPCKCPAPN
LLGGPSVFIF PPKIKDVLMI SLSPIVTCW VDVSEDDPDV QISWFVNNVE VHTAQTQTHR EDYNSTLRW SALPIQHQDW MSGKEFKCKV NNKDLPAPIE RTISKPKGSV RAPQVYVLPP PEEEMTKKQV TLTCMVTDFM PEDIYVEWTN NGKTELNYKN TEPVLDSDGS YFMYSKLRVE KKNWVERNSY SCSWHEGLH NHHTTKSFSR TPGK*
2303 H1L9 Caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaaatatgcacagaagtttcag region ggcagggtctccatgaccagggacacgtccactagcacagcctacatggagctgagcaggctgag nucleic acid atctgacgacacggccgtgtattactgtgcgagggggggagtggctgcgatcttggactactggg gccagggaaccctggtcaccgtctcctctaga
2304 H1L9
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTKY acid AQKFQGRVS TRDTSTSTAY MELSRLRSDD TAVYYCARGG VAAILDYWGQ GTLVTVSSR
2305 H1L9
Heavy chain
gga tac acc ttc acc ggc tac tat
CDR1 nucleic
acid
2306 H1L9
Heavy chain
CDR1 amino
acid GYTFTGYY
2307 H1L9
Heavy chain
CDR2 nucleic
acid ate aac cct aac agt ggt ggc aca
2308 H1L9
Heavy chain
CDR2 amino
acid INPNSGGT
2309 H1L9
Heavy charn
CDR3 nucleic
acid gcg agg ggg gga gtg get gcg ate ttg gac tac
2310 H1L9
Heavy chain
CDR3 amino
acid ARGGVAAILDY
2311 H1L9 cagtctgtgctgactcagccaccctcagcgtctgggacccccggacagtgggtctccatctcttg
Light chain ttctggaagcagctccaacatcggaagtaatactgtgcactggtaccgccaactcccaggaacgg full length cccccaaactcctcatttatagtaataatcagtggccctcaggggtccctgaccgattctctggc nucleic acid tccaagtctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgatta ttactgtgcaacatgggatgacagcctgaatggttgggtgttcggcggagggaccaagctgaccg tcctatctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaa tctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtg gaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaagg acagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtc tacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggaga gtgttaa
2312 H1L9 QSVLTQPPSA SGTPGQWVSI SCSGSSSNIG SNTVHWYRQL PGTAPKLLIY SNNQWPSGVP
Light chain DRFSGSKSGT SASLAISGLQ SEDEADYYCA TWDDSLNGWV FGGGTKLTVL SRTVAAPSVF full length IFPPSDEQLK SGTASWCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS amino acid STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC*
2313 H1L9 cagtctgtgctgactcagccaccctcagcgtctgggacccccggacagtgggtctccatctcttg
Light chain ttctggaagcagctccaacatcggaagt atactgtgcactggtaccgccaactcccaggaacgg variable cccccaaactcctcatttatagtaataatcagtggccctcaggggtccctgaccgattctctggc region tccaagtctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgatta nuclerc acid ttactgtgcaacatgggatgacagcctgaatggttgggtgttcggcggagggaccaagctgaccg tcctatctaga
2314 H1L9
Light chain
variable
region amino QSVLTQPPSA SGTPGQWVSI SCSGSSSNIG SNTVHWYRQL PGTAPKLLIY SNNQWPSGVP acid DRFSGSKSGT SASLAISGLQ SEDEADYYCA TWDDSLNGWV FGGGTKLTVL SR
2315 H1L9 age tec aac ate gga agt aat act Light chain
CDR1 nucleic
acid
2316 H1L9
Light chain
CDR1 amino
acid SSNIGSNT
2317 H1L9
Light chain
agt aat aat
CDR2 nucleic
acid
2318 H1L9
Light chain
CDR2 amino
acid SNN
2319 H1L9
Light chain
gca aca tgg gat gac age ctg aat ggt tgg gtg
CDR3 nucleic
acid
2320 H1L9
Light chain
CDR3 amino
acid ATWDDSLNGWV
2321 H2L4 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg full length ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag nucleic acid ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccc tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacc cagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcc caaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacc tcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctg agccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctg gtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagta ctctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaa tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtc agtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtca ctctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacggg aaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgta cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtcc acgagggtctgcacaatcaecacacgactaagagcttctcccggactccgggtaaatga
2322 H2L4 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY
Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSRAST full length KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY amino acid SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC PRGPTIKPCP PCKCPAPNLL
GGPSVFIFPP KIKDVLMISL SPIVTCVWD VSEDDPDVQI SWFVNNVEVH TAQTQTHRED YNSTLRWSA LPIQHQDWMS GKEFKCKVNN KDLPAP IERT ISKPKGSVRA PQVYVLPPPE EEMTKKQVTL TCMVTDFMPE DIYVEWTNNG KTELNYKNTE PVLDSDGSYF MYSKLRVEKK NWVERNSYSC SWHEGLHNH HTTKSFSRTP GK*
2323 H2L4 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg variable ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag region ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag nucleic acid agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctaga
2324 H2L4 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSR variable
region amino
acid
2325 H2L4
Heavy chain
gga ttc acc ttc aga age tat ggc
CDR1 nucleic
acid
2326 H2L4
Heavy chain
CDR1 amino
acid GFTFRSYG
2327 H2L4
Heavy chain
ata tea tat gat gga agt aat aaa
CDR2 nucleic
acid
2328 H2L4
Heavy chain
CDR2 amino
acid ISYDGSNK
2329 H2L4
Heavy chain
gcg cgc aat egg ggc tac act gac tac
CDR3 nucleic
acid
2330 H2L4
Heavy chain
CDR3 amino
acid ARNRGYTDY
2331 H2L4 gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggcaagagccaccctctc
Light chain ctgcagggccagtcagagtattagttacttcttagcctggtaccaacagaaacctggccaggctc full length ccagactcctcatctatgatgcctccagtagggccactggcatcccagccaggttcagtggcagt nucleic acid gggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattc ctgtcagctgcgtagcagctggcctccggcgttcggccaagggaccaaggtggaaatcaaatcta gaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact gcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtgga taacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacct acagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgc gaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2332 H2L4 EIVLTQSPAT LSLSPGARAT LSCRASQSIS YFLAWYQQKP GQAPRLL IYD ASSRATGIPA
Light chain RFSGSGSGTD FTLTISSLEP EDFAVYSCQL RSSWPPAFGQ GTKVEIKSRT VAAPSVFIFP full length PSDEQLKSGT ASWCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLS STL amino acid TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC *
2333 H2L4 gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggcaagagccaccctctc
Light chain ctgcagggccagtcagagtattagttacttcttagcctggtaccaacagaaacctggccaggctc variable ccagactcctcatctatgatgcctccagtagggccactggcatcccagccaggttcagtggcagt region gggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattc nucleic acid ctgtcagctgcgtagcagctggcctccggcgttcggccaagggaccaaggtggaaatcaaatcta ga
2334 H2L4
Light chain
variable
region amino EIVLTQSPAT LSLSPGARAT LSCRASQSIS YFLAWYQQKP GQAPRLL IYD ASSRATGIPA acid RFSGSGSGTD FTLTISSLEP EDFAVYSCQL RSSWPPAFGQ GTKVEIKSR
2335 H2L4
Light chain
cag agt att agt tac ttc
CDR1 nucleic
acid
2336 H2L4
Light chain
CDR1 amino QSISYF acid
2337 H2L4
Light chain
gat gcc tec
CDR2 nucleic
acid
2338 H2L4
Light chain
CDR2 amino
acid DAS
2339 H2L4
Light chain
cag ctg cgt age age tgg cct ccg gcg
CDR3 nucleic
acid
2340 H2L4
Light chain
CDR3 amino
acid QLRSSWPPA
2341 H2L5 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg full length ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag nucleic acid ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccc tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacc cagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcc caaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacc tcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctg agccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctg gtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagta ctctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaa tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtc agtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtca ctctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacggg aaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgta cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtcc acgagggtctgcacaatcaecacacgactaagagcttctcccggactccgggtaaatga
2342 H2L5 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY
Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSRAST full length KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY amino acid SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC PRGPTIKPCP PCKCPAPNLL
GGPSVFIFPP KIKDVLMISL SPIVTCWVD VSEDDPDVQI SWFVNNVEVH TAQTQTHRED YNSTLRWSA LPIQHQDWMS GKEFKCKVNN KDLPAP IERT ISKPKGSVRA PQVYVLPPPE EEMTKKQVTL TCMVTDFMPE DIYVEWTNNG KTELNYKNTE PVLDSDGSYF MYSKLRVEKK NWVERNSYSC SWHEGLHNH HTTKSFSRTP GK*
2343 H2L5 caggtgcagc ggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg variable ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag region ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag nucleic acid agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctaga
2344 H2L5
Heavy chain
variable
region amino QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY acid ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSR
2345 H2L5
gga ttc acc ttc aga age tat ggc
Heavy chain
Figure imgf000185_0001
Light chain
CDR2 amino
acid
2359 H2L5
Light chain
caa cag act aac agt ttc ccc etc act
CDR3 nucleic
acid
2360 H2L5
Light chain
CDR3 amino
acid QQTNSFPLT
2361 H2L6 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg full length ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag nucleic acid ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccc tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacc cagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcc caaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacc tcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctg agccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctg gtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagta ctctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaa tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtc agtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtca ctctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacggg aaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgta cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtcc acgagggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2362 H2L6 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY
Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSRAST full length KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY amino acid SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC PRGPTIKPCP PCKCPAPNLL
GGPSVFIFPP KIKDVLMISL SPIVTCWVD VSEDDPDVQI SWFVNNVEVH TAQTQTHRED YNSTLRWSA LPIQHQDWMS GKEFKCKVNN KDLPAP IERT ISKPKGSVRA PQVYVLPPPE EEMTKKQVTL TCMVTDFMPE DIYVEWTNNG KTELNYKNTE PVLDSDGSYF MYSKLRVEKK NWVERNSYSC SWHEGLHNH HTTKSFSRTP GK*
2363 H2L6 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg variable ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag region ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag nucleic acid agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctaga
2364 H2L6
Heavy chain
variable
region amino QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWLRQA PGKGLEWLAV I SYDGSNKYY acid ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSR
2365 H2L6
Heavy chain
gga ttc acc ttc aga age tat ggc
CDR1 nucleic
acid
2366 H2L6
Heavy chain
CDR1 amino
acid GFTFRSYG 2367 H2L6
Heavy chain
ata tea tat gat gga agt aat aaa
CDR2 nucleic
