HK40104849A - Monoclonal antibodies against lilrb1 for diagnostic and therapeutic use - Google Patents

Description

Monoclonal antibodies against LILRB1 for diagnostic and therapeutic purposes

Priority Statement

This application claims the benefit of priority to U.S. Provisional Application Serial Nos. 63/057,601 and 63/124,516, filed on July 28, 2020 and December 11, 2020, respectively, the entire contents of which are hereby incorporated by reference.

References to sequence lists

This application contains a sequence list that has been submitted via EFS-Web in ASCII format and is incorporated herein by reference in its entirety. The ASCII text created on July 23, 2021, is named UTFH_P0370WO_ST25.txt and has a size of 319 kilobytes.

Invention Field

This disclosure generally relates to the fields of medicine, oncology, immunology, and immuno-oncology. More specifically, this disclosure relates to agonist and antagonist antibodies that bind to LILRB1 and methods of using said agonist and antagonist antibodies.

Background Technology

NK cells play a crucial role in anticancer immunity, and their function against cancer cells can be enhanced by conjugating activating receptors or blocking inhibitory receptors.¹ Among activating receptors, FcγRIII (CD16) plays a key role in antibody-dependent cytotoxicity (ADCC) induced by therapeutic monoclonal antibodies for the treatment of hematologic malignancies (rituximab for lymphoma and daratumumab for multiple myeloma) and metastatic solid tumors (cetuximab and trastuzumab)). ^²³ Antibodies conjugating activating receptors such as NKG2D and NKp46 have also shown NK-dependent tumor immunity in preclinical studies.^⁴⁵ Importantly, it has also been demonstrated that antibodies blocking inhibitory receptors such as KIR and NKG2A on NK cells can enhance NK cell function against cancer cells. ^⁶⁷ Therefore, developing antibodies targeting immune receptors on NK cells could provide novel cancer immunotherapy strategies.

LILRB1, an ITIM-containing receptor, is expressed on a variety of human immune cells. These include all B cells, monocytes and macrophages, dendritic cells (DCs), and subsets of NK cells and T cells. LILRB1 ligands, including MHC class I molecules, activate LILRB1 and transduce negative signals that downregulate immune responses.^⁸ The percentage of LILRB1 ⁺ NK cells in patients with advanced prostate ^and breast cancer is significantly higher than that in healthy donors or patients with localized cancer.^{^9-11} Using in vitro models, blocking LILRB1 signaling in immune cells activates NK cell activity against solid tumors and leukemia,^{^10-12} and activates T cells or macrophages against solid tumors. ^{^13-15} However, it remains unclear whether targeting LILRB1 can “turn on” immune cells in vivo for cancer therapy. Additionally, there are reports of LILRB1 expression on some tumor cells and stimulating immune responses. ^{^16-17} Therefore, it is unclear whether blocking LILRB1 signaling results in activation or inhibition of antitumor immune responses in tumor cells and immune cells.

Summary of the Invention

Therefore, in one aspect, this disclosure provides an isolated monoclonal antibody or its antigen-binding fragment thereof that specifically binds to LILRB1. In some embodiments, the antibody or antigen-binding fragment modulates LILRB1 activation upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragment activates LILRB1 upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragment inhibits LILRB1 activation upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragment specifically blocks the binding of MHC and other ligands to LILRB1 upon binding to LILRB1.

On one hand, the isolated monoclonal antibody or its antigen-binding fragment comprises a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL), wherein the VH and VL comprise clone-paired CDR sequences as shown in Tables 1 and 3; and variants thereof, wherein one or more of the LC-CDRs have one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. The isolated monoclonal antibody or its antigen-binding fragment may be a murine antibody, rodent antibody, rabbit antibody, chimeric antibody, humanized antibody, or human antibody. The isolated monoclonal antibody or its antigen-binding fragment may have a VH chain and a VL chain, wherein the VH chain and the VL chain have an amino acid sequence that is at least 90% or 95% identical to the clone-paired sequences in Tables 6 and 8, respectively. The isolated monoclonal antibody or its antigen-binding fragment may have a VH chain and a VL chain, wherein the VH chain and the VL chain are encoded by nucleic acid sequences that are at least 80% or 90% identical to the clone-paired sequences in Tables 5 and 7, respectively. The isolated monoclonal antibody or its antigen-binding fragment may have a VH chain and a VL chain, wherein the VH chain and the VL chain have the same amino acid sequences as the clones paired in Tables 6 and 8, respectively. The isolated monoclonal antibody or its antigen-binding fragment may have a VH chain and a VL chain, wherein the VH chain and the VL chain are encoded by nucleic acid sequences that are the same as the clones paired in Tables 5 and 7, respectively.

The variant may be one or more of the HC-CDR or LC-CDR having one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. In some embodiments, each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition of the CDR.

In some embodiments, the isolated monoclonal antibody described herein is a chimeric antibody, a humanized antibody, or a human antibody. In some aspects, the humanized antibody has a VH chain and a VL chain, the VH chain and VL chain having amino acid sequences that are at least 90% or 95% identical to the sequences paired with the clones of Hu-176 VH-1 and Hu-176-K as shown in Tables 6 and 8, respectively. In some aspects, the VH chain and VL chain have amino acid sequences that are at least 90% or 95% identical to the sequences paired with the clones of Hu-176 VH-1 (W48L) and Hu-176-K as shown in Tables 6 and 8, respectively. In some aspects, the humanized antibody has a VH chain and a VL chain, the VH chain and the VL chain having amino acid sequences that are at least 90% or 95% identical to the sequences paired with the clones of Hu-176 VH-1 (W48L) and Hu-176-K as shown in Tables 6 and 8, respectively. In some respects, the VH chain and the VL chain have the same amino acid sequences as the clones of Hu-176 VH-1 (W48L) and Hu-176-K shown in Tables 6 and 8, respectively.

In some aspects, the isolated monoclonal antibodies described herein include amino acid modifications in the IgG Fc region. In some aspects, the IgG Fc region includes amino acid modifications at one or more amino acid positions among amino acid positions 234, 235, 297, and 329. In some aspects, the IgG Fc region includes an amino acid substitution at amino acid position 297 where N is replaced with A. In some aspects, the IgG Fc region includes an amino acid substitution at amino acid position 234 where L is replaced with A, an amino acid substitution at amino acid position 235 where L is replaced with A, and an amino acid substitution at amino acid position 329 where P is replaced with G.

On the other hand, this disclosure provides an isolated monoclonal antibody or antigen-binding fragment thereof that competes with antibodies having clonal pairings of heavy chain CDR amino acid sequences and light chain CDR amino acid sequences from Tables 1 and 3 for the same epitope. In some embodiments, the epitope bound by the antibody or antigen-binding fragment is located in the linker region between the D1 and D2 domains of human LILRB1. In some embodiments, this disclosure provides an isolated monoclonal antibody or antigen-binding fragment thereof, wherein, when bound to LILRB1, the monoclonal antibody binds to residues Y76 and R84 of LILRB1.

In some embodiments, the isolated monoclonal antibody described herein belongs to the IgG1, IgG2, IgG3, or IgG4 type. In some embodiments, the antigen-binding fragment described herein is a recombinant ScFv (single-chain variable fragment) antibody, a Fab fragment, an F(ab')2 fragment, or an Fv fragment.

In some respects, the isolated monoclonal antibodies or antigen-binding fragments thereof described herein are conjugated or fused with imaging agents or cytotoxic agents. In some respects, the isolated monoclonal antibodies or antigen-binding fragments thereof described herein are labeled, for example, with fluorescent labels, enzyme-catalyzed labels, or radioactive labels.

On the other hand, a pharmaceutical composition is provided comprising an isolated monoclonal antibody or an antigen-binding fragment thereof as provided herein, and at least one pharmaceutically acceptable carrier.

On the other hand, an isolated nucleic acid is provided, which encodes the isolated monoclonal antibody or its antigen-binding fragment as provided herein.

On the other hand, a vector is provided that comprises the isolated nucleic acid as described herein.

On the other hand, a host cell is provided, which includes the vector as described herein. The host cell may be a mammalian cell. The host cell may be a CHO cell.

On the other hand, a hybridoma is provided that encodes or produces the isolated monoclonal antibodies as described herein.

On the other hand, a method for generating antibodies is provided. The method may include culturing the host cells described herein under conditions suitable for expressing and recovering the antibodies.

On the other hand, a chimeric antigen receptor (CAR) protein is provided, the CAR protein comprising an antigen-binding fragment as provided herein.

On the other hand, an isolated nucleic acid is provided, which encodes a CAR protein as provided herein.

On the other hand, an engineered cell is provided, comprising the isolated nucleic acids as described herein. In some embodiments, the cell is a T cell, an NK cell, or a myeloid cell.

On the other hand, a method is provided for treating a subject's cancer or improving the effect of a subject's cancer, the method comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding fragment thereof as defined herein.

The method can reduce or eradicate the tumor burden of the subject, reduce the number of tumor cells, reduce tumor size, reduce tumor invasion, reduce tumor metastasis, and eradicate the tumor. The cancer can be a solid tumor or a hematologic malignancy.

In some embodiments, the cancer includes solid tumors such as: adrenal cancer, bile duct cancer, bone cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, esophageal cancer, eye cancer, stomach cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, melanoma, Merkel cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pineal tumor, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma, skin cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, and vaginal cancer.

In some implementations, the cancer is a metastatic cancer, a recurrent cancer, or a drug-resistant cancer.

In some embodiments, the cancer includes the following hematologic malignancies: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell leukemia, blastic plasmacytoid dendritic cell vegetations (BPDCN), chronic lymphocytic leukemia (CLL), chronic myeloid monocytic leukemia (CMML), chronic myeloid leukemia (CML), pre-B acute lymphoblastic leukemia (pre-B ALL), diffuse large B-cell lymphoma (DLBCL), extranodal NK/T-cell lymphoma, hairy cell leukemia, and HHV8-associated primary exudative leukemia. Primary CNS lymphoma, plasmablastic lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histocyte-rich B-cell lymphoma, heavy chain disease, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative vegetations, and polycythemia vera.

The antibody or its antigen-binding fragment can be administered intravenously, intra-arterially, intratumorally, or subcutaneously.

In some aspects, the subject's NK cells have been identified as expressing LILRB1. In some aspects, the subject's NK cells have been identified as expressing LILRB1 levels at an increased level relative to a reference level. The reference level may be the average level found in a subset of healthy individuals. In some aspects, the subject's myeloma cells have been identified as not expressing LILRB1.

In some embodiments, the method may further include administering to the subject one or more drugs selected from the group consisting of: topoisomerase inhibitors, anthracycline topoisomerase inhibitors, anthracycline, daunorubicin, nucleoside metabolism inhibitors, cytarabine, hypomethylating agents, low-dose cytarabine (LDAC), combinations of daunorubicin and cytarabine, liposomes of daunorubicin and cytarabine for injection, azacytidine, and decitabine. Abine, all-trans retinoic acid (ATRA), arsenic, arsenic trioxide, histamine dihydrochloride, interleukin-2, aldesleukin, gemtuzumab ozogamicin, FLT-3 inhibitors, midostaurin, clofarabine, farnesyltransferase inhibitors, decitabine, IDH1 inhibitors, ivosidenib, IDH2 inhibitors Formulations, enasidenib, smooth muscle (SMO) inhibitors, glasdegib, arginase inhibitors, IDO inhibitors, epacadostat, BCL-2 inhibitors, venetoclax, platinum complex derivatives, oxaliplatin, kinase inhibitors, tyrosine kinase inhibitors, PI3 kinase inhibitors, BTK inhibitors, ibrutinib, acalabrutinib, zanubrutinib, PD-1 inhibitors Antibodies, PD-L1 antibodies, CTLA-4 antibodies, LAG3 antibodies, ICOS antibodies, TIGIT antibodies, TIM3 antibodies, CD40 antibodies, 4-1BB antibodies, CD47 antibodies, SIRP1α antibodies or fusion proteins, CD70 antibodies and CLL1 antibodies, CD123 antibodies, E-selectin antagonists, antibodies that bind to tumor antigens, antibodies that bind to T cell surface markers, antibodies that bind to myeloid or NK cell surface markers, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, hormone therapy drugs, hormone antagonists, aromatase inhibitors, and P-glycoprotein inhibitors.

The isolated monoclonal antibody or its antigen-binding fragment may include an antitumor drug conjugated thereto. The antitumor drug may be conjugated to the antibody via a photostable linker. Alternatively, the antitumor drug may be conjugated to the antibody via an enzymatic cleavage linker. The antitumor drug may be a toxin, a radioactive isotope, a cytokine, or an enzyme.

In another embodiment, a method for detecting cancer cells or cancer stem cells in a sample or subject is provided, the method comprising (a) contacting a subject or a sample from the subject with an antibody or an antigen-binding fragment thereof as defined herein; and (b) detecting the binding of the antibody to cancer cells or cancer stem cells in the subject or sample. The sample may be bodily fluid or biopsy, or blood, bone marrow, sputum, tears, saliva, mucus, serum, urine, or feces. Detection may include immunohistochemistry, flow cytometry, immunoassays (including ELISA, RIA, etc.), or Western blotting. The method may further include a second execution of steps (a) and (b) and determination of a change in detection level compared to the first. The isolated monoclonal antibody or its antigen-binding fragment may further include a label, such as a peptide tag, enzyme, magnetic particle, chromophore, fluorescent molecule, chemiluminescent molecule, or dye. The isolated monoclonal antibody or its antigen-binding fragment may be conjugated to liposomes or nanoparticles.

In another aspect, a method is provided for treating or improving an autoimmune disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding fragment thereof as defined herein. The antibody or antigen-binding fragment thereof may be administered intravenously, intra-arterially, intratumorally, or subcutaneously. The method may further comprise administering to the subject one or more drugs selected from the group consisting of steroids or NSAIDs. The autoimmune diseases mentioned can include Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis, reactive arthritis, undifferentiated spondyloarthropathy, juvenile spondyloarthropathy, Behcet's disease, tendonitis, ulcerative colitis, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, fibromyalgia, chronic fatigue syndrome, pain symptoms associated with systemic inflammatory diseases, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile flare-up diabetes (also known as type 1 diabetes), and Wegener's granulomatosis. Polymyositis, dermatomyositis, inclusion body myositis, multiple endocrine failure, Schmidt's syndrome, autoimmune uveitis, Addison's disease, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroid disease, pernicious anemia, gastric atrophy, chronic hepatitis, lupus hepatitis, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis, hypoparathyroidism, Dressler's syndrome, myasthenia gravis, Eaton-Lambert syndrome, autoimmune thrombocytopenic purpura, idiopathic thrombocytopenic purpura, hemolytic anemia, common asthma. Herpes, pemphigus, dermatitis herpetiformis, alopecia, scleroderma, progressive systemic sclerosis, CREST syndrome (calcification, Raynaud's phenomenon, esophageal motility disorder, finger sclerosis and telangiectasia), adult-onset diabetes mellitus (also known as type II diabetes), mixed connective tissue disease, polyarteritis nodosa, systemic necrotizing vasculitis, glomerulonephritis, atopic dermatitis, atopic rhinitis, Goodpasture's syndrome, Chagas' disease, sarcoidosis, rheumatic fever, asthma, antiphospholipid syndrome, erythema multiforme, Cushing's syndrome, autoimmune chronic active hepatitis, allergic diseases, allergic encephalomyelitis, transfusion reactions, leprosy, malaria, leishmaniasis, trypanosomiasis, Takayasu's arteritis (itis), polymyalgia rheumatica, temporal arteritis, schistosomiasis, giant cell arteritis, eczema, lymphomatoid granulomatosis, Kawasaki's disease, endophthalmitis, psoriasis, fetal erythroblastosis, eosinophilic fasciitis, Shulman's syndrome, Felty's syndrome, Fuch's cyclitis, IgA nephropathy, Henoch-Schonlein purpura, graft-versus-host disease, transplant rejection, tularemia, periodic fever syndrome, septic arthritis, familial Mediterranean fever, TNF receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome, or high IgD syndrome.

In another embodiment, this document provides a method for enhancing the immune function of NK cells in a subject, the method comprising administering to the subject an antibody or antigen-binding fragment thereof as defined herein or engineered cells.

Other objects, features, and advantages of the present invention will become clear from the following detailed description. However, it should be understood that while the detailed description and specific examples indicate preferred embodiments of the invention, they are given by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art.

Attached Figure Description

The following drawings form part of this specification and are included to further illustrate certain aspects of the invention. A better understanding of the invention can be achieved by referring to one or more of these drawings in conjunction with the detailed description of the specific embodiments presented herein.

Figures 1A-C: LILRB1 expression on human peripheral blood NK cells. (Figure 1A) PBMCs were isolated from the erythrocyte sedimentation rate (ESR) layer of healthy donors or from peripheral blood of patients with multiple myeloma (MM) or prostate cancer by density gradient centrifugation using Ficoll-Paque PLUS medium, and then stained with anti-CD3-PE, anti-CD56-FITC, anti-LILRB1-APC, or allotype APC antibodies. NK cell gating was SSC ^low, FSC ^low, CD56 ^+, CD3-. LILRB1 expression on NK cells was gated according to allotype APC antibodies. Representative flow cytometry images show that LILRB1 is primarily expressed on CD56 ^dark rather than CD56 ^bright NK cells. (Figure 1B) The percentage of LILRB1+ NK cells in CD56 dark NK cells from healthy donors (n=12), patients with stage 2b or 2c prostate cancer (n=16), and patients with stage 3b ^or 3c prostate cancer (n=17) was determined by ^flow cytometry. (Figure 1C) Percentages of LILRB1+ NK cells from healthy donors (same as Figure 1B), patients with newly diagnosed MM (n=10), patients with MM who had a partial response to treatment or refractory disease (n=8), and patients with MM who had a good response to treatment (CR+VGPR, n=9) were determined by ^flow cytometry. CR = complete remission, VGPR = very good partial remission. *P<0.05;***P<0.001.

Figure 2A-I: Production and characterization of rabbit antagonistic anti-LILRB1 mAb. (Figure 2A) Left inset: Staining of HLA-G expression on the surface of K562 cells and K562 cells overexpressing HLA-G1 (K562-HLA-G) with anti-HLA-G antibody (clone: MEM-G/9, Abcam) and analysis by flow cytometry. Right inset: Co-culturing K562 or K562-HLA-G cells with LILRB1 reporter cells. K562/K562-HLA-G cells were stained with DDAOSE before co-culturing with LILRB1 reporter cells. The percentage of activated LILRB1 reporter cells (GFP) was analyzed by flow cytometry 24 hours after co-culturing. (Figure 2B) Titer of antagonistic anti-LILRB1 mAb blocking the activation of LILRB1 reporter cells stimulated by K562-HLA-G. LILRB1 reporter cells were co-cultured with K562-HLA-G and incubated with different concentrations of antagonistic anti-LILRB1 mAbs. (Fig. 2C) Representative flow cytometry images show the specific binding of B1-176 to LILRB1. LILR reporter cells were incubated with 0.5 μg/mL rabbit B1-176 at 4°C for 30 min. Then, the reporter cells were incubated with anti-rabbit IgGPE antibody (Jackson Laboratory) and analyzed by flow cytometry. (Fig. 2D) Binding specificity of rabbit B1-176 antibody to LILRB and LILRA as determined by ELISA. (Fig. 2E) Affinity of B1-176 as determined by Octet RED96. (Fig. 2F) Screening of B1-176 binding to LILRB1-Fc fusion protein with different domain deletions as determined by ELISA. (Figure 2G) Binding ability of B1-176 to the LILRB1-D1D2 Fc fusion protein with different mutants, as determined by ELISA (top inset). Two amino acids (Y76 and R84) in LILRB1 were identified as essential for the binding of B1-176 (bottom inset). (Figure 2H) Detailed binding surface of rabbit mAb B1-176 to LILRB1 generated by molecular docking using Discovery Studio. (Figure 2I) Cross-reactivity of B1-176 and commercially available anti-LILRB1 mAb with LILR expressed on 2B4 cells, as obtained by flow cytometry.

Figures 3A-D: Humanization of anti-LILRB1 blocking antibody 176. (Figure 3A) The combined Kabat/IMGT/Chothia CDR transplantation strategy was used to humanize rabbit antibody 176. The heavy and light chains of rabbit antibody B1-176 are shown as Rab-176 VH and Rab-176 VL, respectively. The heavy and light chains of the human antibody framework are shown as Hu IGHV3-53*04 and Hu IGKV1-9*01. Amino acids close to the HCDR that differ from the original rabbit amino acids (shown in blue) are shown in green. The heavy chain of B1-176, based on the human antibody framework, is humanized as Hu-176 VH-1 or Hu-176 VH-2 (W48L), which has mutations marked with an asterisk. The light chain of B1-176, based on the human antibody framework, is humanized as Hu-176 VL. (Figure 3B) ELISA results show that rabbit amino acid L48 (marked with an asterisk) in FR2 needs to remain in the same position to maintain the same binding activity between humanized B1-176 and rabbit B1-176. (Figure 3C) Molecular docking data show that rabbit B1-176 is structurally similar to humanized Hu B1-176-N297A. (Figure 3D) Affinity of rabbit-human chimeric anti-LILRB1 antibody B1-176 N297A and humanized anti-LILRB1 antibody expressed in human IgG1 with N297A or LALAPG mutations was determined by Octet RED96 or ELISA.

Figures 4A-C: Antagonistic LILRB1 mAbs can block the activation of LILRB1 receptor cells stimulated by hematologic malignancy and solid tumor cell lines. (Figure 4A) MHC class I levels in hematologic malignancy (left inset) or solid tumor cell lines (right inset) were detected by flow cytometry using an anti-pan-MHC class I antibody (clone: HP-1F7, Santa Cruz Biotechnology). Cancer cell lines (pre-stained with DDAOSE) were co-cultured with LILRB1 reporter cells to test the ability of cancer cells to stimulate LILRB1. The percentage of activated LILRB1 reporter cells (GFP ⁺ ) was analyzed by flow cytometry. (Figure 4B) Rabbit B1-176 (left inset) and humanized Hu B1-176-N297A (right inset) can block the activation of LILRB1 receptor cells induced by hematologic malignancy lines in a dose-dependent manner. LILRB1 reporter cells were co-cultured with K562-HLA-G, multiple myeloma cell line KMS27, or pre-B leukemia cell line 697, and then incubated with anti-LILRB1 mAb. Activation of LILRB1 reporter cells was analyzed by flow cytometry 24 hours after treatment. (Figure 4C) Rabbit B1-176 (left inset) and humanized Hu B1-176-N297A (right inset) were titrated to block activation of LILRB1 receptor cells by solid tumor cell lines. LILRB1 reporter cells were co-cultured with lung cancer cell line H460, melanoma cell line Malme-3m, or triple-negative breast cancer cell line MDA-MB-231, and then incubated with anti-LILRB1 mAb. Activation of LILRB1 reporter cells was analyzed by flow cytometry 24 hours after treatment.

Figures 5A-F: Antagonistic LILRB1 mAbs can modulate the anti-cancer function of NKL cell lines in vitro. (Figure 5A) Multiple myeloma cell line KMS27 was co-cultured with NKL and incubated with 10 μg/mL control human IgG (hIgG) or B1-176-N297A (left inset, n=3), Hu B1-176-N297A (middle inset, n=3), and Hu B1-176-LALAPG (right inset, n=2). After 4 hours, the cytotoxic activity of NKL against cancer cells was analyzed by flow cytometry. (Figure 5B) Multiple myeloma cell lines OPM2, RPMI8226, or acute T-cell leukemia Jurkat cells were co-cultured with NKL and incubated with 10 μg/mL B1-176-N297A or hIgG. n=3. (Fig. 5C) Pre-B leukemia 697 cells (left inset) or Burkitt lymphoma Raji cells (right) overexpressed with MICA (697-MICA, Raji-MICA) and co-cultured with NKL. 10 μg/mL B1-176-N297A or hIgG was added to the culture. (Fig. 5D) 697-MICA was co-cultured with NKL (E:T=20) and incubated with different concentrations of B1-176-N297A. (Fig. 5E) Solid tumor cell lines MDA-MB-231 or MALME-3M were co-cultured with NKL and incubated with 10 μg/mL B1-176-N297A or hIgG. n=3. (Figure 5F) KMS27, OPM2, RPMI8226, Jurkat, or 697/697MICA cells were co-cultured with NKL (E:T ratio = 1:1). 10 μg/mL of control hIgG, B1-176-N297A (for RPMI8226, Jurkat, and 697/697MICA), or HuB1-176-N297A (for KMS27 and OPM2 treatments) was added to the cell cultures. IFN-γ levels in the cell culture supernatant were measured by ELISA after 24 hours. n = 3–4, and statistical significance between anti-LILRB1 antibody and hIgG was analyzed. *P < 0.05; **P < 0.01; ***P < 0.001.

Figures 6A-B: Antagonistic LILRB1 mAb increases the cytotoxic activity of primary NK cells against cancer cells in vitro. (Figure 6A) Multiple myeloma cell lines KMS27 and OPM2, pre-B leukemia cell line 697, or lymphoma cell lines Raji and Daudi were co-cultured with FACS-sorted LILRB1 ⁺ NK cells isolated from PBMCs of healthy donors. 10 μg/mL control hIgG or B1-176N297A was added to the cell culture. n=3, except for Daudi cells, n=2. (Figure 6B) KMS27 cells were co-cultured with NK cells from a multiple myeloma patient (E:T ratio = 2.5:1) and incubated with 10 μg/mL control hIgG or Hu B1-176-N297A. The cytotoxic activity of primary NK cells was analyzed by flow cytometry 4 hours after co-culture. n=3, ***P<0.001.

Figures 7A-C: Antagonistic LILRB1 mAb increases the in vivo cytotoxic activity of NKL cells. (Figure 7A) A mixture of 5 × ^10⁶ CFSE-stained 697 (NKL-resistant) and 697MICA (NKL-sensitive) cells was injected into the peritoneal cavity of NSG mice along with 5 × ^10⁷ NKL cells. Control hIgG or B1-176-N297A was injected into the mice via the retroorbital injection at 10 mg/kg. Peritoneal cells were collected 24 hours later and stained with anti-MICA-APC antibody. The ratio of 697-MICA to 697 cells was quantified by flow cytometry and representative flow chromatograms. The 697-MICA to 697 ratio was used to calculate the in vivo cytotoxic activity of NKL cells. n = 3–4, *P < 0.05. (Figure 7B) 1 × ^10⁶ cells overexpressing 697MICA luciferase (697MICA-luci) were mixed with 5 × ^10⁶ NKL cells and subcutaneously injected into NSG mice. Control hIgG or B1-176-N297A was administered retro-orbitally at 10 mg/kg. Bioluminescence imaging (BLI) was performed 48 hours later. Quantification of BLI data (total throughput (p/s)) from two independent experiments showed that mice receiving B1-176-N297 exhibited significantly lower tumor burden compared to mice treated with control hIgG, indicating that B1-176-N297 improved the in vivo cytotoxic function of NKL cells. n = 8–10, **P < 0.01. (Figure 7C) NSG mice were sublethally irradiated, and on day 0, 5 × ^10⁵ KMS27 cells overexpressing luciferase and 5 × ^10⁶ NKL cells were injected via tail vein. On day 14, an additional 5 × ^10⁶ NKL cells were injected into NSG mice via tail vein injection. Mice received 10 mg/kg of control hIgG or B1-176-N297A post-orbital injection on days 0, 3, and 7, followed by weekly administration for another month. BLI was performed on days 28 and 35. Pooled BLI data showed that B1-176-N297 significantly reduced tumor development in mice (left inset). n = 4, data from one representative experiment. *P < 0.05, statistical significance calculated by one-tailed unpaired t-test. Survival analysis of xenografts in multiple myeloma mice showed that B1-176-N297 treatment significantly improved survival compared to control hIgG-treated mice (right inset). n = 9–10, pooled data from two representative experiments. ***P < 0.001.

Figures 8A-D: Antagonistic LILRB1 mAbs can modulate the anti-cancer function of NK92mi cell lines in vitro. (Figures 8A-C) Leukemia cell lines (RS4-11, MHHCALL2, MOLM13, THP-1, 697, 697MICA), solid tumor cell lines (MDA-MB-231, SW480, MALEM-3M), or multiple myeloma cell line (RMPI8226) were co-cultured with NK92mi and incubated with 10 μg/mL control human IgG (hIgG), B1-#3, or B1-176. After four hours, the cytotoxic activity of NKL against cancer cells was analyzed by flow cytometry. (Figure 8D) Two primary leukemia cell lines were co-cultured with NK92mi and incubated with 10 μg/mL control human IgG (hIgG) or B1-#3N297A. Four hours later, the cytotoxic activity of NK92mi against cancer cells was analyzed by flow cytometry.

Figure 9: The agonist LILRB1 mAb can activate LILRB1 receptor cells. LILRB1 reporter cells were co-cultured with K562 cells and treated with agonist LILRB1 mAb B1-7 or B1-41. After 24 hours, the percentage of GFP ⁺ reporter cells was analyzed by flow cytometry. Elimination of the N297A mutation in Fc cells, while the S267E mutation in Fc cells enhanced the activity of the agonist LILRB1 mAb.

Figures 10A-D: Agonistant LILRB1 mAbs inhibit the cytotoxic activity of NK cells against cancer cells in vitro. NK92mi cells were co-cultured with 697 (Figure 10A) or THP1 cells (Figure 10B) and treated with anti-LILRB1 mAbs. Antagonistic B1-3 increased, while agonist B1-7 inhibited the cytotoxic activity of NK92mi against 697 and THP-1 cells. (Figure 10C) NKL cells were co-cultured with 697/697-MICA and treated with anti-LILRB1 mAbs. Antagonistic B1-3 increased, while agonist B1-7 inhibited the cytotoxic activity of NKL against 697-MICA. (Figure 10D) NKL cells were co-cultured with 697-MICA and treated with B1-7 and B1-7 with mutations in Fc (N297A, S267E). The N297A mutation in Fc eliminated the activity of agonist B1-7. Four hours after co-culture, the cytotoxic activity was analyzed by flow cytometry.

Figure 11: Agonistant LILRB1 mAb inhibits IFN-γ secretion from NKL cells. NKL cells were co-cultured with 697-MICA cells and treated with anti-LILRB1 mAb. Antagonistic B1-3 increased, while agonist B1-7 inhibited IFN-γ secretion from NKL cells. After 24 hours of co-culture, the culture supernatant was collected, and IFN-γ levels were measured by ELISA.

Figures 12A-G: Screening for the generation of anti-LILRB1 mAbs. (Figure 12A) Isolation, in vitro culture, and cloning strategy for anti-LILRB1 specific rabbit memory B cells. After culturing rabbit CD40L feeder cells and a mixture of rabbit cytokines in 96-well plates for 14 days, the binding of B cell supernatants to LILRB1 was screened by ELISA. The antibody heavy chain variable gene and light chain variable gene were then cloned into a rabbit IgG expression vector, and recombinant antibodies were generated using a transient HEK293Expi-F cell expression system. (Figure 12B) Flowchart of the screening process for anti-LILRB1 mAbs. (Figure 12C) _EC50 of 44 anti-LILRB1 rabbit mAbs determined by ELISA. (Figure 12D) 12 epitope bins of the 44 anti-LILRB1 rabbit mAbs were determined using the classic sandwich epitope binning assay (Octet RED96). (Figure 12E) To screen for antagonistic anti-LILRB1 antibodies, LILRB1 reporter cells were co-cultured with K562-HLA-G cells and incubated with anti-LILRB1 mAb (10 μg/mL) for 24 hours. (Figure 12F) Left inset: Homology of LILRB1 with other receptors in the LILR family. Phylogenetic trees of the D1-D2 encoded amino acid sequences from all LILRs, except for the D1 domain selected only for LILRB4, were generated using maximum likelihood analysis with MEGA version 7.0. Right table: Specificity of anti-LILRB1 mAb, analyzed by Octet RED96. (Figure 12G) Affinity of commercial anti-LILRB1 monoclonal antibodies HP-F1 and GHI/75, analyzed by Octet RED96.

Figure 13A-B: Characterization of B1-176. A fusion protein of the LILRB1 ECD mutant and the Fc of hIgG1 was generated to characterize the binding epitope of B1-176. (Figure 13A) Schematic diagram of LILRB1-fc mutation. (Figure 13B) Single or multiple mutations of LILRB1 amino acids.

Figures 14A-D: Expression of LILRB1 on the cell surface. (Figure 14A) A representative flowchart of LILRB1 expression on NKL cells. (Figure 14B) A representative flowchart showing that multiple myeloma cell lines do not express LILRB1 on their cell surface. (Figure 14C) A representative flowchart showing that most malignant plasma cells from patients with MM do not express LILRB1 on their cell surface. (Figure 14D) A representative flowchart showing that pre-BALL cell lines 697, MHHCALL2, RS4;11, RCHACV, REH; acute monocytic leukemia cell lines THP-1, MOLM13, MV4-11; and Raji cells express LILRB1 on their cell membranes, while T-cell leukemia Jurkat cells and chronic myeloid leukemia cell line K562 do not express LILRB1. Cells were incubated with anti-LILRB1-APC (clone: HP-F1, eBioscience) on ice for 30 minutes and analyzed by flow cytometry.

Detailed Implementation

LILRB1, a member of the LILR receptor family containing ITIM, plays a crucial role in the regulation of both innate and adaptive immunity. LILRB1 is expressed on various types of immune cells, including NK cells, and acts as an immune checkpoint protein. Expression of LILRB in myeloid-derived suppressor cells (MDSCs) can promote tumor growth and contribute to a suppressive immune microenvironment that contributes to tumor progression and metastasis. On the other hand, activating LILRB1 signaling using agonist antibodies may reduce tissue inflammation and can be used for the management of autoimmune diseases. This article presents agonist and antagonist human LILRB1 monoclonal antibodies with specific targeting properties for modulating LILRB1 signaling. These LILRB1 antibodies can be used to treat human diseases, including cancer and autoimmune diseases.

I. All aspects of this disclosure

LILRB1 is expressed on both T cells and NK cell subsets. LILRB1 is primarily expressed on CD56 ^dark NK cells from healthy donors and patients with various malignancies. Furthermore, the percentage of LILRB1 ⁺ NK cells in peripheral blood from patients with persistent disease during treatment was significantly higher than that from healthy donors or patients with minimal disease ^{or complete response. The percentage of LILRB1+ NK} cells in peripheral blood from patients with advanced prostate cancer (stages 3B and 3C) was also significantly higher than that from healthy donors. These results are consistent with previous studies indicating that peripheral blood CD56 ^dark NK cells have ^higher LILRB1 levels compared to CD56 ^bright NK cells. Other previous studies have also reported ^{significantly higher} percentages of LILRB1 ⁺ NK cells in peripheral blood from patients with metastatic prostate cancer and breast cancer compared ^to NK cells from healthy donors or patients with localized cancer. Previous studies have also reported a strong correlation between the percentage of circulating CD8 ⁺ LILRB1 T cells and the risk of recurrence in non-muscle-invasive bladder cancer.^⁴¹ In summary, LILRB1 expression on NK cells and T cells has prognostic value. Although the exact mechanism of LILRB1 polymorphism in human NK cells is unknown, LILRB1 expression on NK cells is associated with specific haplotype and polymorphic regulatory regions.^⁴² Increased LILRB1 ⁺ NK cells from certain patients with cancer have been well demonstrated. NK cells upregulate LILRB1 expression when cultured in vitro with cancer cells.^⁹ HLA-G and soluble HLA-G have been reported to upregulate LILRB1 expression on NK cells, T cells, and antigen-presenting cells.^⁴³ Patients with elevated plasma soluble HLA-G may have high LILRB1 expression on NK cells.^¹⁰ Terminally differentiated NK cells marked by expression of CD57 or multiple KIRs exhibit high LILRB1 expression and poor proliferative capacity.^⁴⁴ A large number of circulating CD57 ⁺ NK cells are associated with resistance to HER2-specific therapeutic antibodies in patients with primary breast cancer ^⁴⁵ , which may explain the increase in LILRB1 ⁺ NK cells in cancer patients who have poor response to treatment.

Importantly, blocking LILRB1 with an antagonistic monoclonal antibody increases the immune function of NK cells against multiple myeloma cells both in vitro and in vivo. In an earlier study, Heidenreich and colleagues reported that blocking LILRB1 on the NK92 cell line did not increase their cytotoxic activity against multiple myeloma cell lines. ^⁴⁶ This difference may be related to the use of the NK92 cell line, which may have stronger cytotoxic activity than the NKL cell line and primary NK cells used in this study.^⁴⁷ MHC class I, the ligand for LILRB1, is strongly expressed in advanced MM cell lines, where expression levels are directly correlated with the clinical stage of the disease.^⁴⁸^⁴⁶ The cell line RPMI8226 used in the study and other MM cell lines express high levels of MHC class I molecules on their cell surface and have a strong ability to activate LILRB1 reporter genes. These data suggest that MM cells may become resistant to NK cells by activating LILRB1 on NK cells through binding to MHC class I molecules expressed on MM cells.

NK cell function depends on the balance of various activating and inhibitory signals within the cell. Targeting multiple immune receptors can optimize NK cell function against cancer cells. Combined blockade of LILRB1 and activation of the NKG2D receptor (via its ligand MICA) synergistically enhance NK cell cytotoxicity. These results are consistent with previous reports indicating that overexpression of HLA-G on the MICA-expressing ^M8 melanoma cell line blocks the cytotoxic activity of NK cells against cancer cell lines by activating ^LILRB1.49 Several methods are being developed to increase the surface abundance ^of MICA on cancer cells.419 Other studies have reported the combined effects of LILRB1 blockade with KIR blockade ^or ADCC-induced mAbs in vitro.1012 Adoptively transferred allogeneic haploidentical NK cells are thought to have improved function due to the mismatch between MHC class I molecules ^{and KIRs.150} Since LILRB1 can still be activated on these allogeneic NK cells ^, there may be a combined effect of LILRB1 blockade and allogeneic NK cell adoptive transfer.

Interestingly, it has been reported that LILRB1 on cancer cells such as transformed B lymphoma cells and MGUS cells may activate immune responses. ^¹⁶¹⁷ LILRB1 is expressed on pre-B leukemia cells and Burkitt lymphoma Raji cells. However, administration of anti-LILRB1 blocking antibodies increased NK cell function against LILRB1-positive cell lines 697 and Raji cells, consistent with previous reports that LILRB1 blockade increased NK cell cytotoxic activity against pre-B-ALL. ^¹² These results suggest that the immunostimulatory function of LILRB1 may be environment-dependent. Since LILRB1 expression on NK cells is significantly higher in patients with persistent disease after treatment, LILRB1 blockade may increase NK cell function in patients with persistent MM. However, LILRB1 expression levels on myeloma cells and NK cells should be monitored before and during anti-LILRB1 antibody treatment. To minimize the risk of modulating the LILRB1 receptor on myeloma cells, anti-LILRB1 antibody therapy should be prioritized for patients with high LILRB1 expression levels on NK cells and no LILRB1 expression on myeloma cells.

In summary, blocking LILRB1 with antagonistic antibodies has the potential to be an immunotherapy approach for treating patients with various types of cancer, especially those with high levels of LILRB1 expression on NK cells.

II. Monoclonal Antibodies and Their Production

The monoclonal antibodies described herein can be prepared using standard methods, followed by screening, characterization, and functional evaluation. Variable regions can be sequenced and then subcloned into human expression vectors to generate chimeric antibody genes, which are then expressed and purified. These chimeric antibodies can be tested for antigen binding, signal transduction blocking, and xenograft experiments. The monoclonal antibodies described herein can also be prepared using phage display methods, where a large library of human scFvs displayed by phages is panned against the target protein. Human scFvs selected to specifically bind to the target protein can be sequenced and then subcloned into human expression vectors to generate the desired human antibody.

A. General Method

It should be understood that monoclonal antibodies binding to LILRB1 will have several applications. These applications include the production of diagnostic kits for the detection and diagnosis of cancer, as well as for cancer therapy. In these contexts, such antibodies can be associated with diagnostic or therapeutic agents, used as capture or competing agents in competitive assays, or used alone without the addition of additional reagents. Antibodies can be mutated or modified, as discussed further below. Methods for preparing and characterizing antibodies are well known in the art (see, for example, *Antibodies: A Laboratory Manual*, Cold Spring Harbor Laboratory, 1988; U.S. Patent 4,196,265).

Classical methods for generating monoclonal antibodies (MAbs) generally begin along the same route as methods for preparing polyclonal antibodies. The first step in both methods is to immunize the appropriate host. As is well known in the art, the immunogenicity of a given composition used for immunization may vary. Therefore, it is often necessary to enhance the host's immune system, which can be achieved, for example, by coupling a peptide or polypeptide immunogen to a carrier. Exemplary and preferred carriers are keyfora hemocyanin (KLH) and bovine serum albumin (BSA). Other albumins, such as ovalbumin, mouse serum albumin, or rabbit serum albumin, can also be used as carriers. Methods for conjugating polypeptides to carrier proteins are well known in the art and include glutaraldehyde, m-maleimide benzoyl-N-hydroxysuccinimide ester, carbodiimide, and benzidine dinitrate. As is well known in the art, the immunogenicity of a particular immunogen composition can be enhanced by using a nonspecific stimulant of the immune response known as an adjuvant. Exemplary and preferred adjuvants include complete Freund's adjuvant (a nonspecific stimulant of the immune response containing killed Mycobacterium tuberculosis), incomplete Freund's adjuvant, and aluminum hydroxide adjuvant.

The amount of immunogenic composition used to generate polyclonal antibodies varies depending on the nature of the immunogen and the animal being immunized. Multiple routes can be used to administer the immunogen (subcutaneous, intramuscular, intradermal, intravenous, and intraperitoneal). Polyclonal antibody production can be monitored by sampling the blood of the immunized animal at different points after immunization. A second booster injection may also be given. The booster and titer determination process is repeated until the appropriate titer is achieved. When the desired level of immunogenicity is obtained, blood can be collected from the immunized animal, and the serum can be separated and stored, and/or the animal can be used to generate MAb.

Following immunization, somatic cells with the potential to produce antibodies, particularly B lymphocytes (B cells), are selected for the MAb production protocol. These cells can be obtained from biopsied spleens or lymph nodes, or from circulating blood. Antibody-producing B lymphocytes from the immunized animal are then fused with immortalized myeloma cells, typically one of the same species as the immunized animal or human/mouse chimeric cells. The myeloma cell lines suitable for the hybridoma-producing fusion procedure preferably do not produce antibodies, have high fusion efficiency, and lack the enzymes required to then grow in certain selective media that only support the growth of the desired fused cells (hybridomas). Any of a variety of myeloma cells can be used, as known to those skilled in the art (Goding, pp. 65-66, 1986; Campbell, pp. 75-83, 1984).

Methods for generating antibody-producing hybrids of spleen or lymph node cells and myeloma cells typically involve mixing somatic cells and myeloma cells in a 2:1 ratio, but this ratio can vary from about 20:1 to about 1:1 in the presence of one or more agents (chemical or electro) that promote cell membrane fusion. Kohler and Milstein (1975; 1976) described a fusion method using Sendai virus, and Gefter et al. (1977) described a fusion method using polyethylene glycol (PEG), such as 37% (v/v) PEG. The use of electroinductive fusion methods is also appropriate (Goding, pp. 71–74, 1986). Fusion procedures typically produce viable hybrids at a low frequency, about 1 × ^10⁻⁶ to 1 × ^10⁻⁸ . However, this does not cause problems because, by culturing in selective media, the viable fusion hybrids differentiate with the parental, injected cells (especially the injected myeloma cells, which typically continue to divide indefinitely). Selective culture media are typically media containing agents that block the de novo synthesis of nucleotides in tissue culture media. Exemplary and preferred agents are aminopterin, methotrexate, and diazoserine. Aminopterin and methotrexate block the de novo synthesis of purines and pyrimidines, while diazoserine blocks only the synthesis of purines. When using aminopterin or methotrexate, the medium is supplemented with hypoxanthine and thymidine as a source of nucleotides (HAT medium). When using diazoserine, the medium is supplemented with hypoxanthine. If the B cell source is a human B cell line transformed with Epstein-Barr virus (EBV), ouabain is added to eliminate EBV-transformed lines that have not fused with myeloma.

The preferred selective medium is HAT or HAT containing ouabain. Only cells capable of operating the nucleotide rescue pathway can survive in HAT medium. Myeloma cells are deficient in key enzymes of the rescue pathway, such as hypoxanthine phosphoribosyltransferase (HPRT), and therefore cannot survive. B cells can operate this pathway, but their lifespan in culture is limited, and they typically die within about two weeks. Therefore, the only cells that can survive in selective medium are those heterozygotes formed from myeloma and B cells. When the B cell source used for fusion is an EBV-transformed B cell line, as described here, ouabain is also used for drug selection of the heterozygote because EBV-transformed B cells are susceptible to drug killing, while the myeloma mates used are selected to be resistant to ouabain.

Culture provides a population of hybridomas from which specific hybridomas are selected. Typically, hybridoma selection is performed by diluting cultured cells monoclonal in a microtiter plate, followed by testing the desired reactivity of the supernatant from a single clone (after approximately two to three weeks). Assays should be sensitive, simple, and rapid, such as radioimmunoassays, enzyme immunoassays, cytotoxicity assays, plaque assays, spot immunobinding assays, etc. The selected hybridomas are then serially diluted or single cells are sorted by flow cytometry and cloned into a single antibody-producing cell line, which can then proliferate indefinitely to provide mAbs. The cell line can be used for MAb production in two basic ways. A sample of the hybridoma can be injected (usually into the peritoneal cavity) into an animal (e.g., a mouse). Optionally, the animal is sensitized with hydrocarbons, particularly oils such as pterostilbene (tetramethylpentadecane), prior to injection. When using human hybridomas in this manner, it is best to inject immunocompromised mice, such as SCID mice, to prevent tumor rejection. The injected animal produces a tumor that secretes specific monoclonal antibodies produced by the fused cell hybrid. Animal body fluids, such as serum or ascites, can then be extracted to provide high concentrations of MAb. Single cell lines can also be cultured in vitro, where MAb is naturally secreted into the culture medium from which it can be readily obtained at high concentrations. Alternatively, human hybridoma cell lines can be used in vitro to produce immunoglobulins in the cell supernatant. Cell lines can be adapted for growth in serum-free media to optimize the ability to recover high-purity human monoclonal immunoglobulins.

If desired, the MAb produced by any of these methods can be further purified using various chromatographic methods such as filtration, centrifugation, and affinity chromatography. The monoclonal antibody fragments of this disclosure can be obtained from the purified monoclonal antibody by methods including digestion with enzymes such as pepsin or papain and/or by chemical reduction cleavage of disulfide bonds. Alternatively, the monoclonal antibody fragments covered by this disclosure can be synthesized using an automated peptide synthesizer.

Molecular cloning methods for generating monoclonal antibodies are also considered. For this purpose, RNA can be isolated from hybridoma cell lines, and antibody genes can be obtained via RT-PCR, then cloned into an immunoglobulin expression vector. Alternatively, combined immunoglobulin phage libraries can be prepared from RNA isolated from cell lines, and phages expressing suitable antibodies can be selected using viral antigen panning. Compared to conventional hybridoma techniques, this method has the advantage of generating and screening approximately ^10⁴ times more antibodies in a single round, and generating new specificity through H-chain and L-chain combinations, further increasing the chances of finding suitable antibodies.

Recently, other methods for generating mAbs have been developed, such as scFv phage display (see C.M. Hammers and J.R. Stanley, Antibody phage display: technique and applications, J Invest Dermatol (2014) 134:e17). Typically, a set of human mAbs binding to a target protein (e.g., human LILRB1) is generated by panning a large library of antibodies displaying different human scFv phages.

To generate a human scFv phage-displayed antibody library, RNA is extracted from a selected cellular source, such as peripheral blood mononuclear cells. The RNA is then reverse transcribed into cDNA, which is used for PCR encoding the VH and VL chains of the antibodies. A specific set of primers specific to different VH and VL chain gene families allows amplification of all transcribed rearranged variable regions within a given immunoglobulin lineage, reflecting the specificity of all antibodies in a particular individual.

The VH and VL PCR products, representing antibody lineages, were ligated into a phage display vector engineered to express VH and VL as scFv fused with the pIII minor capsid protein of filamentous phages of *E. coli* originally derived from M13 phage. This produced a phage library in which each phage expressed scFv on its surface and carried a vector containing the corresponding nucleotide sequence.

The library is then screened using a technique called biopanning, targeting phages that bind to the target antigen via their expressed surface scFv. In short, the target protein is coated onto a solid phase for incubation with the phage library. After washing and elution, the antigen-rich phages are recovered and used for the next round of phage panning. After at least three rounds of phage panning, individual bacterial colonies are picked for phage ELISA and other functional/genetic analyses.

Positive hits in the scFv region were sequenced, and these positive hits were converted into fully human IgG heavy and light chain constructs, which were used to generate the mAb of interest using the methods disclosed above. For example, the IgG expression plasmid was co-transfected into Expi293 cells using the transfection reagent PEI. After 7 days of expression, the supernatant was harvested, and the antibody was purified by affinity chromatography using protein A resin.

Other U.S. patents that teach the generation of antibodies useful in this disclosure (each of which is incorporated herein by reference) include U.S. Patent 5,565,332, which describes the generation of chimeric antibodies using a combination method; U.S. Patent 4,816,567, which describes a recombinant immunoglobulin formulation; and U.S. Patent 4,867,973, which describes antibody therapeutic conjugates.

B. The antibodies disclosed herein

1. Antibody against LILRB1

In the first case, the antibody or its antigen-binding fragment according to this disclosure can be defined by its binding specificity, in this case, the binding specificity is against LILRB1. Those skilled in the art can determine whether such an antibody falls within the scope of this claim by evaluating the binding specificity/affinity of a given antibody using techniques well-known to them.

On the one hand, antibodies and antigen-binding fragments that specifically bind to LILRB1 are provided. In some embodiments, such antibodies regulate LILRB1 activation upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragment activates LILRB1 upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragment inhibits LILRB1 activation upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragment can specifically interfere with, block, or reduce the interaction between LILRB1 and its binding partner upon binding to LILRB1. In some embodiments, the antibody or antigen-binding fragments provided herein specifically or selectively bind to human LILRB1.

In some embodiments, the antibody or antigen-binding fragment specifically binds to human LILRB1 and/or substantially inhibits the binding of human LILRB1 to MHC class I molecules, such as HLA-G, by at least about 20% to 40%, 40% to 60%, 60% to 80%, 80% to 85%, or more. In some embodiments, the Kd of the antibody or antigen-binding fragment is less than (more tightly bound) ^10⁻⁶ , ^10⁻⁷ , ^10⁻⁸ , ^10⁻⁹ , ^10⁻¹⁰ , ^10⁻¹¹ , ^10⁻¹² , or ^10⁻¹³ M. In some embodiments, the IC50 of the antibody or antigen-binding fragment for blocking the binding of MHC class I molecules such as HLA-G to LILRB1 is less than 10 μM, 10 μM to 1 μM, 1000 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, and 10 pM to 1 pM.

In some embodiments, the antibody or antigen-binding fragments provided herein have clonal pairings of CDRs shown in Tables 1 and 3.

In some embodiments, the antibody may be defined by a variable sequence comprising an additional “framework” region. The antibody is characterized by heavy chain and light chain amino acid sequences paired from clones in Tables 6 and 8. Furthermore, the antibody sequence may differ from these sequences, particularly in regions outside the CDR. For example, amino acids may differ from those listed above by a given percentage, such as 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology, or amino acids may differ from those listed above by allowing conserved substitutions (discussed below). Each of the foregoing applies to the amino acid sequences in Tables 6 and 8. In another embodiment, the antibody derivative of this disclosure comprises VL and VH domains having up to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more conserved or non-conserved amino acid substitutions while still exhibiting the desired binding and functional properties.

Although the antibodies disclosed herein are produced as IgG, it may be useful to modify the constant region to alter its function. The constant region of an antibody typically mediates the binding of the antibody to host tissues or factors, including different cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. Therefore, the term "antibody" includes complete immunoglobulins of IgA, IgG, IgE, IgD, and IgM types (and their subtypes), wherein the light chain of the immunoglobulin may be of the κ or λ type. Within the light and heavy chains, the variable and constant regions are linked by a 35 "J" region having about 12 or more amino acids, wherein the heavy chain also includes a "D" region having about 10 or more amino acids. See generally *Fundamental Immunology*, Chapter 7 (edited by Paul, W., 2nd ed., Raven Press, N.Y., NY (1989)).

This disclosure further includes nucleic acids that hybridize with nucleic acids encoding the antibodies disclosed herein. Typically, the nucleic acids hybridize with nucleic acids encoding the antibodies disclosed herein and also encoding antibodies that retain specific binding ability to LILRB1 under moderately or highly stringent conditions. The first nucleic acid molecule and the second nucleic acid molecule are “hybridizable” when the single-stranded form of the first nucleic acid molecule can be annealed to the second nucleic acid molecule under appropriate temperature and solution ionic strength conditions (see Sambrook et al., *Molecular Cloning: A Laboratory Manual*, 3rd ed., Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 2001). The temperature and ionic strength conditions determine the “stringency” of the hybridization. Typical moderately stringent hybridization conditions are 40% formamide with 5X or 6X SSC and 0.1% SDS at 42°C. High-strict hybridization conditions are 50% formamide, 5X or 6X SSC (0.15M NaCl and 0.015M sodium citrate) at 42°C, or optionally at higher temperatures (e.g., 57°C, 59°C, 60°C, 62°C, 63°C, 65°C, or 68°C). Hybridization requires the two nucleic acids to contain complementary sequences, but depending on the strictness of hybridization, mismatches between bases are possible. The appropriate strictness for hybridizing nucleic acids depends on the length of the nucleic acids and the degree of complementarity, variables well known in the art. The higher the degree of similarity or homology between the two nucleotide sequences, the higher the strictness of the hybridization that the nucleic acids can achieve. For heterozygotes longer than 100 nucleotides, equations have been derived for calculating the melting temperature (see Sambrook et al., ibid.). For hybridization with shorter nucleic acids (e.g., oligonucleotides), the location of mismatches becomes more important, and the length of the oligonucleotide determines its specificity (see Sambrook et al., ibid.).

Table 1. Amino acid sequence of the CDR of the LILRB1(B1)mAb heavy chain

Table 2. Nucleic acid sequences of the LILRB1(B1)mAb heavy chain CDR

Table 3. Amino acid sequence of the CDR light chain of LILRB1(B1)mAb

Table 4. Nucleic acid sequences of LILRB1(B1)mAb CDR

Table 5. Nucleotide sequence of the variable region of the LILRB1 mAb heavy chain

Table 6. Amino acid sequence of the LILRB1 mAb heavy chain variable region

Table 7. Nucleotide sequence of the variable region of the LILRB1 mAb light chain

Table 8. Amino acid sequence of the LILRB1 mAb light chain variable region

2. Exemplary epitopes and competitive antigen-binding proteins

On the other hand, this disclosure provides epitopes for anti-LILRB1 antibody binding. In some embodiments, the antibody-binding epitopes described herein are useful. In some embodiments, the epitopes provided herein can be used to isolate antibodies or antigen-binding proteins that bind to LILRB1. In some embodiments, the epitopes provided herein can be used to generate antibodies or antigen-binding proteins that bind to LILRB1. In some embodiments, the epitope, or a sequence including the epitope provided herein, can be used as an immunogen to generate antibodies or antigen-binding proteins that bind to LILRB1. In some embodiments, the epitopes described herein, or sequences including the epitope described herein, can be used to interfere with the biological activity of LILRB1.

In some embodiments, antibodies or antigen-binding fragments thereof that bind to any epitope are particularly useful. In some embodiments, the epitopes provided herein regulate the biological activity of LILRB1 upon antibody binding. In some embodiments, the epitopes provided herein activate LILRB1 upon antibody binding. In some embodiments, the epitopes provided herein inhibit the activation of LILRB1 upon antibody binding. In some embodiments, the epitopes provided herein block the interaction between LILRB1 and its binding partner upon antibody binding.

In some implementations, domains/regions containing residues that contact or are buried by the antibody can be identified by mutating specific residues in LILRB1 and determining whether the antibody can bind to the mutated LILRB1 protein. By performing numerous individual mutations, residues that play a direct role in binding or are close enough to the antibody that the mutation can affect the binding between the antibody and the antigen can be identified. Based on knowledge of these amino acids, antigenic domains or regions containing residues that contact the antigen-binding protein or are covered by the antibody can be elucidated. Such domains may include binding epitopes of antigen-binding proteins.

On the other hand, this disclosure provides antigen-binding proteins that compete with one of the illustrated antibodies or antigen-binding fragments that bind to the epitopes described herein for specific binding to LILRB1. Such antigen-binding proteins may also bind to the same epitopes or overlapping epitopes as one of the illustrated antibodies or antigen-binding fragments herein. Antigen-binding proteins that compete with or bind to the same epitopes as illustrated antibodies are expected to exhibit similar functional properties. The illustrated antibodies include those described above, including those having the heavy chain variable regions and light chain variable regions included in Tables 1 and 3, as well as the CDR, the heavy chain and light chain regions shown in Tables 6 and 8, and the heavy chain and light chain coding regions shown in Tables 5 and 7.

C. Engineering of antibody sequences

In various implementations, the sequence of the identified antibody may be engineered for various reasons, such as improved expression, improved cross-reactivity, or reduced off-target binding. The following is a general discussion of the relevant techniques for antibody engineering.

Hybridomas can be cultured, cells lysed, and total RNA extracted. Random hexamers can be used with RT to generate cDNA copies of the RNA, followed by PCR using a multiplex mixture of PCR primers intended to amplify all variable gene sequences. The PCR product can be cloned into the pGEM-T Easy vector and then sequenced using standard vector primers via automated DNA sequencing. Binding and neutralization assays can be performed using antibodies collected from the hybridoma supernatant and purified by FPLC using a Protein G column. Recombinant full-length IgG antibodies can be generated by subcloning the heavy and light chain Fv DNA from the cloning vector into an IgG plasmid vector, transfecting it into 293Freestyle cells or CHO cells, and collecting purified antibodies from the 293 or CHO cell supernatant.

Rapid availability of antibodies produced using the same host cells and cell culture processes as the final cGMP preparation process has the potential to reduce the duration of process development programs. Lonza has developed a universal method for the rapid production of small amounts (up to 50 g) of antibodies in CHO cells using pooled transfectants grown in CDACF medium. While slightly slower than a true transient system, advantages include higher product concentrations and the use of the same host and process as the generating cell lines. An example of growth and productivity of a GS-CHO pool expressing model antibodies in a single-use bioreactor: A collection antibody concentration of 2 g/L was achieved within 9 weeks of transfection in a single-use bag bioreactor culture (5 L working volume) operated in batch feed mode.

Antibody molecules will include fragments, for example, those produced by proteolytic cleavage of mAbs (such as F(ab'), F(ab') ₂ ) or single-chain immunoglobulins, for example, those produced via recombinant processes. Such antibody derivatives are monovalent. In one embodiment, such fragments can combine with each other, or with other antibody fragments or receptor ligands, to form “chimeric” binding molecules. Importantly, such chimeric molecules may contain substituents capable of binding to different epitopes of the same molecule.

1. Antigen binding modification

In relevant embodiments, the antibody is a derivative of the disclosed antibody, for example, an antibody comprising a CDR sequence identical to the CDR sequence in the disclosed antibody (e.g., a chimeric antibody or a CDR-transplanted antibody). Alternatively, modifications may be desired, such as introducing conserved alterations into the antibody molecule. When making such modifications, the hydrophilicity index of the amino acids can be considered. The importance of the hydrophilic amino acid index in conferring interactive biological functions of proteins is widely understood in the art (Kyte and Doolittle, 1982). It is understood that the relative hydrophilicity of amino acids contributes to the secondary structure of the resulting protein, which in turn defines the protein's interactions with other molecules, such as enzymes, substrates, receptors, DNA, antibodies, antigens, etc.

It should also be understood in the art that similar amino acids can be efficiently substituted based on hydrophilicity. U.S. Patent 4,554,101 (incorporated herein by reference) states that the maximum local average hydrophilicity of a protein, governed by the hydrophilicity of adjacent amino acids, is related to the protein's biological properties. As detailed in U.S. Patent 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: basic amino acids: arginine (+3.0), lysine (+3.0), and histidine (-0.5); acidic amino acids: aspartic acid (+3.0±1), glutamic acid (+3.0±1), asparagine (+0.2), and glutamine (+0.2); hydrophilic, nonionic amino acids: serine (+0.3), asparagine (+0.2), and glutamine (+0.2). Amide (+0.2) and threonine (-0.4); sulfur-containing amino acids: cysteine (-1.0) and methionine (-1.3); hydrophobic, non-aromatic amino acids: valine (-1.5), leucine (-1.8), isoleucine (-1.8), proline (-0.5±1), alanine (-0.5) and glycine (0); hydrophobic, aromatic amino acids: tryptophan (-3.4), phenylalanine (-2.5) and tyrosine (-2.3).

It should be understood that amino acids can be substituted for another amino acid with similar hydrophilicity, resulting in a biologically or immunologically modified protein. In such cases, substitution of amino acids with a hydrophilicity value within ±2 is preferred, substitution of amino acids with a hydrophilicity value within ±1 is particularly preferred, and substitution of amino acids with a hydrophilicity value within ±0.5 is even more particularly preferred.

As outlined above, amino acid substitutions are generally based on the relative similarity of the substituents in the amino acid side chains, such as their hydrophobicity, hydrophilicity, charge, size, etc. Exemplary substitutions taking into account the various features described above are well known to those skilled in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine, and isoleucine.

This disclosure also considers isotype modification. By modifying the Fc region to have different isotypes, different functions can be achieved. For example, changing it to _IgG1 can increase antibody-dependent cytotoxicity, changing it to class A can improve tissue distribution, and changing it to class M can improve valence.

Modified antibodies can be prepared using any technique known to those skilled in the art, including expression via standard molecular biotechnology or chemical synthesis of peptides. Methods for recombinant expression are discussed elsewhere in this document.

2. Fc area modification

The antibodies disclosed herein can also be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or effector function (e.g., antigen-dependent cytotoxicity). Furthermore, the antibodies disclosed herein can be chemically modified (e.g., one or more chemical moieties can be linked to the antibody) or modified to alter their glycosylation to again alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The residues in the Fc region are numbered using the EU index of Kabat. The antibodies disclosed herein also include antibodies having a modified (or blocked) Fc region to provide altered effector function. See, for example, U.S. Patent 5,624,821; WO2003/086310; WO2005/120571; WO2006/0057702. Such modifications can be used to enhance or suppress various responses of the immune system, potentially having beneficial effects on diagnosis and therapy. Alterations in the Fc region include amino acid changes (substitution, deletion, and insertion), glycosylation or deglycosylation, and the addition of multiple Fc molecules. Changes in the Fc region can also alter the half-life of the antibody in therapeutic antibodies, enabling lower dosing frequencies and thus increasing convenience and reducing material usage. This mutation has reportedly eliminated the heterogeneity of inter-heavy-chain disulfide bonds in the hinge region.

In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is increased or decreased. This method is further described in U.S. Patent 5,677,425. Changing the number of cysteine residues in the hinge region of CH1 can, for example, promote the assembly of light and heavy chains or increase or decrease antibody stability. In another embodiment, the antibody is modified to improve its biological half-life. Various methods are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Patent 6,277,375. Alternatively, to increase the biological half-life, the antibody can be modified within the CH1 or CL region to contain a salvage receptor-binding epitope of two loops from the CH2 domain of the Fc region of IgG, as described in U.S. Patents 5,869,046 and 6,121,022. In yet another embodiment, the Fc region is modified to alter the effector function of the antibody by substituting at least one amino acid residue with a different amino acid residue. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320, and 322 can be substituted with different amino acid residues, giving the antibody a modified affinity for the effector ligand while retaining the antigen-binding ability of the parent antibody. The effector ligand with modified affinity can be, for example, an Fc receptor or the C1 component of complement. This method is further described in detail in U.S. Patents 5,624,821 and 5,648,260.

In another example, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby change the antibody's ability to fix complement. This method is further described in PCT Publication WO 94/29351. In yet another example, the Fc region is modified by modifying one or more amino acids at the following positions to enhance or reduce the antibody's ability to induce antibody-dependent cytotoxicity (ADCC) and/or enhance or reduce the antibody's affinity for the Fcγ receptor: 238, 239, 243, 248, 249, 252, 254, 255, 256, 258, 264, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 2 90, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438, or 439. This method is further described in PCT Publication WO 00/42072. Furthermore, binding sites on human IgG1 against FcγR1, FcγRII, FcγRIII, and FcRn have been mapped, and variants with improved binding have been described. Specific mutations at positions 256, 290, 298, 333, 334, and 339 are shown to improve binding to FcγRIII. Additionally, the following combined mutants are shown to improve FcγRIII binding: T256A/S298A, S298A/E333A, S298A/K224A, and S298A/E333A/K334A.

In one embodiment, the Fc region is modified to reduce the ability of antibody-mediated effector function and/or increase anti-inflammatory properties by modifying residues 243 and 264. In one embodiment, the Fc region of the antibody is modified by changing the residues at positions 243 and 264 to alanine. In one embodiment, the Fc region is modified to reduce the ability of antibody-mediated effector function and/or increase anti-inflammatory properties by modifying residues 243, 264, 267, and 328.

In one implementation, the Fc region is modified to eliminate the ability of antibody-mediated effector function by modifying residues 234, 235, and 329 to alanine or glycine (L234A-L235A-P329G).

In one implementation, the Fc region is modified to eliminate the ability of antibody-mediated effector function by modifying residue 297 to alanine (N234A).

In another embodiment, the antibody comprises a specific glycosylation pattern. For example, deglycosylated antibodies (i.e., antibodies lacking glycosylation) can be prepared. The glycosylation pattern of the antibody can be altered to, for example, increase the antibody's affinity or cohesion to the antigen. Such modification can be accomplished, for example, by altering one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions can be performed, resulting in the removal of one or more variable region framework glycosylation sites within the variable region framework glycosylation sites, thereby eliminating glycosylation at said sites. Such deglycosylation can increase the antibody's affinity or cohesion to the antigen. See, for example, U.S. Patents 5,714,350 and 6,350,861.

Antibodies can also be prepared in which the glycosylation pattern includes low-fucosylated or non-fucosylated glycans, such as low-fucosylated or non-fucosylated antibodies having a reduced amount of fucosylated residues in the glycan. The antibody may also include a glycan with an increased amount of bimeric GlcNac structures. Such modified glycosylation patterns have been shown to improve the ADCC ability of antibodies. Such modifications can be accomplished, for example, by expressing the antibody in host cells, wherein the glycosylation pathway is genetically engineered to produce glycoproteins with a specific glycosylation pattern. These cells have been described in the art and can be used as host cells for expressing the recombinant antibodies of the present invention to thereby produce antibodies with modified glycosylation. For example, cell lines Ms704, Ms705, and Ms709 lack the fucosylation gene FUT8 (α(1,6)-fucosylation), such that antibodies expressed in Ms704, Ms705, and Ms709 cell lines lack fucosylate on their carbohydrates. The Ms704, Ms705, and Ms709 FUT8-/- cell lines were generated by targeting and disrupting the FUT8 gene in CHO/DG44 cells using two alternative vectors (see U.S. Patent Publication No. 20040110704). For example, EP 1176195 describes cell lines with a functionally disrupted FUT8 gene encoding fucosyltransferase, such that antibodies expressed in these cell lines exhibit low fucosylation by reducing or eliminating α-1,6 bond-associated enzymes. EP 1176195 also describes cell lines with low enzymatic activity for adding fucose to N-acetylglucosamine that binds to the Fc region of an antibody or lacks enzymatic activity, such as the rat myeloma cell line YB2/0 (ATCC CRL 1662). PCT Publication WO03/035835 describes a variant CHO cell line, Lec13 cells, which has the ability to reduce the linking of fucose to Asn(297)-linked carbohydrates, resulting in low fucosylation of antibodies expressed in the host cells. Antibodies with modified glycosylation profiles can also be produced in eggs, as described in PCT Publication WO 06/089231. Alternatively, antibodies with modified glycosylation profiles can be produced in plant cells such as *Lemna* (US Patent 7,632,983). Methods for producing antibodies in plant systems are disclosed in US Patents 6,998,267 and 7,388,081. PCT Publication WO 99/54342 describes cell lines engineered to express glycoprotein-modified glycosyltransferases (e.g., β(1,4)-N-acetylglucosamine transferase III (GnTIII)), such that antibodies expressed in the engineered cell lines exhibit an increased bipartite GlcNac structure, which leads to increased ADCC activity of the antibodies.

Alternatively, fucosidases can be used to cleave the fucosylate residues of antibodies; for example, fucosidase α-L-fucosidase removes fucosylate residues from antibodies. The antibodies disclosed herein further include antibodies produced in lower eukaryotic host cells, specifically fungal host cells such as yeast and filamentous fungi, which have been genetically engineered to produce glycoproteins with mammalian or human-like glycosylation patterns. A specific advantage of these genetically modified host cells compared to currently used mammalian cell lines is the ability to control the glycosylation profile of the glycoproteins produced in the cells, enabling the production of compositions of glycoproteins in which a specific N-glycan structure is dominant (see, for example, U.S. Patents 7,029,872 and 7,449,308). These genetically modified host cells have been used to produce antibodies that predominantly have a specific N-glycan structure.

Furthermore, since fungi such as yeast or filamentous fungi lack the ability to produce fucosylated glycoproteins, antibodies produced in such cells will lack fucosylation unless the cells are further modified to include an enzymatic pathway for the production of fucosylated glycoproteins (see, for example, PCT Publication WO 2008112092). In certain embodiments, the antibodies disclosed herein further include those produced in lower eukaryotic host cells, and said antibodies comprise hybrid and complex N-glycans of fucosylated and non-fucosylated forms, including dichotomous and multitenant species, including but not limited to N-glycans such as GlcNAc(1-4)Man3GlcNAc2; Gal(1-4)GlcNAc(1-4)Man3GlcNAc2; NANA(1-4)Gal(1-4)GlcNAc(1-4)Man3GlcNAc2. In certain embodiments, the antibody compositions provided herein may include antibodies having at least one heterozygous N-glycan selected from the group consisting of: GlcNAcMan5GlcNAc2; GalGlcNAcMan5GlcNAc2; and NANAGalGlcNAcMan5GlcNAc2. In a particular aspect, the heterozygous N-glycan is the predominant N-glycan species in the composition. In another aspect, the heterozygous N-glycan is a specific N-glycan species comprising about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 100% of the heterozygous N-glycan in the composition.

In a particular embodiment, the antibody composition provided herein comprises an antibody having at least one complex N-glycan selected from the group consisting of: GlcNAcMan3GlcNAc2; GalGlcNAcMan3GlcNAc2; NANAGalGlcNAcMan3GlcNAc2; GlcNAc2Man3GlcNAc2; GalGlcNAc2Man3GlcNAc2; Gal2GlcNAc2Man3GlcNAc2; NANAGal2GlcNAc2Man3GlcNAc2; and NANA2Gal2GlcNAc2Man3GlcNAc2. In a particular aspect, the complex N-glycan is the predominant N-glycan species in the composition. In another aspect, the complex N-glycan is a specific N-glycan species comprising about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 100% of the complex N-glycan in the composition. In a particular embodiment, the N-glycan is fucoidylated. Typically, fucose is linked to the GlcNAc at the reducing end of the N-glycan via an α1,3-bond; to the GlcNAc at the reducing end of the N-glycan via an α1,6-bond; to the Gal at the non-reducing end of the N-glycan via an α1,2-bond; to the GlcNac at the non-reducing end of the N-glycan via an α1,3-bond; or to the GlcNAc at the non-reducing end of the N-glycan via an α1,4-bond.

Therefore, in a specific aspect of the above-described glycoprotein composition, the glycoform is α1,3-bonded or α1,6-bonded fucose to produce glycoforms selected from the group consisting of: Man5GlcNAc2(Fuc), GlcNAcMan5GlcNAc2(Fuc), Man3GlcNAc2(Fuc), GlcNAcMan3GlcNAc2(Fuc), GlcNAc2Man3GlcNAc2(Fuc), GalGlcNAc2Man3GlcNAc2(Fuc), Gal2GlcNAc2Man3GlcNAc2(Fuc), NANAGal2GlcNAc2Man3GlcNAc2(Fuc), and NANA2Gal2GlcNAc2Man3GlcNAc2(Fuc); α1,3-bonded or α1,4-bonded fucose to produce glycoforms selected from the group consisting of: GlcNAc(Fuc)Man5GlcNAc2, G lcNAc(Fuc)Man3GlcNAc2, GlcNAc2(Fuc1-2)Man3GlcNAc2, GalGlcNAc2(Fuc1-2)Man3GlcNAc2, Gal2G lcNAc2(Fuc1-2)Man3GlcNAc2, NANAGal2GlcNAc2(Fuc1-2)Man3GlcNAc2 and NANA2Gal2GlcNAc2(Fuc1-2 Man3GlcNAc2; or α1,2-bonded fucose to produce glycoforms selected from the group consisting of: Gal(Fuc)GlcNAc2Man3GlcNAc2, Gal2(Fuc1-2)GlcNAc2Man3GlcNAc2, NANAGal2(Fuc1-2)GlcNAc2Man3GlcNAc2 and NANA2Gal2(Fuc1-2)GlcNAc2Man3GlcNAc2.

In another aspect, the antibody comprises high-mannose N-glycans, including but not limited to Man8GlcNAc2, Man7GlcNAc2, Man6GlcNAc2, Man5GlcNAc2, Man4GlcNAc2, or N-glycans composed of Man3GlcNAc2 N-glycan structures. In another aspect mentioned above, the complex N-glycan further comprises fucosylated and non-fucosylated bifid and multitenant species. As used herein, the terms “N-glycan” and “glycoform” are used interchangeably and refer to N-linked oligosaccharides, for example, oligosaccharides linked to asparagine residues of a polypeptide via an asparagine-N-acetylglucosamine bond. N-linked glycoproteins contain N-acetylglucosamine residues linked to the amide nitrogen of asparagine residues in the protein.

D. Single-chain antibodies

Single-chain variable fragments (scFvs) are fusions of the variable regions of the heavy and light chains of immunoglobulins, linked together by short (typically serine or glycine) linkers. These chimeric molecules retain the specificity of the original immunoglobulin despite the removal of the constant region and the introduction of linker peptides. This modification generally leaves the specificity unchanged. These molecules were historically developed to facilitate phage display, where it is convenient to express the antigen-binding domain as a single peptide. Alternatively, scFvs can be generated directly from the heavy and light chains of a subclone derived from a hybridoma. Single-chain variable fragments lack the constant Fc region visible in intact antibody molecules and therefore lack common binding sites (e.g., protein A/G) used for antibody purification. These fragments are often purified/fixed using protein L because protein L interacts with the variable region of the κ light chain.

Flexible linkers typically include amino acid residues that promote helical and turn-like structures, such as alanine, serine, and glycine. However, other residues can also play a role. Tang et al. (1996) used phage display as a means of rapidly selecting single-chain antibodies (scFvs) from a protein linker library to customize linkers. Random linker libraries were constructed in which genes for variable domains of the heavy and light chains were linked by segments encoding 18-amino acid polypeptides of variable compositions. The scFv library (approximately 5 × ^10⁶ different members) was displayed on filamentous phages and subjected to affinity selection with haptens. The selected variant populations exhibited a significant increase in binding activity while retaining considerable sequence diversity. Screening of 1054 individual variants subsequently yielded catalytically active scFvs, which were efficiently produced in soluble form. Sequence analysis revealed a conserved proline in the two residues following the V- _H- C terminus in the linker, as well as abundant arginine and proline at other positions, as the only common feature of the selected linkers.

The recombinant antibodies disclosed herein may also involve sequences or portions that allow for dimerization or multimerization of the receptor. Such sequences include IgA-derived sequences that allow binding to the J chain to form multimers. Another multimerizing domain is the Gal4 dimerizing domain. In other embodiments, the chain may be modified with agents such as biotin/avidin, which allow for the combination of two antibodies.

In individual implementations, single-chain antibodies can be generated by linking the receptor light and heavy chains using non-peptide linkers or chemical units. Typically, the light and heavy chains are generated and purified in different cells and then linked together in an appropriate manner (i.e., the N-terminus of the heavy chain is linked to the C-terminus of the light chain via an appropriate chemical bridge).

Crosslinking agents are used to form molecular bridges connecting two different molecules with functional groups; examples include stabilizers and coagulants. However, it is also possible to generate dimers or polymers of the same analogues or heteropolymeric complexes comprising different analogues. To link two different compounds in a stepwise manner, heteromorphic bifunctional crosslinking agents can be used to eliminate unwanted homopolymer formation.

An exemplary heterogeneous bifunctional crosslinking agent comprises two reactive groups: one reactive group reacts with a primary amine group (e.g., N-hydroxysuccinimide), and the other reactive group reacts with a thiol group (e.g., pyridyl disulfide, maleimide, halogen, etc.). Through the primary amine reactive group, the crosslinking agent can react with lysine residues of a protein (e.g., a selected antibody or fragment), and through the thiol reactive group, the crosslinking agent already linked to the first protein reacts with cysteine residues (free thiol groups) of other proteins (e.g., a selector).

Crosslinking agents with reasonable stability in blood are preferred. Many types of disulfide-containing linkers are known to be successfully used for conjugating targeting agents and therapeutic/prophylactic agents. Linkers containing sterically hindered disulfide bonds may provide greater stability in vivo, thus preventing the release of the targeting peptide before reaching its site of action. Therefore, these linkers constitute a group of conjugating agents.

Another crosslinking agent is SMPT, a bifunctional crosslinking agent comprising disulfide bonds “sterically hindered” by adjacent benzene rings and methyl groups. It is believed that the steric hindrance of the disulfide bonds protects the bonds from attack by thioglycolic anions such as glutathione, which can be present in tissues and blood, and thereby helps prevent decoupling of the conjugate before the attached drug is delivered to the target site.

Like many other known crosslinking agents, SMPT crosslinking agents possess the ability to crosslink functional groups, such as the SH group of cysteine or primary amines (e.g., the ε-amino group of lysine). Another possible type of crosslinking agent includes heterobifunctional photoactive phenyl azides containing disulfide bonds that can cleave, such as sulfosuccinimide-2-(p-azidosalicylic acid)ethyl-1,3'-dithiopropionate. The N-hydroxy-succinimide group reacts with the primary amine group, and the phenyl azide (on photolysis) reacts nonselectively with any amino acid residue.

In addition to sterically hindered crosslinking agents, non-sterically hindered joints may also be used according to this document. Other useful crosslinking agents that are not considered to include or produce protected disulfides include SATA, SPDP, and 2-iminothionane (Wawrzynczak and Thorpe, 1987). The use of such crosslinking agents is well known in the art. Another embodiment involves the use of flexible joints.

U.S. Patent 4,680,338 describes a bifunctional linker that can be used to generate conjugates of ligands with amine-containing polymers and/or proteins, particularly for forming antibody conjugates with chelating agents, drugs, enzymes, detectable labels, etc. U.S. Patents 5,141,648 and 5,563,250 disclose cleavable conjugates containing unstable bonds that are cleavable under a variety of mild conditions. This linker is particularly useful because the agent of interest can be directly bonded to the linker, where cleavage results in the release of the active agent. Specific uses include adding free amino or free thiol groups to proteins, such as antibodies or drugs.

U.S. Patent 5,856,456 provides peptide linkers for connecting polypeptide components to prepare fusion proteins, such as single-chain antibodies. The linker is up to about 50 amino acids in length, including at least one charged amino acid (preferably arginine or lysine), followed by proline, and is characterized by higher stability and reduced aggregation. U.S. Patent 5,880,270 discloses amino-containing linkers useful in various immunodiagnostic and separation techniques.

E. Purification

In some embodiments, the antibodies of this disclosure may be purified. As used herein, the term "purified" is intended to refer to a composition that can be isolated from other components, wherein the protein is purified to any degree relative to its naturally available state. Thus, a purified protein also refers to a protein that is unaffected by the environment in which it may naturally exist. When the term "substantially purified" is used, this name will refer to a composition in which a protein or peptide forms the major component of the composition, such as constituting about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more of the protein in the composition.

Protein purification techniques are well known to those skilled in the art. These techniques involve, at one level, the coarse separation of the cellular environment into peptide and non-peptide fractions. After separating the peptide from other proteins, chromatographic and electrophoretic techniques can be used to further purify the peptide of interest to achieve partial or complete purification (or purification to homogenization). Analytical methods particularly suitable for preparing pure peptides include ion exchange chromatography, size exclusion chromatography; polyacrylamide gel electrophoresis; and isoelectric focusing. Other methods for protein purification include precipitation with ammonium sulfate, PEG, antibodies, etc., or by heat denaturation followed by centrifugation; gel filtration, reversed-phase chromatography, hydroxyapatite chromatography, and affinity chromatography; and combinations of these and other techniques.

When purifying the antibodies disclosed herein, it may be necessary to express the peptide in a prokaryotic or eukaryotic expression system and extract the protein using denaturing conditions. The peptide can be purified from other cellular components using affinity columns that bind to a labeled portion of the peptide. As is known in the art, it is considered that the order in which different purification steps are performed can be altered, or certain steps can be omitted, and still result in a suitable method for preparing a substantially purified protein or peptide.

Typically, intact antibodies are fractionated using agents that bind to the Fc moiety of the antibody (i.e., protein A). Alternatively, antigens can be used to simultaneously purify and select appropriate antibodies. Such methods typically utilize a selector bound to a carrier, such as a column, filter, or bead. The antibody binds to a support, contaminants are removed (e.g., washed away), and the antibody is released by applying conditions (salt, heat, etc.).

In light of this disclosure, those skilled in the art will recognize various methods used to quantify the degree of purification of proteins or peptides. These methods include, for example, determining the specific activity of an active fraction or assessing the amount of peptide within a fraction using SDS/PAGE analysis. Another method for assessing fraction purity is to calculate the specific activity of the fraction, comparing it to the specific activity of the initial extract, and thus calculating the purity. Of course, the actual unit used to express the amount of activity will depend on the specific assay technique chosen for post-purification and whether the expressed protein or peptide exhibits detectable activity.

It is known that the migration of peptides can vary with different SDS/PAGE conditions, sometimes significantly (Capaldi et al., 1977). Therefore, it should be understood that the apparent molecular weight of purified or partially purified expression products may differ under different electrophoretic conditions.

III. LILRB1-related diseases

LILRB1, a member of the LILR receptor family containing ITIM, plays a crucial role in the regulation of innate and adaptive immunity. LILRB1 is expressed on various types of immune cells, including NK cells, and acts as an immune checkpoint protein. Expression of LILRB in myeloid-derived suppressor cells (MDSCs) can promote tumor growth and contribute to a suppressive immune microenvironment that contributes to tumor progression and metastasis. On the other hand, activating LILRB1 signaling using agonist antibodies may reduce tissue inflammation and can be used for the management of autoimmune diseases. This article presents agonist and antagonist human LILRB1 monoclonal antibodies with specific targeting properties for modulating LILRB1 signaling. These LILRB1 antibodies can be used to treat human diseases including cancer, autoimmune diseases, and inflammatory conditions.

While hyperproliferative disorders can be associated with any disease that causes cells to begin multiplying uncontrollably, a typical example is cancer.

Examples of cancer can generally be classified as solid tumors and hematologic malignancies. Solid tumors include, but are not limited to, adrenal carcinoma, bile duct carcinoma, bone cancer, brain cancer (e.g., astrocytoma, brainstem glioma, craniopharyngioma, ependymoma, hemangioblastoma, medulloblastoma, meningioma, oligodendroglioma, spinal axis tumors), breast cancer (including acoustic neuroma, basal breast cancer, ductal carcinoma, and lobular breast cancer), cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, esophageal cancer, eye cancer, gastric cancer, glioblastoma, head and neck cancer, kidney cancer (including Wilms' tumor), liver cancer (including hepatocellular carcinoma (HCC)), lung cancer (including bronchial carcinoma, non-small cell lung cancer (squamous/non-squamous), bronchioloalveolar carcinoma). Follicular cell lung cancer, papillary adenocarcinoma, mesothelioma, melanoma, Merkel cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pineal tumor, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma (including chondrosarcoma, Ewing's sarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, myxosarcoma, osteoblastic sarcoma, rhabdomyosarcoma, synovial sarcoma), skin cancer (including basal cell carcinoma, sebaceous gland carcinoma, squamous cell carcinoma), testicular cancer (including seminoma), thymic carcinoma, thyroid cancer (e.g., medullary thyroid carcinoma, papillary thyroid carcinoma), uterine cancer, and vaginal cancer.