acid
2368 H2L6
Heavy chain
CDR2 amino
acid ISYDGSNK
2369 H2L6
Heavy chain
gcg cgc aat egg ggc tac act gac tac
CDR3 nucleic
acid
2370 H2L6
Heavy chain
CDR3 amino
acid ARNRGYTDY
2371 H2L6 tcctatgtgctgactcagccaccctcggtgtcagtggccccaggacagacggccataattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgttggtcgtctatgatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagtggggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcaccgggtattcggcggagggaccaagctgaccgtcctat ctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2372 H2L6 SYVLTQPPSV SVAPGQTAII TCGGNNIGSK SVHWYQQKPG QAPVLWYDD SDRPSGIPER
Light chain FSGSNSGNTA TLT I SGVEAG DEADYYCQVW DSSSDHRVFG GGTKLTVLSR TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2373 H2L6 tcctatgtgctgactcagccaccctcggtgtcagtggccccaggacagacggccataattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgttggtcgtctatgatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagtggggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcaccgggtattcggcggagggaccaagctgaccgtcctat ctaga
2374 H2L6
Light chain
variable
region amino SYVLTQPPSV SVAPGQTAII TCGGNNIGSK SVHWYQQKPG QAPVLWYDD SDRPSGIPER acid FSGSNSGNTA TLT I SGVEAG DEADYYCQVW DSSSDHRVFG GGTKLTVLSR
2375 H2L6
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2376 H2L6
Light chain
CDR1 amino
acid NIGSKS
2377 H2L6
Light chain
gat gat age
CDR2 nucleic
acid
2378 H2L6
Light chain
CDR2 amino
acid DDS
2379 H2L6
cag gtg tgg gat agt agt agt gat cac egg gta
Light chain CDR3 nucleic
acid
2380 H2L6
Light chain
CDR3 amino
acid QVWDSSSDHRV
2381 H2L7 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcacct cagaagctatggcatgcactggatccgccaggctccaggcaagg full length ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag nucleic acid ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccc tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacc cagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcc caaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacc tcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctg agccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctg gtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagta ctctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaa tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtc agtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtca ctctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacggg aaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgta cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtcc acgagggtctgcacaatcaecacacgactaagagcttctcccggactccgggtaaatga
2382 H2L7 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY
Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSRAST full length KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY amino acid SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC PRGPTIKPCP PCKCPAPNLL
GGPSVFIFPP KIKDVLMISL SPIVTCWVD VSEDDPDVQI SWFVNNVEVH TAQTQTHRED YNSTLRWSA LPIQHQDWMS GKEFKCKVNN KDLPAP IERT ISKPKGSVRA PQVYVLPPPE EEMTKKQVTL TCMVTDFMPE DIYVEWTNNG KTELNYKNTE PVLDSDGSYF MYSKLRVEKK NWVERNSYSC SWHEGLHNH HTTKSFSRTP GK*
2383 H2L7 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg variable ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag region ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag nucleic acid agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg
gaaccctggtcaccgtctcctctaga
2384 H2L7
Heavy chain
variable
region amino QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV 1 SYDGSNKYY acid ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSR
2385 H2L7
Heavy chain
gga ttc acc ttc aga age tat ggc
CDR1 nucleic
acid
2386 H2L7
Heavy chain
CDR1 amino
acid GFTFRSYG
2387 H2L7
Heavy chai
ata tea tat gat gga agt aat aaa
CDR2 nucle
acid
2388 H2L7 ISYDGSNK Heavy chain
CDR2 amino
acid
2389 H2L7
Heavy chain
gcg cgc aat egg ggc tac act gac tac
CDR3 nucleic
acid
2390 H2L7
Heavy chain
CDR3 amino
acid ARNRGYTDY
2391 H2L7 tcctatgagctgactcagccaccctcagtgtccgtgtccccgggacagacagccagcatcacctg
Light chain ctctggagataaattgggggataaatttgcttgctggtatcagcagaagccaggccagtcccctg full length tgctggtcatctatcaagatactaagcggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacagccactctgaccatcagcgggacccaggctatggatgaggctgactattactg tcaggcgtgggacagcagcactgtggtattcggcggagggaccaagctgaccgtcctatctagaA cggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcc tctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataa cgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctaca gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaa gtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2392 H2L7 SYELTQPPSV SVSPGQTASI TCSGDKLGDK FACWYQQKPG QSPVLVIYQD TKRPSGIPER
Light chain FSGSNSGNTA TLTISGTQAM DEADYYCQAW DSSTWFGGG TKLTVLSRTV AAPSVFIFPP full length SDEQLKSGTA SWCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT amino acid LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC*
2393 H2L7 tcctatgagctgactcagccaccctcagtgtccgtgtccccgggacagacagccagcatcacctg
Light chain ctctggagataaattgggggataaatttgcttgctggtatcagcagaagccaggccagtcccctg variable tgctggtcatctatcaagatactaagcggccctcagggatccctgagcgattctctggctccaac region tctgggaacacagccactctgaccatcagcgggacccaggctatggatgaggctgactattactg nucleic acid tcaggcgtgggacagcagcactgtggtattcggcggagggaccaagctgaccgtcctatctaga
2394 H2L7
Light chain
variable
region amino SYELTQPPSV SVSPGQTASI TCSGDKLGDK FACWYQQKPG QSPVLVIYQD TKRPSGIPER acid FSGSNSGNTA TLTISGTQAM DEADYYCQAW DSSTWFGGG TKLTVLSR
2395 H2L7
Light chain
aaa ttg ggg gat aaa ttt
CDR1 nucleic
acid
2396 H2L7
Light chain
CDR1 amino
acid KLGDKF
2397 H2L7
Light chain
caa gat act
CDR2 nucleic
acid
2398 H2L7
Light chain
CDR2 amino
acid QDT
2399 H2L7
Light chain
cag gcg tgg gac age age act gtg gta
CDR3 nucleic
acid
2400 H2L7
Light chain
CDR3 amino
acid QAWDSSTW 2401 H2L8 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcacct cagaagctatggcatgcactggatccgccaggctccaggcaagg full length ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag nucleic acid ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccc tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacc cagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcc caaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacc tcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctg agccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctg gtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagta ctctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaa tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtc agtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtca ctctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacggg aaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgta cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtcc acgagggtctgcacaatcaecacacgactaagagcttctcccggactccgggtaaatga
2402 H2L8 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY
Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSRAST full length KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY amino acid SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC PRGPTIKPCP PCKCPAPNLL
GGPSVFIFPP KIKDVLMISL SPIVTCWVD VSEDDPDVQI SWFVNNVEVH TAQTQTHRED YNSTLRWSA LPIQHQDWMS GKEFKCKVNN KDLPAP IERT ISKPKGSVRA PQVYVLPPPE EEMTKKQVTL TCMVTDFMPE DIYVEWTNNG KTELNYKNTE PVLDSDGSYF MYSKLRVEKK NWVERNSYSC SWHEGLHNH HTTKSFSRTP GK*
2403 H2L8 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg variable ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag region ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag nucleic acid agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctaga
2404 H2L8
Heavy chain
variable
region amino QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV I SYDGSNKYY acid ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSR
2405 H2L8
Heavy chain
gga ttc acc ttc aga age tat ggc
CDR1 nucleic
acid
2406 H2L8
Heavy chain
CDR1 amino
acid GFTFRSYG
2407 H2L8
Heavy chain
ata tea tat gat gga agt aat aaa
CDR2 nucleic
acid
2408 H2L8
Heavy chain
CDR2 amino
acid ISYDGSNK
2409 H2L8
Heavy chain
gcg cgc aat egg ggc tac act gac tac
CDR3 nucleic
acid
2410 H2L8 ARNRGYTDY Heavy chain
CDR3 amino
acid
2411 H2L8 tcctatgagctgatgcagccaccctcggtgtcagtgtccccaggacagacggccaggatcacctg
Light chain ctctggagatgcattgccaaagcaatatgcttattggtaccagcagaagccaggccaggcccctg full length tgctggtgatatataaagacagtgagaggccctcagggatccctgagcgattctctggctccagc nucleic acid tcagggacaacagtcacgttgaccatcagtggagtccaggcagaagatgaggctgactattactg tcaatcagcagacagcagtggtacttatgtggtactcggcggagggaccaagctgaccgtcctat ctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2412 H2L8 SYELMQPPSV SVSPGQTARI TCSGDALPKQ YAYWYQQKPG QAPVLVIYKD SERPSGIPER
Light chain FSGSSSGTTV TLTISGVQAE DEADYYCQSA DSSGTYWLG GGTKLTVLSR TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2413 H2L8 tcctatgagctgatgcagccaccctcggtgtcagtgtccccaggacagacggccaggatcacctg
Light chain ctctggagatgcattgccaaagcaatatgcttattggtaccagcagaagccaggccaggcccctg variable tgctggtgatatataaagacagtgagaggccctcagggatccctgagcgattctctggctccagc region tcagggacaacagtcacgttgaccatcagtggagtccaggcagaagatgaggctgactattactg nucleic acid tcaatcagcagacagcagtggtacttatgtggtactcggcggagggaccaagctgaccgtcctat ctaga
2414 H2L8
Light chain
variable
region amino SYELMQPPSV SVSPGQTARI TCSGDALPKQ YAYWYQQKPG QAPVLVIYKD SERPSGIPER acid FSGSSSGTTV TLTISGVQAE DEADYYCQSA DSSGTYWLG GGTKLTVLSR
2415 H2L8
Light chain
gca ttg cca aag caa tat
CDR1 nucleic
acid
2416 H2L8
Light chain
CDR1 amino
acid ALPKQY
2417 H2L8
Light chain
aaa gac agt
CDR2 nucleic
acid
2418 H2L8
Light chain
CDR2 amino
acid KDS
2419 H2L8
Light chain
cag tea gca gac age agt ggt act tat gtg gta
CDR3 nucleic
acid
2420 H2L8
Light chain
CDR3 amino
acid QSADSSGTYW
2421 H2L9 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg full length ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag nucleic acid ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccc tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacc cagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcc caaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacc tcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctg agecccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctg gtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagta ctctccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaa tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtc agtaagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtca ctctgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacggg aaaacagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgta cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtcc acgagggtctgcacaatcaecacacgactaagagcttctcccggactccgggtaaatga
2422 H2L9 QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV ISYDGSNKYY
Heavy chain ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSRAST full length KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY amino acid SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC PRGPTIKPCP PCKCPAPNLL
GGPSVFIFPP KIKDVLMISL SPIVTCWVD VSEDDPDVQI SWFVNNVEVH TAQTQTHRED YNSTLRWSA LPIQHQDWMS GKEFKCKVNN KDLPAPIERT ISKPKGSVRA PQVYVLPPPE EEMTKKQVTL TCMVTDFMPE DIYVEWTNNG KTELNYKNTE PVLDSDGSYF MYSKLRVEKK NWVERNSYSC SWHEGLHNH HTTKSFSRTP GK*
2423 H2L9 caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaagtccctgagactctcctg
Heavy chain tgcagcgtctggattcaccttcagaagctatggcatgcactggatccgccaggctccaggcaagg variable ggctggagtggctggcagttatatcatatgatggaagtaataaatactacgcagactccgtgaag region ggccgattcaccatctccagagacaattccaagaacgcgctgtatctgcaaatgaatcgcctgag nucleic acid agctgaggacacggctgtgtattactgtgcgcgcaatcggggctacactgactactggggccagg gaaccctggtcaccgtctcctctaga
2424 H2L9
Heavy chain
variable
region amino QVQLVESGGG WQPGKSLRL SCAASGFTFR SYGMHWIRQA PGKGLEWLAV ISYDGSNKYY acid ADSVKGRFTI SRDNSKNALY LQMNRLRAED TAVYYCARNR GYTDYWGQGT LVTVSSR
2425 H2L9
Heavy chain
gga ttc acc ttc aga age tat ggc
CDR1 nucleic
acid
2426 H2L9
Heavy chain
CDR1 amino
acid GFTFRSYG
2427 H2L9
Heavy chain
ata tea tat gat gga agt aat aaa
CDR2 nucleic
acid
2428 H2L9
Heavy chain
CDR2 amino
acid ISYDGSNK
2429 H2L9
Heavy chain
gcg cgc aat egg ggc tac act gac tac
CDR3 nucleic
acid
2430 H2L9
Heavy chain
CDR3 amino
acid ARNRGYTDY
2431 H2L9 cagtctgtgctgactcagccaccctcagcgtctgggacccccggacagtgggtctccatctcttg
Light chain ttctggaagcagctccaacatcggaagtaatactgtgcactggtaccgccaactcccaggaacgg full length cccccaaactcctcatttatagtaataatcagtggccctcaggggtccctgaccgattctctggc nucleic acid tccaagtctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgatta ttactgtgcaacatgggatgacagcctgaatggttgggtgttcggcggagggaccaagctgaccg tcctatctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaa tctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtg gaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaagg acagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtc tacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggaga gtgttaa
2432 H2L9 QSVLTQPPSA SGTPGQWVSI SCSGSSSNIG SNTVHWYRQL PGTAPKLLIY SNNQWPSGVP
Light chain DRFSGSKSGT SASLAISGLQ SEDEADYYCA TWDDSLNGWV FGGGTKLTVL SRTVAAPSVF full length IFPPSDEQLK SGTASWCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS amino acid STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC*
2433 H2L9 cagtctgtgctgactcagccaccctcagcgtctgggacccccggacagtgggtctccatctcttg
Light chain ttctggaagcagctccaacatcggaagtaatactgtgcactggtaccgccaactcccaggaacgg variable cccccaaactcctcatttatagtaataatcagtggccctcaggggtccctgaccgattctctggc region tccaagtctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgatta nucleic acid ttactgtgcaacatgggatgacagcctgaatggttgggtgttcggcggagggaccaagctgaccg
tcctatctaga
2434 H2L9
Light chain
variable
region amino QSVLTQPPSA SGTPGQWVSI SCSGSSSNIG SNTVHWYRQL PGTAPKLLIY SNNQWPSGVP acid DRFSGSKSGT SASLAISGLQ SEDEADYYCA TWDDSLNGWV FGGGTKLTVL SR
2435 H2L9
Light chain
age tec aac ate gga agt aat act
CDR1 nucleic
acid
2436 H2L9
Light chain
CDR1 amino
acid SSNIGSNT
2437 H2L9
Light chain
agt aat aat
CDR2 nucleic
acid
2438 H2L9
Light chain
CDR2 amino
acid SNN
2439 H2L9
Light chain
gca aca tgg gat gac age ctg aat ggt tgg gtg
CDR3 nucleic
acid
2440 H2L9
Light chain
CDR3 amino
acid ATWDDSLNGW V
2441 H3L4 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag full length ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag nucleic acid ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccctcc tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctac agtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaa atcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacctct tgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctgage cccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctggtt tgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagtactc tccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaatgc aaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtcagt aagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtcactc tgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacgggaaa acagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgtacag caagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtccacg agggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2442 H3L4 QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY
Heavy chain AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSRASTK full length GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS amino acid LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG
GPSVFIFPPK IKDVLMISLS PIVTCWVDV SEDDPDVQIS WFV NVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAP IERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2443 H3L4 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacacct cagcgactactatatatactgggtgcgacaggcccctggacaag variable ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag region ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag nucleic acid atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctaga
2444 H3L4
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY acid AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSR
2445 H3L4
Heavy chain
gga tac acc ttc age gac tac tat
CDR1 nucleic
acid
2446 H3L4
Heavy chain
CDR1 amino
acid GYTFSDYY
2447 H3L4
Heavy chain
ate aac cct aac agt ggt gac aca
CDR2 nucleic
acid
2448 H3L4
Heavy chain
CDR2 amino
acid INPNSGDT
2449 H3L4
Heavy chain
gcg aca ggt gac ccc cct gac tac
CDR3 nucleic
acid
2450 H3L4
Heavy chain
CDR3 amino
acid ATGDPPDY
2451 H3L4 gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggcaagagccaccctctc
Light chain ctgcagggccagtcagagtattagttacttcttagcctggtaccaacagaaacctggccaggctc full length ccagactcctcatctatgatgcctccagtagggccactggcatcccagccaggttcagtggcagt nucleic acid gggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattc ctgtcagctgcgtagcagctggcctccggcgttcggccaagggaccaaggtggaaatcaaatcta gaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact gcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtgga
Figure imgf000195_0001
tgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacgggaaa acagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgtacag caagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtccacg agggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2462 H3L5 QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY
Heavy chain AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSRASTK full length GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS amino acid LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG
GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFV NVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAP IERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2463 H3L5 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag variable ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag region ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag nucleic acid atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctaga
2464 H3L5
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY acid AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSR
2465 H3L5
Heavy chain
gga tac acc ttc age gac tac tat
CDR1 nucleic
acid
2466 H3L5
Heavy chain
CDR1 amino
acid GYTFSDYY
2467 H3L5
Heavy chain
ate aac cct aac agt ggt gac aca
CDR2 nucleic
acid
2468 H3L5
Heavy chain
CDR2 amino
acid INPNSGDT
2469 H3L5
Heavy chain
gcg aca ggt gac ccc cct gac tac
CDR3 nucleic
acid
2470 H3L5
Heavy chain
CDR3 amino
acid ATGDPPDY
2471 H3L5 gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcaccatcac
Light chain ttgtcgggcgagtcaggatataagtagctggttagtctggtatcagcagaaaccagggagagccc full length ctatactcctgatcaacactgcatccagtctgcaa gtggcgtcccatcaaggttcagcggcagt nucleic acid ggatctgggacacttttcactctcaccatcaccaccctgcagcctgaagattttgcaacttacta ttgtcaacagactaacagtttccccctcactttcggcggagggaccaaggtggagatcaaatcta gaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact gcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtgga taacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacct acagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgc gaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2472 H3L5 DIQMTQSPSS VSASVGDRVT ITCRASQDIS SWLVWYQQKP GRAPILLINT ASSLQSGVPS
Light chain RFSGSGSGTL FTLTITTLQP EDFATYYCQQ TNSFPLTFGG GTKVEIKSRT VAAPSVFIFP full length PSDEQLKSGT ASWCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLS STL amino acid TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC *
2473 H3L5 gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcaccatcac
Light chain ttgtcgggcgagtcaggatataagtagctggttagtctggtatcagcagaaaccagggagagccc variable ctatactcctgatcaacactgcatccagtctgcaaagtggcgtcccatcaaggttcagcggcagt region ggatctgggacacttttcactctcaccatcaccaccctgcagcctgaagattttgcaacttacta nucleic acid ttgtcaacagactaacagtttccccctcactttcggcggagggaccaaggtggagatcaaatcta ga
2474 H3L5
Light chain
variable
region amino DIQMTQSPSS VSASVGDRVT ITCRASQDIS SWLVWYQQKP GRAPILLINT ASSLQSGVPS acid RFSGSGSGTL FTLTITTLQP EDFATYYCQQ TNSFPLTFGG GTKVEIKSR
2475 H3L5
Light chain
cag gat ata agt age tgg
CDR1 nucleic
acid
2476 H3L5
Light chain
CDR1 amino
acid QDISSW
2477 H3L5
Light chain
act gca tec
CDR2 nucleic
acid
2478 H3L5
Light chain
CDR2 amino
acid TAS
2479 H3L5
Light chain
caa cag act aac agt ttc ccc etc act
CDR3 nucleic
acid
2480 H3L5
Light chain
CDR3 amino
acid QQTNSFPLT
2481 H3L6 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag full length ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag nucleic acid ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccctcc tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctac agtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaa atcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacctct tgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctgagc cccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctggtt tgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagtactc tccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaatgc aaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtcagt aagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtcactc tgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacgggaaa acagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgtacag caagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtccacg agggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2482 H3L6 QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY
Heavy chain AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSRASTK full length GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS amino acid LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG
GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAP IERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2483 H3L6 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag variable ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag region ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag nucleic acid atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctaga
2484 H3L6
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY acid AQKFQGRVT TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSR
2485 H3L6
Heavy chain
gga tac acc ttc age gac tac tat
CDR1 nucleic
acid
2486 H3L6
Heavy chain
CDR1 amino
acid GYTFSDYY
2487 H3L6
Heavy chain
ate aac cct aac agt ggt gac aca
CDR2 nucleic
acid
2488 H3L6
Heavy chain
CDR2 amino
acid INPNSGDT
2489 H3L6
Heavy charn
gcg aca ggt gac ccc cct gac tac
CDR3 nucleic
acid
2490 H3L6
Heavy chain
CDR3 amino
acid ATGDPPDY
2491 H3L6 tcctatgtgctgactcagccaccctcggtgtcagtggccccaggacagacggccataattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgttggtcgtctatgatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagtggggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcaccgggtattcggcggagggaccaagctgaccgtcctat ctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2492 H3L6 SYVLTQPPSV SVAPGQTAII TCGGNNIGSK SVH YQQKPG QAPVLWYDD SDRPSGIPER