Hematologic malignancies include, but are not limited to, blastic plasmacytic dendritic cell vegetations (BPDCN), heavy chain disease, leukemia (including but not limited to acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) (including but not limited to acute promyelocytic leukemia (APL) or M3 AML, acute myeloid monocytic leukemia or M4 AML, acute monocytic leukemia or M5 AML), B-cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid monocytic leukemia (CMML), and chronic myeloid leukemia (CML). Pre-B acute lymphoblastic leukemia (pre-B ALL), diffuse large B-cell lymphoma (DLBCL), extranodal NK/T-cell lymphoma, hairy cell leukemia, HHV8-associated primary exudative lymphoma, plasmablastic lymphoma, primary CNS lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histocyte-rich B-cell lymphoma, lymphoma (including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia), multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative vegetations, and polycythemia vera.

Immunotherapy holds great promise for achieving durable anti-tumor effects. Immune checkpoint PD-1 and CTLA-4 blockade therapies have been successful in treating some types of cancer but not others. These immunotherapies target inhibitory molecules on T cells to reactivate dysfunctional T cells within the tumor microenvironment (TME). Other immune cell populations, including monocytes, exist in the TME in even greater numbers than T cells. In fact, monocyte-derived macrophages are the most abundant immune cell population in tumor tissue. Although these innate cells have the ability to kill tumor cells and initiate or reactivate T cells, they become dysfunctional in the TME and transform into MDSCs and tumor-associated macrophages (TAMs) that support tumor development and suppress immune surveillance and attack. MDSCs, including monocyte-derived MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs), represent a heterogeneous population of immature myeloid cells that have failed to terminally differentiate. TAMs are a mixed macrophage population in the TME. TAMs are anti-inflammatory and associated with poor prognosis. Despite their phenotypic plasticity, MDSCs and TAMs are defined by their immunosuppressive function. Removing, reprogramming, or blocking the transport of these immunosuppressive monocytes is becoming an attractive anticancer therapeutic strategy.

LILRB1 is expressed on MDSCs and TAMs in the TME. Therapeutic blockade of LILRB1 has the potential to reactivate or enhance the antitumor immune response in patients with disease that is unresponsive to or relapses to T-cell checkpoint inhibitors.

LILRB1 expression on myeloid cells can regulate systems involved in autoimmune and inflammatory diseases. Therapeutic activation or stimulation of LILRB1 has the potential to treat autoimmune or inflammatory diseases.

Autoimmune or inflammatory diseases include, but are not limited to, acquired immunodeficiency syndrome (AIDS, a viral disease with an autoimmune component), alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, stomatitis-diarrhea-herpetic dermatitis, and chronic fatigue immune dysfunction syndrome (CFS). FIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn's disease, Degos disease, juvenile dermatomyositis, discoid lupus, primary mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Stihl's disease), juvenile rheumatoid arthritis, Meniere's disease. Ellison's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polygonatum syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Leter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, systemic scleroderma, progressive systemic sclerosis (PSS), systemic sclerosis (SS), Sjögren's syndrome, stiff-person syndrome, systemic lupus erythematosus (SLE), high Angiotensin II arteritis, temporal arteritis/giant cell arteritis, inflammatory bowel disease (IBD), ulcerative colitis, Cohen's disease, intestinal mucosal inflammation, wasting diseases associated with colitis, uveitis, vitiligo and Wegener's granulomatosis, Alzheimer's disease, asthma, atopic dermatitis, allergies, atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft-versus-host disease, hemolytic anemia, osteoarthritis, sepsis, stroke, tissue and organ transplantation, vasculitis, diabetic retinopathy, ventilator-induced lung injury, viral infections, autoimmune diabetes, etc. Inflammatory conditions include, for example, chronic and acute inflammatory conditions.

IV. Treatment of the Disease

A. Preparation and application

This disclosure provides pharmaceutical compositions comprising an anti-LILRB antibody and an antigen for generating said antibody. Such compositions comprise a preventative or therapeutically effective amount of the antibody or a fragment thereof, and a pharmaceutically acceptable carrier. In specific embodiments, the term "pharmaceuticalally acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals and more specifically in humans. The term "carrier" refers to a diluent, excipient, or mordant with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a particular carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Other suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc.

If desired, the composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers. These compositions can be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable formulations are described in Remington's Pharmaceutical Sciences. Such compositions will contain a preventative or therapeutically effective amount of an antibody or its fragment (preferably in purified form) along with a suitable amount of carrier to provide a form appropriate for administration to the patient. The formulation should be suitable for the route of administration, which may be oral, intravenous, intra-arterial, buccal, intranasal, nebulized, bronchial inhalation, or delivered via mechanical ventilation.

As described herein, the antibodies of this disclosure can be formulated for parenteral administration, for example, for injection via intradermal, intravenous, intraarterial, intramuscular, subcutaneous, intratumoral, or even intraperitoneal routes. Alternatively, the antibodies can be applied directly to mucosa via local routes, such as via nasal drops, inhalation, or nebulizer. Pharmaceutically acceptable salts include acid salts, and said pharmaceutically acceptable salts are formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Salts formed from free carboxyl groups can also be derived from inorganic bases (e.g., sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide) and organic bases (e.g., isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine, etc.).

Passive transfer of antibodies, known as artificially acquired passive immunization, typically involves intravenous injection. Antibodies can be in the form of human or animal plasma or serum, as a mixture of human immunoglobulins for intravenous (IVIG) or intramuscular (IG) administration, as high-titer human IVIG or IG derived from an immunized donor or from a recovered patient, and as monoclonal antibodies (MAbs). This immunity usually lasts only a short period and carries the potential risk of hypersensitivity reactions and serum sickness, especially with non-human gamma globulins. However, passive immunization provides immediate protection. The antibodies are formulated into an injectable (i.e., sterile and injectable) carrier.

Generally, the components of the compositions disclosed herein are provided separately or mixed together in unit dosage forms, for example, as a dry lyophilized powder or anhydrous concentrate in an hermetically sealed container, such as an ampoule indicating the amount of active agent or a typical small capsule. When the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, ampoules of sterile water for injection or saline can be provided so that the components can be mixed prior to administration.

The compositions disclosed herein can be formulated into neutral or salt forms. Pharmaceutically acceptable salts include those that form with anions (such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc.) and those that form with cations (such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.).

B. Cell therapy

On the other hand, this disclosure provides immune cells expressing chimeric antigen receptors (CARs). In some embodiments, the CAR includes the antigen-binding fragments provided herein. In one embodiment, the CAR protein includes, from the N-terminus to the C-terminus: a leader peptide, an anti-LILRB1 heavy chain variable domain, an adaptor domain, an anti-LILRB1 light chain variable domain, a human IgG1-CH2-CH3 domain, a spacer region, a CD28 transmembrane domain, a 4-1BB intracellular co-stimulatory signaling domain, and a CD3ζ intracellular T cell signaling domain.

Methods for immunotherapy are also provided, the methods comprising administering an effective amount of the immune cells of this disclosure. In one embodiment, a medical disease or condition is treated by transferring a population of immune cells that elicit an immune response. In some embodiments of this disclosure, cancer or infection is treated by transferring a population of immune cells that elicit an immune response. This document provides methods for treating cancer in an individual or delaying the progression of cancer, the methods comprising administering an effective amount of antigen-specific cell therapy to the individual.

Immune cells can be T cells (e.g., regulatory T cells, CD4+ T cells, CD8+ T cells, or γ-δ T cells), NK cells, invariant NK cells, NKT cells, or macrophages. This article also provides methods for generating and engineering immune cells, as well as methods for using and administering cells for adoptive cell therapy, in which case the cells can be autologous or allogeneic. Therefore, immune cells can be used as part of immunotherapy, such as targeting cancer cells.

Immune cells can be isolated from subjects, specifically human subjects. Immune cells can be obtained from healthy human subjects, healthy volunteers, or healthy donors. Immune cells can be obtained from subjects of interest, such as subjects suspected of having a specific disease or symptom, subjects suspected of being susceptible to a specific disease or symptom, or subjects receiving therapy for a specific disease or symptom. Immune cells can be collected from any location within the subject's body where they are present, including but not limited to blood, umbilical cord blood, spleen, thymus, lymph nodes, and bone marrow. The isolated immune cells can be used directly, or they can be stored for a period of time, such as by freezing.

Immune cells can be enriched/purified from any tissue in which they reside, including but not limited to blood (including blood collected from a blood bank or cord blood bank), spleen, bone marrow, tissue removed and/or exposed during surgery, and tissue obtained through biopsy. The tissues/organs from which immune cells are enriched, isolated, and/or purified can be isolated from both living and non-living subjects, wherein the non-living subject is an organ donor. In certain embodiments, immune cells are isolated from blood such as peripheral blood or cord blood. In some aspects, immune cells isolated from cord blood have enhanced immunomodulatory capacity, as measured by CD4 or CD8 positive T cell suppression. In certain aspects, immune cells are isolated from pooled blood, particularly pooled cord blood, to enhance immunomodulatory capacity. The pooled blood can be from two or more sources, such as three, four, five, six, seven, eight, nine, ten, or more sources (e.g., donor subjects).

Immune cell populations can be obtained from subjects requiring therapy or suffering from diseases associated with reduced immune cell activity. Therefore, the cells will be autologous to the subject requiring therapy. Alternatively, immune cell populations can be obtained from a donor, preferably a tissue-compatible donor. Immune cell populations can be collected from peripheral blood, umbilical cord blood, bone marrow, spleen, or any other organ/tissue in which immune cells are present in said subject or donor. Immune cells can be isolated from a group of subjects and/or donors, such as from pooled umbilical cord blood.

When the immune cell population is obtained from a donor different from the subject, the donor is preferably allogeneic, provided that the obtained cells are compatible with the subject, as these cells can be introduced into the subject. Allogeneic donor cells may or may not be compatible with human leukocyte antigens (HLA). To ensure compatibility with the subject, allogeneic cells can be treated to reduce immunogenicity.

Immune cells can be genetically engineered to express antigen receptors such as engineered TCRs and/or chimeric antigen receptors (CARs). For example, host cells (e.g., autologous or allogeneic T cells) are modified to express T cell receptors (TCRs) that are antigen-specific to cancer antigens. In a particular embodiment, NK cells are engineered to express TCRs. NK cells can be further engineered to express CARs. Multiple CARs and/or TCRs, such as those targeting different antigens, can be added to a single cell type, such as T cells or NK cells.

Suitable modification methods are known in the art. See, for example, Sambrook et al., ibid.; and Ausubel et al., *Current Protocols in Molecular Biology*, Greene Publishing Associates and John Wiley & Sons, New York, 1994. For example, transduction techniques described in Heemskerk et al. (2008) and Johnson et al. (2009) can be used to transduce cells to express T-cell receptors (TCRs) that are antigen-specific to cancer antigens.

In some embodiments, the cell includes one or more nucleic acids encoding one or more antigen receptors, introduced through genetic engineering, and genetically engineered products of such nucleic acids. In some embodiments, the nucleic acid is heterologous, i.e., not typically present in the cell or in samples obtained from said cell, such as samples obtained from another organism or cell, for example, which are not typically found in engineered cells and/or organisms of such cell origin. In some embodiments, the nucleic acid is not naturally occurring, such as nucleic acids not found in nature (e.g., chimeric nucleic acids).

C. Combination therapy

It may also be desirable to provide combination therapies using the antibodies of this disclosure in combination with other anticancer therapies. These therapies will be provided in combination amounts that effectively reduce one or more disease parameters. This process may involve simultaneously exposing cells/subjects to two agents/therapies, for example, using a single composition or pharmacological formulation comprising two agents, or by simultaneously exposing cells/subjects to two different compositions or formulations, wherein one composition comprises an antibody and the other composition comprises another agent.

Alternatively, antibodies can be administered minutes to weeks before or after other treatments. It is generally ensured that there is no significant time gap between each delivery so that the therapy will still be able to exert a beneficial combined effect on the cells/subject. In such cases, cell contact is considered in two ways: with a delay of approximately 12 to 24 hours between each delivery, with a delay of approximately 6 to 12 hours between each delivery, or with a delay of only approximately 12 hours. In some cases, a significantly longer treatment duration can be expected; however, this involves a time gap of several 10 (2, 3, 4, 5, 6, or 7) days to several (1, 2, 3, 4, 5, 6, 7, or 8) weeks between the respective administrations.

It is also conceivable to expect more than one administration of anti-LILRB1 antibody or other therapy. Various combinations can be used, where the antibody is "A" and another therapy is "B," as illustrated below:

A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/B

A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A

A/A/A/B B/A/A/A A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B

Other combinations have been considered. To kill cells, inhibit cell growth, suppress metastasis, inhibit angiogenesis, or otherwise reverse or reduce the malignant phenotype of tumor cells, the methods and compositions of the present invention can be used to contact target cells or sites with antibodies and at least one other therapy. These therapies will be provided in combined amounts that effectively kill cancer cells or inhibit cancer cell proliferation. This process may involve simultaneously contacting cells/sites/subjects with the agent/therapy.

Specific agents considered for combination therapy with the antibodies disclosed herein include chemotherapy and hematopoietic stem cell transplantation. Chemotherapy may include cytarabine (ara-C) and anthracyclines (most commonly daunorubicin), high-dose cytarabine alone, all-trans retinoic acid (ATRA) in addition to induction chemotherapy, anthracyclines typically after consolidation therapy, histamine dihydrochloride (Ceplene) and interleukin-2 (Proleukin), gemtuzumab ozogamicin (Mylotarg) for patients aged 60 years or older with relapsed AML who are not candidates for high-dose chemotherapy, clofarabine, and targeted therapies such as kinase inhibitors, farnesyltransferase inhibitors, decitabine, and inhibitors of MDR1 (multidrug resistance protein) or arsenic trioxide or relapsed acute promyelocytic leukemia (APL).

In some embodiments, the agents of the combination therapy are one or more drugs selected from the group consisting of: topoisomerase inhibitors, anthracycline topoisomerase inhibitors, anthracycline, daunorubicin, nucleoside metabolism inhibitors, cytarabine, demethylating agents, low-dose cytarabine (LDAC), a combination of daunorubicin and cytarabine, liposomes of daunorubicin and cytarabine for injection, azacytidine, decitabine, all-trans retinoic acid (ATRA), and arsenic. Arsenic trioxide, histamine dihydrochloride, interleukin-2, adeleukin, gemtuzumab/orzomicin, FLT-3 inhibitors, midostaurin, clofarabine, farnesyltransferase inhibitors, decitabine, IDH1 inhibitors, ivosidenib, IDH2 inhibitors, enasidenib, smooth muscle (SMO) inhibitors, glasdegib, arginase inhibitors, IDO inhibitors, icardoles Epicadostat, BCL-2 inhibitors, Venetoclax, platinum complex derivatives, oxaliplatin, kinase inhibitors, tyrosine kinase inhibitors, PI3 kinase inhibitors, BTK inhibitors, ibrutinib, acalabrutinib, zanubrutinib, PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, LAG3 antibodies, ICOS antibodies, TIGIT antibodies, TIM3 antibodies, CD40 antibodies, 4-1BB antibodies, CD47 antibodies, SIRP1α antibodies or fusion proteins, CD70 and CLL1 antibodies, CD123 antibodies, E-selectin antagonists, antibodies binding to tumor antigens, antibodies binding to T cell surface markers, antibodies binding to myeloid or NK cell surface markers, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, hormone therapy drugs, hormone antagonists, aromatase inhibitors, and P-glycoprotein inhibitors.

V. Antibody conjugates

The antibodies disclosed herein can be linked to at least one pharmaceutical agent to form antibody conjugates. To enhance the efficacy of antibody molecules as diagnostic or therapeutic agents, at least one desired molecule or moiety is typically linked, covalently bound, or compounded. Such molecules or moiety can be, but are not limited to, at least one effector or reporter molecule. Effector molecules include molecules with desired activity, such as cytotoxic activity. Non-limiting examples of effector molecules already linked to antibodies include toxins, antitumor agents, therapeutic enzymes, radionuclides, antiviral agents, chelating agents, cytokines, growth factors, and oligonucleotides or polynucleotides. In contrast, a reporter molecule is defined as any moiety that can be detected using an assay. Non-limiting examples of reporter molecules already conjugated to antibodies include enzymes, radiolabeled molecules, haptens, fluorescently labeled molecules, phosphorescent molecules, chemiluminescent molecules, chromophores, photosynthetic molecules, colored particles, or ligands such as biotin.

Antibody-drug conjugates have emerged as a breakthrough approach for developing cancer therapies. Antibody-drug conjugates (ADCs) comprise monoclonal antibodies (MAbs) covalently linked to cytotoxic drugs. This approach combines the high specificity of MAbs against their antigenic targets with highly potent cytotoxic drugs, resulting in “armed” MAbs that deliver a payload (drug) to tumor cells with enriched antigen levels. Targeted drug delivery also minimizes exposure in normal tissues, thereby reducing toxicity and improving the therapeutic index. The FDA’s approval of two ADC drugs—brentuximab vedotin in 2011 and trastuzumab emtansine (T-DM1) in 2013—validates this approach. Currently, more than 30 ADC candidates are in various phases of clinical trials for cancer treatment (Leal et al., 2014). As antibody engineering and linker-payload optimization become increasingly sophisticated, the discovery and development of new ADCs increasingly depends on the identification and validation of novel targets suitable for this approach and the generation of targeted MAbs. Two criteria for ADC targets are upregulated/high-level expression in tumor cells and robust internalization.

Antibody conjugates are also preferred for use as diagnostic agents. Antibody diagnostics are generally divided into two categories: one for in vitro diagnostics, such as various immunoassays, and the other for in vivo diagnostic protocols, often referred to as "antibody-targeted imaging." Many suitable imaging agents are known in the art, as are methods of conjugating them with antibodies (see, for example, U.S. Patents 5,021,236, 4,938,948, and 4,472,509). The imaging component used can be paramagnetic ions, radioactive isotopes, fluorescent dyes, NMR-detectable substances, and X-ray imaging agents.

In the case of paramagnetic ions, ions such as chromium (III), manganese (II), iron (III), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and/or erbium (III) can be mentioned by way of example, with gadolinium being particularly preferred. Ions suitable for other contexts, such as X-ray imaging, include, but are not limited to, lanthanum (III), gold (III), lead (II), and especially bismuth (III).

In the case of radioisotopes used for therapeutic and/or diagnostic applications, references may be made to astatine ^-211 , carbon- ¹⁴ , chromium- ⁵¹ , chlorine- ³⁶ , cobalt- ⁵⁷ , cobalt ^{-58 ,} copper- ⁶⁷ , Eu- ¹⁵² , gallium-67, hydrogen ^-3 , iodine ^-123 , iodine- ¹²⁵ , iodine ^-131 , indium- ¹¹¹ , iron- ⁵⁹ , phosphorus- ³² , rhenium ^-186 , rhenium ^-188 , selenium- ⁷⁵ , sulfur- ³⁵ , technetium ^-99m , and/or yttrium ^-90 . ^I25 is generally preferred in some embodiments, while technetium- ^99m and/or indium ^-111 are also generally preferred due to their low energy and suitability for long-distance detection. The radiolabeled monoclonal antibodies of this disclosure can be produced according to methods well known in the art. For example, monoclonal antibodies can be iodinated by contact with sodium iodide and/or potassium iodide, as well as chemical oxidants such as sodium hypochlorite or enzymatic oxidants such as lactoperoxidase. The monoclonal antibody according to this disclosure can be labeled with technetium- ^99m via a ligand exchange process, for example, by reducing pertechnetium with a stannous solution, chelating the reduced technetium onto a dextran gel column (Sephadex column), and applying the antibody to this column. Alternatively, direct labeling techniques can be used, such as by incubating pertechnetium, a reducing agent such as _SNCl2 , a buffer solution such as sodium potassium phthalate solution, and the antibody. The intermediate functional group commonly used to bind the radioactive isotope, present as a metal ion, to the antibody is diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

Fluorescent labels considered for use as conjugates include Alexa 350, Alexa 430, AMCA, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, Cascade Blue, Cy3, Cy5,6-FAM, fluorescein isothiocyanate, HEX, 6-JOE, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, REG, Rhodamine Green, Rhodamine Red, renal contrast agent (Renographin), ROX, TAMRA, TET, tetramethylrhodamine, and/or Texas Red.

Another type of antibody conjugate considered in this disclosure is an antibody conjugate intended primarily for in vitro use, wherein the antibody is linked to a secondary binding ligand and/or an enzyme (enzyme tag) that produces a colored product upon contact with a chromogenic substrate. Examples of suitable enzymes include urease, alkaline phosphatase, (horseradish) catalase, or glucose oxidase. Preferred secondary binding ligands are biotin and avidin, as well as streptavidin compounds. The use of such tags is well known to those skilled in the art and is described, for example, in U.S. Patents 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, and 4,366,241.

Another known method for site-specific binding of molecules to antibodies involves the reaction of antibodies with hapten-based affinity tags. Essentially, the hapten-based affinity tag reacts with an amino acid at the antigen-binding site, thereby disrupting this site and blocking the specific antigen reaction. However, this may not be advantageous because it causes the antibody conjugate to lose its antigen binding.

Molecules containing azido groups can also be used to form covalent bonds with proteins via reactive daene intermediates generated by low-intensity ultraviolet light (Potter and Haley, 1983). Specifically, 2- and 8-azido analogs of purine nucleotides have been used as site-directed photoprobes to identify nucleotide-binding proteins in crude cell extracts (Owens and Haley, 1987; Atherton et al., 1985). 2- and 8-azidonucleotides have also been used to map the nucleotide-binding domains of purified proteins (Khatoon et al., 1989; King et al., 1989; Dholakia et al., 1989) and can be used as antibody binders.

Several methods for linking or conjugating antibodies to their conjugate moieties are known in the art. Some linking methods involve the use of metal chelating complexes, such as organic chelating agents like diethylenetriaminepentaacetic acid (DTPA); ethylenetriaminetetraacetic acid; N-chloro-p-toluenesulfonamide; and/or tetrachloro-3α-6α-diphenylglyuron-3 linked to the antibody (US Patents 4,472,509 and 4,938,948). Monoclonal antibodies can also be reacted with enzymes in the presence of conjugates such as glutaraldehyde or periodate. Conjugates with fluorescein markers are prepared in the presence of these conjugates or by reaction with isothiocyanates. In US Patent 4,938,948, imaging of breast tumors is achieved using a monoclonal antibody, and the detectable imaging moieties are bound to the antibody using linkers such as methylparaben or N-succinimide-3-(4-hydroxyphenyl)propionate.

In other embodiments, immunoglobulin derivatization is considered by selectively introducing thiol groups into the Fc region of the immunoglobulin using reaction conditions that do not alter the antibody binding site. Antibody conjugates produced according to this method are disclosed to exhibit improved lifetime, specificity, and sensitivity (U.S. Patent 5,196,066, which is incorporated herein by reference). Site-specific linkages of effector or reporter molecules have also been disclosed in the literature (O'Shannessy et al., 1987), in which the reporter or effector molecule is conjugated to carbohydrate residues in the Fc region. This method has been reported to produce antibodies with diagnostic and therapeutic potential currently under clinical evaluation.

VI. Immunological Detection Methods

In yet another embodiment, this disclosure relates to an immunoassay method for binding, purifying, removing, quantifying, and generally otherwise detecting LILRB-associated cancers. While such methods can be applied in a conventional sense, another use would be for the quality control and monitoring of vaccines and other viral stock solutions, where antibodies according to this disclosure can be used to assess the amount or integrity (i.e., long-term stability) of the H1 antigen in the virus. Alternatively, the method can be used to screen various antibodies to obtain a suitable/desired reaction profile.

Some immunoassay methods include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoradioassay, fluorescence immunoassay, chemiluminescence assay, bioluminescence assay, and Western blotting, to name just a few. Specifically, competitive assays for detecting and quantifying LILRB are also provided. The procedures for various useful immunoassay methods have been described in the scientific literature, for example, Doolittle and Ben-Zeev (1999); Gulbis and Galand (1993); DeJager et al. (1993) and Nakamura et al. (1987). Typically, the immunobinding method involves obtaining a sample suspected of containing LILRB-associated cancer and contacting the sample with a first antibody according to this disclosure under conditions that effectively allow for the formation of immune complexes, as appropriate.

These methods include those for detecting or purifying LILRB or LILRB-associated cancer cells from a sample. Antibodies are preferably attached to a solid support, such as a column matrix, and a sample suspected of containing LILRB-associated cancer cells is applied to the immobilized antibody. Unwanted components are washed away from the column, allowing LILRB-expressing cells to immunely recombine with the immobilized antibody, which is then collected by removing the organism or antigen from the column.

Immunobinding methods also include methods for detecting and quantifying the amount of LILRB-associated cancer cells or related components in a sample, as well as detecting and quantifying any immune complexes formed during the binding process. Here, a sample suspected of containing LILRB-associated cancer cells is obtained, and the sample is contacted with an antibody binding LILRB or its components. Subsequently, the amount and quantification of immune complexes formed under specific conditions are detected. For antigen detection, the analyzed biological sample can be any sample suspected of containing LILRB-associated cancer, such as tissue sections or samples, homogenized tissue extracts, biological fluids including blood and serum, or secretions such as feces or urine.

Under effective conditions, contacting the selected biological sample with the antibody for a sufficient period of time to allow for the formation of immune complexes (primary immune complexes) typically involves simply adding the antibody composition to the sample and incubating the mixture for a sufficiently long period to allow the antibody to form an immune complex with LILRB, i.e., to bind to LILRB. After this time, the sample-antibody composition is usually washed, such as with tissue sections, ELISA plates, dot blots, or protein blotting, to remove any non-specifically bound antibody species, thus detecting only those antibodies specifically bound within the primary immune complexes.

Typically, the detection of immune complex formation is well known in the art and can be achieved by applying numerous methods. These methods are generally based on the detection of labels or markers such as those that are radioactive, fluorescent, biological, or enzyme-based. Patents relating to the use of such labels include U.S. Patents 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, and 4,366,241. Of course, as is known in the art, additional advantages can be found by using secondary binding ligands, such as second antibodies and/or biotin/avidin ligands.

The antibody used in the assay can itself be linked to a detectable label, which can then be simply detected to determine the amount of primary immune complex in the composition. Alternatively, the first antibody bound within the primary immune complex can be detected by a second binding ligand having binding affinity for the antibody. In these cases, the second binding ligand can be linked to the detectable label. The second binding ligand itself is typically an antibody, and therefore can be referred to as a “secondary” antibody. The primary immune complex is contacted with the labeled secondary binding ligand or antibody under effective conditions and for a period of time sufficient to allow for the formation of a secondary immune complex. The secondary immune complex is then typically washed to remove any non-specifically bound labeled secondary antibody or ligand, and the remaining label in the secondary immune complex is then detected.

Another method involves detecting primary immune complexes via a two-step approach. As described above, a second binding ligand, such as an antibody with binding affinity to the primary antibody, is used to form secondary immune complexes. After washing, the secondary immune complexes are again contacted with a third binding ligand or antibody with binding affinity to the secondary antibody under effective conditions for a period sufficient to allow for the formation of immune complexes (tertiary immune complexes). The third ligand or antibody is then linked to a detectable label, thereby allowing the detection of the resulting tertiary immune complexes. This system can provide signal amplification if desired.

An immunoassay method uses two different antibodies. A first biotinylated antibody is used to detect a target antigen, and then a second antibody is used to detect biotin linked to a conjugated biotin. In this method, the sample to be tested is first incubated in a solution containing the first-step antibody. If the target antigen is present, one of the antibodies binds to the antigen to form a biotinylated antibody/antigen complex. The antibody/antigen complex is then amplified by incubation in a series of solutions of streptavidin (or avidin), biotinylated DNA, and/or complementary biotinylated DNA, with each step adding an additional biotin site to the antibody/antigen complex. The amplification steps are repeated until a suitable amplification level is reached, at which point the sample is incubated in a solution containing a second-step anti-biotinylated antibody. This second-step antibody is labeled, for example, with an enzyme that can be used for tissue enzymological detection of the presence of the antibody/antigen complex using a chromogenic substrate. With appropriate amplification, a visually visible conjugate can be produced.

Another known immunoassay method utilizes immuno-PCR (polymerase chain reaction). Similar to the Cantor method, the PCR process involves incubation with biotinylated DNA; however, instead of multiple rounds of incubation with streptavidin and biotinylated DNA, the DNA/biotin/streptavidin/antibody complex is washed away with a low-pH or high-salt buffer that releases the antibody. The resulting wash solution is then used with suitable primers and appropriate controls for PCR. At least in theory, the enormous amplification capacity and specificity of PCR can be used to detect single antigen molecules.

A.ELISA

In its simplest and most direct sense, an immunoassay is a binding assay. Some preferred immunoassays are the various types of enzyme-linked immunosorbent assays (ELISA) and radioimmunoassays (RIA) known in the art. Immunohistochemical detection using tissue sections is also particularly useful. However, it is readily understood that detection is not limited to these techniques, and Western blotting, dot blots, FACS analysis, etc., can also be used.

In an exemplary ELISA, the antibody of this disclosure is immobilized onto a selected surface exhibiting protein affinity, such as wells in a polystyrene microtiter plate. A test composition suspected of containing LILRB-associated cancer cells is then added to the wells. After binding and washing to remove non-specifically bound immune complexes, the bound antigen can be detected. Detection can be achieved by adding another anti-LILRB antibody linked to a detectable label. This type of ELISA is a simple “sandwich ELISA.” Detection can also be achieved by adding a second anti-LILRB1 antibody, followed by the addition of a third antibody with binding affinity to the second antibody, wherein the third antibody is linked to a detectable label.

In another exemplary ELISA, a sample suspected of containing LILRB1-associated cancer cells is immobilized onto the surface of a well and then contacted with an anti-LILRB1 antibody of this disclosure. After binding and washing to remove non-specifically bound immune complexes, the bound anti-LILRB1 antibody is detected. In cases where the initial anti-LILRB1 antibody is conjugated to a detectable label, the immune complex can be detected directly. Similarly, the immune complex can be detected using a second antibody with binding affinity to the first anti-LILRB1 antibody, wherein the second antibody is conjugated to a detectable label.

Regardless of the form used, ELISA shares certain common characteristics, such as coating, incubation and binding, washing to remove non-specifically bound species, and detection of bound immune complexes. These are described below.

When coating a plate with an antigen or antibody, the wells of the plate are typically incubated overnight or for a specified period of several hours with the antigen or antibody solution. The wells are then washed to remove any incompletely adsorbed material. Any remaining usable surface of the wells is then “coated” with a nonspecific protein that is antigen-neutral to the test antiserum. These nonspecific proteins include bovine serum albumin (BSA), casein, or a milk powder solution. This coating allows for the closure of nonspecific adsorption sites on the immobilized surface and thus reduces background caused by nonspecific binding of the antiserum to the surface.

In ELISA, it may be more common to use secondary or tertiary detection methods rather than direct procedures. Therefore, after the protein or antibody binds to the well, is coated with a non-reactive material to reduce background, and washed to remove unbound material, the immobilized surface is brought into contact with the biological sample to be tested under conditions that effectively allow for the formation of immune complexes (antigen/antibody). The detection of these immune complexes then requires labeled secondary binding ligands or antibodies, as well as secondary binding ligands or antibodies that bind to labeled tertiary antibodies or third binding ligands.

"Under conditions that effectively allow the formation of immune complexes (antigen/antibody)" means that the conditions preferably include diluting the antigen and/or antibody with a solution such as BSA, bovine gamma globulin (BGG), or phosphate-buffered saline (PBS)/Tween. These added agents also help reduce nonspecific background.

"Suitable" conditions also mean that the temperature or time of incubation is sufficient for effective binding. The incubation process typically lasts about 1 to 2 to 4 hours, with the temperature preferably between 25°C and 27°C, or it can be carried out overnight at around 4°C.

Following all incubation steps in the ELISA, the contacted surfaces are washed to remove non-composite materials. Preferred washing procedures include washing with solutions such as PBS/Tween or borate buffer. The presence of even trace amounts of immune complexes can be identified after specific immune complexes form between the test sample and the initially bound material, followed by washing.

To provide a detection method, the second or third antibody will have a relevant marker that allows for detection. Preferably, this will be an enzyme that will produce color development upon incubation with a suitable chromogenic substrate. Thus, for example, it is desirable to contact or incubate the first and second immune complexes with antibodies conjugated to urease, glucose oxidase, alkaline phosphatase, or catalase, the duration and conditions of such contact and incubation favoring the development of further immune complex formation (e.g., incubation for 2 hours at room temperature in a solution containing PBS, such as PBS-Tween).

The amount of labeling is quantified, for example, by incubation with a chromogenic substrate such as urea or bromocresol purple or 2,2'-azido-di-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) or _{H₂O₂ ,} after incubation with the labeled antibody and washing to remove unbound material. Quantification is then achieved by measuring the resulting color intensity, for example, using a visible spectrophotometer.

B. Protein blotting

Western blotting (or, alternatively, immunoblotting) is an analytical technique used to detect specific proteins in a sample of a given tissue homogenate or extract. Western blotting uses gel electrophoresis to separate native or denatured proteins based on peptide length (denaturing conditions) or the protein's 3-D structure (native/non-denaturing conditions). The proteins are then transferred to a membrane (typically nitrocellulose or PVDF), on which antibodies specific to the target protein are used for detection.

Samples can be taken from whole tissues or cell cultures. In most cases, solid tissues are first mechanically broken down using a stirrer (for larger sample volumes), a homogenizer (for smaller volumes), or by sonication. Cells can also be broken down using one of the aforementioned mechanical methods. However, it should be noted that bacterial, viral, or environmental samples may be sources of proteins, therefore protein blotting is not limited to cell studies. Various detergents, salts, and buffers can be used to promote cell lysis and protein dissolution. Protease and phosphatase inhibitors are typically added to prevent the sample from being digested by its own enzymes. Tissue preparation is usually performed at low temperatures to avoid protein denaturation.

Proteins in a sample are separated using gel electrophoresis. Proteins can be separated by isoelectric point (pI), molecular weight, charge, or a combination of these factors. The nature of the separation depends on the sample preparation and the properties of the gel. This is a very useful method for protein identification. Two-dimensional (2-D) gels can also be used, which unfold the proteins in a single sample in two dimensions. Proteins are separated in the first dimension according to their isoelectric point (which has a neutral net charge at pH) and in the second dimension according to their molecular weight.

To enable antibody detection of proteins, the proteins are transferred from the gel onto a membrane made of nitrocellulose or polyvinylidene fluoride (PVDF). The membrane is placed on top of the gel, and a stack of filter paper is placed on top of the gel. The entire stack is placed in a buffer solution, which moves across the paper via capillary action, causing the proteins to move along with the buffer solution. Another method for transferring proteins is called electroblotting, which uses an electric current to pull the proteins from the gel into a PVDF or nitrocellulose membrane. The proteins move from the gel to the membrane while maintaining their structure within the gel. Due to this blotting process, the proteins are exposed on a thin surface layer for detection (see below). These two membranes were chosen because of their non-specific protein binding properties (i.e., binding is equally good for all proteins). Protein binding is based on hydrophobic interactions and charged interactions between the membrane and the protein. Nitrocellulose membranes are cheaper than PVDF but are more fragile and do not withstand repeated probes well. The uniformity and overall effectiveness of protein transfer from the gel to the membrane can be examined by staining the membrane with Coomassie Brilliant Blue or Ponceau S dye. Once transferred, the protein is detected using either a labeled primary antibody or an unlabeled primary antibody, followed by indirect detection using labeled protein A bound to the Fc region of the primary antibody or a secondary labeled antibody.

C. Immunohistochemistry

The antibodies disclosed herein can also be used in conjunction with fresh, frozen, and/or formalin-fixed, paraffin-embedded tissue blocks prepared for immunohistochemical (IHC) studies. Methods for preparing tissue blocks from these particulate samples have been successfully used in previous IHC studies of various prognostic factors and are well known to those skilled in the art (Brown et al., 1990; Abbondanzo et al., 1990; Allred et al., 1990).

In short, frozen sections can be prepared by: rehydrating 50 ng of frozen “pulverized” tissue in phosphate-buffered saline (PBS) in a small plastic capsule at room temperature; granulating the particles by centrifugation; resuspending the particles in an adhesive embedding medium (OCT); inverting the capsule and/or granulating again by centrifugation; flash freezing in isopentane at -70°C; cutting the plastic capsule and/or removing the frozen cylinder containing the tissue; fixing the tissue cylinder onto a microtome chuck in a cryostat; and/or cutting 25 to 50 consecutive sections from the capsule. Alternatively, the entire frozen tissue sample can be used for sequential section cutting.

Permanent sections can be prepared using a similar method involving rehydration of 50 mg of sample in a plastic microcentrifuge tube; granulation; resuspending in 10% formalin for 4 hours for fixation; washing/granulation; resuspending in warm 2.5% agar; granulation; cooling in ice water to harden the agar; removing the tissue/agar block from the tube; infiltrating and/or embedding the block in paraffin; and/or cutting up to 50 consecutive permanent sections. Similarly, the entire tissue sample can be substituted.

D. Immunoassay kit

In yet another embodiment, this disclosure relates to an immunoassay kit for use with the immunoassay method described above. Since antibodies can be used to detect LILRB-associated cancer cells, these antibodies can be included in the kit. Therefore, the immunoassay kit will include a first antibody that binds to LILRB, and optionally an immunoassay reagent, in a suitable container.

In some embodiments, the antibody may be pre-bound to a solid support, such as a column matrix and/or the wells of a microtiter plate. The immunoassay reagents in the kit can take any of a variety of forms, including those detectable tags that associate with or are conjugated to a given antibody. Detectable tags that associate with or are conjugated to secondary binding ligands are also considered. Exemplary secondary ligands are those secondary antibodies that have binding affinity for the primary antibody.

Other suitable immunoassay reagents for use in this kit include two-component reagents comprising a secondary antibody having binding affinity to a first antibody and a third antibody having binding affinity to a second antibody, the third antibody being linked to a detectable label. As described above, many exemplary labels are known in the art, and all such labels can be used in conjunction with this disclosure.

The kit may further include appropriately aliquots of LILRB composition, whether labeled or unlabeled, for use in preparing a standard curve for the assay. The kit may contain antibody-labeled conjugates in fully conjugated form, intermediate form, or as separate components conjugated by the kit user. Kit components may be packaged in aqueous media or lyophilized form.

The container device of the kit typically includes at least one vial, test tube, flask, bottle, syringe, or other container device in which antibodies can be placed, or preferably suitably aliquoted. The kits disclosed herein will also typically include a device for containing antibodies, antigens, and any other reagents in a tightly sealed manner for commercial sale. Such containers may include injection- or blow-molded plastic containers that retain the desired vials within them.

E. Flow cytometry and FACS

The antibodies disclosed herein can also be used in flow cytometry or FACS. Flow cytometry is a laser- or impedance-based technique used for many assays, including cell counting, cell sorting, biomarker detection, and protein engineering. This technique suspends cells in a fluid stream and passes them through an electronic detection device, allowing for multi-parameter analysis of the physical and chemical properties of up to several thousand particles per second. Flow cytometry is commonly used to diagnose conditions, particularly blood cancers, but it has many other applications in basic research, clinical practice, and clinical trials.

Fluorescence-activated cell sorting (FACS) is a special type of cytology. FACS provides a method for sorting a heterogeneous mixture of biological cells into two or more containers one cell at a time, based on the specific light scattering and fluorescence characteristics of each cell. Typically, the technique involves a cell suspension sandwiched in the center of a narrow, rapidly flowing liquid stream. The liquid stream is arranged such that there is a large separation between cells relative to their diameter. A vibrational mechanism causes the cell stream to split into individual droplets. Just before the stream splits into droplets, the liquid stream passes through a fluorescence measurement station, where the fluorescence of each cell is measured. A charging ring is placed at the point where the stream splits into droplets. A charge is placed on the ring just before the fluorescence intensity is measured, and as the droplets split from the stream, an opposite charge is captured on the droplets. The charged droplets then fall through an electrostatic deflection system, which transfers the droplets into containers based on their charge.

In some embodiments, for use in flow cytometry or FACS, the antibodies of this disclosure are labeled with fluorophores and then allowed to bind to the cells of interest, which are then analyzed in a flow cytometer or sorted by an FACS machine.

VII. Reagent Kit

In various aspects of the embodiments, kits containing therapeutic agents and/or other therapeutic agents and delivery agents are contemplated. In some embodiments, kits for preparing and/or administering the therapies of the embodiments are provided. The kit may include one or more sealed vials containing any of the pharmaceutical compositions of the present embodiments. The kit may include, for example, at least one LILRB1 antibody or LILRB1-specific CAR construct, and reagents for preparing, formulating, and/or administering the components of the embodiments or performing one or more steps of the methods of the present invention. In some embodiments, the kit may also include suitable containers that will not react with the components of the kit, such as eppendorf tubes, assay plates, syringes, bottles, or tubes. The containers may be made of sterilizable materials such as plastic or glass.

The kit may further include a specification outlining the procedural steps of the methods described herein, and will follow substantially the same procedures as those described herein or known to those skilled in the art. Instruction information may be in a computer-readable medium containing machine-readable instructions that, when executed using a computer, result in a real or virtual procedure for delivering a pharmaceutically effective amount of the therapeutic agent.

VIII. Definition

It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only, and are not intended to limit the claimed invention. In this application, the singular is used to include the plural unless otherwise specified. In this application, the word "or" is used to mean "and/or" unless otherwise specified. Furthermore, the use of the term "including" and other forms such as "includes" and "included" is not limiting. Furthermore, unless otherwise specified, terms such as "element" or "assembly" cover both elements and assemblies comprising one unit and elements and assemblies comprising more than one subunit. Furthermore, the use of the term "part" can include a portion or the entirety of a part.

As used herein, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators.

As used herein, the term "about" when referring to measurable values such as amount, duration, etc., is intended to cover a maximum variation of ±10% of the specified value. Unless otherwise indicated, all figures representing the amount, properties (e.g., molecular weight, reaction conditions), etc., of components used in this specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending on the desired characteristics sought to be obtained through the disclosed subject matter. At least, and not in an attempt to limit the application of the equivalence principle to the scope of the claims, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying ordinary rounding techniques. While the numerical ranges and parameters illustrating the broad scope of the invention are approximations, the values set forth in specific examples are reported as precisely as possible. However, any numerical value inherently contains some error that is necessarily caused by the standard deviation found in its corresponding test measurement.