Light chain FSGSNSGNTA TLT I SGVEAG DEADYYCQVW DSSSDHRVFG GGTKLTVLSR TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC*
2493 H3L6 tcctatgtgctgactcagccaccctcggtgtcagtggccccaggacagacggccataattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgttggtcgtctatgatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagtggggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcaccgggtattcggcggagggaccaagctgaccgtcctat ctaga
2494 H3L6
Light chain
variable
region amino SYVLTQPPSV SVAPGQTAII TCGGNNIGSK SVHWYQQKPG QAPVLWYDD SDRPSGIPER acid FSGSNSGNIA TLTISGVEAG DEADYYCQVW DSSSDHRVFG GGTKLTVLSR
2495 H3L6
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2496 H3L6
Light chain
CDR1 amino
acid NIGSKS
2497 H3L6
Light chain
gat gat age
CDR2 nucleic
acid
2498 H3L6
Light chain
CDR2 amino
acid DDS
2499 H3L6
Light chain
cag gtg tgg gat agt agt agt gat cac egg gta
CDR3 nucleic
acid
2500 H3L6
Light chain
CDR3 amino
acid QVWDSSSDHRV
2501 H3L7 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag full length ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag nucleic acid ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccctcc tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctac agtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaa atcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacctct tgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctgagc cccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctggtt tgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagtactc tccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaatgc aaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtcagt aagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtcactc tgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacgggaaa acagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgtacag caagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtccacg agggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2502 H3L7 QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY
Heavy chain AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSRASTK full length GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS amino acid LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG
GPSVFIFPPK IKDVLMISLS PIVTCWVDV SEDDPDVQIS WFV NVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAP IERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2503 H3L7 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag variable ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag region ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag nucleic acid atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctaga
2504 H3L7
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY acid AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSR
2505 H3L7
Heavy chain
gga tac acc ttc age gac tac tat
CDR1 nucleic
acid
2506 H3L7
Heavy chain
CDR1 amino
acid GYTFSDYY
2507 H3L7
Heavy chain
ate aac cct aac agt ggt gac aca
CDR2 nucleic
acid
2508 H3L7
Heavy chain
CDR2 amino
acid INPNSGDT
2509 H3L7
Heavy chain
gcg aca ggt gac ccc cct gac tac
CDR3 nucleic
acid
2510 H3L7
Heavy chain
CDR3 amino
acid ATGDPPDY
2511 H3L7 tcctatgagctgactcagccaccctcagtgtccgtgtccccgggacagacagccagcatcacctg
Light chain ctctggagataaattgggggataaatttgcttgctggtatcagcagaagccaggccagtcccctg full length tgctggtcatctatcaagatactaagcggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacagccactctgaccatcagcgggacccaggctatggatgaggctgactattactg tcaggcgtgggacagcagcactgtggtattcggcggagggaccaagctgaccgtcctatctagaA cggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcc tctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataa cgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctaca gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaa gtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2512 H3L7 SYELTQPPSV SVSPGQTASI TCSGDKLGDK FACWYQQKPG QSPVLVIYQD TKRPSGIPER
Light chain FSGSNSGNTA TLTISGTQAM DEADYYCQAW DSSTWFGGG TKLTVLSRTV AAPSVFIFPP full length SDEQLKSGTA SWCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT amino acid LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC*
2513 H3L7 tcctatgagctgactcagccaccctcagtgtccgtgtccccgggacagacagccagcatcacctg
Light chain ctctggagataaattgggggataaatttgcttgctggtatcagcagaagccaggccagtcccctg variable tgctggtcatctatcaagatactaagcggccctcagggatccctgagcgattctctggctccaac region tctgggaacacagccactctgaccatcagcgggacccaggctatggatgaggctgactattactg nucleic acid tcaggcgtgggacagcagcactgtggtattcggcggagggaccaagctgaccgtcctatctaga
2514 H3L7
Light chain
variable
region amino SYELTQPPSV SVSPGQTASI TCSGDKLGDK FACWYQQKPG QSPVLVIYQD TKRPSGIPER acid FSGSNSGNTA TLTISGTQAM DEADYYCQAW DSSTWFGGG TKLTVLSR 2515 H3L7
Light chain
aaa ttg ggg gat aaa ttt
CDR1 nucleic
acid
2516 H3L7
Light chain
CDR1 amino
acid KLGDKF
2517 H3L7
Light chain
caa gat act
CDR2 nucleic
acid
2518 H3L7
Light chain
CDR2 amino
acid QDT
2519 H3L7
Light chain
cag gcg tgg gac age age act gtg gta
CDR3 nucleic
acid
2520 H3L7
Light chain
CDR3 amino
acid QAWDSSTW
2521 H3L8 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag full length ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag nucleic acid ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccctcc tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctac agtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaa atcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacctct tgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctgage cccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctggtt tgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagtactc tccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaatgc aaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtcagt aagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtcactc tgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacgggaaa acagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgtacag caagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtccacg agggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2522 H3L8 QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY
Heavy chain AQKFQGRVT TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSRASTK full length GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS amino acid LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG
GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFV NVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAP IERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2523 H3L8 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag variable ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag region ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag nucleic acid atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctaga 2524 H3L8
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYY1YWVRQA PGQGLEWTGR INPNSGDTNY acid AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSR
2525 H3L8
Heavy chain
gga tac acc ttc age gac tac tat
CDR1 nucleic
acid
2526 H3L8
Heavy chain
CDR1 amino
acid GYTFSDYY
2527 H3L8
Heavy chain
ate aac cct aac agt ggt gac aca
CDR2 nucleic
acid
2528 H3L8
Heavy chain
CDR2 amino
acid INPNSGDT
2529 H3L8
Heavy chain
gcg aca ggt gac ccc cct gac tac
CDR3 nucleic
acid
2530 H3L8
Heavy chain
CDR3 amino
acid ATGDPPDY
2531 H3L8 tcctatgagctgatgcagccaccctcggtgtcagtgtccccaggacagacggccaggatcacctg
Light chain ctctggagatgcattgccaaagcaatatgcttattggtaccagcagaagccaggccaggcccctg full length tgctggtgatatataaagacagtgagaggccctcagggatccctgagcgattctctggctccagc nucleic acid tcagggacaacagtcacgttgaccatcagtggagtccaggcagaagatgaggctgactattactg tcaatcagcagacagcagtggtacttatgtggtactcggcggagggaccaagctgaccgtcctat ctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2532 H3L8 SYELMQPPSV SVSPGQTARI TCSGDALPKQ YAYWYQQKPG QAPVLVIYKD SERPSGIPER
Light chain FSGSSSGTTV TLTISGVQAE DEADYYCQSA DSSGTYWLG GGTKLTVLSR TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2533 H3L8 tcctatgagctgatgcagccaccctcggtgtcagtgtccccaggacagacggccaggatcacctg
Light chain ctctggagatgcattgccaaagcaatatgcttattggtaccagcagaagccaggccaggcccctg variable tgctggtgatatataaagacagtgagaggccctcagggatccctgagcgattctctggctccagc region tcagggacaacagtcacgttgaccatcagtggagtccaggcagaagatgaggctgactattactg nucleic acid tcaatcagcagacagcagtggtacttatgtggtactcggcggagggaccaagctgaccgtcctat ctaga
2534 H3L8
Light chain
variable
region amino SYELMQPPSV SVSPGQTARI TCSGDALPKQ YAYWYQQKPG QAPVLVIYKD SERPSGIPER acid FSGSSSGTTV TLTISGVQAE DEADYYCQSA DSSGTYWLG GGTKLTVLSR
2535 H3L8
Light chain
gca ttg cca aag caa tat
CDR1 nucleic
acid
2536 H3L8 ALPKQY Light chain
CDR1 amino
acid
2537 H3L8
Light chain
aaa gac agt
CDR2 nucleic
acid
2538 H3L8
Light chain
CDR2 amino
acid KDS
2539 H3L8
Light chain
cag tea gca gac age agt ggt act tat gtg gta
CDR3 nucleic
acid
2540 H3L8
Light chain
CDR3 amino
acid QSADSSGTYW
2541 H3L9 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag full length ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag nucleic acid ggcagggtcaccatgaccagggacacgtcca cagcacagcctacttggagctgagcaggctgag atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctagaGcctccaccaagggcccatcggtcttccccctggcaccctcc tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctac agtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaa atcttgtcccagagggcccacaatcaagccctgtcctccatgcaaatgcccagcacctaacctct tgggtggaccatccgtcttcatcttccctccaaagatcaaggatgtactcatgatctccctgage cccatagtcacatgtgtggtggtggatgtgagcgaggatgacccagatgtccagatcagctggtt tgtgaacaacgtggaagtacacacagctcagacacaaacccatagagaggattacaacagtactc tccgggtggtcagtgccctccccatccagcaccaggactggatgagtggcaaggagttcaaatgc aaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctcaaaacccaaagggtcagt aagagctccacaggtatatgtcttgcctccaccagaagaagagatgactaagaaacaggtcactc tgacctgcatggtcacagacttcatgcctgaagacatttacgtggagtggaccaacaacgggaaa acagagctaaactacaagaacactgaaccagtcctggactctgatggttcttacttcatgtacag caagctgagagtggaaaagaagaactgggtggaaagaaatagctactcctgttcagtggtccacg agggtctgcacaatcaccacacgactaagagcttctcccggactccgggtaaatga
2542 H3L9 QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY
Heavy chain AQKFQGRVT TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSRASTK full length GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS amino acid LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG
GPSVFIFPPK IKDVLMISLS PIVTCWVDV SEDDPDVQIS WFV NVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAP IERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2543 H3L9 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggatacaccttcagcgactactatatatactgggtgcgacaggcccctggacaag variable ggcttgagtggacgggacggatcaaccctaacagtggtgacacaaactatgcacagaagtttcag region ggcagggtcaccatgaccagggacacgtccatcagcacagcctacttggagctgagcaggctgag nucleic acid atctgacgacacggtcgtgtattactgtgcgacaggtgacccccctgactactggggccagggaa cactggtcaccgtctcctctaga
2544 H3L9
Heavy chain
variable
region amino QVQLVQSGAE VKKPGASVKV SCKASGYTFS DYYIYWVRQA PGQGLEWTGR INPNSGDTNY acid AQKFQGRVTM TRDTSISTAY LELSRLRSDD TWYYCATGD PPDYWGQGTL VTVSSR 2545 H3L9
Heavy chain
gga tac acc ttc age gac tac tat
CDRl nucleic
acid
2546 H3L9
Heavy chain
CDRl amino
acid GYTFSDYY
2547 H3L9
Heavy chain
ate aac cct aac agt ggt gac aca
CDR2 nucleic
acid
2548 H3L9
Heavy chain
CDR2 amino
acid INPNSGDT
2549 H3L9
Heavy chain
gcg aca ggt gac ccc cct gac tac
CDR3 nucleic
acid
2550 H3L9
Heavy chain
CDR3 amino
acid ATGDPPDY
2551 H3L9 cagtctgtgctgactcagccaccctcagcgtctgggacccccggacagtgggtctccatctcttg
Light chain ttctggaagcagctccaacatcggaagtaatactgtgcactggtaccgccaactcccaggaacgg full length cccccaaactcctcatttatagtaataatcagtggccctcaggggtccctgaccgattctctggc nucleic acid tccaagtctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgatta ttactgtgcaacatgggatgacagcctgaatggttgggtgttcggcggagggaccaagctgaccg tcctatctagaAcggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaa tctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtg gaaggtggataacgccctccaatcgggt actcccaggagagtgtcacagagcaggacagcaagg acagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtc tacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggaga gtgttaa
2552 H3L9 QSVLTQPPSA SGTPGQWVSI SCSGSSSNIG SNTVHWYRQL PGTAPKLLIY SNNQWPSGVP
Light chain DRFSGSKSGT SASLAISGLQ SEDEADYYCA TWDDSLNGWV FGGGTKLTVL SRTVAAPSVF full length IFPPSDEQLK SGTASWCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS amino acid STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC*
2553 H3L9 cagtctgtgctgactcagccaccctcagcgtctgggacccccggacagtgggtctccatctcttg
Light chain ttctggaagcagctccaacatcggaagtaatactgtgcactggtaccgccaactcccaggaacgg variable cccccaaactcctcatttatagtaataatcagtggccctcaggggtccctgaccgattctctggc region tccaagtctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgatta nucleic acid ttactgtgcaacatgggatgacagcctgaatggttgggtgttcggcggagggaccaagctgaccg tcctatctaga
2554 H3L9
Light chain
variable
region amino QSVLTQPPSA SGTPGQWVSI SCSGSSSNIG SNTVHWYRQL PGTAPKLLIY SNNQWPSGVP acid DRFSGSKSGT SASLAISGLQ SEDEADYYCA TWDDSLNGWV FGGGTKLTVL SR
2555 H3L9
Light chain
age tec aac ate gga agt aat act
CDRl nucleic
acid
2556 H3L9
Light chain
CDRl amino
acid SSNIGSNT
2557 H3L9
agt aat aat
Light chain CDR2 nucleic
acid
2558 H3L9
Light chain
CDR2 amino
acid SNN
2559 H3L9
Light chain
gca aca tgg gat gac age ctg aat ggt tgg gtg
CDR3 nucleic
acid
2560 H3L9
Light chain
CDR3 amino
acid ATWDDSLNGWV
2561 H4L11 caggtacagctgcagcagtcaggtccaggactggtgaagccctcgcagaccctctcactcacctg
Heavy chain tgccatctccggggacagtgtctctagcaacagtgctgcttggaactggatcaggcagtccccat full length cgagaggccttgagtggctgggaaggacatactacaggtccaagtggtataatgattatgcagta nucleic acid tctgtgaaaagtcgaataaccatcaaccctgacacatccaagaaccagttgtccctgcaactgaa ctctgtgactcccgaggacacggctgtgtattactgtgcgggagggaggggaaatatcgatctac cctcatactttgacttctggagccagggcaccctggtcaccgtctcctctagagcctccaccaag ggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgacca gcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtg accgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaa caccaaggtggacaagaaagttgagcccaaatcttgtcccagagggcccacaatcaagccctgtc ctccatgcaaatgcccagcacctaacctcttgggtggaccatccgtcttcatcttccctccaaag atcaaggatgtactcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcga ggatgacccagatgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacac aaacccatagagaggattacaacagtactctccgggtggtcagtgccctccccatccagcaccag gactggatgagtggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcga gagaaccatctcaaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccag aagaagagatgactaagaaacaggtcactctgacctgcatggtcacagactteatgectgaagae atttacgtggagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcct ggactctgatggttcttactteatgtacagcaagctgagagtggaaaagaagaactgggtggaaa gaaatagctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttc tcccggactccgggtaaatga
2562 H4L11 QVQLQQSGPG LVKPSQTLSL TCAISGDSVS SNSAAWNWIR QSPSRGLEWL GRTYYRSKWY
Heavy chain NDYAVSVKSR ITINPDTSKN QLSLQLNSVT PEDTAVYYCA GGRGNIDLPS YFDFWSQGTL full length VTVSSRASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP amino acid AVLQSSGLYS LSSWTVPSS SLGTQTYICN VNHKP SNTKV DKKVEPKSCP RGPTIKPCPP
CKCPAPNLLG GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2563 H4L11 caggtacagctgcagcagtcaggtccaggactggtgaagccctcgcagaccctctcactcacctg
Heavy chain tgccatctccggggacagtgtctctagcaacagtgctgcttggaactggatcaggcagtccccat variable cgagaggccttgagtggctgggaaggacatactacaggtccaagtggtataatgattatgcagta region tctgtgaaaagtcgaataaccatcaaccctgacacatccaagaaccagttgtccctgcaactgaa nucleic acid ctctgtgactcccgaggacacggctgtgtattactgtgcgggagggaggggaaatatcgatctac cctcatactttgacttctggagccagggcaccctggtcaccgtctcctctaga
2564 H4L11
Heavy chain
variable QVQLQQSGPG LVKPSQTLSL TCAISGDSVS SNSAAWNWIR QSPSRGLEWL GRTYYRSKWY region amino NDYAVSVKSR ITINPDTSKN QLSLQLNSVT PEDTAVYYCA GGRGNIDLPS YFDFWSQGTL acid VTVSSR
2565 H4L11
Heavy chain
ggg gac agt gtc tct age aac agt get get
CDR1 nucleic
acid 2566 H4L11
Heavy chain
CDR1 amino
acid GDSVSSNSAA
2567 H4L11
Heavy chain
aca tac tac agg tec aag tgg tat aat
CDR2 nucleic
acid
2568 H4L11
Heavy chain
CDR2 amino
acid TYYRSKWYN
2569 H4L11
Heavy chain
gcg gga ggg agg gga aat ate gat eta ccc tea tac ttt gac ttc CDR3 nucleic
acid
2570 H4L11
Heavy chain
CDR3 amino
acid AGGRGNIDLPSYFDF
2571 H4L11 tcctatgagctgactcagccactctcagtgtcagtggccctgggacaggcggccaggattacctg
Light chain tgggggaaacaaccttggatataaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgctggtcatctatagggataacaaccggccctctggcattcctgaccgagtgtctggctccaat nucleic acid tcgggaaacacggccaccctgaccatcagcagagcccaagccggggatgaggctcactattactg tcaggtgtgggacagcagtactgcgatattcggcggagggaccaagctgaccgtcctagctagca cggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcc tctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataa cgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctaca gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaa gtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2572 H4L11 SYELTQPLSV SVALGQAARI TCGGNNLGYK SVH YQQKPG QAPVLVIYRD NNRPSGIPDR
Light chain VSGSNSGNTA TLT I SRAQAG DEAHYYCQVW DSSTAIFGGG TKLTVLASTV AAPSVFIFPP full length SDEQLKSGTA SWCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT amino acid LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC*
2573 H4L11 tcctatgagctgactcagccactctcagtgtcagtggccctgggacaggcggccaggattacctg
Light chain tgggggaaacaaccttggatataaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgctggtcatctatagggataacaaccggccctctggcattcctgaccgagtgtctggctccaat region tcgggaaacacggccaccctgaccatcagcagagcccaagccggggatgaggctcactattactg nucleic acid tcaggtgtgggacagcagtactgcgatattcggcggagggaccaagctgaccgtcctagctagc
2574 H4L11
Light chain
variable
region amino SYELTQPLSV SVALGQAARI TCGGNNLGYK SVHWYQQKPG QAPVLVIYRD NNRPSGIPDR acid VSGSNSGNTA TLT I SRAQAG DEAHYYCQVW DSSTAIFGGG TKLTVLAS
2575 H4L11
Light chain
aac ctt gga tat aaa agt
CDR1 nucleic
acid
2576 H4L11
Light chain
CDR1 amino
acid NLGYKS
2577 H4L11
Light chain
agg gat aac
CDR2 nucleic
acid
2578 H4L11
Light chain
CDR2 amino
acid RDN 2579 H4L11
Light chain
cag gtg tgg gac age agt act gcg ata
CDR3 nucleic
acid
2580 H4L11
Light chain
CDR3 amino
acid QVWDSSTAI
2581 H4L12 caggtacagctgcagcagtcaggtccaggactggtgaagccctcgcagaccctctcactcacctg
Heavy chain tgccatctccggggacagtgtctctagcaacagtgctgcttggaactggatcaggcagtccccat full length cgagaggccttgagtggctgggaaggacatactacaggtccaagtggtataatgattatgcagta nucleic acid tctgtgaaaagtcgaataaccatcaaccctgacacatccaagaaccagttgtccctgcaactgaa ctctgtgactcccgaggacacggctgtgtattactgtgcgggagggaggggaaatatcgatctac cctcatactttgacttctggagccagggcaccctggtcaccgtctcctctagagcctccaccaag ggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgacca gcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtg accgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaa caccaaggtggacaagaaagttgagcccaaatcttgtcccagagggcccacaatcaagccctgtc ctccatgcaaatgcccagcacctaacctcttgggtggaccatccgtcttcatcttccctccaaag atcaaggatgtactcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcga ggatgacccagatgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacac aaacccatagagaggattacaacagtactctccgggtggtcagtgccctccccatccagcaccag gactggatgagtggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcga gagaaccatctcaaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccag aagaagagatgactaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagac atttacgtggagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcct ggactctgatggttcttactteatgtacagcaagctgagagtggaaaagaagaactgggtggaaa gaaatagctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttc tcccggactccgggtaaatga
2582 H4L12
Heavy chain
full length QVQLQQSGPG LVKPSQTLSL TCAISGDSVS SNSAAWNWIR QSPSRGLEWL GRTYYRSKWY amino acid NDYAVSVKSR ITINPDTSKN QLSLQLNSVT PEDTAVYYCA GGRGNIDLPS YFDFWSQGTL
VTVSSRASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSWTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCP RGPTIKPCPP CKCPAPNLLG GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED lYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2583 H4L12 caggtacagctgcagcagtcaggtccaggactggtgaagccctcgcagaccctctcactcacctg
Heavy chain tgccatctccggggacagtgtctctagcaacagtgctgcttggaactggatcaggcagtccccat variable cgagaggccttgagtggctgggaaggacatactacaggtccaagtggtataatgattatgcagta region tctgtgaaaagtcgaataaccatcaaccctgacacatccaagaaccagttgtccctgcaactgaa nucleic acid ctctgtgactcccgaggacacggctgtgtattactgtgcgggagggaggggaaatatcgatctac cctcatactttgacttctggagccagggcaccctggtcaccgtctcctctaga
2584 H4L12
Heavy chain
variable QVQLQQSGPG LVKPSQTLSL TCAISGDSVS SNSAAWNWIR QSPSRGLEWL GRTYYRSKWY region amino NDYAVSVKSR ITINPDTSKN QLSLQLNSVT PEDTAVYYCA GGRGNIDLPS YFDFWSQGTL acid VTVSSR
2585 H4L12
Heavy chain
ggg gac agt gtc tct age aac agt get get
CDR1 nucleic
acid
2586 H4L12
Heavy chain
CDR1 amino
acid GDSVSSNSAA
2587 H4L12 aca tac tac agg tec aag tgg tat aat Heavy chain
CDR2 nucleic
acid
2588 H4L12
Heavy chain
CDR2 amino
acid TYYRSKWYN
2589 H4L12
Heavy chain
gcg gga ggg agg gga aat ate gat eta ccc tea tac ttt gac ttc CDR3 nucleic
acid
2590 H4L12
Heavy chain
CDR3 amino
acid AGGRGNIDLPSYFDF
2591 H4L12 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcccgtggtattcggcggagggaccaagctgaccgtcctag ctagcacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2592 H4L12 SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER
Light chain FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDPWFG GGTKLTVLAS TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC*
2593 H4L12 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcccgtggtattcggcggagggaccaagctgaccgtcctag ctagc
2594 H4L12
Light chain
variable
region amino SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER acid FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDPWFG GGTKLTVLAS
2595 H4L12
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2596 H4L12
Light chain
CDR1 amino
acid NIGSKS
2597 H4L12
Light chain
tat gat age
CDR2 nucleic
acid
2598 H4L12
Light chain
CDR2 amino
acid YDS
2599 H4L12
Light chain cag gtg tgg gat agt agt agt gat ccc gtg gta
CDR3 nucleic acid
2600 H4L12
Light chain
CDR3 amino
acid QVWDSSSDPW
2601 H5L11 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactatgcacagaagctccag nucleic acid ggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgac atctgacgacacggccgtttattactgtgcgagagagaatgtggtggtgactgctacacaaattg aaaattggttcgacccctggggccagggaaccctggtcaccgtctcctctagagcctccaccaag ggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgacca gcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtg accgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaa caccaaggtggacaagaaagttgagcccaaatcttgtcccagagggcccacaatcaagccctgtc ctccatgcaaatgcccagcacctaacctcttgggtggaccatccgtcttcatcttccctccaaag atcaaggatgtactcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcga ggatgacccagatgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacac aaacccatagagaggattacaacagtactctccgggtggtcagtgccctccccatccagcaccag gactggatgagtggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcga gagaaccatctcaaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccag aagaagagatgactaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagac atttacgtggagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcct ggactctgatggttcttactteatgtacagcaagctgagagtggaaaagaagaactgggtggaaa gaaatagctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttc tcccggactccgggtaaatga