The term "antibody" refers to any intact immunoglobulin of the same type or a fragment thereof that can compete with an intact antibody for specific binding to a target antigen, and includes, for example, chimeric antibodies, humanized antibodies, fully human antibodies, and bispecific antibodies. An antibody is an antigen-binding protein. An intact antibody will generally consist of at least two full-length heavy chains and two full-length light chains, but in some cases may include fewer chains, such as naturally occurring antibodies in the Camelidae family, which may consist only of heavy chains. Antibodies may be derived from a single source or may be "chimeric," meaning that different parts of the antibody may be derived from two different antibodies, as further described below. Antigen-binding proteins, antibodies, or binding fragments can be produced in hybridomas via recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term "antibody" includes derivatives, variants, fragments, and mutant proteins other than antibodies comprising two full-length heavy chains and two full-length light chains, examples of which are described below. Furthermore, unless explicitly excluded, antibodies include monoclonal antibodies, bispecific antibodies, microantibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimics”), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), and fragments thereof. In some embodiments, the terminology also encompasses peptide bodies.

Naturally occurring antibody structural units typically comprise tetramers. Each such tetramer typically consists of two pairs of identical polypeptide chains, each pair having a full-length "light" chain (approximately 25 kDa in some embodiments) and a full-length "heavy" chain (approximately 50 kDa to 70 kDa in some embodiments). The amino-terminal portion of each chain typically includes a variable region of approximately 100 to 110 or more amino acids that is generally responsible for antigen recognition. The carboxyl-terminal portion of each chain typically defines a constant region that can be responsible for effector function. Human light chains are typically classified as κ and λ light chains. Heavy chains are typically classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including but not limited to IgM1 and IgM2. IgA is similarly divided into subclasses, including but not limited to IgA1 and IgA2. In both the full-length light and heavy chains, the variable and constant regions are typically linked by a “J” region having about 12 or more amino acids, with the heavy chain also including a “D” region having about 10 or more amino acids. See, for example, *Basic Immunology*, Chapter 7 (edited by Paul, W., 2nd ed., Raven Press, New York (1989)) (the cited literature is incorporated herein by reference in its entirety for all purposes). The variable region of each light/heavy chain pair typically forms an antigen-binding site.

The term "variable region" or "variable domain" refers to a portion of the light and/or heavy chain of an antibody, typically comprising an amino terminus of approximately 120 to 130 amino acids in the heavy chain and an amino terminus of approximately 100 to 110 amino acids in the light chain. In some embodiments, the variable regions of different antibodies can vary considerably in amino acid sequence, even among antibodies of the same species. The variable region of an antibody often determines the specificity of a particular antibody for its target.

The variable regions typically exhibit the same general structure as the relatively conservative frame regions (FRs) connected by three supervariable regions (also known as complementarity-determining regions or CDRs). The CDRs from the two chains in each pair are typically aligned by the frame regions, which can bind to specific epitopes. From the N-terminus to the C-terminus, both the light chain and heavy chain variable regions typically comprise the structural domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignment for each domain generally conforms to the definition of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991), Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987) or Chothia et al., Nature, 342:878-883 (1989).

In some embodiments, the antibody heavy chain binds to the antigen in the absence of the antibody light chain. In some embodiments, the antibody light chain binds to the antigen in the absence of the antibody heavy chain. In some embodiments, the antibody-binding region binds to the antigen in the absence of the antibody light chain. In some embodiments, the antibody-binding region binds to the antigen in the absence of the antibody heavy chain. In some embodiments, a single variable region specifically binds to the antigen in the absence of other variable regions.

In some embodiments, the precise characterization of the CDR region and the identification of residues including the antibody binding site are accomplished by resolving the structure of the antibody and/or the antibody-ligand complex. In some embodiments, this can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In some embodiments, various analytical methods can be employed to identify or simulate the CDR region. Examples of such methods include, but are not limited to, Kabat definition, Chothia definition, AbM definition, and contact definition.

Kabat definitions are a standard for numbering residues in antibodies and are commonly used to identify CDR regions. See, for example, Johnson and Wu, *Nucleic Acids Res.*, 28:214-8 (2000). Chothia definitions are similar to Kabat definitions, but Chothia definitions take into account the location of certain structural loop regions. See, for example, Chothia et al., *Journal of Molecular Biology*, 196:901-17 (1986); Chothia et al., *Nature*, 342:877-83 (1989). AbM definitions use an integrated suite of computer programs produced by the Oxford Molecular Group for modeling antibody structures. See, for example, Martin et al., *Proceedings ^of the National Academy of Sciences (ProcNatl Acad Sci (USA))*, 86:9268-9272 (1989); "AbM ^™ , A Computer Program for Modeling Variable Regions of Antibodies", Oxford, UK; Oxford Molecular, Ltd. AbM is defined as using a combination of knowledge databases and ab initio methods to model the tertiary structure of antibodies derived from primary sequences, as described in the following literature: Samudrala et al., "Ab initio Protein Structure Prediction Using a Combined Hierarchical Approach", *Proteins, Structure, Function and Genetics* Supplement, 3:194-198 (1999). Contact is defined as being based on the analysis of available complex crystal structures. See, for example, MacCallum et al., Journal of Molecular Biology, 5:732-45 (1996).

By convention, the CDR regions in heavy chains are usually referred to as H1, H2, and H3, and numbered sequentially from the amino terminus to the carboxyl terminus. The CDR regions in light chains are usually referred to as L1, L2, and L3, and numbered sequentially from the amino terminus to the carboxyl terminus.

The term "light chain" includes full-length light chains and fragments thereof with a sufficient variable region sequence to confer binding specificity. A full-length light chain includes a variable region domain (VL) and a constant region domain (CL). The variable region domain of a light chain is located at the amino terminus of the polypeptide. Light chains include κ chains and λ chains.

The term "heavy chain" includes full-length heavy chains and fragments thereof with a sufficient variable region sequence to confer binding specificity. A full-length heavy chain comprises a variable region domain (VH) and three constant region domains (CH1, CH2, and CH3). The VH domain is located at the amino terminus of the polypeptide, and the CH domain is located at the carboxyl terminus, with CH3 being closest to the carboxyl terminus of the polypeptide. Heavy chains can be any isoform, including IgG (including IgG1, IgG2, IgG3, and IgG4 isoforms), IgA (including IgA1 and IgA2 isoforms), IgM, and IgE.

A "reversal mutation" is a mutation introduced into the nucleotide sequence encoding a humanized antibody, resulting in an amino acid corresponding to an amino acid in the parent antibody (e.g., a donor antibody, such as a rabbit antibody). During the humanization of the antibodies of the present invention, certain framework residues from the parent antibody can be retained to substantially preserve the binding properties of the parent antibody while minimizing the potential immunogenicity of the resulting antibody. In one embodiment of the invention, the parent antibody is derived from a mouse. For example, a reversal mutation changes human framework residues to parent mouse residues. Examples of framework residues that can be reversibly mutated include, but are not limited to, canonical residues, interfacial stacking residues, unusual parent residues near the binding site, residues in the "vernier region" (forming a platform on which the CDR is located) (Foote and Winter, 1992, Journal of Molecular Biology 224, 487-499), and residues near CDR H3.

Bispecific or bifunctional antibodies are typically artificial hybrid antibodies with two distinct heavy/light chain pairs and two distinct binding sites. Bispecific antibodies can be produced by a variety of methods, including but not limited to fusion hybridomas or Fab' fragment linkages. See, for example, Songsivilai et al., *Clinical and Experimental Immunology*, 79:315-321 (1990); Kostelny et al., *Journal of Immunology*, 148:1547-1553 (1992).

The term "antigen" refers to a substance capable of inducing an adaptive immune response. Specifically, an antigen is a substance that serves as a target for receptors in the adaptive immune response. Typically, an antigen is a molecule that binds to an antigen-specific receptor but cannot induce an immune response in vivo on its own. Antigens are usually proteins and polysaccharides, and less commonly lipids. Suitable antigens include, but are not limited to, parts of bacteria (capsids, capsules, cell walls, flagella, pili, and toxins), viruses, and other microorganisms. Antigens also include tumor antigens, such as antigens arising from mutations in tumors. As used herein, antigens also include immunogens and haptens.

As used herein, “antigen-binding protein” (“ABP”) means any protein that binds to a specific target antigen. In this application, the specific target antigen is the LILRB protein or a fragment thereof. “Antigen-binding protein” includes, but is not limited to, antibodies and their antigen-binding fragments. Peptides are another example of antigen-binding proteins.

As used herein, the term "antigen-binding fragment" refers to a portion of a protein capable of specifically binding to an antigen. In some embodiments, the antigen-binding fragment is derived from an antibody comprising one or more CDRs, or any other antibody fragment that binds to an antigen but does not include the complete structure of the native antibody. In some embodiments, the antigen-binding fragment is derived from a receptor rather than an antibody. Examples of antigen-binding fragments include, but are not limited to, bifunctional antibodies, Fab, Fab', F(ab') ₂ , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv) ₂ , bispecific dsFv (dsFv-dsFv'), disulfide-stabilized bifunctional antibodies (ds bifunctional antibodies), single-chain antibody molecules (scFv), scFv dimers (bivalent bifunctional antibodies), multispecific antibodies, single-domain antibodies (sdAb), camelified antibodies or nanobodies, domain antibodies, and bivalent domain antibodies. In some embodiments, the antigen-binding fragment is capable of binding to the same antigen bound to the parent antibody. In some embodiments, the antigen-binding fragment may include one or more CDRs from a specific human antibody transplanted into a framework region from one or more different human antibodies. In some embodiments, the antigen-binding fragment is derived from a receptor and contains one or more mutations. In some embodiments, the antigen-binding fragment does not bind to the natural ligand of the receptor from which the antigen-binding fragment originates.

The "Fab fragment" consists of a light chain and a heavy chain with a CH1 and variable region. The heavy chain of the Fab molecule cannot form a disulfide bond with another heavy chain molecule.

The “Fab’ fragment” comprises a light chain and a portion of a heavy chain, such that interchain disulfide bonds can be formed between the two heavy chains of the two Fab’ fragments to form the F(ab’) ₂ molecule, wherein the portion of the heavy chain contains a VH domain and a CH1 domain, as well as a region located between the CH1 domain and the CH2 domain.

The “F(ab') ₂ segment” contains two light chains and two heavy chains, such that interchain disulfide bonds are formed between the two heavy chains, which contain a portion of a constant region located between the CH1 and CH2 domains. Therefore, the F(ab') ₂ segment consists of two Fab' segments held together by disulfide bonds between the two heavy chains.

The “Fc” region comprises two heavy chain segments, which include the antibody’s CH1 and CH2 domains. The two heavy chain segments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domain.

The “Fv region” includes variable regions from both heavy and light chains but lacks constant regions.

A "single-chain antibody" is an Fv molecule in which the variable regions of the heavy chain and the variable regions of the light chain are linked by a flexible linker to form a single polypeptide chain, which forms the antigen-binding region. Single-chain antibodies are discussed in detail in International Patent Application Publication No. WO 88/01649 and U.S. Patent Nos. 4,946,778 and 5,260,203, the disclosures of which are incorporated herein by reference.

"Domain antibodies" are immunoglobulin fragments containing only the variable region of the heavy chain or the variable region of the light chain. In some cases, two or more VH regions are covalently linked to peptide linkers to produce bivalent domain antibodies. The two VH regions of a bivalent domain antibody can target the same or different antigens.

A “bivalent antigen-binding protein” or “bivalent antibody” comprises two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. Bivalent antigen-binding proteins and bivalent antibodies can be bispecific, see below. In some embodiments, bivalent antibodies, other than “multispecific” or “multifunctional” antibodies, are generally understood to have the same binding sites at each of their binding sites.

A "multispecific antigen-binding protein" or "multispecific antibody" is an antibody that targets more than one antigen or epitope.

“Bispecific,” “dual-specific,” or “bifunctional” antigen-binding proteins or antibodies are hybrid antigen-binding proteins or antibodies that each have two distinct antigen-binding sites. Bispecific antigen-binding proteins and antibodies are a type of multispecific antigen-binding protein antibody and can be produced by a variety of methods, including but not limited to hybridoma fusion or Fab' fragment linkage. See, for example, Songsivilai and Lachmann, 1990, *Clinical and Experimental Immunology* 79:315-321; Kostelny et al., 1992, *Journal of Immunology* 148:1547-1553. The two binding sites of a bispecific antigen-binding protein or antibody will bind to two distinct epitopes, which may reside on the same or different protein targets.

"Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies typically bind slowly to antigens and tend to dissociate easily, while high-affinity antibodies typically bind to antigens more quickly and tend to maintain a longer binding. A variety of methods for measuring binding affinity are known in the art, and any of these methods can be used for the purposes of this invention. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An antibody that "specifically binds to" or is "specific to" a particular polypeptide or an epitope on a particular polypeptide is an antibody that binds to said particular polypeptide or epitope without substantially binding to any other polypeptide or polypeptide epitope. For example, the LILRB1-specific antibody of the present invention is specific to LILRB1. In some embodiments, the dissociation constant (Kd) of the antibody binding to LILRB1 is ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., ^10⁻⁸ M or less, e.g., ^10⁻⁸ M to ^10⁻¹³ M, e.g., ^10⁻⁹ M to ^10⁻¹³ M). The dissociation constant Kd as used herein refers to the ratio of the dissociation rate to the association rate ( _koff / _kon ), which can be determined using any conventional method known in the art, including but not limited to surface plasmon resonance, microthermophoresis, HPLC-MS, and flow cytometry (e.g., FACS). In some implementations, the Kd value can be appropriately determined using flow cytometry.

The term “competition” in the context of competing antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof) for the same epitope means competition between antigen-binding proteins determined by an assay in which the tested antigen-binding protein (e.g., antibody or antigen-binding fragment thereof) prevents or inhibits (e.g., reduces) the specific binding of a reference antigen-binding protein (e.g., ligand or reference antibody) to a common antigen (e.g., LILRB or a fragment thereof). Various types of competitive binding assays can be used to determine whether one antigen-binding protein competes with another, such as: solid-phase direct or indirect radioimmunoassay (RIA), solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, for example, Stahli et al., 1983, Methods in Enzymology 9:242-253); solid-phase direct biotin-avidin EIA (see, for example, Kirkland et al., 1986, Journal of Immunology 137:3614-3619), solid-phase direct labeling assay, and solid-phase direct labeling sandwich assay (see, for example, Harl et al.). (See ow and Lane, 1988, *Antibodies: A Laboratory Manual*, Cold Spring Harbor Press); solid-phase directly labeled RIAs using 1–125 labels (see, for example, Morel et al., 1988, *Molec. Immunol.* 25:7–15); solid-phase direct biotin-avidin EIAs (see, for example, Cheung et al., 1990, *Virology* 176:546–552); and directly labeled RIAs (Moldenhauer et al., 1990, *Scand. J. Immunol.* 32:77–82). Typically, such assays involve using purified antigens or cells carrying either of these bound to a solid surface, an unlabeled test antigen-binding protein, and a labeled reference antigen-binding protein. Competitive inhibition is measured by determining the amount of labeling bound to the solid surface or cells in the presence of the test antigen-binding protein. Typically, an excess of the test antigen-binding protein is present. Antigen-binding proteins identified by competitive assays (competitive antigen-binding proteins) include antigen-binding proteins that bind to the same epitope as a reference antigen-binding protein, and antigen-binding proteins that bind to adjacent epitopes, said adjacent epitopes being sufficiently close to the epitope bound by the reference antigen-binding protein to cause steric hindrance. Examples herein provide further details regarding methods for determining competitive binding. Typically, when an excess of a competitive antigen-binding protein is present, it will inhibit (e.g., reduce) the specific binding of the reference antigen-binding protein to the common antigen by at least 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, or 75% or more. In some cases, binding is inhibited by at least 80% to 85%, 85% to 90%, 90% to 95%, 95% to 97%, or 97% or more.

As used herein, the term "epitope" refers to a specific set of atoms or amino acids on an antigen that an antibody binds to. Epitopes can be linear or conformational. Linear epitopes are formed from a continuous amino acid sequence of the antigen and interact with the antibody based on its primary structure. Conformational epitopes, on the other hand, are formed from discontinuous segments of the amino acid sequence of the antigen and interact with the antibody based on the 3D structure of the antigen. Typically, epitopes are about five or six amino acids long. If two antibodies exhibit competitive binding to an antigen, both antibodies can bind to the same epitope within the antigen.

As used herein, "cell" can be prokaryotic or eukaryotic. Prokaryotic cells include, for example, bacteria. Eukaryotic cells include, for example, fungi, plant cells, and animal cells. Animal cell types (e.g., mammalian cells or human cells) include, for example, cells from the circulatory/immune system or organs, such as B cells, T cells (cytotoxic T cells, natural killer T cells, regulatory T cells, T helper cells), natural killer cells, granulocytes (e.g., basophils, eosinophils, neutrophils, and hypersegmented neutrophils), monocytes or macrophages, erythrocytes (e.g., reticulocytes), mast cells, platelets or megakaryocytes, and dendritic cells; cells from the endocrine system or organs, such as thyroid cells (e.g., thyroid epithelial cells, parafollicular cells), parathyroid cells (e.g., parathyroid chief cells, eosinophils), adrenal cells (e.g., chromaffin cells), and pineal gland cells (e.g., pineal gland cells); and cells from the nervous system or organs. For example, glial cells (e.g., astrocytes and oligodendrocytes), microglia, large neurosecreting cells, stellate cells, Boettcher cells, and pituitary cells (e.g., gonadotropin-producing cells, adrenocorticotropic hormone-producing cells, thyroid-stimulating hormone-producing cells, growth hormone-producing cells, and prolactin-producing cells); cells from the respiratory system or organs, such as lung cells (type I and type II lung cells), clara cells, goblet cells, and alveolar macrophages; cells from the circulatory system or organs (e.g., cardiomyocytes and pericytes); cells from the digestive system or organs, such as chief cells, parietal cells, goblet cells, paneth cells, G cells, D cells, ECL cells, I cells, K cells, S cells, enteroendocrine cells, enterochromaffin cells, APUD cells, and hepatocytes ( For example, hepatocytes and Kupffer cells; cells from the skin system or organs, such as bone cells (e.g., osteoblasts, osteocytes, and osteoclasts), dental cells (e.g., cementoblasts and ameloblasts), chondrocytes (e.g., chondrocytes and chondrocytes), skin/hair cells (e.g., hair cells, keratinocytes, and melanocytes (nevus cells), muscle cells (e.g., myocytes), adipocytes, fibroblasts, and tendon cells); cells from the urinary system or organs (e.g., foot process cells, juxtaglomerular cells, intraglomerular mesangial cells, extraglomerular mesangial cells, proximal brush border cells of the kidney, and dense macula cells); and cells from the reproductive system or organs (e.g., sperm, Sertoli cells, Leydig cells, ovum, oocytes). Cells can be normal, healthy cells; or diseased or abnormal cells. Healthy cells (e.g., cancer cells). Cells further include mammalian zygotes or stem cells, including embryonic stem cells, fetal stem cells, induced pluripotent stem cells, and adult stem cells. Stem cells are cells capable of undergoing a cycle of cell division while remaining undifferentiated and differentiating into specialized cell types. Stem cells can be totipotent stem cells, pluripotent stem cells, multipotent stem cells, oligopotent stem cells, and unipotent stem cells, any of which may be induced from somatic cells. Stem cells may also include cancer stem cells. Mammalian cells can be rodent cells, such as mouse cells, rat cells, or hamster cells. Mammalian cells can be rabbit cells, such as rabbit cells. Mammalian cells can also be primate cells, such as human cells.

The term “chimeric antigen receptor” or, as used herein, “CAR”, refers to an artificially constructed hybrid protein or polypeptide containing an antigen-binding domain (e.g., a single-chain variable fragment (scFv)) of an antibody linked to a domain that activates immune cells (e.g., T cells or NK cells) or a signaling domain (e.g., T cell signaling or T cell activation domain) (see, for example, Kershaw et al., ibid., Eshhar et al., Proceedings of the National Academy of Sciences, 90(2):720-724 (1993) and Sadelain et al., Current Views in Immunology (Curr. Opin. Immunol.) 21(2):215-223 (2009)). CARs can utilize the antigen-binding properties of monoclonal antibodies to redirect immune cell specificity and responsiveness to selected targets in a non-MHC-restricted manner. Non-MHC-restricted antigen recognition enables CAR-expressing immune cells to recognize antigens independent of antigen processing, thereby bypassing key mechanisms of tumor escape. In addition, when expressed in T cells, CAR advantageously does not dimerize with the endogenous T cell receptor (TCR) α and β chains.

The term "host cell" refers to a cell that has been transformed with a nucleic acid sequence or is capable of being transformed with a nucleic acid sequence and thereby expressing the gene of interest. The term also includes the offspring of the parent cell, regardless of whether the offspring are morphologically or genetically identical to the original parent cell, as long as the gene of interest is present.

The term "identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by sequence alignment and comparison. "Identity percentage" refers to the percentage of identical residues among amino acids or nucleotides in the compared molecules and is calculated based on the size of the smallest molecule being compared. For these calculations, gaps in the alignment (if any) are preferably resolved using a specific mathematical model or computer program (i.e., an "algorithm"). Methods that can be used to calculate the identity of aligned nucleic acids or peptides include those described in the following literature: *Computational Molecular Biology*, (edited by Lesk, A.M.), 1988, New York: Oxford University Press; *Biocomputing Informatics and Genome Projects*, (edited by Smith, D.W.), 1993, New York: Academic Press; *Computer Analysis of Sequence Data*, Part I, (Griffi... n, A.M. and Griffin, H.G. (eds.), 1994, New Jersey: Humana Press; von Heinje, G., 1987, Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence Analysis Primers, (Gribskov, M. and Devereux, J. (eds.), 1991, New York: M. Stockton Press); and Carillo et al., 1988, SIAM J. Applied Mathematics 48:1073.

When calculating the percentage of identity, the sequences being compared are typically aligned in a way that maximizes the match between the sequences. An example of a computer program that can be used to determine the percentage of identity is the GCG package, which includes GAP (Devereux et al., 1984, Nucleic Acid Research 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wisconsin). The computer algorithm GAP is used to align two polypeptides or polynucleotides whose percentage of identity is to be determined. The sequences are aligned to achieve the best match (“match range”, as determined by the algorithm) for their corresponding amino acids or nucleotides. Vacancy open penalty (calculated as 3 × mean diagonal, where “mean diagonal” is the average of the diagonals of the comparison matrices used; “diagonal” is the score or number assigned to each perfect amino acid match by a particular comparison matrix) and vacancy extension penalty (typically 1/10 of the vacancy open penalty) and comparison matrices such as PAM 250 or BLOSUM 62 are used with the algorithm. In some implementations, standard comparison matrices (see, for example, Dayhoff et al., 1978, Atlas of Protein Sequence and Structure, 5:345-352 regarding the PAM 250 comparison matrix; Henikoff et al., 1992, Proceedings of the National Academy of Sciences 89:10915-10919 regarding the BLOSUM 62 comparison matrix) are also used by the algorithm.

Examples of parameters that can be used to determine the percentage of identity of a polypeptide or nucleotide sequence using the GAP procedure can be found in the following literature: Needleman et al., 1970, Journal of Molecular Biology 48:443-453.

Some alignment protocols used to align two amino acid sequences may result in a match for only a short region in the two sequences, and this small aligned region may have high sequence identity, even though there is no significant relationship between the two full-length sequences. Therefore, if desired, the chosen alignment method (GAP procedure) can be modified to produce alignments spanning at least 50 or other numbers of consecutive amino acids across the target polypeptide.

As used herein, the term “connection” refers to association through intramolecular interactions, such as covalent, metallic and/or ionic bonds, or intermolecular interactions, such as hydrogen bonds or non-covalent bonds.

Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB1) is a protein encoded by the LILRB1 gene in humans. This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is located in the gene cluster of chromosome 19q13.4. The encoded protein belongs to subfamily B of LIR receptors and contains two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The receptor is expressed on immune cells, where it binds to MHCI class molecules on antigen-presenting cells and transduces negative signals that inhibit the immune response. The receptor is believed to control inflammatory responses and cytotoxicity, helping to focus the immune response and limit autoreactivity.

The term "operably linked" refers to an arrangement of elements in which the components described therein are configured to perform their usual functions. Thus, a given signal peptide operably linked to a polypeptide guides the secretion of the polypeptide from the cell. In the case of a promoter, a promoter operably linked to a coding sequence will guide the expression of the coding sequence. The promoter or other control element need not be adjacent to the coding sequence, as long as the promoter or other control element serves to guide its expression. For example, an intermediate untranslated but still transcribed sequence may exist between the promoter sequence and the coding sequence, and the promoter sequence and coding sequence can still be considered "operably linked."

The terms "polynucleotide" or "nucleic acid" include both single-stranded and double-stranded nucleotide polymers. Nucleotides comprising polynucleotides can be ribonucleotides, deoxyribonucleotides, or modified forms of any type of nucleotide. These modifications include base modifications, such as bromouracil nucleosides and inosine derivatives; ribose modifications, such as 2',3'-dideoxyribose; and internucleotide bonding modifications, such as thiophosphates, dithiophosphates, selenophosphates, diselenophosphates, phosphoroanilothioate, phoshoraniladate, and aminophosphates.

The terms "peptide" or "protein" refer to a large molecule having the amino acid sequence of a natural protein, i.e., a protein produced by naturally occurring and non-recombinant cells; or a protein produced by genetically engineered or recombinant cells and comprising a molecule having the amino acid sequence of a natural protein or a molecule having one or more amino acids with a natural sequence that are missing, added, and/or substituted. The term also includes amino acid polymers, wherein one or more amino acids are chemical analogs of corresponding naturally occurring amino acids, and polymers. The terms "peptide" and "protein" specifically cover LILRB antigen-binding proteins, antibodies, or sequences having one or more amino acids with missing, added, and/or substituted amino acids. The term "peptide fragment" refers to a peptide that, compared to a full-length natural protein, has an amino-terminal deletion, a carboxyl-terminal deletion, and/or an internal deletion. Such fragments may also contain modified amino acids compared to natural proteins. In some embodiments, the fragment length is from about five to 500 amino acids. For example, the length of the fragment can be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids. Useful peptide fragments include immunofunctional fragments of antibodies, including binding domains. In the case of LILRB-binding antibodies, useful fragments include, but are not limited to, CDR regions, variable domains of the heavy and/or light chains, portions of the antibody chain, or its variable regions comprising only two CDRs.

Pharmaceutically acceptable carriers useful in this invention are conventional. E.W. Martin, Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 15th edition (1975), describes compositions and formulations suitable for drug delivery of the fusion proteins disclosed herein. Generally, the nature of the carrier will depend on the specific administration method employed. For example, parenteral formulations typically include injectable fluids, including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous glucose solutions, glycerol, etc., as a medium. For solid compositions (e.g., in powder, pill, tablet, or capsule form), conventional nontoxic solid carriers may include, for example, pharmaceutical-grade mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the pharmaceutical composition to be administered may contain small amounts of nontoxic excipients such as humectants or emulsifiers, preservatives, and pH buffers, for example, sodium acetate or sorbitol monolaurate.

As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Humans include both prenatal and postnatal forms. In many embodiments, the subject is a human. A subject may be a patient, meaning a person presented to a healthcare provider for the diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may have or be susceptible to a disease or condition, but may or may not exhibit symptoms of the disease or condition.

As used herein, the terms "therapeutic effective amount" or "effective dose" refer to the dosage or concentration of a drug that is effective in treating a disease or symptom. For example, in relation to the use of the monoclonal antibodies or antigen-binding fragments thereof disclosed herein in the treatment of cancer, a therapeutic effective amount is a dosage or concentration of a monoclonal antibody or antigen-binding fragment thereof that is capable of reducing tumor volume, eradicating all or part of a tumor, inhibiting or slowing tumor growth or the invasion of cancer cells into other organs, inhibiting the growth or proliferation of cells mediating cancerous symptoms, inhibiting or slowing tumor cell metastasis, improving any symptoms or markers associated with a tumor or cancerous symptom, preventing or delaying the development of a tumor or cancerous symptom, or combinations thereof.

As used herein, “treating” or “treatment” for a symptom includes preventing or alleviating the symptom, slowing the onset or progression of the symptom, reducing the risk of developing the symptom, preventing or delaying the development of symptoms associated with the symptom, reducing or ending symptoms associated with the symptom, producing complete or partial resolution of the symptom, curing the symptom, or some combination thereof.

As used herein, "vector" refers to a nucleic acid molecule introduced into a host cell to produce a transformed host cell. A vector may include a nucleic acid sequence, such as an origin of replication, that allows it to replicate within the host cell. A vector may also include one or more therapeutic genes and/or optional biomarker genes, as well as other genetic elements known in the art. A vector can transduce, transform, or infect cells, thereby causing the cells to express nucleic acids and/or proteins other than those native to the cell. Optionally, a vector may include materials that facilitate the entry of nucleic acids into the cell, such as viral particles, liposomes, protein coatings, etc.

As used herein, "substantially free" with respect to a specified component means that the specified component was not intentionally formulated into the composition and/or is present only as a contaminant or in trace amounts. Therefore, the total amount of the specified component resulting from any unintended contamination of the composition is well below 0.05%, preferably below 0.01%. Most preferably, the composition in which the amount of the specified component is undetectable using standard analytical methods.

Unless explicitly indicated to refer only to alternatives or alternatives are mutually exclusive, the term "or" is used in the claims to mean "and/or," but this disclosure supports the definition of referring only to alternatives and referring to "and/or." As used herein, "another" may mean at least a second or more.

IX. Implementation Examples

The following embodiments are included to illustrate preferred embodiments of the present invention. Those skilled in the art should understand that the techniques disclosed in the following embodiments represent techniques discovered by the inventors that work well in the practice of the present invention and can therefore be considered to constitute a preferred mode of practice of the present invention. However, based on this disclosure, those skilled in the art should understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the present invention and still obtaining the same or similar results.

Example 1 - Materials and Methods

Mice. Female NOD-SCID IL2Rγ-nullable (NSG) mice, 6–8 weeks old (approximately 20 g in weight), were purchased from the Animal Core Facility at the University of Texas Southwestern Medical Center (UT Southwestern). Mice were housed in a specific pathogen-free (SPF) room with a 12-hour light/dark cycle, controlled room temperature, and free access to food and water. Mice were randomly assigned to each treatment group for the experiments.

Cell lines and original samples. Expi293F (catalog number A14528) were obtained from Life Technologies (Carlsbad). Hematologic cancer cell lines 697, MHH-CALL-2, and OPM2 were purchased from DSMZ (Braunschweig, Germany). KMS27, KMS26, KMS12PE, and KMS20 were purchased from the Health Sciences Research Resources Bank (HSRRB) of the Japan Health Sciences Foundation. LILRB1 reporter cell line ¹⁸ was previously described. Unless otherwise noted, all other cell lines were purchased from ATCC. Hematologic cancer cell lines were maintained in RPMI 1640 (Sigma Aldrich) (R10) supplemented with 10% heat-inactivated FBS. Except for H460 and H1299 in R10, solid tumor cell lines were maintained in DMEM with 10% heat-inactivated FBS. ^NKL cells were cultured as previously described. All cell cultures were supplemented with +1% penicillin and streptomycin.

Peripheral blood mononuclear cells (PBMCs) were separated from the erythrocyte sedimentation rate (ESR) layer of healthy donors (interstate blood bank) using gradient centrifugation on Ficoll medium (GE Lifesciences). To isolate LILRB1-positive NK cells, PBMCs were incubated with anti-human CD56 microbeads (Miltenyi Biotech) and isolated using the AutoMACS Pro separation system. The isolated CD56 ⁺ cells were then stained with the following: anti-CD3-PE (clone: HIT3a, BioLegend), anti-CD56-FITC (clone: TULY56, eBioscience), anti-LILRB1-APC (clone: HP-F1, eBioscience), or mouse IgG1κ isotype control-APC (eBioscience). LILRB1 ⁺ NK cells (CD56 ^{+ CD3-} ) were sorted using the FACSAria I system. Sorted LILRB1 ⁺ NK cells were maintained in the same culture medium as NKL cells for 2–3 days. Cancer patient samples were obtained from the University of Texas Southwestern Medical Center (UTSW) and the UTSW Blood Malignancy Tissue Bank. Patient NK cells were isolated using the same protocol, except that NK cells isolated by AutoMACS were cultured, activated, and used for cytotoxicity assays without FACS.

Anti-LILRB1 monoclonal antibody (mAb) was generated. Two New Zealand white rabbits were subcutaneously immunized with 0.5 mg of recombinant human LILRB1 protein (unlabeled ECD, Sino Biological). Four booster immunizations were administered at three-week intervals after the initial immunization. Serum anti-LILRB1 titers were assessed by indirect enzyme-linked immunosorbent assay (ELISA). Single LILRB1-positive memory B cells enriched using antigen pull-down were cultured in 96-well plates for 14 days, and antibody binding to LILRB1 in the culture supernatant was analyzed by ELISA. The antibody variable region gene was cloned from those positive B cells and its sequence was determined.

Expression and purification of mAbs. Heavy and light chain expression constructs were co-transfected into HEK293 cells using the ExpiFectamine ^™ 293 transfection kit (catalog number: A14528, Gibco), generating full-length IgG in human embryonic kidney Expi293F cells. After 7 days of fed-batch culture, the culture supernatant was collected, and the antibody was purified by affinity chromatography using Protein A resin (catalog number: 10-2001-XM, Repligen).

Epitope binning and affinity measurements were performed using biolayer interferometry. A classic sandwich epitope binning experiment was conducted on an 8-channel Octet RED96 system. First, a baseline was established in kinetic buffer (catalog number 18-1105, ForteBio) for 3 minutes. Then, antibody (30 μg/mL) was captured by a protein A biosensor (catalog number 18-5010, ForteBio) for 4 minutes. The remaining Fc binding sites on the biosensor were then blocked with an unrelated rabbit antibody (200 μg/mL) for 4 minutes, followed by immersion in kinetic buffer for 10 seconds. The biosensor was exposed to recombinant LILRB1 (25 μg/mL) for 4 minutes, followed by incubation with a secondary antibody (40 μg/mL). The surface was regenerated in 100 mM glycine (pH 2.6) for 45 seconds. Competitive binding of the antibody pairs was evaluated. Additional binding signals observed with secondary antibodies indicate unoccupied epitopes (non-competitors). The absence of secondary antibody binding (blocked by primary antibody binding) suggests that the two antibodies are competing for similar epitopes (competitors).

For antibody affinity measurements, the antibody (analyte, 30 μg/mL) was loaded onto a Protein G biosensor (catalog number 18-5082, Fudi Biotechnology) for 4 minutes. Twenty seconds after a short baseline in kinetic buffer, the loaded biosensor was exposed to a solution of recombinant LILRB1 at a concentration range (0-500 nM). After background subtraction, the data were fitted to a 1:1 binding model to extract the association rate (k _{_on} ) and dissociation rate (k _{_off} ). KD was calculated using the ratio k _{_off} /k_{_on}. The kinetic constants of the OctetRED96 system range from 1 mM to 10 pM. Therefore, affinities above 10 pM will be shown as KD < 10 pM. All experiments were performed with oscillations at 1,000 rpm. All raw data were processed using Octet data analysis software 9.0 from Fudi Biotechnology.

Generation of LILRB1-Fc, mutant-Fc, and LILRB-Fc fusion proteins. The Ig-like C2-type domain (D), comprising the D1, D2, D3, and D4 domains of LILRB1, was cloned by PCR for expression. The motif between D4 and the transmembrane domain was defined as the stem or linker region. Different mutants of LILRB1 were generated using a lightning site-directed mutagenesis kit (Agilent, catalog number 210519) with wild-type LILRB1 DNA constructs as templates. LILRB ECD, LILRB1 mutants, and different domains were cloned via Fc fusion in the expression vector and the Fc moiety of human IgG1. Expression and purification of the LILRB Fc fusion protein were performed using the same procedure as described above for the antibody.

ELISA. Recombinant LILRB1 protein (50 ng/well, 100 μL/well) was plated onto Corning 96-well ELISA plates at 37°C for 4 hours. The plates were then blocked with 5% skim milk at 37°C for 2 hours. After washing with PBST, 100 μL of serially diluted anti-LILRB1 antibody was added, and the plates were incubated at 37°C for 60 minutes. Subsequently, the plates were washed five times with PBST and incubated for 30 minutes with anti-rabbit or anti-human F(ab')2HRP conjugate antibodies (Jackson Immuno Research Inc., catalogue numbers 111-036-003 and 109-036-003). The plate was washed five more times with PBST, then the immunoreaction was developed with TMB substrate (Sigma, catalog number T0440), and terminated by adding 2M _H2SO4 before the plate was read at 450 _nm .

Humanization of Rabbit mAb. Anti-LILRB1 rabbit antibody was humanized via CDR transplantation into a human germline-matched framework. Briefly, the CDRs in both the heavy and light chains of the rabbit antibody were defined by a combination of three online programs: Kabat, IMGT, and Paratome. Parental rabbit mAbs were aligned to the most homologous human germline sequences, and residues known to be structurally non-critical or unchanging during in vivo maturation were identified and humanized in mutation lineage-guided analysis. DNA sequences encoding humanized VK and VH (GENEWIZ) were synthesized, and human IgG signal peptides and Kozak sequences were engineered at the 5' ends of the VK and VH sequences. The humanized VK and VH fragments were then cloned and fused with intact human constant regions.

Lentiviral/retroviral infection. HLA-G-1 cDNA ²³ with a signal peptide mutant was cloned into the pLentiLox3.7-PuroR plasmid. As previously described, the lentiviral plasmids pLentiLox3.7-luciferase-PuroR, pLentiLox3.7-HLA-G-PuroR, and pLVX-MICA-ZsGreen plasmid were used to overexpress target protein ²⁴ in cell lines. Infected cells overexpressing luciferase or HLA-G were enriched by selection with 1 μg/mL puromycin. MICA-positive cells were enriched ^{three times} by FACS (clone: 6D4, Baijin Biotechnology Co., Ltd.). Based on previous reports, LILRB2-5 reporter cells and LILRA1-6 reporter cells were prepared by retroviral infection.

In vitro cell killing assay based on flow cytometry. Carboxyfluorescein succinimide (CFSE, Thermo Fisher Scientific) labeling of target cells combined with propidium iodide (PI) staining of dead cells is a reliable method for measuring in vitro cell killing by flow cytometry.^{^26-28} Briefly, NK cells were co-cultured with CFSE-labeled leukemia cells in U-bottom 96-well plates for 4 hours. Each sample was then mixed with PI and analyzed by FACSCalibur. Cell lysis was calculated as the percentage of PI-positive leukemia cells in the total leukemia cells. Spontaneous cell death in the absence of NK cells was less than 5%, and spontaneous cell death in the absence of NK cells was subtracted from the total killing.

Cytokine measurement. A total of 5 × ^10⁴ NKL cells and 5 × ^10⁴ cancer cells were co-cultured in 96-well U-bottom plates for 24 hours. IFN-γ release was detected in the culture supernatant by ELISA (Baijin Biotechnology Co., Ltd.) according to the supplier's manual.

In vivo cytotoxicity assay. A total of 5 × ^10⁶ (CFSE) labeled 697 (NKL-resistant) and 697-MICA (NKL-sensitive) cells were mixed and injected intraperitoneally (IP) with 5 × ^10⁷ NKL into NSG mice. Anti-LILRB1 antibody (10 mg/kg) or control human IgG (hIgG) was administered retroperitoneally. Twenty-four hours later, cells were collected from the peritoneal cavity of mice and stained with anti-MICA antibody, and analyzed using FACS Calibur1 (BD Biosciences). The in vivo cytotoxic activity of NKL was calculated as follows:

NK = the ratio of 697-MICA/697 in mice that received 697, 697-MICA, and NKL cells.

CN = The ratio of 697-MICA/697 in mice that received 697 and 697-MICA cells.

In vivo cytotoxicity activity % = (1-NK/CN)*100.

The in vivo cytotoxic activity of NKL cells against 697-MICA was also tested subcutaneously in NSG mice. A total of 1 × ^10⁶ luciferase-expressing 697-MICA cells (697MICA-luci) were mixed with 5 × ^10⁶ NKL cells and injected subcutaneously (sc) into mice. Anti-LILRB1 antibody (10 mg/kg) or control hIgG was administered retro-orbitally to each mouse. Bioluminescence imaging (BLI) was performed 48 hours later to monitor the remaining 697-MICA cells in the mice.

Multiple myeloma xenograft. Six- to eight-week-old NSG mice were sublethally irradiated with 200 cGy X-rays on day -1. On day 0, each mouse was administered 5 × ^10⁵ KMS27-luci and 5 × ^10⁶ NKL cells via tail vein injection. Anti-LILRB1 antibody (10 mg/kg) or control hIgG was administered post-orbital on days 0, 3, and 7, followed by weekly administration for one month. An additional 5 × ^10⁶ NKL cells were injected on day 14. A total of 10,000 IU human IL-2 was administered to each mouse via intraperitoneal injection every other day. BLI was assessed on days 28 and 35.

Statistical analysis. Data are presented as mean ± SE (standard deviation). Unless otherwise stated, statistical significance between two groups was calculated using a two-tailed unpaired t-test. The Kaplan-Meier survival curve was analyzed using the log-rank test. A difference was considered statistically significant if p < 0.05.

Antibody structure modeling for .176Fv was performed using Discovery Software 2017 R2 (DS). The optimally matched homologous template structures predicted by the identification framework template protocol were selected. These structures were used as input structures, forming the basis for constructing the chimeric antibody Fab structure using the model antibody framework protocol. The model antibody looping method used a Hidden Markov Model (HMM) to identify the template and model the CDR. This method was used to reconstruct the CDR loop. Finally, a CHARMM force field was used to minimize the energy of the homologous model of .176Fv. In this way, a lowest-energy structure was developed for docking and further analysis.

The structure of antibody docking with LILBR1 (PDB ID: 5KNM) was retrieved from the Protein Database (PDB) and subjected to energy minimization during structure preparation using the CHARMm force field. Rigid docking between 176 and LILBR1 was performed using the ZDock algorithm, as described (Chen and Weng, 2002). Next, hierarchical clusters with different docking postures were generated based on the antibody location. The postures were re-scored using a ZRank scoring function based on electrostatics, van der Waals, and desolvation energy terms.

Docking postures were filtered based on the identified ligand binding sites Arg-84 and Tyr-76. Next, 56 ranked postures with ZRank scores below -55 were selected from the ten largest clusters. These were then fed into the RDock program. The input docking structures were improved by eliminating small steric hindrance and optimizing polarity and charge interactions, and then re-ranked according to electrostatic and solvation energy terms (Chen et al., 2003). All 56 docking postures were executed by RDock using default parameters.

Interaction analysis was performed. RDock was used to identify residues at the antibody-antigen interface and to calculate the binding energy between antibody 176 and LILBR1. Interaction analysis was performed using DS and PyMOL. Nonpolar interaction energies were calculated using an interaction energy calculation protocol implemented in DS. Complexes with higher binding affinity between Tyr-76 and Arg-84 of LILBR1 and 176Fv were considered to exhibit a favorable docking conformation.

The structure of h176 was predicted using DS. Docking of LILRB1-D1D2 with the h176 Fab was performed using the ZDOCKpro module of the Insight II package. The general protocol for running ZDOCK consists of two consecutive computational steps, described as a geometry search in ZDOCK and an energy search in RDOCK. The crystal structure of LILRB1-D1D2 was obtained from the PDB database. RDOCK was used to refine the optimal ZDOCK pose. Poses scoring highly in both ZDOCK and RDOCK were selected as candidate complexes.

Sequence alignment and phylogenetic analysis. The D1 and D2 amino acid sequences of all LILRA and LILRB family members were analyzed. LILRB4 was an exception, for which the D1 domain was analyzed. The accession numbers of the proteins in GenBank are as follows: LILRB1, Q8NHL6; LILRB2, Q8N423; LILRB3, O75022; LILRB4, Q8NHJ6; LILRB5, O75023; LILRA1, O75019; LILRA2, Q8N149; LILRA3, Q8N6C8; LILRA4, P59901; LILRA5, A6NI73; LILRA6, Q6PI73. The D1 region was defined as positions 27 to 115, and the D2 region was defined as positions 116 to 221. Multiple alignment of all D1 and D2 sequences was performed using ClustalX (version 2.1). MEGA (version 7.0) is used to generate phylogenetic trees.

Example 2 – LILRB1 is highly expressed on NK cells in the peripheral blood of patients with MM and prostate cancer.

The functions of LILRB family immunosuppressive receptors and immune-activating receptor NKG2D in cancer development have been characterized ^1–8 . To investigate whether LILRB1 could be a molecular target for cancer immunotherapy, LILRB1 expression on NK cells from patients with cancer was determined and compared with LILRB1 expression in healthy donors. LILRB1 was primarily expressed on CD56 ^dark NK cells from healthy donors and patients with cancer, but not on CD56 ^bright NK cells (Figure 1A). The percentage of NK cells expressing LILRB1 in CD56 ^dark NK cells from peripheral blood of patients with prostate cancer or multiple myeloma (MM) was assessed. The percentage of LILRB1 ⁺ NK cells (in CD56 ^dark NK cells) in the blood of patients with advanced prostate cancer (3b and 3c) was significantly higher than that in the blood of healthy donors (Figure 1B, Table 9). Furthermore, the percentage of LILRB1 ⁺ NK cells (CD56 ^dark NK) from peripheral blood of MM patients with persistent disease during treatment was higher than that from healthy donors or patients with mild to complete response (Figure 1C, Table 10). These results suggest that the percentage of LILRB1 ⁺ NK cells is significantly higher in patients with advanced cancer or poor prognosis, and ^that LILRB1 may be a molecular target for immunotherapy in these patients.

Table 9. Clinical characteristics of patients with prostate cancer before treatment

Table 10. Treatment response in patients with multiple myeloma

Example 3 – Generation and Characterization of Antagonistic and Agonistant Monoclonal Antibodies Against LILRB1

To evaluate the therapeutic potential of anti-LILRB1 mAbs in activating NK cells, a panel of anti-LILRB1 mAbs (Fig. 12A-B) was generated by screening single memory B clones, cloning antibody genes, and assessing the blocking activity of recombinant mAbs (Fig. 12A-B) ^32-34 . A total of 229 anti-LILRB1-specific single B cell clones were generated from 384 LILRB1 B cell culture wells and evaluated by ELISA (Table 11). Of these, 174 single B cell clones were identified that produced mAbs that bind to LILRB1, which is expressed on the cell surface of LILRB1 NFAT-GFP reporter cells (Table 12), expressing GFP ¹⁸ when LILRB1 is cross-linked on the cell surface. Sixty conjugates were selected for further cloning and expression, and 44 of these antibodies were found to have low EC50 in the nanomolar range (0.05-3 nM) (Fig. 12C). Estimated EC50 based on antibody concentration titration binding curves are provided in Table 13. To group the 44 mAbs according to their binding epitopes, classic sandwich epitope binning was performed using the Octet RED96, and twelve epitope binnings were identified for these 44 highly bound abs (Fig. 12D).

Table 11. mAb binding in the supernatant of 229 B cell clones as determined by ELISA

Table 12. Binding of mAbs in the supernatant of 229 B cell clones to LILRB1 on the cell surface of reporter cells. Anti-mAbs in the supernatant were immobilized using protein A-coated cell culture plates. 96-well cell culture plates were coated with phosphate-buffered saline (PBS) containing 5 μg/mL protein A at 37°C for 2 hours. After washing three times with PBS, the plates were incubated overnight at 4°C with the supernatant of 229 B cell clones. LILRB1 reporter cells were cultured in the plates for 24 hours. The percentage of GFP reporter cells was analyzed by flow cytometry.

Table 13. _EC50 estimated based on antibody concentration titration binding curves

mAb <![CDATA[EC₅₀(ng/mL)]]> mAb <![CDATA[EC₅₀(ng/mL)]]> B1-#202-2 59.39 B1-#79 15.36 B1-#204 7.366 B1-#15 9.303 B1-#176 2.237 B1-#173-2 6.565 B1#56 43.8 B1-#28 24.24 B1#3 11.92 B1-#41-1 94.38 B1#5 6.024 B1-#72-1 10.97 B1-#190 6.777 B1-#74 130.1 B1-#220 10.62 B1-#22 29.19 B1-#175 5.296 B1-#93 482.5 B1#58-1 17.1 B1-#160 28.52 B1#27 7.941 B1-#189 14.46 B1#38 181.2 B1-#224 10.95 B1#83 15.55 B1-#198 9.422 B1#76 28.41 B1-#115 52.03 B1#25 13.24 B1-#98 38.03 B1-#166 8.614 B1-#19 19.58 B1-#226 8.261 B1-#10 20.94 B1-#179 6.467 B1-#128 40.02 B1-#125 7.603 B1-#205 98.6 B1-#7 15.93 B1-#209 11 B1-#18 18.19 B1-#196-2 151.5 B1-#178-2 14.25 B1-#14-2 21.45 B1-#110 17.77  

To screen for antagonistic anti-LILRB1 mAbs, LILRB1 receptor cells were co-cultured with K562 cells overexpressing HLA-G1 (an MHC class I molecule with the highest affinity for LILRB1) (K562-HLA-G) (Fig. 2A). LILRB1 reporter cells were activated by K562-HLA-G cells but not by parental K562 cells (MHC class I negative) (Fig. 2A). All antibodies were screened using this reporter assay. Antibodies in bins 1, 7, 8, and 9 showed antagonistic activity (Fig. 12E). Antibodies in bins 2, 3, 4, 5, 6, 10, 11, and 12 showed agonistic activity (Fig. 12D-E). Cross-binding of B1-176 and other commercial anti-LILRB1 antibodies was analyzed by flow cytometry (Fig. 2I).

Among the agonist antibodies, the antibody from Box 1 showed the strongest blocking efficacy (Fig. 2B). Evaluation by flow cytometry (Fig. 2C), ELISA (Fig. 2D), and Octet RED96 (Fig. 12F; Table 14) showed that B1-176 in Box 1 specifically binds to LILRB1. B1-176 exhibited high affinity for LILRB1, with a KD value of approximately 10 pM (Fig. 2E), significantly higher than the affinity of two commercial anti-LILRB1 monoclonal antibodies, HP-F1 and GHI/75 (Fig. 12G). Therefore, B1-176 was selected to further evaluate its function in binding epitopes and regulating NK cell activation.

Table 14. Binding affinity of LILRB1 monoclonal antibody measured using Octet 96Red instrument

mAb KD(M) kon (1/millisecond) kdis (1/second) Complete R^2 B1-#3 5.05E-10 1.12E+05 5.63E-05 0.9974 B1-#176 6.19E-10 9.03E+04 5.59E-05 0.996 B1-#27 1.27E-09 1.27E+05 1.61E-04 0.9993 B1-#178-2 1.59E-09 1.72E+05 2.73E-04 0.9992 B1-#41-1 1.58E-08 3.20E+05 5.06E-03 0.8535 B1-#173-2 1.37E-09 1.92E+05 2.62E-04 0.9983 B1-#72-1 3.14E-09 7.57E+04 2.37E-04 0.9982 B1-#22 6.11E-10 1.41E+05 8.62E-05 0.9971 B1-#74 1.61E-08 8.99E+04 1.45E-03 0.948 B1-#93 8.54E-09 3.96E+04 3.38E-04 0.9772 B1-#198 2.72E-11 2.18E+05 5.92E-06 0.999 B1-#209 3.03E-09 6.89E+04 2.09E-04 0.9993

To understand the mechanism by which B1-176 blocks LILRB1 activation, its binding epitopes were identified. Evaluation by ELISA (Figure 2F) showed that B1-176 specifically binds to the D1D2 region of LILRB1 (Figure 13A), but not to other domains. A series of amino acid mutations were performed in the D1D2 region of LILRB1 to identify the key amino acids for B1-176 binding (Figure 13B). Two amino acids (R84 and Y76; corresponding to positions 107 and 99 of SEQ ID NO:1, respectively) were found to facilitate the interaction between LILRB1 and B1-176 (Figure 2G). Molecular docking of B1-176 was performed using Discovery Studio 2017. Based on the PDB structure of the LILRB1 D1D2 region (PDBID: 1UFU) and the modeling structure of B1-176 using the two key amino acids R84 and Y76, the most probable binding model was determined. In this model, the long HCDR3 of B1-176 is inserted into a narrow ligand-binding pocket on the LILRB1 D1 domain. Arg-84 of LILRB1 interacts with Tyr-102, Glu-103, and Asp-109 from the HCDR3 ring via hydrogen bonding and electrostatic interactions. Tyr-76 of LILRB1 may form a hydrogen bond with Asp-104 from HCDR3 (Figure 2H).

Example 4 – Humanization of Rabbit Anti-LILRB1 mAb

To minimize the immunogenicity of B1-176 for clinical application, B1-176 was humanized and molecularly engineered to optimize the antibody sequence. The Kabat/IMGR/Paratome combinatorial CDR ²⁰ in the heavy and light chains of B1-176 was identified as previously described. The CDR sequence shown here is as short as HCDR and LCDR. Human lines IGHV3-53*04 and IGKV1-9*01 were selected as the backbone. The heavy chain Hu-176 VH-1 and light chain Hu-176 VL were generated by CDR grafting. However, the antibody with the humanized heavy chain sequence VH-1 showed reduced binding to LILRB1 (Figure 3B). Mutation assessment after multiple rounds of single-reversion mutations in VH-1 showed that amino acid L48 in FR2 was important for restoring binding activity (Figures 3A and 3B). Molecular docking showed that the humanized and rabbit B1-176 Fabs have similar stacked structures (Figure 3C).

Given the widespread expression of LILRB1 on normal immune cells, rabbit B1-176 expressed human IgG1 with the N297A mutation (B1-176-N297A), and humanized B1-176 expressed human IgG1 with the N297A mutation (Hu B1-176-N297A) or with the L234A, L235A, and P329G mutations (Hu B1-176-LALAPG) to eliminate Fc-mediated immune effector function.35 ³⁶ All B1-176 cells with Fc mutants maintained a strong affinity for LILRB1 (Figure 3D).

Example 5 – Antagonistic anti-LILRB1 mAb blocks activation of LILRB1 reporter gene cells by cancer cells

Cancer cell lines capable of activating LILRB1 were identified by co-culturing cancer cells with LILRB1 reporter cells (Fig. 4A). Flow cytometry was used to assess the expression of MHC class I molecules (antibody clone: HP-1F7, Santa Cruz)—ligands of LILRB1—on the cell surface of hematologic and solid tumor cancer cell lines (Fig. 4A). Most cancer cell lines expressed MHC class I molecules and stimulated LILRB1 reporter cell activation. K562, DLD1, and Daudi cells were exceptions, as they did not express MHC class I molecules on their cell surface. Therefore, the ability of cancer cells to activate LILRB1 reporter cells was positively correlated with their MHC class I expression levels. B1-176 and Hu B1-176-N297A blocked LILRB1 reporter cell activation stimulated by hematologic cancer cell lines (Fig. 4B) and solid tumor cell lines (Fig. 4C). These results indicate that rabbit and humanized versions of B1-176 can block HLA-G and other MHC class I molecule-induced LILRB1 activation. Notably, LILRB1 ^binds to the conserved α3 domain of MHC class I cells. This may explain why antagonistic anti-LILRB1 antibodies screened from K562-HLA-G cells can block LILRB1 activation in other cancer cell lines.

Example 6 – In vitro function of NK cells by antagonistic anti-LILRB1 mAb

The in vitro efficacy of anti-LILRB1 mAbs was evaluated using the NK cell line NKL. NKL cells express high levels of LILRB1 on their surface (Fig. 14A). Treatment with different versions of anti-LILRB1 mAbs—B1-176-N297A, Hu B1-176-N297A, and HuB1-176-LALAPG—increased the cytotoxic activity of NKL cells against the MM cell line KMS27 to similar levels (Fig. 5A). The anti-LILRB1 antibody also increased the cytotoxic activity of NKL against other MM cell lines OPM2 and RPMI8226, as well as the T-cell leukemia cell line Jurkat (Fig. 5B). Flow cytometry revealed that LILRB1 is expressed on the cell surface of some leukemia and lymphoma cell lines, such as 697 and Raji cells, but not on MM cell lines, Jurkat cells, or most malignant plasma cells from patients with MM (Fig. 14B-D). Since the N297A mutation or LALAPG on Fc cells eliminates the ADCC function of antibodies, these results indicate that antagonistic anti-LILRB1 antibodies increase the native cytotoxic activity of NKL cells against MM cell lines. Interestingly, even with anti-LILRB1 antibody treatment, the pre-B-cell leukemia cell line 697 and the Burkitt lymphoma cell line Raji also exhibited resistance to NKL cytotoxicity (Fig. 5C). Previous studies have reported that the MHC class I chain-associated gene AB (MICA/B), a ligand for the NK cell activation receptor NKG2D, is expressed on NK-sensitive acute lymphoblastic leukemia (ALL) cells but ^absent on NK-resistant ALL cells. To sensitize 697 and Raji cells, MICA was overexpressed on both 697 and Raji cells. As expected, MICA on the surface of cancer cells stimulated the cytotoxic activity of NKL cells against these cells, and the anti-LILRB1 antibody further increased the cytotoxic activity of NKL cells (Fig. 5C-D). These results indicate that LILRB1 blockade and NKG2D activation synergistically increase the cytotoxic activity of NKL cells. In addition to hematologic malignancies, anti-LILRB1 antibodies also stimulate NKL cells to kill solid tumor cancer cell lines, such as the breast cancer cell line MDA-MB-231 and the melanoma cell line MALME-3M (Figure 5E).

NK cells can also enhance the response of other immune cells to cancer cells by secreting cytokines. Anti-LILRB1 antibody increased IFN-γ secretion from NKL cells stimulated by T-cell leukemia Jurkat cells and MM cell lines RPMI8226, OPM2, and KMS27 (Fig. 5F). Anti-LILRB1 antibody increased IFN-γ secretion from 697-MICA cells without increasing 697-induced IFN-γ secretion from NKL cells. This result indicates that LILRB1 blockade and NKG2D activation synergistically stimulate IFN-γ from NKL cells (Fig. 5F). The function of antagonistic anti-LILRB1 antibody was also confirmed using another NK cell line, NK92m. Antagonistic anti-LILRB1 antibody enhanced the cytotoxic activity of NK92mi against leukemia cell lines (Fig. 8A-B), solid tumor cell lines (Fig. 8B), multiple myeloma cell lines (Fig. 8C), and primary leukemia cells (Fig. 8D).

Furthermore, the function of the anti-LILRB1 antibody was confirmed using primary NK cells. Primary NK cells from the erythrocyte sedimentation rate (ESR) amber layer of healthy donors were isolated, and LILRB1 ⁺ NK cells were enriched by FACS. The anti-LILRB1 antibody increased the cytotoxic activity of primary LILRB1 ⁺ NK cells from healthy donors against multiple myeloma cell lines (KMS27 and OPM2), 697 cells, or Raji cells, but did not increase the cytotoxic activity against Daudi cells that do not express LILRB1 ligand MHC class I (Fig. 6A). Since NK cells also express MHC class I, this result indicates that MHC class I or cis-MHC class I on neighboring NK cells does not inhibit the cytotoxic activity of NK cells against cancer cells. Here, 697 and Raji cells were sensitive to the cytotoxic activity of primary NK cells, which may be because the cytotoxic activity of primary NK cells is stronger than that of NKL cells. A previous publication also reported that activated primary NK cells exhibited stronger cytotoxic activity than NKL cells, likely due to relatively higher levels of cytotoxic receptors and NK94 on primary NK cells.^³⁹ NK cells were also isolated from the peripheral blood of a patient with multiple myeloma (MM) whose NK cells were approximately 80% LILRB1 positive, and these NK cells were used for cytotoxicity assays. Anti-LILRB1 mAb increased the cytotoxic activity of the patient's NK cells against the MM cell line KMS27 (Figure 6B).

Example 7 – In vivo function of NK cells by antagonistic anti-LILRB1 mAb

The in vivo function of the anti-LILRB1 antibody was tested in NSG mice. A mixture of NKL-resistant 697 cells and NKL-sensitive 697MICA cells was injected into the peritoneum of NSG mice along with NKL cells. After 24 hours, the 697-MICA/697 ratio was analyzed and calculated as the in vivo cytotoxic activity of NKL cells (Fig. 7A). These results indicate that the anti-LILRB1 antibody increased the in vivo cytotoxic activity of NKL cells against 697-MICA cells. The cytotoxic activity of NKL cells was also tested in vivo in NSG mice by subcutaneous injection of a mixture of NKL and luciferase-overexpressing 697-MICA cells. After 48 hours, bioluminescence imaging (BLI) showed a significant reduction in tumor burden in mice receiving the anti-LILRB1 antibody compared to control hIgG-treated mice (Fig. 7B). In conclusion, the anti-LILRB1 antibody can improve the in vivo cytotoxic function of NKL cells.

The efficacy of anti-LILRB1 antibody in preventing the development of multiple myeloma was further evaluated in a xenograft mouse model. NSG mice were implanted with KMS27 cells and NKL cells via their tail vein and administered either control IgG or anti-LILRB1 antibody, with cancer development monitored via BLI. Mice receiving NKL cells and anti-LILRB1 antibody had significantly lower disease burden and longer survival time compared to mice receiving NKL cells and control IgG or mice receiving phosphate-buffered saline (PBS) alone (Figure 7C). In summary, these results indicate that antagonistic anti-LILRB1 antibody can enhance the function of NKL cells in suppressing the development of multiple myeloma in vivo.

Example 8 – In vitro function of agonist anti-LILRB1 mAb

B1-7 and B1-41 were selected to determine the function of agonistic LILRB1. B1-7 and B1-41 exhibited agonistic function in LILRB1 reporter cells co-cultured with K562 cells (Fig. 9). In the absence of K562 cells, B1-7 and B1-41 did not activate LILRB1 reporter cells. Considering that K562 cells possess Fc receptors, this result indicates that agonistic LILRB1 mAbs only function when their Fc cells bind to Fc receptors in the environment. To confirm this, N297A or S267E was introduced into the Fc cells of agonistic LILRB1 mAbs to eliminate or enhance Fc binding to Fc receptors, respectively. The results showed that N297A eliminated binding, while S267E enhanced B1-7 and B1-41-induced activation of LILRB1 reporter cells (Fig. 9). These results suggest that the agonistic effect of anti-LILRB1 is Fc-dependent. Agonistant LILRB1 mAbs inhibited the cytotoxic activity of NK92mi (Fig. 10A-B) and NKL (Fig. 10C) cells against cancer cells in vitro. The N297A mutation in Fc cells eliminated the activity of agonist B1-7 (Fig. 10D). Agonistant LILRB1 mAbs also inhibited IFN-γ secretion from NKL cells (Fig. 11).

**********

According to this disclosure, all methods disclosed and claimed herein can be prepared and performed without excessive experimentation. Although the compositions and methods of the invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that the methods and the steps or sequences of steps described herein can be altered without departing from the concept, spirit, and scope of the invention. More specifically, it will be apparent that certain chemically and physiologically relevant agents can replace the agents described herein while achieving the same or similar results. All such similar substitutions and modifications that are apparent to those skilled in the art are considered to be within the spirit, scope, and concept of the invention as defined by the appended claims.

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38. Romanski A, Bug G, Becker S, et al. Mechanisms of resistance to natural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia. *Exp Hematol*, 2005; 33:344-52. doi:10.1016/j.exphem.2004.11.006

39. Gross C, Schmidt-Wolf IGH, Nagaraj S, et al. Heat shock protein 70 reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell Stress Chaperon 2003; 8:348-60. doi:10.1379/1466-1268(2003)008<0348:Hspria>2.0.Co;2

40. Morandi F, Ferretti E, Castriconi R, et al. Soluble HLA-G inhibits CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD56 bright and CD56 dim NK cells. Blood 2011; 118:5840-50. doi:10.1182/blood-2011-05-352393

41. Desgrandchamps F, LeMaoult J, Goujon A, et al., predicted the recurrence of non-muscle-invasive bladder cancer by measuring the checkpoint HLAG receptor ILT2 on peripheral CD8(+) T cells. *Oncotarget*, 2018; 9:33160-69. doi:10.18632/oncotarget.26036

42. Yu K, Davidson CE, Burshtyn DN. LILRB1 intron 1 is a polymorphic regulatory region that enhances transcription in NK cells and recruits YY1. Journal of Immunology 2020; 204:3030-41. doi:10.4049/jimmunol.2000164

43. LeMaoult J, Zafaranloo K, Le Danff C, et al. HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen-presenting cells, NK cells, and T cells. *FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology*, 2005; 19:662-4. doi:10.1096/fj.04-1617fje

44. Bjorkstrom NK, Riese P, Heuts F, et al., defined the expression patterns of NKG2A, KIR, and CD57 as a process of CD56-dim NK-cell differentiation uncoupled from NK-cell education. *Blood* 2010; 116:3853-64. doi:10.1182/blood-2010-04-281675

45. Muntasell A, Servitja S, Cabo M, et al. High Numbers of Circulating CD57(+) NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2(+) Primary Breast Cancer. Cancer Immunology Research 2019; 7:1280-92. doi:10.1158/2326-6066.CIR-18-0896

46. Heidenreich S, Zu Eulenburg C, Hildebrandt Y, et al. Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. Clinical & Developmental Immunology, 2012; 2012:652130. doi:10.1155/2012/652130

47. Suck G, Odendahl M, Nowakowska P, et al. NK-92: an 'off-the-shelf therapy' for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunology 2016; 65:485-92. doi:10.1007/s00262-015-1761-x

48. Carbone E, Neri P, Mesuraca M, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood 2005; 105:251-58. doi:10.1182/blood-2004-04-1422

49. Menier C, Riteau B, Carosella ED, et al., MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal. *International Journal of Cancer*, 2002; 100:63-70. doi:10.1002/ijc.10460

50. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood, 2005; 105:3051-57. doi:10.1182/blood-2004-07-2974

Sequence List

<110> Board of Regents, The University of Texas System

<120> Monoclonal antibodies against LILRB1 for diagnostic and therapeutic purposes

<130> UTFH.P0370WO

<140> Not yet allocated

<141> 2021-07-26

<150> 63/057,601

<151> 2020-07-28

<150> 63/124,516

<151> 2020-12-11

<160> 875

<170> PatentIn version 3.5

<210>  1

<211> 650

<212> PRT

<213> Homo sapiens

<400>  1

Met Thr Pro Ile Leu Thr Val Leu Ile Cys Leu Gly Leu Ser Leu Gly

1 5 10 15

Pro Arg Thr His Val Gln Ala Gly His Leu Pro Lys Pro Thr Leu Trp

20 25 30

Ala Glu Pro Gly Ser Val Ile Thr Gln Gly Ser Pro Val Thr Leu Arg

35 40 45

Cys Gln Gly Gly Gln Glu Thr Gln Glu Tyr Arg Leu Tyr Arg Glu Lys

50 55 60

Lys Thr Ala Leu Trp Ile Thr Arg Ile Pro Gln Glu Leu Val Lys Lys

65 70 75 80

Gly Gln Phe Pro Ile Pro Ser Ile Thr Trp Glu His Ala Gly Arg Tyr

85 90 95

Arg Cys Tyr Tyr Gly Ser Asp Thr Ala Gly Arg Ser Glu Ser Ser Asp

100 105 110

Pro Leu Glu Leu Val Val Thr Gly Ala Tyr Ile Lys Pro Thr Leu Ser

115 120 125

Ala Gln Pro Ser Pro Val Val Asn Ser Gly Gly Asn Val Ile Leu Gln

130 135 140

Cys Asp Ser Gln Val Ala Phe Asp Gly Phe Ser Leu Cys Lys Glu Gly

145 150 155 160

Glu Asp Glu His Pro Gln Cys Leu Asn Ser Gln Pro His Ala Arg Gly

165 170 175

Ser Ser Arg Ala Ile Phe Ser Val Gly Pro Val Ser Pro Ser Arg Arg

180 185 190

Trp Trp Tyr Arg Cys Tyr Ala Tyr Asp Ser Asn Ser Pro Tyr Glu Trp

195 200 205

Ser Leu Pro Ser Asp Leu Leu Glu Leu Leu Val Leu Gly Val Ser Lys

210 215 220

Lys Pro Ser Leu Ser Val Gln Pro Gly Pro Ile Val Ala Pro Glu Glu

225 230 235 240

Thr Leu Thr Leu Gln Cys Gly Ser Asp Ala Gly Tyr Asn Arg Phe Val

245 250 255

Leu Tyr Lys Asp Gly Glu Arg Asp Phe Leu Gln Leu Ala Gly Ala Gln

260 265 270

Pro Gln Ala Gly Leu Ser Gln Ala Asn Phe Thr Leu Gly Pro Val Ser

275 280 285

Arg Ser Tyr Gly Gly Gln Tyr Arg Cys Tyr Gly Ala His Asn Leu Ser

290 295 300

Ser Glu Trp Ser Ala Pro Ser Asp Pro Leu Asp Ile Leu Ile Ala Gly

305 310 315 320

Gln Phe Tyr Asp Arg Val Ser Leu Ser Val Gln Pro Gly Pro Thr Val

325 330 335

Ala Ser Gly Glu Asn Val Thr Leu Leu Cys Gln Ser Gln Gly Trp Met

340 345 350

Gln Thr Phe Leu Leu Thr Lys Glu Gly Ala Ala Asp Asp Pro Trp Arg

355 360 365

Leu Arg Ser Thr Tyr Tyr Gln Ser Gln Lys Tyr Gln Ala Glu Phe Pro Met

370 375 380

Gly Pro Val Thr Ser Ala His Ala Gly Thr Tyr Tyr Arg Cys Tyr Gly Ser

385 390 395 400

Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu

405 410 415

Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly

420 425 430

Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly

435 440 445

Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly

450 455 460

Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe

465 470 475 480

Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln

485 490 495

Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro

500 505 510

Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln

515 520 525

Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly

530 535 540

Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val

545 550 555 560

Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser

565 570 575

Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln

580 585 590

Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala

595 600 605

Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg

610 615 620

Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val

625 630 635 640

Pro Ser Ile Tyr Ala Thr Leu Ala Ile His

645 650

<210>  2

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  2

Gly Phe Asp Phe Ser Ser Asp Ala

1 5

<210> 3

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 3

Ile Tyr Asn Gly Asp Glu Ile

1 5

<210> 4

<211>  20

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  4

Ala Arg Ala Val Tyr Ser Asp Gly Gly Ala Gly Tyr Pro Tyr Met Tyr

1 5 10 15

Gly Met Asp Leu

20

<210> 5

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 5

Gly Phe Asp Phe Ser Gly Ile Tyr Trp

1 5

<210> 6

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 6

Phe Asp Ala Glu Arg Thr Gly Asn Thr

1 5

<210> 7

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 7

Ala Arg Ser Tyr Tyr Met

1 5

<210> 8

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 8

Glu Leu Ser Phe Ser Ser Ala Tyr Tyr

1 5

<210> 9

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  9

Ile Tyr Ser Gly Asp Gly Asp

1 5

<210> 10

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 10

Ala Arg Ala Leu Asp Ser His Tyr Ser Ser Phe Asp Leu

1 5 10

<210> 11

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 11

Gly Phe Ser Leu Asn Ser Tyr Ala

1 5

<210> 12

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 12

Ile Asp Thr Gly Ala Ser Ile

1 5

<210> 13

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 13

Ala Arg Gly Phe Ser Met Phe Lys Leu

1 5

<210> 14

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 14

Gly Leu Asp Phe Ser Ser Ser Tyr Trp

1 5

<210> 15

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 15

Ile Asp Thr Gly Ser Ser Gly Ser Thr

1 5

<210> 16

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 16

Ala Ser Thr Pro Asn Ser Leu Gly Tyr Asp Leu

1 5 10

<210> 17

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 17

Gly Phe Ser Ser Ser Ser Ala Tyr

1 5

<210> 18

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 18

Ile Phe Ile Gly Ser Gly Ser Asp Ser

1 5

<210> 19

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 19

Ala Arg Asn Thr Tyr Tyr Asp Trp Asn Gly Tyr Ile Tyr Gly Pro Cys Tyr

1 5 10 15

Phe Gly Leu

<210>  20

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  20

Gly Phe Ser Leu Ser Arg Tyr Ala

1 5

<210>  21

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  21

Ile Asp Thr Ser Ser Gly Asn

1 5

<210>  22

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  22

Ala Arg Gly Phe Ser Met Phe Lys Leu

1 5

<210> 23

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 23

Gly Leu Asp Phe Ser Ser Ser Tyr Trp

1 5

<210>  24

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  24

Ile Asp Val Gly Ser Ser Gly Gly Ser

1 5

<210> 25

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 25

Ala Ser Thr Thr Thr Asn Val Phe Gly Tyr Asp Leu

1 5 10

<210> 26

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 26

Gly Phe Asp Phe Ser Ser Asn Asp Tyr

1 5

<210>  27

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 27

Ile Tyr Gly Gly Asp Gly His Thr

1 5

<210>  28

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 28

Arg Gly Tyr Ser Tyr Gly Asp Thr Gly Tyr Ala Asp Ala Ile Leu Thr

1 5 10 15

Leu Asp Leu

<210>  29

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  29

Phe Asn Tyr Tyr Asn Tyr Tyr Tyr

1 5

<210> 30

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 30

Met Ser Thr Ala Ser Ala Asn

1 5

<210> 31

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 31

Ala Lys Ser His Gly Gly Asp Gly Gly Tyr Gly Val Val Leu

1 5 10

<210> 32

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 32

Gly Phe Ser Phe Ser Gly Ser Tyr Trp

1 5

<210> 33

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 33

Ile Tyr Gly Asp Ser Ile Ala

1 5

<210> 34

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 34

Ala Arg Asp Arg Asn Gly Gly Ser Gly Ala Tyr Gly Trp Asp Leu

1 5 10 15

<210> 35

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 35

Gly Phe Ser Phe Ser Ser Asp Tyr Asp

1 5

<210> 36

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 36

Ile Val Thr Gly Phe Ser Gly Arg Ile

1 5

<210> 37

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 37

Ala Arg Asp Ser Gly Asn Tyr Asn Trp Asp Leu

1 5 10

<210> 38

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 38

Gly Phe Ser Phe Ser Asn Asp Tyr Trp

1 5

<210> 39

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 39

Gly His Ile Gly Ser Phe Arg Thr Thr

1 5

<210> 40

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  40

Ala Arg Ser Pro Tyr Asp Asp Gly Tyr Gly Gly Phe Thr Phe Asn Leu

1 5 10 15

<210> 41

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  41

Gly Phe Ser Phe Ser Ser Ser Tyr Trp

1 5

<210> 42

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  42

Ile Tyr Ala Gly Ser Ser Gly Ser Thr

1 5

<210> 43

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  43

Ala Arg Ser Thr Ser Gly Ser Tyr Gly Ala Gly Leu Gly Leu

1 5 10

<210> 44

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  44

Gly Phe Ser Phe Ser Ile Asn Leu Tyr

1 5

<210> 45

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  45

Ile Tyr Gly Asn Asn Asn Ala Asn Thr

1 5

<210> 46

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  46

Ala Arg Asp Thr Ala Ala Tyr Tyr Ala Phe Ser Leu

1 5 10

<210> 47

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  47

Ser Gly Phe Thr Phe Ser Gly Tyr Tyr

1 5

<210> 48

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  48

Ile Tyr Val Gly Ser Gly Gly Ser Thr

1 5

<210> 49

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  49

Ala Arg Gly Val Asn Asp Tyr Gly Trp Ala Leu Lys Leu

1 5 10

<210> 50

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 50

Ala Phe Ser Phe Ser Ser Ser Ser Trp

1 5

<210> 51

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 51

Ile Tyr Gly Gly Ser Val Gly Thr Thr

1 5

<210> 52

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 52

Ala Thr Asn Thr Asp Ser Ser Arg Ser Tyr Tyr Asn Leu

1 5 10

<210> 53

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 53

Gly Ile Asp Leu Ser Asn Tyr Trp Tyr

1 5

<210> 54

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 54

Val Ala Thr Asp Ser Ser Arg Thr

1 5

<210> 55

<211>  20

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 55

Arg Gly Ser Gly Ala Ser Thr Asn Gly Val Trp Trp Val Met Gly Asp

1 5 10 15

Gly Met Asp Leu

20

<210> 56

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 56

Gly Phe Ser Leu Asn Arg Tyr Tyr

1 5

<210> 57

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 57

Ile Tyr Ser Gly Ser Gly Ser

1 5

<210> 58

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 58

Gly Arg Leu Asp Tyr Arg Val Ile Tyr Ala Phe Asn Leu

1 5 10

<210> 59

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 59

Gly Phe Ser Phe Ser Gly Ser Cys Asp

1 5

<210> 60

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 60

Ile Val Leu Ser Asn Gly Asn

1 5

<210> 61

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 61

Ala Arg Glu Arg Tyr Pro Gly Ala Phe Ser Ser Gly Leu Asp Leu

1 5 10 15

<210> 62

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 62

Gly Phe Ser Phe Ser Ser Ser Trp Tyr

1 5

<210> 63

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 63

Ile Tyr Thr Leu Arg Ser Gly Ala Ala

1 5

<210> 64

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 64

Ala Arg Ala Thr Tyr Ala Tyr Ala Gly Ala Gly Asp Leu

1 5 10

<210> 65

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 65

Ala Phe Ser Phe Ser Ser Ser Ser Trp

1 5

<210> 66

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 66

Ile Tyr Gly Gly Ser Val Ala Thr Thr

1 5

<210> 67

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 67

Ala Thr Asn Thr Asp Ser Ser Arg Ser Tyr Tyr Asn Leu

1 5 10

<210> 68

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 68

Gly Phe Ser Phe Ser Gly Asn Thr

1 5

<210> 69

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 69

Ile Tyr Pro Ser Ser Thr Ser Ile

1 5

<210> 70

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 70

Ala Arg Arg Tyr Ala Ala Phe Leu Thr Tyr Gly Ser Gly Ala Phe Asp

1 5 10 15

Pro

<210> 71

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 71

Gly Phe Ser Phe Ser Ser Ser Tyr Trp

1 5

<210> 72

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 72

Val Ala Thr Gly Ser Gly Thr

1 5

<210> 73

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 73

Ala Arg Ile Gly Ala Phe Tyr Ser Phe Arg Leu

1 5 10

<210> 74

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 74

Gly Phe Ser Phe Ser Ser Ser Tyr Trp

1 5

<210> 75

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 75

Ile Tyr Ala Gly Asn Ser Ala Asn Thr

1 5

<210> 76

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 76

Ala Ser Arg Asn Gly Gly Ala Pro Asp Gly Leu Asn Leu

1 5 10

<210> 77

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 77

Gly Phe Ser Phe Ser Ser Ser Tyr Trp

1 5

<210> 78

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 78

Ile Ala Thr Gly Thr Gly Ser

1 5

<210> 79

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 79

Ala Arg Gly Gly Gly Tyr Trp Ser Phe Ser Leu

1 5 10

<210> 80

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 80

Gly Phe Ser Phe Ser Ser Ser Tyr Tyr

1 5

<210> 81

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 81

Ile Tyr Thr Gly Ser Asp Ser Thr

1 5

<210> 82

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 82

Gly Asp Trp Asp Tyr Ala Asp Ala Ala Gly Tyr Tyr Val Ala Arg Gly

1 5 10 15

Phe Asn Leu

<210> 83

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 83

Gly Phe Ser Phe Thr Lys Asn Tyr Tyr

1 5

<210> 84

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 84

Ile Tyr Ala Gly Ser Thr Asn Thr

1 5

<210> 85

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 85

Arg Asp Phe Val Ser Tyr Leu Asn Leu

1 5

<210> 86

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 86

Gly Ile Asp Leu Ser Asn Phe Tyr Tyr

1 5

<210> 87

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 87

Val Ala Ser Asp Ser Ser Arg

1 5

<210> 88

<211>  21

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 88

Ala Arg Gly Ser Gly Ala Ser Thr Asn Gly Val Trp Trp Val Met Gly

1 5 10 15

Asp Gly Met Asp Leu

20

<210> 89

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 89

Gly Phe Ser Phe Ser Ser Gly His Tyr

1 5

<210> 90

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 90

Ile Tyr Ala Gly Ser Asp Thr Gly Ser

1 5

<210> 91

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 91

Cys Ala Arg Ser Ser Asn Ser Tyr Gly Asn Tyr Gly Val Ser Asn Leu

1 5 10 15

<210> 92

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 92

Gly Ile Asp Phe Ser Ser Gly Tyr Trp

1 5

<210> 93

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 93

Ile Phe Thr Ser Ser Ser Gly Thr Thr

1 5

<210> 94

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 94

Arg Asp Ile Tyr Ser Tyr Gly Met Asp Leu

1 5 10

<210> 95

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 95

Gly Ile Asp Phe Ser Ser Ala Tyr

1 5

<210> 96

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 96

Met Arg Ile Asn Asp Arg Ser

1 5

<210> 97

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 97

Ala Arg Ile Ala Thr Gly Thr Asn Val Asp Asp Phe

1 5 10

<210> 98

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 98

Gly Phe Ser Phe Ser Ser Lys Gln Tyr

1 5

<210> 99

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 99

Ile Val Thr Val Asn Asn Lys

1 5

<210> 100

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 100

Ala Arg Trp Arg Thr Phe Gly Leu

1 5

<210> 101

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 101

Arg Phe Ser Leu Ser Asn Met Asn Val

1 5

<210> 102

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 102

Ile Asn Ile Gly Gly Thr Asn

1 5

<210> 103

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 103

Ala Arg Ser Tyr Ile Thr Asp Arg Ile Tyr Asp Tyr Asp Phe

1 5 10

<210> 104

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 104

Gly Phe Asp Phe Ser Ser Lys Tyr Tyr

1 5

<210> 105

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 105

Ile Tyr Gly Gly Ser Ser Asp Ser Thr

1 5

<210> 106

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 106

Gly Arg Val Ile Asp Gly Ala Cys Gly Tyr Asp Leu

1 5 10

<210> 107

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 107

Gly Phe Asp Phe Ser Ser Asn Ala Tyr

1 5

<210> 108

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 108

Ile Tyr Asp Gly Thr Ser Gly Asp Thr

1 5

<210> 109

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 109

Ala Arg Asp Thr Arg Ser Ser Asn Tyr Tyr Phe Asn Leu

1 5 10

<210>  110

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 110

Asn Ser Tyr Lys Tyr Tyr Tyr Met

1 5

<210>  111

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 111

Ser Thr Ala Ser Arg Asn Ile

1 5

<210> 112

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 112

Ala Lys Ser His Gly Gly Asp Gly Gly Tyr Gly Val Val Leu

1 5 10

<210> 113

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 113

Gly Phe Ser Phe Ser Ser Ser Tyr Cys

1 5

<210> 114

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 114

Ile Tyr Thr Asp Ser Ser Gly Ala Thr

1 5

<210> 115

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 115

Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr Thr Tyr

1 5 10 15

Phe Ser Leu

<210> 116

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 116

Gly Phe Ser Phe Ser Ser Ser Tyr Trp

1 5

<210> 117

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 117

Ile Tyr Ala Gly Ser Ser Gly Ser Thr

1 5

<210> 118

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 118

Ala Arg Gly Gly Thr Ser Tyr Arg Leu Asp Leu

1 5 10

<210> 119

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 119

Gly Phe Ser Phe Ser Ser Lys Gln Tyr

1 5

<210> 120

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 120

Ile Val Thr Val Asn Asn Lys

1 5

<210>  121

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 121

Thr Arg Trp Arg Thr Phe Gly Leu

1 5

<210> 122

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 122

Gly Ile Asp Phe Asn Asn Asp Tyr Asn

1 5

<210> 123

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 123

Ile Tyr Thr Gly Ser Asp Ser Thr

1 5

<210> 124

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 124

Ala Arg Asp Leu Val Thr Gly Tyr Ala Thr Tyr Gly Tyr Gly Phe Ile

1 5 10 15

Leu

<210> 125

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 125

Ser Ser Ser Tyr Trp Ile Cys Trp

1 5

<210> 126

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 126

Gly Ile Gly Ser Ser Gly Thr Thr

1 5

<210> 127

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 127

Ala Arg Val Gly Gly Tyr Trp Thr Phe Asp Leu

1 5 10

<210> 128

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 128

Gly Phe Ser Phe Ser Ser Asp Tyr Trp

1 5

<210> 129

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 129

Ile Tyr Thr Gly Asp Asp Asp

1 5

<210> 130

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 130

Ala Arg Gly Leu Thr Ile Gly Thr Ala Glu Leu Tyr Phe

1 5 10

<210> 131

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 131

Gly Phe Ser Phe Thr Lys Asn Tyr Tyr

1 5

<210> 132

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 132

Ile Tyr Ala Gly Ser Thr Asn

1 5

<210> 133

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 133

Ala Arg Asp Phe Val Ser Tyr Leu Asn Leu

1 5 10

<210> 134

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 134

Gly Phe Asp Leu Ser Asn Asn Tyr Tyr

1 5

<210> 135

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 135

Val Asp Ser Asp Leu Thr Asp Ser Ala

1 5

<210> 136

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 136

Ala Gly Ser Gly Ser Gly Tyr Tyr Tyr Tyr Tyr Tyr Gly Met Asp Leu

1 5 10 15

<210> 137

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 137

Gly Phe Ser Phe Asn Gly Asp Tyr Tyr

1 5

<210> 138

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 138

Ile Tyr Ala Ala Gly Asp Asp

1 5

<210> 139

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 139

Ala Arg Asp Gln Ala Asp Ser Tyr Ala Phe Gly Leu

1 5 10

<210> 140

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 140

Gly Phe Ser Phe Ser Ser Ser Tyr Trp

1 5

<210>  141

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 141

Ile Tyr Ala Gly Ser Ser Gly Ser Thr

1 5

<210> 142

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 142

Ala Arg Gly Phe Ser Met Phe Lys Leu

1 5

<210> 143

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 143

Gly Phe Ser Phe Ser Ser Ser Tyr Cys

1 5

<210> 144

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 144

Ile Tyr Thr Asp Ser Ser Gly Ala Thr

1 5

<210> 145

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 145

Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr Thr Tyr

1 5 10 15

Phe Ser Leu

<210> 146

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 146

Arg Ile Asp Leu Asn Asn Tyr Tyr Tyr

1 5

<210> 147

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 147

Val Ala Thr Asp Ser Ser Val Thr

1 5

<210> 148

<211>  20

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 148

Arg Gly Ser Gly Ala Ala Thr Asn Gly Val Trp Trp Val Met Gly Asp

1 5 10 15

Gly Met Asp Leu

20

<210> 149

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 149

Gly Ile Asp Leu Ser Ser Tyr Ala

1 5

<210> 150

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 150

Ile Gly Lys Ser Gly Thr Thr

1 5

<210> 151

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 151

Ala Arg Ala Gly Ala Ser Arg Ser Ile Tyr Tyr Asp Leu

1 5 10

<210> 152

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 152

Gly Phe Ser Phe Ser Gly Ile Val Tyr

1 5

<210> 153

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 153

Ala Phe Val Gly Ser Gly Gly Ser Thr

1 5

<210> 154

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 154

Ala Lys Ser Tyr Asn Tyr Asn Gly Leu Gly Leu

1 5 10

<210> 155

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 155

Gly Phe Ser Phe Ser Ser Ser Tyr Tyr

1 5

<210> 156

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 156

Ile Tyr Gly Gly Ser Thr Gly Thr Thr

1 5

<210> 157

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 157

Ala Arg Ser Tyr Asn Ser Ala Ser Ser Gly Tyr Tyr Trp Asp Leu

1 5 10 15

<210> 158

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 158

Gly Ile Asp Phe Ser Ser Gly Ala Trp

1 5

<210> 159

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 159

Ile Phe Thr Thr Ser Gly Phe Thr

1 5

<210> 160

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 160

Arg Asp Ile Tyr Ser Tyr Gly Met Asp Leu

1 5 10

<210> 161

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 161

Gly Phe Ser Phe Ser Ser Arg Gln Tyr

1 5

<210> 162

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 162

Ile Val Thr Val Asn Asn Lys

1 5

<210> 163

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 163

Ala Arg Trp Arg Thr Phe Gly Leu

1 5

<210> 164

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 164

Gly Phe Ser Phe Ser Ser Ser Tyr Cys

1 5

<210> 165

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 165

Ile Tyr Thr Asp Ser Ser Gly Ala Thr

1 5

<210> 166

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 166

Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr Thr Tyr

1 5 10 15

Phe Ser Leu

<210> 167

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 167

cagaacattt acagctac                                                              18