2602 H5L11 QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW I SAYNGNTNY
Heavy chain AQKLQGRVTM TTDTSTSTAY MELRSLTSDD TAVYYCAREN VWTATQIEN WFDPWGQGTL full length VTVSSRASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP amino acid AVLQSSGLYS LSSWTVPSS SLGTQTYICN VNHKP SNTKV DKKVEPKSCP RGPTIKPCPP
CKCPAPNLLG GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2603 H5L11 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactatgcacagaagctccag region ggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgac nucleic acid atctgacgacacggccgtttattactgtgcgagagagaatgtggtggtgactgctacacaaattg aaaattggttcgacccctggggccagggaaccctggtcaccgtctcctctaga
2604 H5L11
Heavy chain
variable QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW I SAYNGNTNY region amino AQKLQGRVTM TTDTSTSTAY MELRSLTSDD TAVYYCAREN VWTATQIEN WFDPWGQGTL acid VTVSSR
2605 H5L11
Heavy chain
ggt tac acc ttt acc age tat ggt
CDR1 nucleic
acid
2606 H5L11
Heavy chain
CDR1 amino
acid GYTFTSYG
2607 H5L11
Heavy chain
ate age get tac aat ggt aac aca
CDR2 nucleic
acid
2608 H5L11 I SAYNGNT Heavy chain
CDR2 amino
acid
2609 H5L11
Heavy chain gcg aga gag aat gtg gtg gtg act get aca caa att gaa aat tgg ttc CDR3 nucleic gac ccc
acid
2610 H5L11
Heavy chain
CDR3 amino
acid ARENWVTATQIENWFDP
2611 H5L11 tcctatgagctgactcagccactctcagtgtcagtggccctgggacaggcggccaggattacctg
Light chain tgggggaaacaaccttggatataaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgctggtcatctatagggataacaaccggccctctggcattcctgaccgagtgtctggctccaat nucleic acid tcgggaaacacggccaccctgaccatcagcagagcccaagccggggatgaggctcactattactg tcaggtgtgggacagcagtactgcgatattcggcggagggaccaagctgaccgtcctagctagca cggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcc tctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataa cgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctaca gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaa gtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttaa
2612 H5L11 SYELTQPLSV SVALGQAARI TCGGNNLGYK SVHWYQQKPG QAPVLVIYRD NNRPSGIPDR
Light chain VSGSNSGNTA TLTISRAQAG DEAHYYCQVW DSSTAIFGGG TKLTVLASTV AAPSVFIFPP full length SDEQLKSGTA SWCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT amino acid LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC*
2613 H5L11 tcctatgagctgactcagccactctcagtgtcagtggccctgggacaggcggccaggattacctg
Light chain tgggggaaacaaccttggatataaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgctggtcatctatagggataacaaccggccctctggcattcctgaccgagtgtctggctccaat region tcgggaaacacggccaccctgaccatcagcagagcccaagccggggatgaggctcactattactg nucleic acid tcaggtgtgggacagcagtactgcgatattcggcggagggaccaagctgaccgtcctagctagc
2614 H5L11
Light chain
variable
region amino SYELTQPLSV SVALGQAARI TCGGNNLGYK SVHWYQQKPG QAPVLVIYRD NNRPSGIPDR acid VSGSNSGNTA TLTISRAQAG DEAHYYCQVW DSSTAIFGGG TKLTVLAS
2615 H5L11
Light chain
aac ctt gga tat aaa agt
CDR1 nucleic
acid
2616 H5L11
Light chain
CDR1 amino
acid NLGYKS
2617 H5L11
Light chain
agg gat aac
CDR2 nucleic
acid
2618 H5L11
Light chain
CDR2 amino
acid RDN
2619 H5L11
Light chain
cag gtg tgg gac age agt act gcg ata
CDR3 nucleic
acid
2620 H5L11
Light chain
CDR3 amino
acid QVWDSSTAI 2621 H5L12 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcccctggacaag full length ggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactatgcacagaagctccag nucleic acid ggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgac atctgacgacacggccgtttattactgtgcgagagagaatgtggtggtgactgctacacaaattg aaaattggttcgacccctggggccagggaaccctggtcaccgtctcctctagagcctccaccaag ggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgacca gcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtg accgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaa caccaaggtggaca gaaagttgagccc a tcttgtcccagagggcccac atcaagccctgtc ctccatgcaaatgcccagcacctaacctcttgggtggaccatccgtcttcatcttccctccaaag atcaaggatgtactcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcga ggatgacccagatgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacac aaacccatagagaggattacaacagtactctccgggtggtcagtgccctccccatccagcaccag gactggatgagtggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcga gagaaccatctcaaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccag aagaagagatgactaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagac atttacgtggagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcct ggactctgatggttcttactteatgtacagcaagctgagagtggaaaagaagaactgggtggaaa gaaatagctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttc tcccggactccgggtaaatga
2622 H5L12 QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW I SAYNGNTNY
Heavy chain AQKLQGRVTM TTDTSTSTAY MELRSLTSDD TAVYYCAREN VWTATQIEN WFDPWGQGTL full length VTVSSRASTK GPSVFPLAPS SKSTSGGTAA IGCLVKDYFP EPVTVSWNSG ALTSGVHTFP amino acid AVLQSSGLYS LSSWTVPSS SLGTQTYICN VNHKP SNTKV DKKVEPKSCP RGPTIKPCPP
CKCPAPNLLG GPSVFIFPPK IKDVLMISLS PIVTCVWDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY NSTLRWSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN WVERNSYSCS WHEGLHNHH TTKSFSRTPG K*
2623 H5L12 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctg
Heavy chain caaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcccctggacaag variable ggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactatgcacagaagctccag region ggcagagtcaccatgaccacagacacatccacgagcacagcctacatggagctgaggagcctgac nucleic acid atctgacgacacggccgtttattactgtgcgagagagaatgtggtggtgactgctacacaaattg aaaattggttcgacccctggggccagggaaccctggtcaccgtctcctctaga
2624 H5L12
Heavy chain
variable QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW I SAYNGNTNY region amino AQKLQGRVTM TTDTSTSTAY MELRSLTSDD TAVYYCAREN VWTATQIEN WFDPWGQGTL acid VTVSSR
2625 H5L12
Heavy chain
ggt tac acc ttt acc age tat ggt
CDR1 nucleic
acid
2626 H5L12
Heavy chain
CDR1 amino
acid GYTFTSYG
2627 H5L12
Heavy chain
ate age get tac aat ggt aac aca
CDR2 nucleic
acid
2628 H5L12
Heavy chain
CDR2 amino
acrd I SAYNGNT
2629 H5L12
Heavy chain gcg aga gag aat gtg gtg gtg act get aca caa att gaa aat tgg ttc CDR3 nucleic gac ccc
acid 2630 H5L12
Heavy chain
CDR3 amino
acid ARENWVTATQIENWFDP
2631 H5L12 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcccgtggtattcggcggagggaccaagctgaccgtcctag ctagcacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2632 H5L12 SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER
Light chain FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDPWFG GGTKLTVLAS TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2633 H5L12 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcccgtggtattcggcggagggaccaagctgaccgtcctag ctagc
2634 H5L12
Light chain
variable
region amino SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER acid FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDPWFG GGTKLTVLAS
2635 H5L12
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2636 H5L12
Light chain
CDR1 amino
acid NIGSKS
2637 H5L12
Light chain
tat gat age
CDR2 nucleic
acid
2638 H5L12
Light chain
CDR2 amino
acid YDS
2639 H5L12
Light chain
cag gtg tgg gat agt agt agt gat ccc gtg gta
CDR3 nucleic
acid
2640 H5L12
Light chain
CDR3 amino
acid QVWDSSSDPW
2641 H6L13 caggtgcagctggtgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtctcctg
Heavy chain caaggcttctggaggcaccttcagcagctatgctatcagctgggtgcgacaggcccctggacaag full length ggcttgagtggatgggagggatcatccctatctttggtacagcaaactacgcacagaagttccag nucleic acid ggcagagtcacgattaccgcggacgaatccacgagcacagcctacatggagctgagaagcctgag atctgaggacgcggccgtgtattactgtgcgagagggacgggtgatagtagtggttattattacg tctactggggtcagggaaccctggtcaccgtctcctctagagcctccaccaagggcccatcggtc ttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaa ggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcaca ccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtgga caagaaagttgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaat gcccagcacctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgta ctcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccaga tgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagag aggattacaacagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagt ggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctc aaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatga ctaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggag tggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatgg ttcttacttcatgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctact cctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccg ggtaaatga
2642 H6L13 QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGG I IP IFGTANY
Heavy chain AQKFQGRVTI TADESTSTAY MELRSLRSED AAVYYCARGT GDSSGYYYVY WGQGTLVTVS full length SRASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ amino acid SSGLYSLSSV VTVPSSSLGT QTYICNVNHK P S TKVDKKV EPKSCPRGPT IKPCPPCKCP
APNLLGGPSV FIFPPKIKDV LMISLSPIVT CVWDVSEDD PDVQISWFVN NVEVHTAQTQ THREDYNSTL RWSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV LPPPEEEMTK KQVTLTCMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL RVEKKNWVER NSYSCSWHE GLHNHHTTKS FSRTPGK*
2643 H6L13 caggtgcagctggtgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtctcctg
Heavy chain caaggcttctggaggcaccttcagcagctatgctatcagctgggtgcgacaggcccctggacaag variable ggcttgagtggatgggagggatcatccctatctttggtacagcaaactacgcacagaagttccag region ggcagagtcacgattaccgcggacgaatccacgagcacagcctacatggagctgagaagcctgag nucleic acid atctgaggacgcggccgtgtattactgtgcgagagggacgggtgatagtagtggttattattacg tctactggggtcagggaaccctggtcaccgtctcctctaga
2644 H6L13
Heavy chain
variable QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGG I IP IFGTANY region amino AQKFQGRVTI TADESTSTAY MELRSLRSED AAVYYCARGT GDSSGYYYVY WGQGTLVTVS acid SR
2645 H6L13
Heavy chain
gga ggc acc ttc age age tat get
CDR1 nucleic
acid
2646 H6L13
Heavy chain
CDR1 amino
acid GGTFSSYA
2647 H6L13
Heavy chain
ate ate cct ate ttt ggt aca gca
CDR2 nucleic
acid
2648 H6L13
Heavy chain
CDR2 amino
acid IIPIFGTA
2649 H6L13
Heavy chain
gcg aga ggg acg ggt gat agt agt ggt tat tat tac gtc tac
CDR3 nucleic
acid
2650 H6L13
Heavy chain
CDR3 amino
acid ARGTGDSSGYYYVY
Figure imgf000214_0001
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtgga caagaaagttgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccatgcaaat gcccagcacctaacctcttgggtggaccatccgtcttcatcttccctccaaagatcaaggatgta ctcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatgacccaga tgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacacaaacccatagag aggattacaacagtactctccgggtggtcagtgccctccccatccagcaccaggactggatgagt ggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaaccatctc aaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaagagatga ctaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagacatttacgtggag tggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcctggactctgatgg ttcttacttcatgt cagcaagctgagagtggaaaagaagaactgggtggaaagaaatagctact cctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttctcccggactccg ggtaaatga
2662 H6L14 QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGG I IP IFGTANY