<210> 168

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 168

aaggcatcc                                                            

<210> 169

<211> 60

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 169

gcgagagctg tctatagtga tggtggtgct ggttatcctt atatgtatgg catggacctc 60

<210> 170

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 170

cagagtcttt ataatgcgaa cgac                         24

<210> 171

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 171

tgggcatcc                                                              

<210> 172

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 172

gcgagatcat attatg                                                               

<210> 173

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 173

cagagcattt acaggtac                             18

<210> 174

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 174

tatggatcc                                                       

<210> 175

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 175

gcgagggctc tggatagtca ttatcttcc tttgacttg 39

<210> 176

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 176

cagagtgttt atggtaacaa ccgc                                     24

<210> 177

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 177

ctggcatcc                                                               

<210> 178

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 178

gcgaggggtt tttcgatgtt taagttg                         27

<210> 179

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 179

cagaacattg tcagtaat 18

<210> 180

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 180

tatgcatcc                                                             

<210>  181

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 181

gcgagtactc ctaatagtct aggttacgac tta               33

<210> 182

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 182

cagagcattt acaactac                             18

<210> 183

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 183

gatgtatcc                                                            

<210> 184

<211> 57

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 184

gcgagaaata cttatgattg gaatggttat atttatggcc cgtgttattt tggcttg 57

<210> 185

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 185

cagagtgttt ataataacaa caac                       24

<210> 186

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 186

tctgcatcc                                                             

<210> 187

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 187

gcgagaggtt tttctatgtt taagttg                         27

<210> 188

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 188

cagaacattt acaacaat 18

<210> 189

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 189

tatgcatcc                                                             

<210> 190

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 190

gcgagcacta cgactaatgt tttcggttac gactta 36

<210> 191

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 191

cagactattg gtagctac                                   18

<210> 192

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 192

gaagcatcc                                                          

<210> 193

<211> 57

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 193

aggggatata gttatggtga tactggatat gctgatgcta ttcttacctt ggacttg 57

<210> 194

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 194

gagaccatta gtaataga                                                                                              

<210> 195

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 195

tctgcatcc                                                               

<210> 196

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 196

gcgaaatccc atggtggtga tggtggttat ggggttgtat ta 42

<210> 197

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 197

cagagcatta gtagttac 18

<210> 198

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 198

aaggcatcc                                                            

<210> 199

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 199

gcgagagatc gaaatggtgg ttctggtgct tatggttggg acttg 45

<210> 200

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 200

cagagcatta gtgattac 18

<210>  201

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 201

agggcatcc                                                           

<210>  202

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 202

gcgagagata gtggtaatta taattgggac ttg 33

<210>  203

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 203

cagagcattg gcaatgca 18

<210>  204

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  204

aaggcatcc                                                            

<210>  205

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 205

gcgaggtccc catatgatga tggttatggt ggtttcactt ttaattta 48

<210>  206

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 206

cagaacattt ataataac                                                                        18

<210>  207

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 207

ggtccatcc                                                         

<210>  208

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 208

gcgagatcga ctagtggtag ttatggtgcg ggtttgggct tg 42

<210>  209

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 209

cagagtattg gtagtaga 18

<210>  210

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 210

gaagcatcc                                                          

<210>  211

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  211

gcgagagata ctgctgctta ttacgccttt agctta 36

<210>  212

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  212

catatcatta ctaactac                                   18

<210>  213

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 213

gatgcatcg                                              

<210>  214

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  214

gcgaggggtg ttaatgatta tggttgggcc cttaagttg 39

<210>  215

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 215

ccgagcatta gtacttac 18

<210>  216

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 216

agggcatcc                                                           

<210>  217

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 217

gcgaccaata cggatagtag taggtcttat tataatttg 39

<210>  218

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 218

cagagtattg gtagtggtaa t                       21

<210>  219

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 219

ctggcatcc                                                               

<210>  220

<211> 60

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  220

agaggatccg gtgctagcac caatggtgtt tggtgggtaa tgggagacgg catggacctc 60

<210>  221

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 221

cagattgttg ctaacggccg c                               21

<210>  222

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  222

gctacatcc                                                              

<210>  223

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 223

gggagattgg attcgtgt tatttatgcc tttaatttg 39

<210>  224

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 224

gaggacattg ataggtat                                   18

<210>  225

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 225

gatgcatcc                                                                  

<210>  226

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 226

gcgagaggc gctatcctgg tgctttttca agtggattgg atctc 45

<210>  227

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 227

catatcatta ctaactac                                   18

<210>  228

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 228

gatgcatcg                                              

<210>  229

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 229

gcgagagcga cttatgctta tgctggtgct ggggacttg 39

<210>  230

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 230

gagagcattg gcagtgca 18

<210>  231

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 231

tctgcatcc                                                             

<210>  232

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 232

gcgaccaata cggatagtag taggtcttat tataatttg 39

<210>  233

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 233

cagagcattt acaactac                             18

<210>  234

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 234

tctgcatcc                                                             

<210>  235

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 235

gcgcgaagat atgctgcttt tcttacttat ggtagtgggg cttttgatcc c 51

<210>  236

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 236

ctgaacatta atagttgg                                     18

<210>  237

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 237

tatacatcc                                                       

<210>  238

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 238

gcgagaattg gtgcttttta ttcctttaga tta                 33

<210>  239

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 239

gaggacattt atagcaat 18

<210>  240

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 240

ggtgcaacc 9

<210>  241

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  241

gcgagccgaa atggtggtgc gcctgatggt ttgaacttg 39

<210>  242

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 242

gaggatattt atagtaat                               18

<210> 243

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 243

aaggcatcc                                                            

<210>  244

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 244

gcgagaggtg gtggttattg gtcttttagt ttg 33

<210>  245

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 245

cagagtgttt ataataagaa ctac                     24

<210>  246

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 246

tatgcttcc                                                                    

<210>  247

<211> 57

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 247

ggagaattggg attgctga tgctgctggt tattatgttg cgagaggttt taacttg 57

<210>  248

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 248

cagagcatta gtagttac 18

<210>  249

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 249

aaggcatcc                                                            

<210> 250

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 250

agagatttcg ttagttattt gaatttg                         27

<210>  251

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 251

cagagcatta gttatac

<210> 252

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 252

aaggcatcc                                                            

<210> 253

<211> 63

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 253

gcgagaggat ccggtgctag taccaatggt gtttggtggg taatgggaga cggcatggac 60

CTC

<210> 254

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 254

cagagtatta gtagtagcta c                         21

<210> 255

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 255

tctgcgtcc                                                                        

<210> 256

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 256

tgtgcgagat ctagtaatag ttatggtaat tatggtgttt ctaacttg 48

<210> 257

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 257

cagagtgttt atagtaacaa ctgg                           24

<210> 258

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 258

aaggcatcc                                                            

<210> 259

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 259

agagatatct attcctacgg catggacctc 30

<210>  260

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 260

cagactattt ataataacaaaat                           24

<210>  261

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 261

caggcatcc                                                               

<210>  262

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 262

gcgagaatcg ctactggtac taatgttgat gacttc 36

<210>  263

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 263

gagaacattt atagctac                               18

<210>  264

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 264

tctgcatcc                                                             

<210>  265

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 265

gcgagatggc ggacttttgg cttg                                       24

<210>  266

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 266

cagaccgttc ataataatca atgg                           24

<210>  267

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 267

gatgcatcc                                                                  

<210>  268

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 268

gcgagatcat atattactga tcgtattttat gattacgact tt             42

<210>  269

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 269

caaagtgttg ataacaacaa acaa 24

<210>  270

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 270

tctgcatcc                                                             

<210>  271

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 271

gggagagtaa ttgatggtgc ttgtggttat gacttg 36

<210>  272

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 272

gagaccatta gtaataga                                                                                              

<210> 273

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 273

tctgcatcc                                                             

<210> 274

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 274

gcgagggata ctcggagtag taattattat tttaatttg 39

<210> 275

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 275

cagaccatt ataccaat 18

<210>  276

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 276

gctgcatcc                                                                  

<210>  277

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 277

gcgaaatccc atggtggtga tggtggttat ggggttgtgt ta               42

<210>  278

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 278

gataatgttt atagtaataa ctac                       24

<210>  279

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 279

tatgcggcc                                                                    

<210>  280

<211> 57

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 280

gcgagggggt gggattacga ggatcctggt tatactgata ctacctactt ttccttg 57

<210>  281

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 281

gataatgttt atagtaataa ctac                       24

<210>  282

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 282

tatgcggcc                                                                    

<210> 283

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 283

gcgagaggtg gtactagtta ccgccttgat ttg 33

<210>  284

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 284

gaggatatta gtagtaat 18

<210>  285

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 285

ggtgcatcc                                                             

<210>  286

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 286

acgagatggc ggacttttgg cttg                                       24

<210>  287

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 287

cagagcatta gcaatgaa 18

<210>  288

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 288

ctggcatcc                                                               

<210>  289

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 289

gccagagatc ttgttatactgg ttatgctact tatggttatg gattttatctt a 51

<210>  290

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 290

caaagtgttt acaataacaa ccaa 24

<210>  291

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 291

ggtgcatcc                                                             

<210>  292

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 292

gcgagagttg gtggttatactg gacttttgac ttg 33

<210>  293

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 293

cagagtattg gtagctat                             18

<210>  294

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 294

tatgcttcc                                                                    

<210>  295

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 295

gcgagaggac tcactattgg tactgctgag ttgtacttc 39

<210> 296

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 296

cagaacattt acagcaat 18

<210>  297

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 297

tctgcatcc                                                             

<210>  298

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 298

gcgagagatt tcgttagtta tttgaatttg 30

<210> 299

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 299

cagagcattg gtagctac 18

<210> 300

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 300

aaggcatcc                                                            

<210> 301

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 301

gcgggaagtg ggagtggtta ttattattac tacggcatgg atctc 45

<210> 302

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 302

gaggacattg ataggtat                                   18

<210> 303

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 303

agggcatcc                                                           

<210> 304

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 304

gcgagagatc aggctgacag ttatgccttt ggtttg 36

<210> 305

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 305

cagagcatta gtagttac 18

<210> 306

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 306

aaggcttcc                                                                                                            

<210> 307

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 307

gcgaggggtt tttcgatgtt taagttg                         27

<210> 308

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 308

cagaccatt ataccaat 18

<210> 309

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 309

gctgcatcc                                                                  

<210> 310

<211> 57

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 310

gcgagggggt gggattacga ggatcctggt tatactgata ctacctactt ttccttg 57

<210> 311

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 311

gagagtgttt atggtaacaa ccgt                                   24

<210> 312

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 312

caggcttcc                                                                                                                    

<210> 313

<211> 60

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 313

agaggatccg gtgctgctac taatggtgtt tggtgggtga tgggagacgg catggacctc 60

<210> 314

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 314

cagagcatta ccaatgca 18

<210> 315

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 315

agggcatcc                                                           

<210> 316

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 316

gccagggcag gtgctagtag gagtatttat tatgacttg 39

<210> 317

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 317

cagagcatta gtagtagcta c                         21

<210> 318

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 318

tctgcatcc                                                             

<210> 319

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 319

gcgaaatctt atattataa tggtttaggc ttg 33

<210> 320

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 320

cagagcattg gtagtaat 18

<210> 321

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 321

aaggcatcc                                                            

<210> 322

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 322

gcgagatcat atatagtgc tagtagtggt tattattggg acttg 45

<210> 323

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 323

gagaatgttt atagtaataa ctac                         24

<210> 324

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 324

tatgcggcc                                                                    

<210> 325

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 325

agagatatct attcctacgg catggacctc 30

<210> 326

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 326

cagagcattg ctagcgac 18

<210> 327

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 327

gctgcatcc                                                                  

<210> 328

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 328

gcgagatggc ggacttttgg cttg                                       24

<210> 329

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 329

ggattctcct tcagtagcag ctactgt                             27

<210> 330

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 330

atttatactg atagtagtgg tgccact                         27

<210> 331

<211> 57

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 331

gcgagggggt gggattacga ggatcctggt tatactgata ctacctactt ttccttg 57

<210> 332

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 332

Gln Asn Ile Tyr Ser Tyr

1 5

<210> 333

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 333

Lys Ala Ser

1

<210> 334

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 334

Gln Thr Asn Tyr Phe Ser Ser Thr Ser His Phe Gly Val Phe Thr

1 5 10 15

<210> 335

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 335

Gln Ser Leu Tyr Asn Ala Asn Asp

1 5

<210> 336

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 336

Trp Ala Ser

1

<210> 337

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 337

Leu Gly Glu Phe Ser Cys Ser Ser Phe Asp Cys His Val

1 5 10

<210> 338

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 338

Gln Ser Ile Tyr Arg Tyr

1 5

<210> 339

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 339

Tyr Gly Ser

1

<210> 340

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 340

Gln Thr Thr Tyr Tyr Asp Asp Tyr His Asn Gly Trp Ala

1 5 10

<210> 341

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 341

Gln Ser Val Tyr Gly Asn Asn Arg

1 5

<210> 342

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 342

Leu Ala Ser

1

<210> 343

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 343

Ala Gly Gly Tyr Ala Gly Asn Phe Asn Ala

1 5 10

<210> 344

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 344

Gln Asn Ile Val Ser Asn

1 5

<210> 345

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 345

Tyr Ala Ser

1

<210> 346

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 346

Gln Asn Asn Ala Gly Ile Tyr Gly Asn Tyr Gly His Gly

1 5 10

<210> 347

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 347

Gln Ser Ile Tyr Asn Tyr

1 5

<210> 348

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 348

Asp Val Ser

1

<210> 349

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 349

Gln Ser Tyr Tyr Gly Asn Thr Val Ser Phe Thr

1 5 10

<210> 350

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 350

Gln Ser Val Tyr Asn Asn Asn Asn

1 5

<210> 351

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 351

Ser Ala Ser

1

<210> 352

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 352

Ala Gly Gly Tyr Thr Tyr Asn Ile Asn Ile

1 5 10

<210> 353

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 353

Gln Asn Ile Tyr Asn Asn

1 5

<210> 354

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 354

Tyr Ala Ser

1

<210> 355

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 355

Gln Asn Asn Ala Gly Ile Tyr Gly Gly Tyr Gly His Gly

1 5 10

<210> 356

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 356

Gln Thr Ile Gly Ser Tyr

1 5

<210> 357

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 357

Glu Ala Ser

1

<210> 358

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 358

Gln Ser Asn Tyr Tyr Arg Ala Gly Gly Asn Tyr Gly Gly Ala

1 5 10

<210> 359

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 359

Glu Thr Ile Ser Asn Arg

1 5

<210> 360

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 360

Ser Ala Ser

1

<210> 361

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 361

Gln Ser Ile Arg Ser Ser Ser Gly Ile Val His Pro Asn Thr

1 5 10

<210> 362

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 362

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210> 363

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 363

Lys Ala Ser

1

<210> 364

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 364

Gln Ser Tyr Tyr Tyr Tyr Ile Ser Ala Thr Val Asp Asn Thr

1 5 10

<210> 365

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 365

Gln Ser Ile Ser Asp Tyr

1 5

<210> 366

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 366

Arg Ala Ser

1

<210> 367

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 367

Gln Ser Asn Tyr Tyr Gly Ser Gln Gly Cys Thr

1 5 10

<210> 368

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 368

Gln Ser Ile Gly Asn Ala

1 5

<210> 369

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 369

Lys Ala Ser

1

<210> 370

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 370

Gln Asn Tyr Tyr Tyr Ser Asn Thr Asn Ser

1 5 10

<210> 371

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 371

Gln Asn Ile Tyr Asn Asn

1 5

<210> 372

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 372

Gly Pro Ser

1

<210> 373

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 373

Gln Ser Asp Asp Trp Met Ser Ile Ser Pro Asp Ile Val

1 5 10

<210> 374

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 374

Gln Ser Ile Gly Ser Arg

1 5

<210> 375

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 375

Glu Ala Ser

1

<210> 376

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 376

Gln Cys Thr Tyr Tyr Glu Ser Ser Ser Gly Gly Gly

1 5 10

<210> 377

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 377

Pro Ser Ile Ser Thr Tyr

1 5

<210> 378

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 378

Arg Ala Ser

1

<210> 379

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 379

Gln Asn Asn Tyr His Ser Gly Ser Ser Asn Gly Gly Gly Val Ala

1 5 10 15

<210> 380

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 380

Gln Ser Ile Gly Ser Gly Asn

1 5

<210> 381

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 381

Leu Ala Ser

1

<210> 382

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 382

Gln Tyr Thr Tyr Tyr Tyr Gly Thr Thr Tyr Asp Asn Ala

1 5 10

<210> 383

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 383

Gln Ile Val Ala Asn Gly Arg

1 5

<210> 384

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 384

Ala Thr Ser

1

<210> 385

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 385

Gln Gly Ala Tyr Ser Ser Gly Asp Val Arg Thr

1 5 10

<210> 386

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 386

Glu Asp Ile Asp Arg Tyr

1 5

<210> 387

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 387

Asp Ala Ser

1

<210> 388

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 388

Gln Ser Tyr Asp Asn Ser Asp Asn Asn Gly

1 5 10

<210> 389

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 389

His Ile Ile Thr Asn Tyr

1 5

<210> 390

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 390

Asp Ala Ser

1

<210> 391

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 391

Gln Asn Tyr Leu Tyr Phe Ser Ser Gly Asp Trp Asn Val

1 5 10

<210> 392

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 392

Glu Ser Ile Gly Ser Ala

1 5

<210> 393

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 393

Ser Ala Ser

1

<210> 394

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 394

Gln Ser Tyr Tyr Gly Ser Gly Thr Thr Ala Leu Asp Thr

1 5 10

<210> 395

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 395

Gln Ser Ile Tyr Asn Tyr

1 5

<210> 396

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 396

Ser Ala Ser

1

<210> 397

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 397

Gln Asn Asn Tyr Gly Ile Gly Ser Asn Tyr Gly Pro Gly

1 5 10

<210> 398

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 398

Leu Asn Ile Asn Ser Trp

1 5

<210> 399

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 399

Tyr Thr Ser

1

<210> 400

<211>  11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  400

Gln Thr Thr Tyr Tyr Phe Gly Thr Asn Gly Gly Gly

1 5 10

<210> 401

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  401

Glu Asp Ile Tyr Ser Asn

1 5

<210> 402

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  402

Gly Ala Thr

1

<210> 403

<211>  9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  403

Gln Ala Glu Ser Asn Asp Val Trp Ala

1 5

<210> 404

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  404

Gln Ser Val Tyr Asn Lys Asn Tyr

1 5

<210> 405

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  405

Tyr Ala Ser

1

<210> 406

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  406

Ala Ala Tyr Lys Gly Val Ser Asp Asp Gly Ile Ser

1 5 10

<210> 407

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  407

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210> 408

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  408

Lys Ala Ser

1

<210> 409

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  409

Gln Asn Asn Tyr His Ser Gly Ser Ser Asn Gly Gly Gly Phe Ala

1 5 10 15

<210>  410

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  410

Gln Ser Ile Ser Tyr Tyr

1 5

<210>  411

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  411

Lys Ala Ser

1

<210> 412

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  412

Gln Ser Thr Tyr Gly Arg Asp Asn Asn Asp Leu Phe Phe Ala

1 5 10

<210> 413

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  413

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210>  414

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  414

Ser Ala Ser

1

<210> 415

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  415

Gln Ser Thr Tyr Ile Ser Ser Ser Lys Tyr Gly Ala Val

1 5 10

<210> 416

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  416

Gln Ser Val Tyr Ser Asn Asn Trp

1 5

<210> 417

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  417

Lys Ala Ser

1

<210> 418

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  418

Ala Gly Gly Tyr Ser Gly Asp Leu Tyr Ala

1 5 10

<210> 419

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  419

Gln Thr Ile Tyr Asn Asn Lys Asn

1 5

<210> 420

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  420

Gln Ala Ser

1

<210>  421

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  421

Gln Gly Glu Phe Ser Cys Ser Ser Gly Asp Cys Thr Thr

1 5 10

<210> 422

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  422

Glu Asn Ile Tyr Ser Tyr

1 5

<210> 423

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  423

Ser Ala Ser

1

<210> 424

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  424

Gln Tyr Ser Asn Phe Arg Val Asn Asp Pro Ser Val

1 5 10

<210> 425

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  425

Gln Thr Val His Asn Asn Gln Trp

1 5

<210> 426

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  426

Asp Ala Ser

1

<210> 427

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  427

Gln Gly Gly Tyr Ser Tyr Gly Asp Val Tyr Gly

1 5 10

<210> 428

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  428

Gln Ser Val Asp Asn Asn Lys Gln

1 5

<210> 429

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  429

Ser Ala Ser

1

<210> 430

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  430

Ala Gly Tyr Tyr Tyr Tyr Ser Gly Ser Ala Thr Asp Ala Trp Ala

1 5 10

<210> 431

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  431

Glu Thr Ile Ser Asn Arg

1 5

<210> 432

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 432

Ser Ala Ser

1

<210> 433

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 433

Gln Ser Ile Arg Ser Ser Ser Gly Val Val His Pro Asn Thr

1 5 10

<210> 434

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  434

Gln Thr Ile Tyr Thr Asn

1 5

<210> 435

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 435

Ala Ala Ser

1

<210> 436

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  436

Gln Ser Tyr Tyr Gly Ser Ser Thr Thr Gly Asn Gly

1 5 10

<210> 437

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  437

Asp Asn Val Tyr Ser Asn Asn Tyr

1 5

<210> 438

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  438

Tyr Ala Ala

1

<210> 439

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  439

Ser Gly His Lys Asp Tyr Ser Asp Asp Gly Ser Thr

1 5 10

<210> 440

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  440

Asp Asn Val Tyr Ser Asn Asn Tyr

1 5

<210> 441

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  441

Tyr Ala Ala

1

<210> 442

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  442

Ser Gly His Lys Asp Tyr Ser Asp Asp Gly Ser Thr

1 5 10

<210> 443

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  443

Glu Asp Ile Ser Ser Asn

1 5

<210> 444

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  444

Gly Ala Ser

1

<210> 445

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  445

Gln Gly Ala Tyr Tyr Gly Ser Ser Tyr Gly

1 5 10

<210> 446

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  446

Gln Ser Ile Ser Asn Glu

1 5

<210> 447

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  447

Leu Ala Ser

1

<210> 448

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  448

Gln Ser His Tyr Tyr Gly Gly Ser Ser Asp Tyr Gly Trp Ala

1 5 10

<210> 449

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  449

Gln Ser Val Tyr Asn Asn Asn Gln

1 5

<210> 450

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 450

Gly Ala Ser

1

<210> 451

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 451

Gln Gly Ala Val Ser Ser Asp Tyr Tyr Pro

1 5 10

<210> 452

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  452

Gln Ser Ile Gly Ser Tyr

1 5

<210> 453

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 453

Tyr Ala Ser

1

<210> 454

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 454

Gln Ser Asn Arg Leu Ser Ser Ser Asp Val Asn Ala

1 5 10

<210> 455

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 455

Gln Asn Ile Tyr Ser Asn

1 5

<210> 456

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 456

Ser Ala Ser

1

<210> 457

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  457

Gln Ser Tyr Tyr Tyr Thr Ala Ser Ala Asp Thr Thr

1 5 10

<210> 458

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 458

Gln Ser Ile Gly Ser Tyr

1 5

<210> 459

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 459

Lys Ala Ser

1

<210> 460

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  460

Gln Tyr Thr Ser Tyr Ser Ser Gly Gly Ala

1 5 10

<210> 461

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  461

Glu Asp Ile Asp Arg Tyr

1 5

<210> 462

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  462

Arg Ala Ser

1

<210> 463

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 463

Gln Gly Asp Phe Ile Gly Ser Ser Tyr Gly Val Ala

1 5 10

<210> 464

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  464

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210> 465

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 465

Lys Ala Ser

1

<210> 466

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  466

Gln Asn Asn Tyr His Ser Gly Ser Ser Asn Gly Gly Gly Phe Ala

1 5 10 15

<210> 467

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  467

Gln Thr Ile Tyr Thr Asn

1 5

<210> 468

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  468

Ala Ala Ser

1

<210> 469

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  469

Gln Ser Tyr Tyr Gly Ser Ser Thr Thr Gly Asn Gly

1 5 10

<210> 470

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  470

Glu Ser Val Tyr Gly Asn Asn Arg

1 5

<210> 471

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  471

Gln Ala Ser

1

<210> 472

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  472

Ala Gly His Lys Gly Thr Thr Asn Asp Gly Asn Asp

1 5 10

<210> 473

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 473

Gln Ser Ile Thr Asn Ala

1 5

<210> 474

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  474

Arg Ala Ser

1

<210> 475

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 475

Gln Cys Ser Tyr Tyr Gly Ser Thr Tyr Phe Gly Ser Pro

1 5 10

<210> 476

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  476

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210> 477

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  477

Ser Ala Ser

1

<210> 478

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  478

Gln Ser Thr Tyr Ile Ser Ser Ser Asn Tyr Gly Ala Ala

1 5 10

<210> 479

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  479

Gln Ser Ile Gly Ser Asn

1 5

<210> 480

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  480

Lys Ala Ser

1

<210> 481

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  481

Gln Asn Asn Asn Tyr Trp Ser Asn Gly Asn His

1 5 10

<210> 482

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  482

Glu Asn Val Tyr Ser Asn Asn Tyr

1 5

<210> 483

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  483

Tyr Ala Ala

1

<210> 484

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  484

Ser Gly His Lys Asp Tyr Ser Asp Asp Gly Ser Thr

1 5 10

<210> 485

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  485

Gln Ser Ile Ala Ser Asp

1 5

<210> 486

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  486

Ala Ala Ser

1

<210> 487

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  487

Gln Ser Tyr Tyr Gly Ser Ser Thr Thr Gly Asn Gly

1 5 10

<210> 488

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  488

cagaacattt acagctac                                                              18

<210> 489

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  489

aaggcatcc                                                            

<210> 490

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  490

caaaccaatt attttagtag tactagtcat tttggtgttt ttact 45

<210> 491

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  491

cagagtcttt ataatgcgaa cgac                         24

<210> 492

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  492

tgggcatcc                                                              

<210> 493

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  493

ctaggcgaat ttagttgcag tagttttgat tgtcatgtt 39

<210> 494

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  494

cagagcattt acaggtac                             18

<210> 495

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  495

tatggatcc                                                       

<210> 496

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  496

caaaccactt atgatgatta tcataatggt tgggct 36

<210> 497

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  497

cagagtgttt atggtaacaa ccgc                                     24

<210> 498

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  498

ctggcatcc                                                               

<210> 499

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  499

gcaggcggtt atgctgggaa tttcaatgct 30

<210> 500

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 500

cagaacattg tcagtaat 18

<210> 501

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 501

tatgcatcc                                                             

<210> 502

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 502

caaaacaatg ctggtattta tggtaattat ggtcatggt 39

<210> 503

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 503

cagagcattt acaactac                             18

<210> 504

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 504

gatgtatcc                                                            

<210> 505

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 505

caaagttatt atggtaatac tgtttctttt act             33

<210> 506

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 506

cagagtgttt ataataacaa caac                       24

<210> 507

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 507

tctgcatcc                                                             

<210> 508

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 508

gcaggcggtt atacttacaa tatcaatatt                       30

<210> 509

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 509

cagaacattt acaacaat 18

<210> 510

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 510

tatgcatcc                                                             

<210> 511

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 511

caaaacaatg ctggtattta tggtggttat ggtcatggt 39

<210> 512

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 512

cagactattg gtagctac                                   18

<210> 513

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 513

gaagcatcc                                                          

<210> 514

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 514

caaagcaatt attcgtgc tggtggtaat tatggtggag ct             42

<210> 515

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 515

gagaccatta gtaataga                                                                                              

<210> 516

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 516

tctgcatcc                                                             

<210> 517

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 517

caaagtattc gtagtagtag tggtattgtt catccgaata ct           42

<210> 518

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 518

cagagcatta gtagttac 18

<210> 519

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 519

aaggcatcc                                                            

<210> 520

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 520

caaagctatt actatattag tgctactgtt gataatact 39

<210> 521

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 521

cagagcatta gtgattac 18

<210> 522

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 522

agggcatcc                                                           

<210> 523

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 523

caaagtaatt atttggtag tcagggttgt act 33

<210> 524

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 524

cagagcattg gcaatgca 18

<210> 525

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 525

aaggcatcc                                                            

<210> 526

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 526

caaaactatt attatagtaa tactaatagt 30

<210> 527

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 527

cagaacattt ataataac                                                                        18

<210> 528

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 528

ggtccatcc                                                         

<210> 529

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 529

caaagtgatg attggatgag tatcagtcct gatattgtt 39

<210> 530

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 530

cagagtattg gtagtaga 18

<210> 531

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 531

gaagcatcc                                                          

<210> 532

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 532

caatgtactt attgaaag tagtagtggt ggtggt 36

<210> 533

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 533

catatcatta ctaactac                                   18

<210> 534

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 534

gatgcatcg                                              

<210> 535

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 535

caaaactatc tttattttag tagtggtgat tggaatgtt 39

<210> 536

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 536

ccgagcatta gtacttac 18

<210> 537

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 537

agggcatcc                                                           

<210> 538

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 538

caaaacaatt accatagtgg tagtagtaat ggtggtggtg ttgct 45

<210> 539

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 539

cagagtattg gtagtggtaa t                       21

<210> 540

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 540

ctggcatcc                                                               

<210> 541

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 541

caatatactt attatggtac tacttatgat aatgct 36

<210> 542

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 542

cagattgttg ctaacggccg c                               21

<210> 543

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 543

gctacatcc                                                              

<210> 544

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 544

caaggcgctt atagtagtgg ggatgttcgg act 33

<210> 545

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 545

gaggacattg ataggtat                                   18

<210> 546

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 546

gatgcatcc                                                                  

<210> 547

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 547

caaagctatg ataatagtga taataatggt 30

<210> 548

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 548

catatcatta ctaactac                                   18

<210> 549

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 549

gatgcatcg                                              

<210> 550

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 550

caaaactatc tttattttag tagtggtgat tggaatgtt 39

<210> 551

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 551

gagagcattg gcagtgca 18

<210> 552

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 552

tctgcatcc                                                               

<210> 553

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 553

caaagttatt atggaagtgg tacgactgct ttagatact 39

<210> 554

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 554

cagagcattt acaactac                             18

<210> 555

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 555

tctgcatcc                                                             

<210> 556

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 556

caaaacaatt atggtattgg tagtaattat ggtcctggt 39

<210> 557

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 557

ctgaacatta atagttgg                                     18

<210> 558

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 558

tatacatcc                                                       

<210> 559

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 559

caaaccacat attttggtac taatggtggt ggt 33

<210> 560

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 560

gaggacattt atagcaat 18

<210> 561

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 561

ggtgcaacc 9

<210> 562

<211>  27

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 562

caggccgaaa gtaatgatgt ttgggct                                 27

<210> 563

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 563

gaggatattt atagtaat                               18

<210> 564

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 564

aaggcatcc                                                            

<210> 565

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 565

cagactactt attggactac tactgatgat aatcct 36

<210> 566

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 566

cagagtgttt ataataagaa ctac                     24

<210> 567

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 567

tatgcttcc                                                                    

<210> 568

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 568

gcagcttata aaggtgttag tgatgatggt atttct 36

<210> 569

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 569

cagagcatta gtagttac 18

<210> 570

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 570

aaggcatcc                                                            

<210> 571

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 571

caaaacaatt atcatagtgg tagtagtaat ggtggtggtt ttgct 45

<210> 572

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 572

cagagcatta gttatac

<210> 573

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 573

aaggcatcc                                                            

<210> 574

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 574

caaagcactt atggtaggga taataatgat ctttttttcg ct               42

<210> 575

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 575

cagagtatta gtagtagcta c                         21

<210> 576

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 576

tctgcgtcc                                                                        

<210> 577

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 577

caaagcactt atattagtag tagtaagtat ggtgctgtt 39

<210> 578

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 578

cagagtgttt atagtaacaa ctgg                           24

<210> 579

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 579

aaggcatcc                                                            

<210> 580

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 580

gcaggcgggt atagtggtga tctttatgct                                                                                                                                                                                                                                                               

<210> 581

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 581

cagactattt ataataacaaaat                           24

<210> 582

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 582

caggcatcc                                                               

<210> 583

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 583

caaggcgaat ttagttgtag tagtggtgat tgtactact 39

<210> 584

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 584

gagaacattt atagctac                               18

<210> 585

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 585

tctgcatcc                                                             

<210> 586

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 586

caatatagta attttagggt gaatgatcct agtgtt 36

<210> 587

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 587

cagaccgttc ataataatca atgg                           24

<210> 588

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 588

gatgcatcc                                                                  

<210> 589

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 589

caaggcggtt atagttatgg tgatgtgtat ggt 33

<210> 590

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 590

caaagtgttg ataacaacaa acaa 24

<210> 591

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 591

tctgcatcc                                                             

<210> 592

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 592

gcaggctatt attatagtgg tagtgccact gatgcgtggg ct             42

<210> 593

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 593

gagaccatta gtaataga                                                                                              

<210> 594

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 594

tctgcatcc                                                             

<210> 595

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 595

caaagtattc gtagtagtag tggtgttgtg catccaaata ct           42

<210> 596

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 596

cagaccatt ataccaat 18

<210> 597

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 597

gctgcatcc                                                                  

<210> 598

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 598

caaagctatt atggtagtag tactactggt aatggt 36

<210> 599

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 599

gataatgttt atagtaataa ctac                       24

<210> 600

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 600

tatgcggcc                                                                    

<210> 601

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 601

tcaggccata aagattatag tgatgatggt agtact 36

<210> 602

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 602

gataatgttt atagtaataa ctac                       24

<210> 603

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 603

tatgcggcc                                                                    

<210> 604

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 604

tcaggccata aagattatag tgatgatggt agtact 36

<210> 605

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 605

gaggatatta gtagtaat 18

<210> 606

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 606

ggtgcatcc                                                             

<210> 607

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 607

caaggcgctt atttggtag tagttatggt 30

<210> 608

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 608

cagagcatta gcaatgaa 18

<210> 609

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 609

ctggcatcc                                                               

<210>  610

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 610

caaagtcatt attggtgg tagtagtgat tatggatggg ct             42

<210> 611

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 611

caaagtgttt acaataacaa ccaa 24

<210> 612

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 612

ggtgcatcc                                                        

<210> 613

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 613

caaggcgctg ttagtagtga ttactatcct 30

<210> 614

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 614

cagagtattg gtagctat                             18

<210> 615

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 615

tatgcttcc                                                                    

<210> 616

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 616

caaagtaatc gtcttagtag tagtgacgtt aatgct 36

<210> 617

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 617

cagaacattt acagcaat 18

<210> 618

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 618

tctgcatcc                                                             

<210> 619

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 619

caaagctatt attactgc tagtgctgat actact 36

<210> 620

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 620

cagagcattg gtagctac 18

<210> 621

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 621

aaggcatcc                                                            

<210> 622

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 622

caatatacta gttatagtag tggtggggct 30

<210> 623

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 623

gaggacattg ataggtat                                   18

<210> 624

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 624

agggcatcc                                                           

<210> 625

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 625

caaggcgatt ttatggtag tagttatggc gttgct 36

<210> 626

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 626

cagagcatta gtagttac 18

<210> 627

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 627

aaggcttcc                                                                                                            

<210> 628

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 628

caaaacaatt atcatagtgg tagtagtaat ggtggtggtt ttgct 45

<210> 629

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 629

cagaccatt ataccaat 18

<210> 630

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 630

gctgcatcc                                                                  

<210> 631

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 631

caaagctatt atggtagtag tactactggt aatggt 36

<210> 632

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 632

gagagtgttt atggtaacaa ccgt                                   24

<210> 633

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 633

caggcttcc                                                                                                                    

<210> 634

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 634

gcaggacata aaggaactac taatgatggg aatgat 36

<210> 635

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 635

cagagcatta ccaatgca 18

<210> 636

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 636

agggcatcc                                                           

<210> 637

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 637

caatgtagtt atttggtag tacttatttt gggagtcct 39

<210> 638

<211>  21

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 638

cagagcatta gtagtagcta c                         21

<210> 639

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 639

tctgcatcc                                                             

<210> 640

<211> 39

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 640

caaagcactt atattagtag tagtaattat ggtgctgct 39

<210> 641

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 641

cagagcattg gtagtaat 18

<210> 642

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 642

aaggcatcc                                                            

<210> 643

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 643

caaaacaata attattggag taatggtaac cat 33

<210> 644

<211>  24

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 644

gagaatgttt atagtaataa ctac                         24

<210> 645

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 645

tatgcggcc                                                                    

<210> 646

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 646

tcaggccata aagattatag tgatgatggt agtact 36

<210> 647

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 647

cagagcattg ctagcgac 18

<210> 648

<211>  9

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 648

gctgcatcc                                                                  

<210> 649

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 649

caaagctatt atggtagtag tactactggt aatggt 36

<210> 650

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 650

cagtcgttgg aggagtccga gggagacctg gtcaagcctg agggatccct gacactcacc 60

tgcaaagcct ctggattcga cttcagtagt gatgcaatgt gctgggtccg ccaggctcca 120

gggaaggggc tggagtggat cggatgcatt tataatggtg atgaaattac agaccacgcg 180

agctgggcga aaggccgatt caccatctcc aaaacctcgc cgaccacggt gactctgcaa 240

atgaccagtc tgacagtcgc ggacacggcc acctatttct gtgcgagagc tgtctatagt 300

gatggtggtg ctggttatcc ttatatgtat ggcatggacc tctggggccc agggaccctc 360

gtcaccgtct cttca 375

<210> 651

<211> 342

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 651

cgagcagtcg ggaaggagtc cgggggaggc ctggtcaagc ctggggcatc cctgacactc 60

acctgcaaag cctctggatt cgacttcagt ggcatttatt gggtatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgcg tgttttgatg ctgaaaggac tggtaacact 180

tattacgcga cctgggcgaa aggccgcttc accatctcca gaacctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gacagccgcg gacacggcca cctatttctg tgcgagatca 300

tattatatgt ggggcccagg caccctggtc accgtctctt ca 342

<210> 652

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 652

gagcagtcgt tggaggagtc cgggggagac ctggtcaagc ctgagggatc cctgacactc 60

acctgcacag cctctgaatt gtccttcagt agcgcctact acatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcatttata gtggtgatgg tgacacttac 180

tacgcgaact gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agacgcggac acggccacct atttctgtgc gaggctctg 300

gatagtcatt attcttcctt tgacttgtgg ggcccaggca ccctggtcac catctcttca 360

<210> 653

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 653

gagcagtcgt tggaggagtc cgggggaggc ctggtcaagc ctggggcatc cctgacagtc 60

acctgcgcag tctctggatt ctccctcaat agctatgcaa taacttgggt ccgccaggct 120

ccagggaaag ggctggaata catcggatac attgatactg gtgctagtat cacagactac 180

gcgagctggg cgaaaggccg attcaccatc tccaaaacct cgtcgaccac ggtgactctg 240

gaaatgacca gtctgacaga cgcggacacg gccacctatt tctgtgcgag gggtttttcg 300

atgtttaagt tgtggggccc aggcaccctg gtcaccatct cttca 345

<210> 654

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 654

gagcagtcgg tggaggagtc cgggggaggc ctggtcaagc ctgagggatc cctgacactc 60

acctgcaaag cctctgggtt agacttcagt agcagctact ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgcattgata ctggtagtag tggtagcact 180

tactacgcga gctgggcgaa aggccgattc accgtctcca aaacctcgtc gaccacggtg 240

tctctgcaaa tgaccagtct gacagccgcg gacacggcca cctatttctg tgcgagtact 300

cctaatagtc taggttacga cttatggggc ccaggcaccc tggtcaccat ctcttca 357

<210> 655

<211> 381

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 655

gagcagtcgg tggaggagtc cgggggagac ctggtcaagc ctggggcatc cctgacactc 60

acctgcacag cctctggatt ctcctccagt agtagcgcct atatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgtattttta ttggtagtgg tagtgactct 180

tactacgcga cctgggcgaa aggccgattc accatctcca aaacctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gacagccgcg gacacggcca cctatttctg tgcgagaaat 300

acttatgatt ggaatggtta tatttatggc ccgtgttatttggcttgtg gggcccaggc 360

accctggtca ccatctcctc a 381

<210> 656

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 656

gagcagtcgg tgaaggagtc cgggggaggc ctggtcaagc ctggaggaac cctgacactc 60

acctgcatag tctctggatt ctccctcagt aggtatgcag tcacctgggt ccgccaggct 120

ccagggaagg ggcctgagtg gatcggatac attgacacta gtagtggtaa caaagactac 180

gcgaactggg tgaatggccg attcaccatc tccaaaacct cgtcgaccac ggtgactctg 240

caaatgacca gtctgacagc cgcggacacg gccacctatt tctgtgcgag aggtttttct 300

atgtttaagt tgtggggccc aggcaccctg gtcaccatct cttca 345

<210> 657

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 657

gagcagtcgg tggaggagtc cgggggaggc ctggtcaagc ctgagggatc cctgacactc 60

acctgcaaag cctctggatt ggacttcagt agcagctatt ggagctgctg ggtccgccag 120

actccaggga gggggctgga gtggatcgga tgcattgatg ttggggagtag tggtggctca 180

tactacgcga gctgggcgag aggccgattc accgtctcca aaggctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gacagccgcg gacacggcca cctatttctg tgcgagcact 300

acgactaatg ttttcggtta cgacttatgg ggcccaggca ctctggtcac cgtctcttca 360

<210> 658

<211> 381

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 658

gagcagtcgt tggaggagtc cgggggaggc ctggtcaagc ctggggcatc cctgacactc 60

acctgcaaag cctctggatt cgacttcagt agtaatgact acatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcatttatg gtggtgatgg gcacacttac 180

tacgcgacct gggcgaaagg ccgattcacc atctccaaag cctcgtcgac cacggtgacg 240

ctgcaaatga ccagtctgac agccgcggac acggccagct atttctgtgc gaggggatat 300

agttatggtg atactggata tgctgatgct attctttacct tggacttgtg gggcccaggc 360

accctggtca ccgtctcttc a                       381

<210> 659

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 659

gagcagtcgg tgaaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcaaag tctctggaat cgacttcaat tattacaact actactacat gtgctgggtc 120

cgccaggctc cagggaaggg gctggagtgg atcggatgca tgtccactgc cagtgcgaat 180

atttaccttg cgagctgggc gaaaggccga ttcaccatct ccgaggcctc gtcgaccacg 240

gtgactctgc aaatgaccag tctgacagcc gcggacacgg ccacctattt ctgtgcgaaa 300

tcccatggtg gtgatggtgg ttatggggtt gtattatggg gcccaggcac cctggtcacc 360

atctcctca 369

<210> 660

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 660

gagcagtcgg tgaaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag tctctggatt ctccttcagt ggcagctact ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgcatttatg gtgatagtat tgccacttac 180

tacccgaact gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctacaaatgg ccagtctgac aggcgcggac acggccacct atttctgtgc gagagatcga 300

aatggtggtt ctggtgctta tggttgggac ttgtggggcc caggcaccct ggtcaccatc 360

tcctca 366

<210> 661

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 661

gagcagtcgt tggaggagtc cgggggaggc ctggtcaagc ctggggcatc cctgacactc 60

acctgcaaag cctctggatt ctccttcagt agcgactatg acatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcattgtga ctggttttag tggtcgtatt 180

tattacgcga cctgggcgag aggccgattc accttctcca gaacctcgtc gaccacgctg 240

actctgcaaa tgaccagtct gacagccgcg gacacggcca cttatttctg tgcgagagat 300

agtggtaatt ataattggga cttgtggggc ccaggcaccc tggtcaccat ctcttca 357

<210> 662

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 662

gagcagtcgg tggaggagtc cgagggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cttctggatt ctccttcagt aacgactact ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcggacata taggtagttt tcgtaccact 180

tactacgcga gctgggcgaa aggccgattc agcatctcca aaacctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gacaggcgcg gacacggcca cctatttctg tgcgaggtcc 300

ccatatgatg atggttatgg tggtttcact tttaatttat ggggcccagg caccctggtc 360

accatctctt ca 372

<210> 663

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 663

cagtcggtga aggagtccgg gggagacctg gtcaagcctg gggcatccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactgga tatgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcatgc atttatgctg gtagtagtgg tagcacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagatcgact 300

agtggtagtt atggtgcggg tttgggcttg tggggcccag gcaccctggt caccatctcc 360

tca 363

<210> 664

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 664

cagtcgctgg aggagtccgg gggagacctg gtccagcctg agggatccct gacactcacc 60

tgcacagctt ctggattctc cttcagtatc aacttataca tgtgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcatgc atttatggta atataatgc taacacttac 180

tacacaacct gggcgaaagg ccgattcacc atctccaaaa cctcgccgac cacggtgact 240

ctgcaaatga ccagtctgac aggcgcggac acggccacct atttctgtgc gagagatact 300

gctgcttatt acgcctttag cttatggggc ccaggcaccc tggtcaccat ctcctca 357

<210> 665

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 665

cagtcgttgg aggagtccgg gggtcgcctg gtcaatcctg acgaatccct gacactcacc 60

tgcacagcct ctggattcac cttcagtggc tactacatgt actgggtccg ccaggctcca 120

gggaaggggc tggagtggat cggatggatt tatgttggta gtggtggtag cacttactac 180

gcgagctggg cgaaaggccg attcaccatc tccaaaacct cgtcgaccac ggtgactctg 240

caaatgccca gtctgacagc cgcggacacg gccacctatt tctgtgcgag gggtgttaat 300

gattatggtt gggcccttaa gttgtggggc ccaggcactc tggtcaccgt ctcttca 357

<210> 666

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 666

gagcagtcgt tggaggagtc cgggggagac ctggtcaagc ctggggcatc cctgacactc 60

acctgcacag cttctgcgtt ctccttcagt agcagttcct ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgcatttatg gtggtagtgt tggtactact 180

tactacgcga gttgggcgaa aggccgattc accatctcca aaccctcgtc gaccacggtg 240

actctgcaaa tgaccagtct ggcagccgcg gacacggcca cctatttctg tgcgaccaat 300

acggatagta gtaggtctta ttataatttg tggggcccag gcaccctggt caccatctcc 360

tca 363

<210> 667

<211> 381

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 667

cagtcggtga aggagtccgg gggaggcctg gtccagcctg agggatccct ggcactcacc 60

tgcaaagcct ctggaatcga cctcagtaac tattggtaca tgtgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcggatgc gttgctactg atagtagtcg cacgcattac 180

gcgacctggg cgaaaggccg attcaccgtc tccaagacct cgtcgaccac ggtgactctg 240

caaatgacca gtctgacagc ggcggacacg gccacctatt tctgtgcgag aggatccggt 300

gctagcacca atggtgtttg gtgggtaatg ggagacggca tggacctctg gggcccaggg 360

accctcgtca ccatctcctc a 381

<210> 668

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 668

cagtcgttgg aggagtccgg gggaggcctg gtcaagcctg gggcttcct gacactcacc 60

tgcacagctt ctggattcag cctcaataga tactatatgt gctgggtccg ccaggctcca 120

gggaaggggc tggagtggat cggatgcatt tattctggta gtggtagcac ttactacgcg 180

agctgggcga aaggccgatt caccatctcc aaaacctcgt cgaccacggt gactctgcaa 240

atgaccagtc tgccagccgc ggacacggcc acctatttct gtggggagatt ggattatcgt 300

gttatttatg cctttaattt gtggggccca ggcaccctgg tcaccatctc ctca 354

<210> 669

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 669

gagcagtcgg tggaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cttctggatt ctccttcagt ggcagctgcg acatgtcctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgcatcgtgc ttagtaatgg taatacatac 180

tacgcgggct gggcgcaagg ccgattcacc atctccaaaa tctcgtcgac cacggtgact 240

ctggaaatga ccagtctgac agccgcggac acggccacgt atttctgtgc gagagagcgc 300

tatcctggtg ctttttcaag tggattggat ctctggggcc aggcaccct ggtcaccgtc 360

tcttca 366

<210> 670

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 670

cagtcgttgg aggagtccgg gggaggcctg gtccagcctg agggatccct gacactcacc 60

tgcacagtct ctggtttctc cttcagtagc agctggtaca tgtgctgggt ccgccaggct 120

ccagggaagg ggctggaatg gatcgcatgc atttatactc ttagaagtgg tgccgcgcat 180

tacgcgaact gggcgaaagg ccgattcacc atctccaaag cctcgtcgac cacggtgact 240

ctgcaaatga acagtctgac agccgcggac acggccacct atttctgtgc gagagcgact 300

tatgctttatg ctggtgctgg ggacttgtgg ggcccaggca ccctggtcac cgtctcttca 360

<210> 671

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 671

gagcagtcgt tgaaggagtc cgggggagac ctggtcaagc ctggggcatc cctgacactc 60

acctgcacag cttctgcgtt ctccttcagt agcagttcct ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgcatttatg gtggtagtgt tgctactact 180

tactacgcga cttgggcgaa aggccgattc accatctcca aaccctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gccagccgcg gacacggcca cctatttctg tgcgaccaat 300

acggatagta gtaggtctta ttataatttg tggggcccag gcaccctggt caccgtctcc 360

tca 363

<210> 672

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 672

gagcagtcgg tggaggagtc cgggggagac ctggtcaagc ctgggacatc cctgacactc 60

acctgcacag cttctggatt ctccttcagt ggcaatacaa tttgctgggt ccgccaggct 120

ccagggaaga ggcctgaatg gatcgcatgc atttatccta gcagtacttc tattactacc 180

tacgcgacct gggcgaaagg ccgattcacc gtctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gcgaagatat 300

gctgcttttc ttacttatgg tagtggggct tttgatccct ggggcccagg caccctagtc 360

accatctctt ca 372

<210> 673

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 673

gagcagtcgt tggaggagtc cgggggagac ctggtcaagc ctgagggatc cctgacactc 60

acctgcacag cctctggatt ctccttcagt agcagctact ggatatgctg ggtccgccag 120

gctccaggga agggactgga gtggatcgca tgcgttgcta ctggtagtgg taccactgac 180

tacgcgagct gggcgaaagg ccgattcacc atgtccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agtcgcggac acggccacct atttctgtgc gagaattggt 300

gctttttatt cctttagatt atggggccca ggcaccctgg tcaccatctc ttca 354

<210> 674

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 674

cagtcgttgg aggagtccgg gggagacctg gtcaagcctg agggatccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactgga tatgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcggatgc atttatgctg gtaatagtgc taacacttat 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaactga ccagtctgac agccgcggac acggccacct attctgtgc gagccgaaat 300

ggtggtgcgc ctgatggttt gaacttgtgg ggcccaggca ccctggtcac catctcttca 360

<210> 675

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 675

gagcagtcgg tgaaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cttctggatt ctccttcagt agcagctact ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcattgcta ctggtactgg tagcacttac 180

tacgcgaact gggtgaatgg ccgattcacc atgtccaaac cctcgtcgac cacggtgact 240

ctgcaaatga ccactctgac agccgcggac acggccacct atttctgtgc gagaggtggt 300

ggttattggt cttttagttt gtggggccca ggcaccctgg tcaccatctc ttca 354

<210> 676

<211> 381

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 676

gagcagtcgt tggaggagtc cgggggagac ctggtcaagc ctgagggatc cctgacactc 60

acctgcacag cctctggatt ctccttcagt agtagttatt atatgtgttg gatccgccag 120

cctccaggga gggggctgga gtggctcgca tgcatttata ctggtagtga tagcacttac 180

tacgcgccct gggcgaaagg ccgattcacc atctccagaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gggagattgg 300

gattatgctg atgctgctgg ttattatgtt gcgagaggtt ttaacttgtg gggcccaggc 360

accctggtca ccatctcctc a 381

<210> 677

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 677

gagcagtcgt tggaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cttctggatt ctccttcact aaaaactact acatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcatttatg ctggtagtac taatacattt 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaag cctcgtcgac cacggtggat 240

ctgaaaatga ccagtctgac agtcgcggac acggccacct atttctgtgc gagagatttc 300

gttagttatttgaatttgtg gggcccaggc accctggtca ccgtctcttc a 351

<210> 678

<211> 381

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 678

cgagcagtcg ggaaggagtc cgggggagac ctggtcacgc ttgggggatc cctgaaactc 60

tcctgcaaag cctctggaat cgacctcagt aacttttact acatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcgttgcta gtgatagtag ccgcacgcat 180

tacgcgacct ggccgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agcggcggac acggccacct atttctgtgc gagaggatcc 300

ggtgctagta ccaatggtgt ttggtgggta atgggagacg gcatggacct ctggggccca 360

gggaccctcg tcaccgtctc c 381

<210> 679

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 679

cagtcggtga aggagtccgg gggagacctg gtcaagcctg gggcatccct gacactcacc 60

tgcaaagcct ctggattctc cttcagtagc ggccactaca tgtactgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcatgt atttatgctg gtagtgatac tggtagcaca 180

tggtacgcga gctgggcgaa aggccgattc accatctcca aaacctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gacagccgcg gatacggcca cctatttctg tgcgagatct 300

agtaatagtt atggtaatta tggtgtttct aacttgtggg gcccaggcac cctggtcacc 360

gtctcttca 369

<210> 680

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 680

caggagcagc tggtggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcaaag cctctggaat cgacttcagt agcggctact ggatatgctg ggtccgccag 120

gctccaggga aggggctgga attgatcgca tgcattttta ctagtagtgg taccacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagagatatc 300

tattcctacg gcatggacct ctggggccca gggaccctcg tcaccgtctc ttca 354

<210> 681

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 681

cagtcggtga aggagtccga gggaggcctg gtccagcctg ggggatccct gacactctcc 60

tgcaaagcct ctggaatcga cttcagtagc gcctatatga gctgggtccg ccaggctcca 120

gggaaggggc tggagtggat cggaaagatg cgtattaatg atagaagtca ctacgcgaac 180

tgggtgaatg gccgattcac catctccaac cacaatgacc agaacacggt ggagctgcaa 240

ctgaacagtc tgacagccgc ggacacggcc acctatttct gtgcgagaat cgctactggt 300

actaatgttg atgacttctg gggcccaggc accctggtca ccatctcctc a 351

<210> 682

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 682

caggagcagc tggtggagtc cgggggaggc ctggtaacgc ctggaggatc cctgacactc 60

acctgcacag cctctggatt ctccttcagt agcaagcaat acattcctg ggtccgccgg 120

gctccaggga aggggctgga gtggatcggg gccattgtca ctgttaataa taaagtccac 180

tacgcgaact gggcgaaagg ccggttcacc atctccgaag cctcgtcgac cacggtgact 240

ctacaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagatggcgg 300

acttttggct tgtggggccc aggcaccctg gtcaccgtct cttca 345

<210> 683

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 683

gagcagctga tggaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacgg cttctagatt ctccctcagt aacatgaacg tgatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcattaata ttggcggtac taatatatgg 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agtcgcggac acggccacct attctgtgc gagatcatat 300

attactgatc gtatttatga ttacgacttt tggggcccag gcaccctggt caccatctct 360

tca 363

<210> 684

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 684

cagtcggtgg aggagtccgg gggaggcctg gtcaagcctg gggcatccct gacactctcc 60

tgcacagcct ctggattcga cttcagtagc aaatactaca tgtggtgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcgcgc atttatggtg gtagtagtga tagtacagac 180

tacgcgacct gggcgagagg ccggttcgcc atctccagaa cctcgtcgac cacggtgact 240

ctgcgaatga ccagtctgac agccgcggac acggccacct atttctgtgg gagagtaatt 300

gatggtgctt gtggttatga cttgtggggc ccaggcaccc tggtcaccgt ctcttca 357

<210> 685

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 685

cagtcggtgg aggagtccgg gggagacctg gtcaagcctg gggcatccct gacactcacc 60

tgcacagcct ctggattcga cttcagtagc aatgcctact tgtgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcggatgc atttatgatg gtacaagtgg tgacacttac 180

tacgcgaact gggcgaaagg ccgattcacc atctccagaa gttcgtcgac tacggtgact 240

ctccaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagggatact 300

cggagtagta attattattt taatttgtgg ggcccaggca ccctggtcac catctcttca 360

<210> 686

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 686

gagtccgagg gagcctggt caagcctgga ggaaccctga cactcacctg caaagtctct 60

ggaatcgact tcaatagcta caagtactac tacatgtgct gggtccgcca ggctccaggg 120

aaggggctgg agtggatcgg atgcatgtcc actgccagtc gtaatattta ctacgcgagc 180

tgggcgaaag gccgattcac catctccgaa acctcgtcga cctcggtgac tctgcaaatg 240

accactctga cagccgcgga cacggccacc tatttctgtg cgaaatccca tggtggtgat 300

ggtggttatg gggttgtgtt atggggccca ggcaccctgg tcaccatctc ctca 354

<210> 687

<211> 378

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 687

cagtcgttgg aggagtccga gggaggcctg gtcaagcctg gaggaaccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactgta tgtgttgggt ccgccaggct 120

ccagggaagg ggctggagtt gatcgcatgc atttatactg atagtagtgg tgccacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaagt cctcgtcgac cacgataact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagggggtgg 300

gattacgagg atcctggtta tactgatact acctactttt ccttgtgggg cccaggcacc 360

ctggtcaccg tctcttca 378

<210> 688

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 688

cagaagcagc tggtggagtc cgggggaggc ctggtccagc ctgagggatc cctggcactc 60

acctgcacag cttctggatt ctccttcagt agcagctact ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgca tgcatttatg ctggtagtag tggtagcact 180

tactacgcga gctgggtgaa tggccgattc accgtcttca aaacctcgtc gaccacggtg 240

actctgcaaa tgaccagtct gacagccgcg gacacggcca cctatttctg tgcgagaggt 300

ggtactagtt accgccttga tttgtggggc ccaggcaccc tggtcaccgt ctcttca 357

<210> 689

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 689

tcgcagcagc tgaaggagtc cgggggaggc ctggtcaagc ctggaggaac cctgacactc 60

acctgcaaag cctctggaat cgacttcaat aatgactata acatctgctg ggtccgccag 120

cctccaggga aggggctgga atggatcgga tgcatttata ctggtagtga tagtacagac 180

tacgcgagct gggtgaatgg ccgattcacc atctccgaaa gcaccagcct aaacacggtg 240

gatctgaaag tgaccagtct gacagacgcg gacacggcca cgtatttctg tgccagagat 300

cttgttatactg gttatgctac ttatggttat ggatttatct tatggggccc aggcaccctg 360

gtcaccgtct cctca 375

<210> 690

<400> 690

000

<210> 691

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 691

caggagcagc tgaaggagtc cgggggagac ctggtcaagc ctgagggatc cctgacactc 60

acctgcacag cctctggatt ctccttcagt agcgactatt gggtatgctg ggtccgccag 120

gctccaggga aggggccgga gtggatcgga tgcatttata ctggtgatga tgacacatac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctggaagtga ccagtctgac agccgcggac acggccacct atttctgtgc gagaggactc 300

actattggta ctgctgagtt gtacttctgg ggcccaggca ctgtggtcac cgtctcttca 360

<210> 692

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 692

caggagcagc tggtggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag attctggatt ctccttcact aaaaactact acatgtgctg ggtccgccag 120

gctccaggga aggggctgga gtggatcgga tgcatttatg ctggtagtac taatacattt 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaag cctcgtcgac cacggtggat 240

ctgaaaatga ccagtctgac agtcgcggac acggccacct atttctgtgc gagagatttc 300

gttagttatttgaatttgtg gggcccaggc accctggtca ccgtctcctc a 351

<210> 693

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 693

cagtcgttgg aggagtccgg gggtggcctg gtcaagcctg agggatccct gacactcacc 60

tgcacagcct ctggatttga cctcagtaac aactactaca tctgctgggt ccgccaggct 120

ccagggaagg ggctggaatt gatcgcatgt gttgattctg atcttactga tagtgcagac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gggaagtggg 300

agtggttatattattacta cggcatggat ctctggggcc cagggaccct cgtcaccatc 360

tcctca 366

<210> 694

<211> 358

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 694

tcgcagtcgt tggaggagtc cgggggaggc ctggtcaagc ctggggcatc cctgacactc 60

acctgcaaag gctctggatt ctccttcaat ggcgactatt atatgtgctg ggtccgccag 120

actccaggga aggggctgga gtggatcggg tgcatttatg ctgctggtga tgacacttac 180

tacgcgacct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct attttgtgc gagagatcag 300

gctgacagtt atgcctttgg tttgtggggc ccaggcacac tggtcaccat ctcctcag 358

<210> 695

<211> 348

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 695

cagtcgttga aggagtccga gggagacctg gtcaagcctg gggcatccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactgga tatgctgggt ccgccaggct 120

ccagggaagg ggctagagtg gatcgcatgc atttatgctg gtagtagtgg tagcacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctggaaatga ccagtctgac agacgcggac acggccacct atttctgtgc gagggtttt 300

tcgatgttta agttgtgggg cccaggcacc ctggtcacca tctcttca 348

<210> 696

<211> 378

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 696

cagtcggtga aggagtccgg gggaggcctg gtcaagcctg gaggaaccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactgta tgtgttgggt ccgccaggct 120

ccagggaagg ggctggagtt gatcgcatgc atttatactg atagtagtgg tgccacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaagt cctcgtcgac cacgataact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagggggtgg 300

gattacgagg atcctggtta tactgatact acctactttt ccttgtgggg cccaggcacc 360

ctggtcaccg tctcttca 378

<210> 697

<211> 384

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 697

tcgcagtcgg tggaggagtc cgggggagac ctggtcaagc ctggaggaac cctgacactc 60

acctgcacag cctctagaat cgacctcaac aactattatt acatatcctg ggtccgccag 120

gctccaggga agggactgga gtggatcgga gtcgttgcta ctgatagtag tgtcacatgg 180

tacgcgagct gggcgaaagg ccagttcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agcggcggac acggccacct atttctgtgc gagaggatcc 300

ggtgctgcta ctaatggtgt ttggtgggtg atgggagacg gcatggacct ctggggccca 360

gggaccctcg tcaccgtctc ttca 384

<210> 698

<211> 348

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 698

cagtcggtgg aggagtccga gggtcgcctg gtcacgcctg gaggatccct gacactcacc 60

tgcacagtct ctggaatcga cctcagtagc tatgcaatgg gctgggtccg ccaggctcca 120

gggaaggggc tggaatggat cggggtcatt ggtaaaagtg gaaccacata ctacgcgaac 180

tgggcgaaag gccgattcac catctccaag acctcgacca cggtggatct gcaaatcgcc 240

agtccgacaa ccgaggacac ggccacctat ttctgtgcca gggcaggtgc tagtaggagt 300

atttattatg acttgtgggg ccaaggcacc ctggtcacca tctcctca 348

<210> 699

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 699

cagtcggtgg aggagtccgg gggaggcctg gtccagcctg agggatccct gacactcacc 60

tgcacagctt ctggattctc cttcagtggc attgtctata tgtgttgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcatgt gcttttgttg gtagtggtgg tagcacttac 180

tacgcgacct gggcgacagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctacagatga ccagtctgac agccgcggac acggccacct atttctgtgc gaaatctttat 300

aattataatg gtttaggctt gtggggccca ggcaccctgg tcaccgtctc ctca 354

<210> 700

<211> 367

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 700

cagtcgttgg aggagtccgg gggagacctg gtcaagcctg gggcatccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactaca tgtgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcatgc atttatggtg gtagtactgg taccacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac aggcgcagac acggccacct atttctgtgc gagatcatat 300

aatagtgcta gtagtggtta ttatgggac ttgtggggcc caggcaccct ggtcaccgtc 360

tcttcag 367

<210> 701

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 701

gagcagtcgg tggaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cctctggaat cgacttcagt agcggcgcct ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gttgatcgca tgcattttta cactagtgg tttcacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaaaa cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagagatatc 300

tattcctacg gcatggacct ctggggccca gggaccctcg tcaccatctc ttca 354

<210> 702

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 702

caggagcagc tggtggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cttctggatt ctccttcagt agcaggcaat acattcctg ggtccgccgg 120

gctccaggga aggggctgga gtggatcggg gccattgtca ctgttaataa taaagtccac 180

tacgccaact gggcgaaagg ccggttcacc atctccgaag cctcgtcgac cacggtgact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagatggcgg 300

acttttggct tgtggggccc aggcaccctg gtcaccgtct cttca 345

<210> 703

<211> 378

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 703

cagtcggtga aggagtccgg gggaggcctg gtcaagcctg gaggaaccct gacactcacc 60

tgcacagcct ctggattctc cttcagtagc agctactgta tgtgttgggt ccgccaggct 120

ccagggaagg ggctggagtt gatcgcatgc atttatactg atagtagtgg tgccacttac 180

tacgcgagct gggcgaaagg ccgattcacc atctccaagt cctcgtcgac cacgataact 240

ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagggggtgg 300

gattacgagg atcctggtta tactgatact acctactttt ccttgtgggg cccaggcacc 360

ctggtcaccg tctcttca 378

<210> 704

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 704

Gln Ser Leu Glu Glu Ser Ser Glu Gly Asp Leu Val Lys Pro Glu Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Asp Phe Ser Ser Asp Ala

20 25 30

Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly

35 40 45

Cys Ile Tyr Asn Gly Asp Glu Ile Thr Asp His Ala Ser Trp Ala Lys

50 55 60

Gly Arg Phe Thr Ile Ser Lys Thr Ser Pro Thr Thr Val Thr Leu Gln

65 70 75 80

Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg

85 90 95

Ala Val Tyr Ser Asp Gly Gly Ala Gly Tyr Pro Tyr Met Tyr Gly Met

100 105 110

Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 705

<211>  114

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 705

Arg Ala Val Gly Lys Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Asp Phe Ser Gly Ile

20 25 30

Tyr Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Phe Asp Ala Glu Arg Thr Gly Asn Thr Tyr Tyr Ala Thr

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Thr Ser Ser Thr Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Ser Tyr Tyr Met Trp Gly Pro Gly Thr Leu Val Thr Val

100 105 110

Ser Ser

<210> 706

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 706

Glu Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Glu Leu Ser Phe Ser Ser Ala

20 25 30

Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Ser Gly Asp Gly Asp Thr Tyr Tyr Ala Asn Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Asp Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ala Leu Asp Ser His Tyr Ser Ser Phe Asp Leu Trp Gly Pro

100 105 110

Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 707

<211>  115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 707

Glu Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Val Thr Cys Ala Val Ser Gly Phe Ser Leu Asn Ser Tyr

20 25 30

Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile

35 40 45

Gly Tyr Ile Asp Thr Gly Ala Ser Ile Thr Asp Tyr Ala Ser Trp Ala

50 55 60

Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu

65 70 75 80

Glu Met Thr Ser Leu Thr Asp Ala Asp Thr Ala Thr Tyr Phe Cys Ala

85 90 95

Arg Gly Phe Ser Met Phe Lys Leu Trp Gly Pro Gly Thr Leu Val Thr

100 105 110

Ile Ser Ser

115

<210> 708

<211>  119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 708

Glu Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Leu Asp Phe Ser Ser Ser

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Asp Thr Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Thr Val Ser Lys Thr Ser Ser Thr Thr Val

65 70 75 80

Ser Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Ser Thr Pro Asn Ser Leu Gly Tyr Asp Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Ile Ser Ser

115

<210> 709

<211> 127

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 709

Glu Gln Ser Val Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Ser Ser Ser Ser

20 25 30

Ala Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Phe Ile Gly Ser Gly Ser Asp Ser Tyr Tyr Ala Thr

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Asn Thr Tyr Asp Trp Asn Gly Tyr Ile Tyr Gly Pro Cys

100 105 110

Tyr Phe Gly Leu Trp Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120 125

<210> 710

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 710

Glu Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Thr Leu Thr Leu Thr Cys Ile Val Ser Gly Phe Ser Leu Ser Arg Tyr

20 25 30

Ala Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile

35 40 45

Gly Tyr Ile Asp Thr Ser Ser Gly Asn Lys Asp Tyr Ala Asn Trp Val

50 55 60

Asn Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu

65 70 75 80

Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala

85 90 95

Arg Gly Phe Ser Met Phe Lys Leu Trp Gly Pro Gly Thr Leu Val Thr

100 105 110

Ile Ser Ser

115

<210> 711

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 711

Glu Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Leu Asp Phe Ser Ser Ser

20 25 30

Tyr Trp Ser Cys Trp Val Arg Gln Thr Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Asp Val Gly Ser Ser Gly Gly Ser Tyr Tyr Ala Ser

50 55 60

Trp Ala Arg Gly Arg Phe Thr Val Ser Lys Gly Ser Ser Thr Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Ser Thr Thr Thr Thr Asn Val Phe Gly Tyr Asp Leu Trp Gly Pro

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 712

<211>  127

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 712

Glu Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Asp Phe Ser Ser Asn

20 25 30

Asp Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Gly Gly Asp Gly His Thr Tyr Tyr Ala Thr Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Ser Tyr Phe Cys

85 90 95

Ala Arg Gly Tyr Ser Tyr Gly Asp Thr Gly Tyr Ala Asp Ala Ile Leu

100 105 110

Thr Leu Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 713

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 713

Glu Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Val Ser Gly Ile Asp Phe Asn Tyr Tyr

20 25 30

Asn Tyr Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

35 40 45

Glu Trp Ile Gly Cys Met Ser Thr Ala Ser Ala Asn Ile Tyr Leu Ala

50 55 60

Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Glu Ala Ser Ser Thr

65 70 75 80

Val Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr

85 90 95

Phe Cys Ala Lys Ser His Gly Gly Asp Gly Gly Tyr Gly Val Val Leu

100 105 110

Trp Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 714

<211>  122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 714

Glu Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Phe Ser Gly Ser

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Tyr Gly Asp Ser Ile Ala Thr Tyr Tyr Pro Asn Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Ala Ser Leu Thr Gly Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Arg Asn Gly Gly Ser Gly Ala Tyr Gly Trp Asp Leu Trp

100 105 110

Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 715

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 715

Glu Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Ser Phe Ser Ser Asp

20 25 30

Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Val Thr Gly Phe Ser Gly Arg Ile Tyr Tyr Ala Thr

50 55 60

Trp Ala Arg Gly Arg Phe Thr Phe Ser Arg Thr Ser Ser Ser Thr Thr Leu

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Asp Ser Gly Asn Tyr Asn Trp Asp Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Ile Ser Ser

115

<210> 716

<211>  124

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 716

Glu Gln Ser Val Glu Glu Ser Glu Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Asn Asp

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Gly His Ile Gly Ser Phe Arg Thr Thr Tyr Tyr Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Ser Ile Ser Lys Thr Ser Ser Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Gly Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Ser Pro Tyr Asp Asp Gly Tyr Gly Gly Phe Thr Phe Asn

100 105 110

Leu Trp Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 717

<211>  121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 717

Gln Ser Val Lys Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Thr Ser Gly Ser Tyr Gly Ala Gly Leu Gly Leu Trp Gly

100 105 110

Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 718

<211>  119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 718

Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Gln Pro Glu Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ile Asn Leu

20 25 30

Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Gly Asn Asn Asn Ala Asn Thr Tyr Tyr Tyr Thr Thr Thr Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Pro Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Gly Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Thr Ala Ala Tyr Tyr Ala Phe Ser Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Ile Ser Ser

115

<210> 719

<211>  119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 719

Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Asn Pro Asp Glu Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Thr Phe Ser Gly Tyr Tyr

20 25 30

Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly

35 40 45

Trp Ile Tyr Val Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Ser Trp Ala

50 55 60

Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu

65 70 75 80

Gln Met Pro Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala

85 90 95

Arg Gly Val Asn Asp Tyr Gly Trp Ala Leu Lys Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 720

<211>  121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 720

Glu Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Ala Phe Ser Phe Ser Ser Ser

20 25 30

Ser Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Tyr Gly Gly Ser Val Gly Thr Thr Tyr Tyr Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Pro Ser Ser Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Ala Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Thr Asn Thr Asp Ser Ser Arg Ser Tyr Tyr Asn Leu Trp Gly

100 105 110

Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 721

<211> 127

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 721

Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser

1 5 10 15

Leu Ala Leu Thr Cys Lys Ala Ser Gly Ile Asp Leu Ser Asn Tyr Trp

20 25 30

Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Cys Val Ala Thr Asp Ser Ser Arg Thr His Tyr Ala Thr Trp Ala

50 55 60

Lys Gly Arg Phe Thr Val Ser Lys Thr Ser Ser Thr Thr Val Thr Leu

65 70 75 80

Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala

85 90 95

Arg Gly Ser Gly Ala Ser Thr Asn Gly Val Trp Trp Val Met Gly Asp

100 105 110

Gly Met Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120 125

<210> 722

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 722

Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Asn Arg Tyr Tyr

20 25 30

Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly

35 40 45

Cys Ile Tyr Ser Gly Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys

50 55 60

Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu Gln

65 70 75 80

Met Thr Ser Leu Pro Ala Ala Asp Thr Ala Thr Tyr Phe Cys Gly Arg

85 90 95

Leu Asp Tyr Arg Val Ile Tyr Ala Phe Asn Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Ile Ser Ser

115

<210> 723

<211>  122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 723

Glu Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Gly Ser

20 25 30

Cys Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Val Leu Ser Asn Gly Asn Thr Tyr Tyr Ala Gly Trp

50 55 60

Ala Gln Gly Arg Phe Thr Ile Ser Lys Ile Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Glu Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Glu Arg Tyr Pro Gly Ala Phe Ser Ser Gly Leu Asp Leu Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 724

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 724

Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Phe Ser Ser Ser Ser Trp

20 25 30

Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Thr Leu Arg Ser Gly Ala Ala His Tyr Ala Asn Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Gln Met Asn Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ala Thr Tyr Ala Tyr Ala Gly Ala Gly Asp Leu Trp Gly Pro

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 725

<211>  121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 725

Glu Gln Ser Leu Lys Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Ala Phe Ser Phe Ser Ser Ser

20 25 30

Ser Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Tyr Gly Gly Ser Val Ala Thr Thr Tyr Tyr Tyr Ala Thr

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Pro Ser Ser Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Pro Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Thr Asn Thr Asp Ser Ser Arg Ser Tyr Tyr Asn Leu Trp Gly

100 105 110

Pro Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 726

<211>  124

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 726

Glu Gln Ser Val Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Thr

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Gly Asn

20 25 30

Thr Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Pro Ser Ser Thr Ser Ile Thr Thr Tyr Tyr Ala Thr Trp

50 55 60

Ala Lys Gly Arg Phe Thr Val Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Arg Tyr Ala Ala Phe Leu Thr Tyr Gly Ser Gly Ala Phe Asp

100 105 110

Pro Trp Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 727

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 727

Glu Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Val Ala Thr Gly Ser Gly Thr Thr Asp Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Met Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ile Gly Ala Phe Tyr Ser Phe Arg Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Ile Ser Ser

115

<210> 728

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 728

Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Cys Ile Tyr Ala Gly Asn Ser Ala Asn Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Leu Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Ser Arg Asn Gly Gly Ala Pro Asp Gly Leu Asn Leu Trp Gly Pro

100 105 110

Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 729

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 729

Glu Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Ala Thr Gly Thr Gly Ser Thr Tyr Tyr Ala Asn Trp

50 55 60

Val Asn Gly Arg Phe Thr Met Ser Lys Pro Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Thr Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Gly Gly Tyr Trp Ser Phe Ser Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Ile Ser Ser

115

<210> 730

<211> 127

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 730

Glu Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Tyr Met Cys Trp Ile Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Leu Ala Cys Ile Tyr Thr Gly Ser Asp Ser Thr Tyr Tyr Ala Pro Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Arg Thr Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Gly Asp Trp Asp Tyr Ala Asp Ala Ala Gly Tyr Tyr Val Ala Arg

100 105 110

Gly Phe Asn Leu Trp Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120 125

<210> 731

<211>  117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 731

Glu Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Thr Lys Asn

20 25 30

Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Ala Gly Ser Thr Asn Thr Phe Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr Thr Thr Val Asp

65 70 75 80

Leu Lys Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Phe Val Ser Tyr Leu Asn Leu Trp Gly Pro Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 732

<211> 128

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 732

Arg Ala Val Gly Lys Glu Ser Gly Gly Asp Leu Val Thr Leu Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Lys Ala Ser Gly Ile Asp Leu Ser Asn Phe

20 25 30

Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Val Ala Ser Asp Ser Ser Arg Thr His Tyr Ala Thr Trp

50 55 60

Pro Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Ser Gly Ala Ser Thr Asn Gly Val Trp Trp Val Met Gly

100 105 110

Asp Gly Met Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 733

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 733

Gln Ser Val Lys Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Ser Phe Ser Ser Gly His

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Ala Gly Ser Asp Thr Gly Ser Thr Trp Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Ser Ser Asn Ser Tyr Gly Asn Tyr Gly Val Ser Asn Leu

100 105 110

Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 734

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 734

Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Ile Asp Phe Ser Ser Gly

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu

35 40 45

Ile Ala Cys Ile Phe Thr Ser Ser Gly Thr Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Ile Tyr Ser Tyr Gly Met Asp Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 735

<211>  117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 735

Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Val Gln Pro Gly Gly Ser

1 5 10 15

Leu Thr Leu Ser Cys Lys Ala Ser Gly Ile Asp Phe Ser Ser Ala Tyr

20 25 30

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly

35 40 45

Lys Met Arg Ile Asn Asp Arg Ser His Tyr Ala Asn Trp Val Asn Gly

50 55 60

Arg Phe Thr Ile Ser Asn His Asn Asp Gln Asn Thr Val Glu Leu Gln

65 70 75 80

Leu Asn Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg

85 90 95

Ile Ala Thr Gly Thr Asn Val Asp Asp Phe Trp Gly Pro Gly Thr Leu

100 105 110

Val Thr Ile Ser Ser

115

<210> 736

<211>  115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 736

Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Thr Pro Gly Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Lys

20 25 30

Gln Tyr Ile Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Ala Ile Val Thr Val Asn Asn Lys Val His Tyr Ala Asn Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Glu Ala Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Trp Arg Thr Phe Gly Leu Trp Gly Pro Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 737

<211>  121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 737

Glu Gln Leu Met Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Arg Phe Ser Leu Ser Asn Met

20 25 30

Asn Val Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Asn Ile Gly Gly Thr Asn Ile Trp Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Tyr Ile Thr Asp Arg Ile Tyr Asp Tyr Asp Phe Trp Gly

100 105 110

Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 738

<211>  119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 738

Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Ser Cys Thr Ala Ser Gly Phe Asp Phe Ser Ser Lys Tyr

20 25 30

Tyr Met Trp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Arg Ile Tyr Gly Gly Ser Ser Asp Ser Thr Asp Tyr Ala Thr Trp

50 55 60

Ala Arg Gly Arg Phe Ala Ile Ser Arg Thr Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Arg Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Gly Arg Val Ile Asp Gly Ala Cys Gly Tyr Asp Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 739

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 739

Gln Ser Val Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Phe Ser Ser Asn Ala

20 25 30

Tyr Leu Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Cys Ile Tyr Asp Gly Thr Ser Gly Asp Thr Tyr Tyr Ala Asn Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Arg Ser Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Thr Arg Ser Ser Asn Tyr Tyr Phe Asn Leu Trp Gly Pro

100 105 110

Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 740

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 740

Glu Ser Glu Gly Gly Leu Val Lys Pro Gly Gly Thr Leu Thr Leu Thr

1 5 10 15

Cys Lys Val Ser Gly Ile Asp Phe Asn Ser Tyr Lys Tyr Tyr Tyr Met

20 25 30

Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Cys

35 40 45

Met Ser Thr Ala Ser Arg Asn Ile Tyr Tyr Ala Ser Trp Ala Lys Gly

50 55 60

Arg Phe Thr Ile Ser Glu Thr Ser Ser Ser Thr Ser Val Thr Leu Gln Met

65 70 75 80

Thr Thr Leu Thr Ala Ala Asp Thr Ala Thr Tyr Tyr Phe Cys Ala Lys Ser

85 90 95

His Gly Gly Asp Gly Gly Tyr Gly Val Val Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Ile Ser Ser

115

<210> 741

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 741

Gln Ser Leu Glu Glu Ser Glu Gly Gly Leu Val Lys Pro Gly Gly Thr

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Cys Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Ile

35 40 45

Ala Cys Ile Tyr Thr Asp Ser Ser Gly Ala Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ser Ser Ser Thr Thr Thr Ile Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr Thr Tyr

100 105 110

Phe Ser Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 742

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 742

Gln Lys Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Ala Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Ala Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser

50 55 60

Trp Val Asn Gly Arg Phe Thr Val Phe Lys Thr Ser Ser Thr Thr Val

65 70 75 80

Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Gly Gly Thr Ser Tyr Arg Leu Asp Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 743

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 743

Ser Gln Gln Leu Lys Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Thr Leu Thr Leu Thr Cys Lys Ala Ser Gly Ile Asp Phe Asn Asn Asp

20 25 30

Tyr Asn Ile Cys Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Thr Gly Ser Asp Ser Thr Asp Tyr Ala Ser Trp

50 55 60

Val Asn Gly Arg Phe Thr Ile Ser Glu Ser Thr Ser Leu Asn Thr Val

65 70 75 80

Asp Leu Lys Val Thr Ser Leu Thr Asp Ala Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Asp Leu Val Thr Gly Tyr Ala Thr Tyr Gly Tyr Gly Phe

100 105 110

Ile Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 744

<400> 744

000

<210> 745

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 745

Gln Glu Gln Leu Lys Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Asp

20 25 30

Tyr Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Thr Gly Asp Asp Asp Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Glu Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Leu Thr Ile Gly Thr Ala Glu Leu Tyr Phe Trp Gly Pro