Heavy chain AQKFQGRVTI TADESTSTAY MELRSLRSED AAVYYCARGT GDSSGYYYVY WGQGTLVTVS full length SRASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ amino acid SSGLYSLSSV VTVPSSSLGT QTYICNVNHK P SNTKVDKKV EPKSCPRGPT IKPCPPCKCP
APNLLGGPSV FIFPPKIKDV LMISLSPIVT CVWDVSEDD PDVQISWFVN NVEVHTAQTQ THREDYNSTL RWSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV LPPPEEEMTK KQVTLTCMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL RVEKKNWVER NSYSCSWHE GLHNHHTTKS FSRTPGK*
2663 H6L14 caggtgcagctggtgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtctcctg
Heavy chain caaggcttctggaggcaccttcagcagctatgctatcagctgggtgcgacaggcccctggacaag variable ggcttgagtggatgggagggatcatccctatctttggtacagcaaactacgcacagaagttccag region ggcagagtcacgattaccgcggacgaatccacgagcacagcctacatggagctgagaagcctgag nucleic acid atctgaggacgcggccgtgtattactgtgcgagagggacgggtgatagtagtggttattattacg tctactggggtcagggaaccctggtcaccgtctcctctaga
2664 H6L14
Heavy chain
variable QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGG I IP IFGTANY region amino AQKFQGRVTI TADESTSTAY MELRSLRSED AAVYYCARGT GDSSGYYYVY WGQGTLVTVS acid SR
2665 H6L14
Heavy chain
gga ggc acc ttc age age tat get
CDR1 nucleic
acid
2666 H6L14
Heavy chain
CDR1 amino
acid GGTFSSYA
2667 H6L14
Heavy chain
ate ate cct ate ttt ggt aca gca
CDR2 nucleic
acid
2668 H6L14
Heavy chain
CDR2 amino
acid IIPIFGTA
2669 H6L14
Heavy chain
gcg aga ggg acg ggt gat agt agt ggt tat tat tac gtc tac
CDR3 nucleic
acid
2670 H6L14
Heavy chain
CDR3 amino
acid ARGTGDSSGYYYVY
2671 H6L14 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg full length tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcatgtggtattcggcggagggaccaagctgaccgtcctag ctagcacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2672 H6L14 SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVH YQQKPG QAPVLVIYYD SDRPSGIPER
Light chain FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDHWFG GGTKLTVLAS TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC *
2673 H6L14 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcatgtggtattcggcggagggaccaagctgaccgtcctag ctagc
2674 H6L14
Light chain
variable
region amino SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER acid FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDHWFG GGTKLTVLAS
2675 H6L14
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2676 H6L14
Light chain
CDR1 amino
acid NIGSKS
2677 H6L14
Light chain
tat gat age
CDR2 nucleic
acid
2678 H6L14
Light chain
CDR2 amino
acid YDS
2679 H6L14
Light chain
cag gtg tgg gat agt agt agt gat cat gtg gta
CDR3 nucleic
acid
2680 H6L14
Light chain
CDR3 amino
acid QVWDSSSDHW
2681 H7L13 gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgaaactctcctg
Heavy chain tgcagcctctgggttcaccttcagtggctctgctatgcactgggtccgccaggcttccgggaaag full length ggctggagtgggttggccgtattagaagcaaagctaacagttacgcgacagcatatgctgcgtcg nucleic acid gtgaaaggcaggttcaccatctccagagatgattcaaggaacacggcgtatctgcaaatgaacag cctgaaaaccgaggacacggccgtgtattactgttctagcccccaggcgacggtgacttcggtgg ggatggccccctggggccagggaaccctggtcaccgtctcctctagagcctccaccaagggccca tcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcct ggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcg tgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtg ccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaa ggtggacaagaaagttgagcccaaatcttgtcccagagggcccacaatcaagccctgtcctccat gcaaatgcccagcacctaacctcttgggtggaccatccgtctteatcttecctccaaagatcaag gatgtactcatgatctccctgagccccatagtcacatgtgtggtggtggatgtgagcgaggatga cccagatgtccagatcagctggtttgtgaacaacgtggaagtacacacagctcagacacaaaccc atagagaggattacaacagtactctccgggtggtcagtgccctccccatccagcaccaggactgg atgagtggcaaggagttcaaatgcaaggtcaacaacaaagacctcccagcgcccatcgagagaac catctcaaaacccaaagggtcagtaagagctccacaggtatatgtcttgcctccaccagaagaag agatgactaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagacatttac gtggagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcctggactc tgatggttcttacttcatgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaata gctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttctcccgg actccgggtaaatga
2682 H7L13 EVQLVESGGG LVQPGGSLKL SCAASGFTFS GSAMHWVRQA SGKGLEWVGR IRSKANSYAT
Heavy chain AYAASVKGRF TISRDDSRNT AYLQMNSLKT EDTAVYYCSS PQATVTSVGM AP GQGTLVT full length VSSRASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV amino acid LQSSGLYSLS SWTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCPRG PTIKPCPPCK
CPAPNLLGGP SVFIFPPKIK DVLMISLSPI VTCWVDVSE DDPDVQISWF VNNVEVHTAQ TQTHREDYNS TLRWSALPI QHQDWMSGKE FKCKVNNKDL PAPIERTISK PKGSVRAPQV YVLPPPEEEM TKKQVTLTCM VTDFMPED IY VE TNNGKTE LNYKNTEPVL DSDGSYFMYS KLRVEKKNWV ERNSYSCSW HEGLHNHHTT KSFSRTPGK*
2683 H7L13 gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgaaactctcctg
Heavy chain tgcagcctctgggttcaccttcagtggctctgctatgcactgggtccgccaggcttccgggaaag variable ggctggagtgggttggccgtattagaagcaaagctaacagttacgcgacagcatatgctgcgtcg region gtgaaaggcaggttcaccatctccagagatgattcaaggaacacggcgtatctgcaaatgaacag nucleic acid cctgaaaaccgaggacacggccgtgtattactgttctagcccccaggcgacggtgacttcggtgg ggatggccccctggggccagggaaccctggtcaccgtctcctctaga
2684 H7L13
Heavy chain
variable EVQLVESGGG LVQPGGSLKL SCAASGFTFS GSAMHWVRQA SGKGLEWVGR LRSKANSYAT region amino AYAASVKGRF TISRDDSRNT AYLQMNSLKT EDTAVYYCSS PQATVTSVGM APWGQGTLVT acid VSSR
2685 H7L13
Heavy chain
ggg ttc acc ttc agt ggc tct get
CDR1 nucleic
acid
2686 H7L13
Heavy chain
CDR1 amino
acid GFTFSGSA
2687 H7L13
Heavy chain
att aga age aaa get aac agt tac gcg aca
CDR2 nucleic
acid
2688 H7L13
Heavy chain
CDR2 amino
acid IRSKANSYAT
2689 H7L13
Heavy chain
tct age ccc cag gcg acg gtg act teg gtg ggg atg gec ccc
CDR3 nucleic
acid
2690 H7L13
Heavy chain
CDR3 amino
acid SSPQATVTSVGMAP
2691 H7L13 gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctc
Light chain ctgcagggccagtcagagtgttagcagcagctacttagcctggtaccagcagaaacctggccagg full length ctcccaggctcctcatctatggtgcatccagcagggccactggcatcccagacaggttcagtggc nucleic acid agtgggtctgggacagacttcactctcaccatcagcagactggagcctgaagattttgcagtgta ttactgtcagcagtatggtagctcaccgtacacttttggcggagggaccaaggtggagatcaaag ctagcacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca
Figure imgf000218_0001
agatgactaagaaacaggtcactctgacctgcatggtcacagacttcatgcctgaagacatttac gtggagtggaccaacaacgggaaaacagagctaaactacaagaacactgaaccagtcctggactc tgatggttcttacttcatgtacagcaagctgagagtggaaaagaagaactgggtggaaagaaata gctactcctgttcagtggtccacgagggtctgcacaatcaccacacgactaagagcttctcccgg actccgggtaaatga
2702 H7L14 EVQLVESGGG LVQPGGSLKL SCAASGFTFS GSAMHWVRQA SGKGLEWVGR IRSKANSYAT
Heavy chain AYAASVKGRF TISRDDSRNT AYLQMNSLKT EDTAVYYCSS PQATVTSVGM APWGQGTLVT full length VSSRASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV amino acid LQSSGLYSLS SWTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCPRG PTIKPCPPCK
CPAPNLLGGP SVFIFPPKIK DVLMISLSPI VTCWVDVSE DDPDVQISWF VNNVEVHTAQ TQTHREDYNS TLRWSALPI QHQDWMSGKE FKCKVNNKDL PAPIERTISK PKGSVRAPQV YVLPPPEEEM TKKQVTLTCM VTDFMPED IY VEWTNNGKTE LNYKNTEPVL DSDGSYFMYS KLRVEKKNWV ERNSYSCSW HEGLHNHHTT KSFSRTPGK*
2703 H7L14 gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgaaactctcctg
Heavy chain tgcagcctctgggttcaccttcagtggctctgctatgcactgggtccgccaggcttccgggaaag variable ggctggagtgggttggccgtattagaagcaaagctaacagttacgcgacagcatatgctgcgtcg region gtgaaaggcaggttcaccatctccagagatgattcaaggaacacggcgtatctgcaaatgaacag nucleic acid cctgaaaaccgaggacacggccgtgtattactgttctagcccccaggcgacggtgacttcggtgg ggatggccccctggggccagggaaccctggtcaccgtctcctctaga
2704 H7L14
Heavy chain
variable EVQLVESGGG LVQPGGSLKL SCAASGFTFS GSAMHWVRQA SGKGLEWVGR IRSKANSYAT region amino AYAASVKGRF TISRDDSRNT AYLQMNSLKT EDTAVYYCSS PQATVTSVGM APWGQGTLVT acid VSSR
2705 H7L14
Heavy chain
ggg ttc acc ttc agt ggc tct get
CDR1 nucleic
acid
2706 H7L14
Heavy chain
CDR1 amino
acid GFTFSGSA
2707 H7L14
Heavy chain
att aga age aaa get aac agt tac gcg aca
CDR2 nucleic
acid
2708 H7L14
Heavy chain
CDR2 amino
acid IRSKANSYAT
2709 H7L14
Heavy chain
tct age ccc cag gcg acg gtg act teg gtg ggg atg gee ccc
CDR3 nucleic
acid
2710 H7L14
Heavy chain
CDR3 amino
acid SSPQATVTSVGMAP
2711 H7L14 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagcc ggccaggcccctg full length tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac nucleic acid tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg tcaggtgtgggatagtagtagtgatcatgtggtattcggcggagggaccaagctgaccgtcctag ctagcacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgga actgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggt ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcc tgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtta a
2712 H7L14 SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER Light chain FSGSNSGNTA TL I SRVEAG DEADYYCQVW DSSSDHWFG GGTKLTVLAS TVAAPSVFIF full length PPSDEQLKSG TASWCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST amino acid LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC*
2713 H7L14 tcctatgtgctgactcagccaccctcagtgtcagtggccccaggaaagacggccaggattacctg
Light chain tgggggaaacaacattggaagtaaaagtgtgcactggtaccagcagaagccaggccaggcccctg variable tgctggtcatctattatgatagcgaccggccctcagggatccctgagcgattctctggctccaac region tctgggaacacggccaccctgaccatcagcagggtcgaagccggggatgaggccgactattactg nucleic acid tcaggtgtgggatagtagtagtgatcatgtggtattcggcggagggaccaagctgaccgtcctag ctagc
2714 H7L14
Light chain
variable
region amino SYVLTQPPSV SVAPGKTARI TCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER acid FSGSNSGNTA TLT I SRVEAG DEADYYCQVW DSSSDHWFG GGTKLTVLAS
2715 H7L14
Light chain
aac att gga agt aaa agt
CDR1 nucleic
acid
2716 H7L14
Light chain
CDR1 amino
acid NIGSKS
2717 H7L14
Light chain
tat gat age
CDR2 nucleic
acid
2718 H7L14
Light chain
CDR2 amino
acid YDS
2719 H7L14
Light chain
cag gtg tgg gat agt agt agt gat cat gtg gta
CDR3 nucleic
acid
2720 H7L14
Light chain
CDR3 amino
acid QVWDSSSDHW

Claims

1. A method of identifying one or a plurality of nucleic acid sequences encoding an antibody or antibody fragment from a transcriptome of a subject comprising:
a. screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
b. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
c. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
2. The method of claim 1 further comprising a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
3. The method of claim 2 further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences.
4. The method of claim 2 further comprising:
e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
f. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject;
wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c);
and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
5. The method of any of claims 1 through 4, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
6. The method of any of claims 1 through 5, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
7. The method of any of claims 1 through 6, wherein the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation:
!og2(N)
wherein where Ci is the clone fraction of rearrangement i and N is the total number of
rearrangements.
8. The method of any of claims 1 through 7, wherein the screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
9. The method of any of claims 1 through 8, wherein the screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
10. The method of claim 9, wherein the alignment of clonal sequences comprises performing an immunoSEQ function.
11. The method of any of claims 1 through 10, wherein the sample is a tissue sample from a subject having or suspected as having a hyperproliferative disorder.
12. The method of any of claims 1 through 10, wherein the sample comprises one or more hyperproliferative cells chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
13. A computer-implemented method of detecting the presence of a nucleic acid sequence encoding an antibody or antibody fragment in a transcriptome of a sample, the method comprising: in a system comprising at least one processor and a memory,
a. screening, by the at least one processor, the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
b. calculating, by the at least one processor, a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
c. sorting, by the at least one processor, the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
14. The method of claim 13 further comprising a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
15. The method of claim 14 further comprising repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences
16. The method of claim 14 further comprising:
e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
f. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject;
wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c);
and wherein the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
17. The method of any of claims 13 through 16, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment
(ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a
F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
18. The method of any of claims 13 through 17, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
19. The method of any of claims 13 through 18, wherein the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation:
' Ci log2(Cf
1 "
Iog2 (N)
wherein where Ci is the clone fraction of rearrangement i and N is the total number of
rearrangements.
20. The method of any of claims 16 through 19, wherein the screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
21. The method of any of claims 13 through 20, wherein the screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
22. The method of claim 21, wherein the alignment of clonal sequences comprises performing an immunoSEQ function.
23. The method of any of claims 13 through 22, wherein the sample is a tissue sample from a subject having or suspected as having a hyperproliferative disorder.
24. The method of any of claims 13 through 23, wherein the sample comprises one or more hyperproliferative cells chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
25. The method of claims 1 or 13, wherein the first set of nucleic acids that encode an antibody or antibody fragment encode an antibody capable of binding one or a plurality of cells from the sample and/or subject.
26. A method of compiling a set of nucleic acid sequences encoding an antibody or antibody fragment from a sample, the method comprising:
(a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25; and
(b) repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample.
27. A method of designing an antibody or antibody fragment capable of binding to an epiptope on a cell from a sample, the method comprising:
(a) obtaining at least one a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject from any of the methods of claims 1 through 25; and
(b) repeating set (a) until amassing a plurality of nucleic acid sequences encoding an antibody or antibody fragments from a sample;
(c) cloning the one or plurality of nucleic acids in a vector or synthesizing the antibody from solid state chemical synthesis; and
if the one or plurality of nucleic acid sequences are cloned into a vector, (d) transforming the vector into a host cell and (e) allowing a time period to elapse sufficient for the host cell to recombinantly produce the encoded antibody or antibody fragment.
28. A composition comprising an antibody or antibody fragment comprising at least one CDR sequence obtained from performing any of the methods of claims 1 through 25
29. A library of antibodies comprising at least one amino acid sequence obtaining from perfroming the methods of any of claim 1 through 27.
30. A non-transitory computer program product encoded on compueter-readbale storage medium comprising instructions for:
a. screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
b. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
c. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
31. The non-transitory computer program product of claim 30 further comprising instructions for a step of: (d) identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from the first set of nucleic acid sequences after performing the step of sorting.
32. The non-transitory computer program product of claim 31 further comprising instruction for repeating the step of identifying a nucleic acid sequence encoding at least one CDR of a variable chain and compiling a plurality of CDR sequences.
33. The non-transitory computer program product of claim 31 further comprising instructions for:
e. screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments, wherein the nucleic acid sequences encoding one or a plurality of antibody fragments comprise a first set of abundantly expressed nucleic acid sequences and a second set of uncommonly expressed nucleic acid sequences;
f. calculating a clonality score corresponding to one or a plurality of the nucleic acid sequences in each of the first set and second set of nucleic acid sequences
g. sorting the nucleic acid sequence into the first set and the second set of nucleic acid sequences based upon the clonality score.
h. obtaining a set of abundantly expressed nucleic acid sequences encoding an antibody fragment from the series of control subjects and comparing the nucleic acid sequences of the first set from the series of control subjects with the first set of nucleic acid sequences from the subject;
wherein steps (e) through (h) are performed prior to, contemporaneously with or after steps (a) through (c);
and wherein the step of identifying a nucleic acid sequence encoding at least one complementarity determining region (CDR) of a variable chain from a transcriptome of the subject is based upon the step of comparing sets of abundantly expressed nucleic acid sequences from step (h).
34. The non-transitory computer program product of claim 31, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of an antibody fragments chosen from: a Fc portion of an antibody, single-chain variable fragment (ScFv) of an antibody, an Fv portion of the antibody, a Fab fragment of the antibody, a F(ab')2 fragment of an antibody, a Fd fragment of an antibody, an IgG-like fragment of the antibody, a variable chain of the antibody, and a constant region of the antibody.
35. The non-transitory computer program product of claims 30 through 34, wherein the first set of abundantly expressed nucleic acid sequences from the subject encodes one or a combination of encodes one of a combination of variable heavy chain and/or variable light chain portions of the antibody.
36. The non-transitory computer program product of any of claims 30 - 35, wherein the step of screening comprises screening for nucleic acid sequences encoding one or a plurality of antibody fragments that are B cell receptor (BCR) sequences and the step of calculating the clonality score of the antibody is determined, at least in part, by the following equation:
Figure imgf000228_0001
wherein where Ci is the clone fraction of rearrangement i and N is the total number of rearrangements.
37. The non-transitory computer program product of claims 30 through 36, wherein the screening the transcriptome of a series of control subjects for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing FASTQ, MIXCR, and VDJtools functions on the transcriptome data.
38. The non-transitory computer program product of claims 30 through 37, wherein the screening the transcriptome of the subject for nucleic acid sequences encoding one or a plurality of antibody fragments comprises performing an alignment of clonal sequences.
39. The non-transitory computer program product of claim 38, wherein the alignment of clonal sequences comprises performing an immunoSEQ function.
40. The non-transitory computer program product of any claims 30 through 39, wherein the sample is a tissue sample from a subject having a hyperproliferative cell disorder.
41. The non-transitory computer program product of claims 30 through 40, wherein the sample is a cancer tissue chosen from: glioblastoma multiforme, lower grade glioma, lung adenocarcinoma, lung squamous carcinoma, pancreatic adenocarcinoma, and skin cutaneous carcinoma.
42. An antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising:
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2206, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2208, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2210, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2216, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2218, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2220;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2226, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID
NO:2228, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
NO:2230, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2236, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2238, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2240;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2246, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2248, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2250, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2256, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2258, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2260;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2266, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2268, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2270, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2276, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2278, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2280;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2286, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2288, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2290, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2296, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2298, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2300;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2306, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2308, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2310, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2316, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2318, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2320;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2326 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2328, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2330 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2336, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2338, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2340;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2346, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2348, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2350, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2356, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2358, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2360;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2366, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2368, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2370, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2376, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2378, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2380;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2386, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2388, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2390, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2396, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2398, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2400;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2406, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2408, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2410, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2416, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2418, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2420;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2426 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2428 a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2430, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2436, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2438, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2440;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2446, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2448, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2450, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2456, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2458, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2460;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2466, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2468, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2470, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2476, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2478, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2480;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2486, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2488, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2490, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2496, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2498, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2500;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2506, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2508, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2510, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2516, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2518, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2520;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2526, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2528, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2530 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2536 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2538, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2540
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2546 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2548, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2550 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2556 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2558, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2560
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2566 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2568 a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2570 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2576 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2578, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2580
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2586 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2588 a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2590 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2596 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2598 and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2600
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2606 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2608 a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2610 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2616 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2618 and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2620 a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2626, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID
NO:2628 a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2630 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2636 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2638 and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID
NO:2640;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2646, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2648, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2650, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2656, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2658, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2660;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2666, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2668, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2670, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2676, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2678, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2680;
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2686, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2688, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2690, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2696, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2698, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2700; and
a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID
NO:2706 a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2708 a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2710 a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:2716 a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:2718, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:2720.
43. An antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising:
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2204, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2204, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2214, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2214;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2224, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2224, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2234, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2234;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2244, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2244, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2254, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2254;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2264, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2264, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2274, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2274;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2284, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2284, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2294, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2294;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2304, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2304, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2314, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2314;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2324, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2324, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2334, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2334;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2344, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2344, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2354, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2354;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2364, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2364, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2374, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2374;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2384, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2384, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2394, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2394;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2404, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2404, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2414, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2414;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2424, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2424, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2434, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2434;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2444, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2444, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2454, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2454;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2464, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2464, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2474, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2474;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2484, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2484, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2494, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2494;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2504, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2504, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2514, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2514;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2524, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2524, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2534, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2534;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2544, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2544, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2554, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2554;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2564, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2564, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2574, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2574; a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2584, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2584, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2594, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2594;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2604, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2604, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2614, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2614;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2624, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2624, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2634, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2634;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2644, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2644, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2654, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2654;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2664, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2664, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2674, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2674;
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2684, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2684, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2694, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2694; and
a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2704, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2704, an/or a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 2714, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2714.
44. An antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, comprising:
a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2202, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2202, and/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2212, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2212; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2222, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2222, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2232, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2232; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2242, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2242, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2252, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2252; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2262, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2262, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2272, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2272; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2282, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2282, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2292, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2292; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2302, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2302, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2312, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2312; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2322, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2322, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2332, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2332; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2342, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2342, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2352, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2352; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2362, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2362, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2372, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2372; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2382, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2382, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2392, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2392; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2402, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2402, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2412, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2412; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2422, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2422, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2432, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2432; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2442, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2442, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2452, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2452; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2462, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2462, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2472, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2472; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2482, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2482, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2492, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2492; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2502, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2502, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2512, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2512; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2522, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2522, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2532, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2532; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2542, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2542, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2552, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2552; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2562, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2562, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2572, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2572; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2582, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2582, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2592, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2592; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2602, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2602, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2612, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2612; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2622, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2622, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2632, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2632; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2642, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2642, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2652, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2652; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2662, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2662, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2672, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2672; a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2682, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2682, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2692, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2692; and
a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 2702, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2702, an/or a light chain comprising an amino acid sequence set forth in SEQ ID NO: 2712, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2712.
45. The antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, of claim 44, wherein
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2202, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2212;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2222, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2232;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2242, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2252;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2262, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2272;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2282, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2292;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2302, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2312;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2322, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2332;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2342, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2352;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2362, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2372;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2382, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2392;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2402, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2412; the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2422, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2432;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2442, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2452;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2462, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2472;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2482, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2492;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2502, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2512;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2522, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2532;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2542, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2552;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2562, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2572;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2582, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2592;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2602, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2612;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2622, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2632;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2642, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2652;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2662, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2672;
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2682, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2692; or
the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 2702, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 2712.
46. The antibody, or antigen-binding fragment thereof, of any one of claims 42-45, wherein the fragment is selected from the group consisting of a Fab, a Fab', a F(ab')2, an Fv, a domain antibody, and a single-chain antibody.
47. The antibody, or antigen-binding fragment thereof, of any one of claims 42-46, wherein the antibody, or antigen binding portion fragment thereof, is classified as an isotype selected from the group consisting of an IgG, an IgM, an IgD, an IgA, and an IgE.
48. An antibody, or antigen-binding fragment thereof, that binds to a tumor tissue, that competes with the antibody, or antigen binding portion thereof, of any one of the preceding claims.
49. An antibody, or antigen-binding fragment thereof, of any one of claims 42-48, wherein the antibody, or antigen binding portion thereof, is humanized.
50. A pharmaceutical composition comprising the antibody, or antigen binding fragment thereof, of any one of claims 42-49, and a pharmaceutically acceptable carrier.
51. The pharmaceutical composition of claim 50, which is lyophilized.
52. An isolated nucleic acid encoding an antibody, or antigen-binding fragment thereof, of any one of claims 42-48.
53. A vector comprising an isolated nucleic acid of claim 52.
54. A host cell comprising a vector of claim 53.
55. The host cell of claim 54, wherein the host cell is a prokaryotic cell or a eukaryotic cell.
56. The host cell of claim 55, wherein the eukaryotic cell is a protist cell, an animal cell, a plant cell, a fungal cell, a yeast cell, a mammalian cell, an avian cell, or an insect cell.
57. The host cell of claim 56, wherein the mammalian cell is a CHO cell or a COS cell.
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