100 105 110

Gly Thr Val Val Thr Val Ser Ser

115 120

<210> 746

<211>  117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 746

Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Asp Ser Gly Phe Ser Phe Thr Lys Asn

20 25 30

Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Ala Gly Ser Thr Asn Thr Phe Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr Thr Thr Val Asp

65 70 75 80

Leu Lys Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Phe Val Ser Tyr Leu Asn Leu Trp Gly Pro Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 747

<211>  122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 747

Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Glu Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Leu Ser Asn Asn Tyr

20 25 30

Tyr Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Ile

35 40 45

Ala Cys Val Asp Ser Asp Leu Thr Asp Ser Ala Asp Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Gly Ser Gly Ser Gly Tyr Tyr Tyr Tyr Tyr Gly Met Asp Leu Trp

100 105 110

Gly Pro Gly Thr Leu Val Thr Ile Ser Ser

115 120

<210> 748

<211>  119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 748

Ser Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Thr Leu Thr Cys Lys Gly Ser Gly Phe Ser Phe Asn Gly Asp

20 25 30

Tyr Tyr Met Cys Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Cys Ile Tyr Ala Ala Gly Asp Asp Thr Tyr Tyr Ala Thr Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Gln Ala Asp Ser Tyr Ala Phe Gly Leu Trp Gly Pro Gly

100 105 110

Thr Leu Val Thr Ile Ser Ser

115

<210> 749

<211>  116

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 749

Gln Ser Leu Lys Glu Ser Ser Glu Gly Asp Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Glu Met Thr Ser Leu Thr Asp Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Phe Ser Met Phe Lys Leu Trp Gly Pro Gly Thr Leu Val

100 105 110

Thr Ile Ser Ser

115

<210> 750

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 750

Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Cys Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Ile

35 40 45

Ala Cys Ile Tyr Thr Asp Ser Ser Gly Ala Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ser Ser Ser Thr Thr Thr Ile Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr Thr Tyr

100 105 110

Phe Ser Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 751

<211> 128

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 751

Ser Gln Ser Val Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Ala Ser Arg Ile Asp Leu Asn Asn Tyr

20 25 30

Tyr Tyr Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Val Val Ala Thr Asp Ser Ser Val Thr Trp Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Gln Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Ser Gly Ala Ala Thr Asn Gly Val Trp Trp Val Met Gly

100 105 110

Asp Gly Met Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 752

<211>  116

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 752

Gln Ser Val Glu Glu Ser Ser Glu Gly Arg Leu Val Thr Pro Gly Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Ala

20 25 30

Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly

35 40 45

Val Ile Gly Lys Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asn Trp Ala Lys Gly

50 55 60

Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Gln Ile Ala

65 70 75 80

Ser Pro Thr Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ala Gly

85 90 95

Ala Ser Arg Ser Ile Tyr Tyr Asp Leu Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Ile Ser Ser

115

<210> 753

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 753

Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Gly Ile Val

20 25 30

Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ala Phe Val Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Thr Trp

50 55 60

Ala Thr Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Lys Ser Tyr Asn Tyr Asn Gly Leu Gly Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 754

<211>  122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 754

Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ala Cys Ile Tyr Gly Gly Ser Thr Gly Thr Thr Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Gly Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Tyr Asn Ser Ala Ser Ser Gly Tyr Tyr Trp Asp Leu Trp

100 105 110

Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 755

<211>  118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 755

Glu Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Ile Asp Phe Ser Ser Gly

20 25 30

Ala Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu

35 40 45

Ile Ala Cys Ile Phe Thr Thr Ser Gly Phe Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Ile Tyr Ser Tyr Gly Met Asp Leu Trp Gly Pro Gly Thr

100 105 110

Leu Val Thr Ile Ser Ser

115

<210> 756

<211>  115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 756

Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly

1 5 10 15

Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Arg

20 25 30

Gln Tyr Ile Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Ala Ile Val Thr Val Asn Asn Lys Val His Tyr Ala Asn Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Glu Ala Ser Ser Thr Thr Val Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Trp Arg Thr Phe Gly Leu Trp Gly Pro Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 757

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 757

Gln Ser Val Lys Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr

1 5 10 15

Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser Tyr

20 25 30

Cys Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Ile

35 40 45

Ala Cys Ile Tyr Thr Asp Ser Ser Gly Ala Thr Tyr Tyr Ala Ser Trp

50 55 60

Ala Lys Gly Arg Phe Thr Ile Ser Lys Ser Ser Ser Thr Thr Thr Ile Thr

65 70 75 80

Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr Thr Tyr

100 105 110

Phe Ser Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 758

<211> 128

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 758

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Cys Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Val Ser Cys Ile Tyr Thr Asp Ser Ser Gly Ala Thr Tyr Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr

100 105 110

Thr Tyr Phe Ser Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 759

<211> 128

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 759

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Cys Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu

35 40 45

Val Ser Cys Ile Tyr Thr Asp Ser Ser Gly Ala Thr Tyr Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr

100 105 110

Thr Tyr Phe Ser Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 760

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 760

gagctcgata tgacccagac tccagcctcc gtggaggcgg ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gaacatttac agctacttag tctggtatca gcagaaacca 120

gggcagcctc ccaagctcct aatctcaaag gcatccactc tggcatctgg ggtctcatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcaacga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaacc aattatttta gtagtactag tcattttggt 300

gtttttactt tcggcggagg gaccgagctg gaaatcaaa 339

<210> 761

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 761

gagctcgtgc tgacccagac tccatcccct gtgtctgcag ttgtgggagg ctcagtcacc 60

atcaattgcc agtccagtca gagtctttat aatgcgaacg acttatcctg gtatcagcag 120

aaaccagggc agcctcccaa gcaactgatc tactgggcat ccactctggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acaagttca ctctcagcat cagcgacgtg 240

cagtgtgacg atgctgccac ttaactactgt ctaggcgaat ttagttgcag tagttttgat 300

tgtcatgttt tcggcggagg gaccgaggtg gtggtcaaa 339

<210> 762

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 762

gagctcgata tgacccagac tccatcctcc gtgtctgcag ctgtgggaga cacagtcacc 60

atcaagtgcc aggccagtca gagcatttac aggtacttag cctggtatca acagaaacca 120

gggcagcgtc ccagcctcct aatatattat ggatccgatc tggcatctgg ggtcccatcg 180

cggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccagttacta ctgtcaaacc acttatgatg attcataa tggttgggct 300

ttcggcggag ggaccaatgt ggaaatcaac 330

<210> 763

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 763

gagctcgatc tgacccagac tccatcgtcc gtgtctgcag ctgtggggacacagtcacc 60

atcagttgcc aggccagtca gagtgtttat ggtaacaacc gcttagcctg gtatcatcag 120

aaaccaggac agcctcccaa acgcctgatc tatctggcat ccactctgga ttctggggtc 180

ccatcacggt tcaaaggcgc tggatctggg acaagttca ctctcaccat cagcgacctg 240

gagtgtgacg atgctgccac ttaactactgt gcaggcggtt atgctgggaa tttcaatgct 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 764

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 764

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtggggagg cacagtcacc 60

atcaagtgcc aggccagtca gaacattgtc agtaatttag cctggtatca gcagaaacca 120

gggcagcgtc ccaagctcct gatctattat gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag tacactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaaac aatgctggta tttatggtaa ttatggtcat 300

ggtttcggcg gagggaccga gctggaaatc aaa 333

<210> 765

<211> 327

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 765

gagctcgatc tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcatttac aactacttag cctggtatca gcagaaacca 120

gggcactctc ctaagctcct gatctacgat gtatccaaat tggcatctgg ggtctcatcg 180

cggttcaaag gtagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttatta ctgtcaaagt tattatggta atactgtttc ttttactttc 300

ggcggaggga ccgaggtgga aatcaaa 327

<210> 766

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 766

gagctcgtga tgacccagac tccatcgtcc gtgtctgcag ctgtggggacacagtcacc 60

atcagttgcc aggccagtca gagtgtttat aataacaaca acttagcctg gtatcagcag 120

aaaccagggc agcctcccaa acgcctgatc tattctgcat ccactctgga ttctggggtc 180

ccatcgcggt tcagcggcag tggatctggg acaagttca ctctcaccat cagcgacctg 240

gagtgtgacg atgctgccac ttactattgt gcaggcggtt atacttacaa tatcaatatt 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 767

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 767

gagctcgatc tgacccagac accagcctct gtgtctgaac ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gaacatttac aacaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctattat gcatccactc tggcatctgg ggtcccaccg 180

cggttcagcg gcagtggatc tgggacagag tatactctca ccatcagcga cctcgagtgt 240

gacgatgctg ccacttacta ctgtcaaaac aatgctggta tttatggtgg ttatggtcat 300

ggtttcggcg gagggaccga ggtggtggtc aaa 333

<210> 768

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 768

gagctcgatc tgacccagac tccagcctcc gtagaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gactattggt agctacctat cctggtatca gcagaaacca 120

gggcagcgtc ccaaactcct gatctatgaa gcatccaaac tggcatctgg ggtcccatcg 180

tggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaagc aattattatc gtgctggtgg taattatggt 300

ggagctttcg gcggagggac cgaggtggaa atcaaa 336

<210> 769

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 769

gagctcgatc tgacccagac tccattctcc gtgtctgcag ctgtggggagg cacagtcacc 60

atcaagtgcc aggccagtga gaccattagt aatagattag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctattct gcatccactc tggaatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttatta ttgtcaaagt attcgtagta gtagtggtat tgttcatccg 300

aatactttcg gcggagggac cgaggtggaa atcaaa 336

<210> 770

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 770

gagctcgatc tgacccagac tccagcctct gtgtctgaac ctgtgggagg cacagtcacc 60

atcacgtgcc aggccagtca gagcattagt agttacttat cctggtatca gcagacacca 120

gggcagcctc ccaagctcct aatctacaag gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaagc tattactata ttagtgctac tgttgataat 300

actttcggcg gagggaccga ggtggaaatc aaa 333

<210> 771

<211> 327

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 771

gagctcgatc tgacccagac tccaacctcc gtgtctgcag ctgtggggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattagt gattacttat cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctacagg gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ttgtcaaagt aattattatg gtagtcaggg ttgtactttc 300

ggcggaggga ccgaggtgga aatcaaa 327

<210> 772

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 772

gagctcgata tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60

gtcaagtgcc aggtcagtca gagcattggc aatgcaatag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctacaag gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagaa ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaaac tattattata gtaatactaa tagtttcggc 300

ggagggaccg aggtggtggt caaa 324

<210> 773

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 773

gagctcgata tgacccagac tgcatccccc gtgtctggag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gaacatttat aataacatag ggtggtatca gcagaaacca 120

gggcagcctc ccaacctcct gatctatggt ccatcctatc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtagatc tgggacagag tacactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaagt gatgattgga tgagtatcag tcctgatatt 300

gttttcggcg gagggaccga ggtggaaatc aaa 333

<210> 774

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 774

gagctcgtga tgacccagac accatcatcc tcgtctgcag ctgtggggacacagtcacc 60

atcaagtgcc aggccagtca gagtattggt agtagattcg cctggtatca gcagaaacca 120

gggcagcgtc ccaagctcct gatctatgaa gcatccaaac tgccatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcacgctca ccatcagcga cctggagtgt 240

gccgatgctg ccatttta ctgtcaatgt acttattatg aaagtagtag tggtggtggt 300

ttcggcggag ggaccgaggt ggtggtcaaa 330

<210> 775

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 775

gagctcgtgc tgacccagac tccatcctcc gtggaggtag ctgtggggagg cgcagtcacc 60

atcaagtgcc aggccagtca tatcattact aactacttag cctggtatca gcagagacca 120

gggcagcctc ccaagctcct gatctacgat gcatcgaagc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaaac tatctttattttagtagtgg tgattggaat 300

gttttcggcg gagggaccga ggtggtggtc aaa 333

<210> 776

<400> 776

000

<210> 777

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 777

gagctcgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtcc gagcattagt acttacttgt cctggtatca gcagaaacca 120

gggcagcctc ccaagcgcct gatcaacagg gcatccactc tggcatctgg ggtcccaccg 180

cggttcaaag gcagtggagc tgggacacag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttatta ttgtcaaaac aattaccata gtggtagtag taatggtggt 300

ggtgttgctt tcggcggagg gaccgaggtg gaaatcaaa 339

<210> 778

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 778

gagctcgtgc tgacccagac tccagcctcc gtgtctgcgg ctgtggggacacagtcacc 60

atcaattgcc aggccagtca gagtattggt agtggtaatt tagcctggta tcagcagaaa 120

ccagggcagc ctcccaagct cctgatctat ctggcatcca ctctggcatc tggggtccca 180

ccgcggttca aaggcagtgg atctgggaca gagttcactc tcaccatcag cgacctggag 240

tgtgacgatg ctgccactta ctactgtcaa tatacttatt atggtactac ttatgataat 300

gctttcggcg gagggaccga gctggaaatc aaa 333

<210> 779

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 779

gagctcgatc tgacccagac tccatcccca gtgtctgcag ctgtggggagg cacagtcacc 60

atcaattgcc aggccagtca gattgttgct aacggccgct tagcctggta tcagcagaaa 120

ccagggcagc ctcccaagct cctgatctat gctacatcca ctctggcatc tggggtccca 180

tcgcggttca agggcagtgg atctgggaca cagttcactc tcaccatcaa cggtgtgcag 240

tgtgacgatg ctgccactta ctactgtcaa ggcgcttata gtagtgggga tgttcggact 300

ttcggcggag ggaccgaggt ggtggtcaaa 330

<210> 780

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 780

gagctcgtgc tgacccagac accatcctcc gtgtctgcag ctgtggggacacagtcacc 60

atcaattgcc aggccagtga ggacattgat aggtatttag cctggtatca acagaaacca 120

gggcagcgtc ccaagctcct gatcgtcgat gcatccactc tgccatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatggtg ccacttacta ctgtcaaagc tatgataata gtgataataa tggtttcggc 300

ggagggaccg aggtggtggt caaa 324

<210> 781

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 781

gagctcgatc tgacccagac tccatcctcc gtggaggtag ctgtgggagg cgcagtcacc 60

atcaagtgcc aggccagtca tatcattact aactacttag cctggtatca gcagagacca 120

gggcagcctc ccaagctcct gatctacgat gcatcgaagc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaaac tatctttattttagtagtgg tgattggaat 300

gttttcggcg gagggaccga ggtggtggtc aaa 333

<210> 782

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 782

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtggggagg cacagtcacc 60

atcaattgcc aggccagtga gagcattggc agtgcattag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctattct gcatccgctc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag tacactctca ccatcagcga cttggagtgt 240

gccgatgctg ccacttatta ctgtcaaagt tattatggaa gtggtacgac tgctttagat 300

actttcggcg gagggaccga ggtggaaatc aaa 333

<210> 783

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 783

gagctcgatc tgacccagac tccaggctcc gtggaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccggtca gagcatttac aactacttat cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctattct gcatccactc tggaatctgg ggtcccaccg 180

cggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttactc ctgtcaaaac aattatggta ttggtagtaa ttatggtcct 300

ggtttcggcg gagggaccga ggtggaaatc aaa 333

<210> 784

<211> 327

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 784

gagctcgatc tgacccagac tccagcctcc gtggaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtct gaacattaat agttggttgg cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctcttat acatccagtc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag tacactctca ccatcaacga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaacc acatattttg gtactaatgg tggtggtttc 300

ggcggaggga ccgaggtgga aatcaaa 327

<210> 785

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 785

gagctcgtga tgacccagac accatcctcc gtggaggcag ctgtggggagg cacagtcacc 60

aacaagtgcc aggccagtga ggacatttat agcaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctatggt gcaaccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ttgtcaggcc gaaagtaatg atgtttgggc tttcggcgga 300

gggaccgagg tggtggtcaa a 321

<210> 786

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 786

gagctcgatc tgacccagac accagcctcc gtgtctgcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtga ggatatttat agtaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctacaag gcatccactc tggcatctgg ggtcccaccg 180

cggttcaaag gcagtggatc tgggacagaa tacactctca ccatcagcgg tgtgcagtgt 240

gacgatgctg ccacttacgc ctgtcagact acttattgga ctactactga tgataatcct 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 787

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 787

gagctcgatc tgacccagac tccatcatcc tcgtctgcag ctgtggggagg cacagtcacc 60

atcaattgcc aggccagtca gagtgtttat aataagaact acttatcctg gtttcagcag 120

aaaccagggc agcctcccaa gctcctgatc tattatgctt ccactctggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acaggttca ctctcaccat cagcgatgtg 240

gtgtgtgacg atgctgccac ttactactgt gcagcttata aaggtgttag tgatgatggt 300

atttctttcg gcggagggac cgaggtggaa atcaaa 336

<210> 788

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 788

gagctcgata tgacccagac tccatcctcc gtgtctgcag ctgtgggggg cacagtcacc 60

atcaagtgcc aggccagtca gagcattagt agttacttat cctggtatca gcagaaacca 120

gggcagcctc ccaagcgcct gatctacaag gcatccactc tgccatctgg ggtcccaccg 180

cggtttaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaaac aattatcata gtggtagtag taatggtggt 300

ggttttgctt tcggcggagg gacccaggtg gaaatcaaa 339

<210> 789

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 789

gagctcgatc tgacccagac tccagcctcc gtggaggcag ctgtgagagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattagt tactacttag cctggtatca gcagaaacca 120

gggcagcctc ccaaggtcct gatctacaag gcatccactc tggcatctgg ggtcccaccg 180

cggttcaaag gcagtggatt tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttatta ctgtcaaagc acttatggta gggataataa tgatcttttt 300

ttcgctttcg gcggagggac cgaggtggaa atcaaa 336

<210> 790

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 790

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtggggagg cacggtcacc 60

atcaagtgcc aggccagtca gagtattagt agtagctact tagcctggta tcagcagaaa 120

ccagggcagc ctcccaagct cctgatctat tctgcgtcca gtacggcatc tggggtccca 180

tcgcggttca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacctggag 240

tgtgccgatg ctgccactta ctactgtcaa agcacttata ttagtagtag taagtatggt 300

gctgttttcg gcggagggac cgagctggaa atcaaa 336

<210> 791

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 791

gagctcgtga tgacccagac tgcatcgccc gtgtctgcag ctgtggggacacagtcacc 60

atcagttgcc agtccagtca gagtgtttat agtaacaact ggttatcctg gtatcagcag 120

aaaccagggc agcctcccaa acgcctgatc tacaaggcat ccactctgga aactggggtc 180

ccatcgcggt tcaaaggcag tggatctggg aaacagttca ctctcaccat cagcgacctg 240

gagtgtgacg atgctgccac ttattactgt gcaggcgggt atagtggtga tctttatgct 300

ttcggcggag ggaccgaggt ggtggtcaaa 330

<210> 792

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 792

gagctcgata tgacccagac tccatctccc gtgtctgcag ctgtggggagg ctcagtcacc 60

atcagttgcc aggccagtca gactattttat aataacaaaa atttggcctg gtatcagcag 120

aaaccagggc aacctcccaa gctcctgatc taccaggcat ccaaactggc atctggggtc 180

tcatcgcggt tcagtggcag tggatctggg acaagttca ctctcaccat cagcggcgtg 240

cagtgtgacg atgctgccac ttactactgt caaggcgaat ttagttgtag tagtggtgat 300

tgtactactt tcggcggagg gaccgaggtg gtggtcaaa 339

<210> 793

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 793

gagctcgata tgacccagac tccagcctcc gtgtctgaac ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtga gaacatttat agctacttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctattct gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ttgtcaatat agtaatttta gggtgaatga tcctagtgtt 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 794

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 794

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtggggagg cacagtcacc 60

atcagttgcc agtccagtca gagcgttcat catagtcaga ccgttcataa taatcaatgg 120

ttagcctggt atcagcagaa accagggcag cctcccaagc tcctgatcta tgatgcatcc 180

aaactggcat ctggggtccc atcgcggttc acaggtagtg gatctgggac acagttctct 240

ctcaccatca gtgcagtgca gtgtgacgat gctgccactt actactgtca aggcggttat 300

agttatggtg atgtgtatgg tttcggcgga gggaccgagc tggaaatcaa g 351

<210> 795

<211> 342

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 795

gagctcgtgc tgacccagac tccatcttcc acgtctgcgg ctgtgggagg cacagtcacc 60

atcaattgcc aggccagtca aagtgttgat aacaacaaac aattatcctg gtatcagcag 120

aaaccagggc agcctcccaa gcaactgatc tactctgcat ccaaactggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acaagttca ctctcaccat cagcgacctg 240

gagtgtgacg atgctgccac ttaactactgt gcaggctatt attatagtgg tagtgccact 300

gatgcgtggg ctttcggcgg agcgaccgag gtggaaatca ac 342

<210> 796

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 796

gagctcgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggaga cacactcacc 60

atcaattgcc aggccagtga gaccattagt aatagattag cctggtatca acagaaacca 120

gggcagcctc ccaagctcct gatctattct gcatccactc tggaatctgg ggtcccatcg 180

cggttcagag gcagtggatc tgggacacag ttcactctca ccataagtga cctggagtgt 240

gccgatgctg ccacttatta ttgtcaaagt attcgtagta gtagtggtgt tgtgcatcca 300

aatactttcg gcggagggac cgaggtggaa atcaaa 336

<210> 797

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 797

gagctcgatc tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gaccatttat accaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaacctcct gatctatgct gcatccactc tggcatctgg ggtctcatcg 180

cggttcaaag gcagtggatc cgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaagc tattatggta gtagtactac tggtaatggt 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 798

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 798

gagctcgtgc tgacccagac accatcttcc aagtctgtcg ctgtgggaga cacagtcacc 60

atcaattgcc aggccagtga taatgtttat agtaataact acacatcctg gtttcagcag 120

aaaccagggc agcctcccaa acaactgctc tattatgcgg cctatcgggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acaggttca ctctctccat cagcgatgtg 240

gtgtgtgacg atgctgccac ttactattgt tcaggccata aagattatag tgatgatggt 300

agtactttcg gcggagggac cgaggtggaa atcaaa 336

<210> 799

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 799

gagctcgtgc tgacccagac accatcttcc aagtctgtcg ctgtgggaga cacagtcacc 60

atcaattgcc aggccagtga taatgtttat agtaataact acacatcctg gtttcagcag 120

aaaccagggc agcctcccaa acaactgctc tattatgcgg cctatcgggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acaggttca ctctctccat cagcgatgtg 240

gtgtgtgacg atgctgccac ttactattgt tcaggccata aagattatag tgatgatggt 300

agtactttcg gcggagggac cgaggtggaa atcaaa 336

<210> 800

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 800

gagctcgtga tgacccagac accagcctcc gtgtctgcag ctgtggggacacagtcacc 60

atcaattgcc aggccagtga ggatattagt agtaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatcagtggt gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagac ttcactctca ccatgagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaggc gcttattatg gtagtagtta tggtttcggg 300

ggagggaccg aggtggtggt caaa 324

<210> 801

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 801

gagctcgtgc tgacccagac accatccccc gtgtctgcag ctgtgggagg cacagtcacc 60

atcaattgcc aggccagtca gagcattagc aatgaattat cctggtatca acagaaacca 120

gggcagcctc ccaagctcct gatctatctg gcatccactc tggattctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacccag ttcactctca ccatcagcga cctggagtgt 240

gccgacgctg ccacttacta ctgtcaaagt cattattatg gtggtagtag tgattatgga 300

tgggctttcg gcggagggac cgaggtggtg gtcaaa 336

<210> 802

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 802

gagctcgata tgacccagac tccatcttcc acgtctgcag ctgtggggacacagtcacc 60

atcaagtgcc aggccagtca aagtgtttac aataacaacc aattatcctg gtttcagcag 120

aaaccagggc agcctcccaa acgcctgatc tatggtgcat ccactctgga atctggggtc 180

ccatcgcggt tcagcggcag tggatctggg acaagttca ctctcaccat tagtgacctg 240

gagtgtgacg atgctgccac ttactactgt caaggcgctg ttagtagtga ttactatcct 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 803

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 803

gagctcgata tgacccagac accagcctcc gtgtctgaac ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gagtattggt agctatttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct ggccttttat gcttccactc tgaagtctgg ggtcccaccg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttatta ctgtcaaagt aatcgtctta gtagtagtga cgttaatgct 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 804

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 804

gagctcgtgc tgacccagac tgcatccccc gtgtctggag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gaacatttac agcaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctattct gcatccaaac tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag tacactctca ccatcagcgg cgtgcagtgt 240

gaagatgctg ccacttacta ctgtcaaagc tattattata ctgctagtgc tgatactact 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 805

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 805

gagctcgtgc tgacccagac tccatcctcc gtggaggcag ctgtggggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattggt agctacttag cctggtatca gcagaaacca 120

gggcagcctc ccaagctcct gatctacaag gcatccactc tgtcatctgg ggtctcatca 180

cggtacaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240

gacgatgctg ccacttacta ctgtcaatat actagttata gtagtggtgg ggctttcggc 300

ggagggaccg aggtggtggt caaa 324

<210> 806

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 806

gagctcgata tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gaccatttat accaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaacctcct gatctatgct gcatccactc tggcatctgg ggtctcatcg 180

cggttcaaag gcagtggatc cgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaagc tattatggta gtagtactac tggtaatggt 300

ttcggcggag ggaccgaggt ggaaatcaac 330

<210> 807

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 807

gagctcgtga tgacccagac tccagcctct gtgtctgaac ctgtggggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattagt agttacttat cctggtatca gcagaaacca 120

gggcagcctc ccaagcgcct gatctacaag gcttccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcgg cgtgcagtgt 240

gccgatgctg ccacttacta ctgtcaaaac aattatcata gtggtagtag taatggtggt 300

ggttttgctt tcggcggagg gaccgaggtg gaaatcaaa 339

<210> 808

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 808

gagctcgtgc tgacccagac tccatcttcc aagtctgtcg ctgtgggaga cacagtcacc 60

atcaattgcc aggccagtga gagtgtttat ggtaacaacc gttgctcctg gtatcagcag 120

aaaccagggc agcctcccaa gctcctgatc taccaggctt ccactctggc ctctggggtc 180

ccatcgcggt tcagcggcag tggatctggg acaagttca ctctcaccat cagcgatgtg 240

gtgtgtgacg atgctgccac ttatactgt gcaggacata aaggaactac taatgatggg 300

aatgatttcg gcggagggac cgaggtggaa atcaaa 336

<210> 809

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 809

gagctcgata tgacccagac tccagcctcc gtgtctgcag ctgtggggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattacc aatgcattag cctggtatca acagaaacca 120

gggcagcctc ccaagctcct gatctacagg gcatccactc tggcatctgg ggtctcatcg 180

cggttcaaag gcagcggatc tgggacagag ttcactctca ccatcagtga ccttgagtgt 240

gccgatgctg ccacttacta ttgtcaatgt agttattatg gtagtactta ttttgggagt 300

cctttcggcg gagggaccga ggtggaaatc aaa 333

<210>  810

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  810

gagctcgtgc tgacccagac tccatcctcc gtgtctgaac ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattagt agtagctact tagcctggta tcagcagaaa 120

ccagggcagc ctcccaagtt cctgatctat tctgcatcca ctctggcatc tggggtccca 180

tcgcggttca aaggcagtgg atctgggaca gagttcactc tcaccatcag cgacctggag 240

tgtgccgatg ctgccactta ctactgtcaa agcacttata ttagtagtag taattatggt 300

gctgctttcg gcggagggac cgaggtggaa atcaaa 336

<210> 811

<211> 327

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 811

gagctcgatc tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattggt agtaatttag cctggtatca gcagaaacca 120

gggcagcctc ccaaggtcct gatctacaag gcatccactc tggcatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttatta ctgtcaaaac aataattatt ggagtaatgg taaccatttc 300

ggcggaggga ccgaggtggt ggtcaaa 327

<210> 812

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 812

gagctcgtgc tgacccagac tccatcttcc aagtctgtcg ctgtgggaga cacagtcacc 60

atcaattgcc aggccagtga gaatgtttat agtaataact acacatcctg gtttcagcag 120

aaaccagggc agcctcccaa acaactgctc tattatgcgg cctatcgggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acaggttca ctctctccat cagcgatgtg 240

gtgtgtgacg atgctgccac ttactattgt tcaggccata aagattatag tgatgatggt 300

agtactttcg gcggagggac cgaggtggtg gtcaaa 336

<210> 813

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 813

gagctcgatc tgacccagac tgcatccccc gtgtctggag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gagcattgct agcgacttag cctggtatca gcagaaacca 120

gggcagcctc ccaacctcct gatctatgct gcatccactc tggcatctgg ggtctcatcg 180

cggttcaaag gcagtggatc cgggacagag ttcactctca ccatcagcga cctggagtgt 240

gccgatgctg ccacttacta ctgtcaaagc tattatggta gtagtactac tggtaatggt 300

ttcggcggag ggaccgaggt ggtggtcaaa 330

<210> 814

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 814

Glu Leu Asp Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Tyr Ser Tyr

20 25 30

Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Ser Lys Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Thr Asn Tyr Phe Ser Ser Thr

85 90 95

Ser His Phe Gly Val Phe Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile

100 105 110

Lys

<210> 815

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 815

Glu Leu Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Val Val Gly

1 5 10 15

Gly Ser Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Leu Tyr Asn Ala

20 25 30

Asn Asp Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln

35 40 45

Leu Ile Tyr Trp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Ser Ile Ser Asp Val

65 70 75 80

Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Glu Phe Ser Cys

85 90 95

Ser Ser Phe Asp Cys His Val Phe Gly Gly Gly Thr Glu Val Val Val

100 105 110

Lys

<210> 816

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 816

Glu Leu Asp Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Asp Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Tyr Arg Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Ser Leu Leu Ile

35 40 45

Tyr Tyr Gly Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Ser Tyr Tyr Cys Gln Thr Thr Tyr Tyr Asp Asp Tyr His

85 90 95

Asn Gly Trp Ala Phe Gly Gly Gly Thr Asn Val Glu Ile Asn

100 105 110

<210> 817

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 817

Glu Leu Asp Leu Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Ser Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn

20 25 30

Asn Arg Leu Ala Trp Tyr His Gln Lys Pro Gly Gln Pro Pro Lys Arg

35 40 45

Leu Ile Tyr Leu Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ala Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu

65 70 75 80

Glu Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Ala Gly

85 90 95

Asn Phe Asn Ala Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 818

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 818

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Val Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Ala Gly Ile Tyr Gly

85 90 95

Asn Tyr Gly His Gly Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys

100 105 110

<210> 819

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 819

Glu Leu Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Tyr Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly His Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Val Ser Lys Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Asn Thr Val

85 90 95

Ser Phe Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105

<210>  820

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 820

Glu Leu Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Ser Cys Gln Ala Ser Gln Ser Val Tyr Asn Asn

20 25 30

Asn Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg

35 40 45

Leu Ile Tyr Ser Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu

65 70 75 80

Glu Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Thr Tyr

85 90 95

Asn Ile Asn Ile Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 821

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 821

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Tyr Asn Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Ala Gly Ile Tyr Gly

85 90 95

Gly Tyr Gly His Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 822

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 822

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Thr Ile Gly Ser Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile

35 40 45

Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Trp Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Tyr Arg Ala Gly

85 90 95

Gly Asn Tyr Gly Gly Ala Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 823

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 823

Glu Leu Asp Leu Thr Gln Thr Pro Phe Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Thr Ile Ser Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Ile Arg Ser Ser Ser Gly

85 90 95

Ile Val His Pro Asn Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 824

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 824

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly

1 5 10 15

Gly Thr Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Thr Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Tyr Ile Ser Ala

85 90 95

Thr Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 825

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 825

Glu Leu Asp Leu Thr Gln Thr Pro Thr Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Asp Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Tyr Gly Ser Gln

85 90 95

Gly Cys Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105

<210> 826

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 826

Glu Leu Asp Met Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Val Lys Cys Gln Val Ser Gln Ser Ile Gly Asn Ala

20 25 30

Ile Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Tyr Tyr Tyr Ser Asn Thr

85 90 95

Asn Ser Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105

<210> 827

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 827

Glu Leu Asp Met Thr Gln Thr Ala Ser Pro Val Ser Gly Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Tyr Asn Asn

20 25 30

Ile Gly Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile

35 40 45

Tyr Gly Pro Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Asp Asp Trp Met Ser Ile

85 90 95

Ser Pro Asp Ile Val Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 828

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 828

Glu Leu Val Met Thr Gln Thr Pro Ser Ser Ser Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Arg

20 25 30

Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile

35 40 45

Tyr Glu Ala Ser Lys Leu Pro Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Ile Tyr Tyr Cys Gln Cys Thr Tyr Tyr Tyr Glu Ser Ser

85 90 95

Ser Gly Gly Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 829

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 829

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Val Glu Val Ala Val Gly

1 5 10 15

Gly Ala Val Thr Ile Lys Cys Gln Ala Ser His Ile Ile Thr Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Tyr Leu Tyr Phe Ser Ser

85 90 95

Gly Asp Trp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 830

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 830

Glu Leu Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Pro Ser Ile Ser Thr Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg Leu Ile

35 40 45

Asn Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Pro Arg Phe Lys Gly

50 55 60

Ser Gly Ala Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr His Ser Gly Ser

85 90 95

Ser Asn Gly Gly Gly Val Ala Phe Gly Gly Gly Thr Glu Val Glu Ile

100 105 110

Lys

<210> 831

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 831

Glu Leu Val Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Gly Ser Gly

20 25 30

Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu

35 40 45

Ile Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Pro Arg Phe Lys

50 55 60

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu

65 70 75 80

Cys Asp Asp Ala Ala Thr Tyr Tyr Tyr Cys Gln Tyr Thr Tyr Tyr Tyr Gly Thr

85 90 95

Thr Tyr Asp Asn Ala Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys

100 105 110

<210> 832

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 832

Glu Leu Asp Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ile Val Ala Asn Gly

20 25 30

Arg Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu

35 40 45

Ile Tyr Ala Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys

50 55 60

Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Asn Gly Val Gln

65 70 75 80

Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Ala Tyr Ser Ser Gly

85 90 95

Asp Val Arg Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 833

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 833

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Asp Arg Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile

35 40 45

Val Asp Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Gly Ala Thr Tyr Tyr Cys Gln Ser Tyr Asp Asn Ser Asp Asn

85 90 95

Asn Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105

<210> 834

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 834

Glu Leu Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Val Ala Val Gly

1 5 10 15

Gly Ala Val Thr Ile Lys Cys Gln Ala Ser His Ile Ile Thr Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Tyr Leu Tyr Phe Ser Ser

85 90 95

Gly Asp Trp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 835

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 835

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ala Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Gly Thr

85 90 95

Thr Ala Leu Asp Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 836

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 836

Glu Leu Asp Leu Thr Gln Thr Pro Gly Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Gly Gln Ser Ile Tyr Asn Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Thr Leu Glu Ser Gly Val Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Ser Cys Gln Asn Asn Tyr Gly Ile Gly Ser

85 90 95

Asn Tyr Gly Pro Gly Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 837

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 837

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Leu Asn Ile Asn Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Ser Tyr Thr Ser Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Asn Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Thr Thr Thr Tyr Phe Gly Thr Asn

85 90 95

Gly Gly Gly Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105

<210> 838

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 838

Glu Leu Val Met Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Asn Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ala Glu Ser Asn Asp Val Trp

85 90 95

Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105

<210> 839

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 839

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Gly Val Gln Cys

65 70 75 80

Asp Asp Ala Ala Thr Tyr Tyr Ala Cys Gln Thr Thr Tyr Tyr Trp Thr Thr Thr

85 90 95

Asp Asp Asn Pro Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 840

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400>  840

Glu Leu Asp Leu Thr Gln Thr Pro Ser Ser Ser Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asn Lys

20 25 30

Asn Tyr Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

35 40 45

Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Val

65 70 75 80

Val Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Ala Tyr Lys Gly Val

85 90 95

Ser Asp Asp Gly Ile Ser Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 841

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 841

Glu Leu Asp Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Pro Ser Gly Val Pro Pro Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr His Ser Gly Ser

85 90 95

Ser Asn Gly Gly Gly Phe Ala Phe Gly Gly Gly Thr Gln Val Glu Ile

100 105 110

Lys

<210> 842

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 842

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Arg

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Tyr Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Arg Phe Lys Gly

50 55 60

Ser Gly Phe Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Gly Arg Asp Asn

85 90 95

Asn Asp Leu Phe Phe Ala Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 843

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 843

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Ala Ser Ser Thr Ala Ser Gly Val Pro Ser Arg Phe Lys

50 55 60

Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu

65 70 75 80

Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Tyr Ile Ser

85 90 95

Ser Lys Tyr Gly Ala Val Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys

100 105 110

<210> 844

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 844

Glu Leu Val Met Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Gln Ser Val Tyr Ser Asn

20 25 30

Asn Trp Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg

35 40 45

Leu Ile Tyr Lys Ala Ser Thr Leu Glu Thr Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Lys Gln Phe Thr Leu Thr Ile Ser Asp Leu

65 70 75 80

Glu Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Ser Gly

85 90 95

Asp Leu Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 845

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 845

Glu Leu Asp Met Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly

1 5 10 15

Gly Ser Val Thr Ile Ser Cys Gln Ala Ser Gln Thr Ile Tyr Asn Asn

20 25 30

Lys Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

35 40 45

Leu Ile Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Ser Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val

65 70 75 80

Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Glu Phe Ser Cys

85 90 95

Ser Ser Gly Asp Cys Thr Thr Phe Gly Gly Gly Thr Glu Val Val Val

100 105 110

Lys

<210> 846

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 846

Glu Leu Asp Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Tyr Ser Asn Phe Arg Val Asn

85 90 95

Asp Pro Ser Val Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 847

<211>  117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 847

Glu Leu Asp Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Gln Ser Val His His Ser

20 25 30

Gln Thr Val His Asn Asn Gln Trp Leu Ala Trp Tyr Gln Gln Lys Pro

35 40 45

Gly Gln Pro Pro Lys Leu Leu Ile Tyr Asp Ala Ser Lys Leu Ala Ser

50 55 60

Gly Val Pro Ser Arg Phe Thr Gly Ser Gly Ser Gly Thr Gln Phe Ser

65 70 75 80

Leu Thr Ile Ser Ala Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys

85 90 95

Gln Gly Gly Tyr Ser Tyr Gly Asp Val Tyr Gly Phe Gly Gly Gly Thr

100 105 110

Glu Leu Glu Ile Lys

115

<210> 848

<211>  114

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 848

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Thr Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Asp Asn Asn

20 25 30

Lys Gln Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln

35 40 45

Leu Ile Tyr Ser Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu

65 70 75 80

Glu Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Tyr Tyr Tyr Tyr Ser

85 90 95

Gly Ser Ala Thr Asp Ala Trp Ala Phe Gly Gly Ala Thr Glu Val Glu

100 105 110

Ile Asn

<210> 849

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 849

Glu Leu Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly

1 5 10 15

Asp Thr Leu Thr Ile Asn Cys Gln Ala Ser Glu Thr Ile Ser Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Arg Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Ile Arg Ser Ser Ser Gly

85 90 95

Val Val His Pro Asn Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 850

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 850

Glu Leu Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Thr Ile Tyr Thr Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Ser Thr

85 90 95

Thr Gly Asn Gly Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 851

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 851

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Lys Ser Val Ala Val Gly

1 5 10 15

Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Asp Asn Val Tyr Ser Asn

20 25 30

Asn Tyr Thr Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln

35 40 45

Leu Leu Tyr Tyr Ala Ala Tyr Arg Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Asp Val

65 70 75 80

Val Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ser Gly His Lys Asp Tyr

85 90 95

Ser Asp Asp Gly Ser Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 852

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 852

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Lys Ser Val Ala Val Gly

1 5 10 15

Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Asp Asn Val Tyr Ser Asn

20 25 30

Asn Tyr Thr Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln

35 40 45

Leu Leu Tyr Tyr Ala Ala Tyr Arg Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Asp Val

65 70 75 80

Val Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ser Gly His Lys Asp Tyr

85 90 95

Ser Asp Asp Gly Ser Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 853

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 853

Glu Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Ser Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Met Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Ala Tyr Tyr Gly Ser Ser

85 90 95

Tyr Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105

<210> 854

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 854

Glu Leu Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Ser Asn Glu

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Leu Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser His Tyr Tyr Gly Gly Ser

85 90 95

Ser Asp Tyr Gly Trp Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 855

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 855

Glu Leu Asp Met Thr Gln Thr Pro Ser Ser Thr Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Val Tyr Asn Asn

20 25 30

Asn Gln Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg

35 40 45

Leu Ile Tyr Gly Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu

65 70 75 80

Glu Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Ala Val Ser Ser

85 90 95

Asp Tyr Tyr Pro Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 856

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 856

Glu Leu Asp Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ala

35 40 45

Phe Tyr Ala Ser Thr Leu Lys Ser Gly Val Pro Pro Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Asn Arg Leu Ser Ser Ser

85 90 95

Asp Val Asn Ala Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 857

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 857

Glu Leu Val Leu Thr Gln Thr Ala Ser Pro Val Ser Gly Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Tyr Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Gly Val Gln Cys

65 70 75 80

Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Tyr Thr Ala Ser

85 90 95

Ala Asp Thr Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 858

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 858

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ser Ser Gly Val Ser Ser Arg Tyr Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Tyr Thr Ser Tyr Ser Ser Gly

85 90 95

Gly Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105

<210> 859

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 859

Glu Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Gln Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr His Ser Gly Ser

85 90 95

Ser Asn Gly Gly Gly Phe Ala Phe Gly Gly Gly Thr Glu Val Glu Ile

100 105 110

Lys

<210> 860

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 860

Glu Leu Asp Met Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Thr Ile Tyr Thr Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Ser Thr

85 90 95

Thr Gly Asn Gly Phe Gly Gly Gly Thr Glu Val Glu Ile Asn

100 105 110

<210> 861

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 861

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Lys Ser Val Ala Val Gly

1 5 10 15

Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Val Tyr Gly Asn

20 25 30

Asn Arg Cys Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

35 40 45

Leu Ile Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val

65 70 75 80

Val Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Gly His Lys Gly Thr

85 90 95

Thr Asn Asp Gly Asn Asp Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 862

<211>  111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 862

Glu Leu Asp Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Thr Asn Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Cys Ser Tyr Tyr Gly Ser Thr

85 90 95

Tyr Phe Gly Ser Pro Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 863

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 863

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Val Ser Glu Pro Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Phe Leu

35 40 45

Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys

50 55 60

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu

65 70 75 80

Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Tyr Ile Ser

85 90 95

Ser Asn Tyr Gly Ala Ala Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105 110

<210> 864

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 864

Glu Leu Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Asn Tyr Trp Ser Asn

85 90 95

Gly Asn His Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105

<210> 865

<211>  112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 865

Glu Leu Val Leu Thr Gln Thr Pro Ser Ser Lys Ser Val Ala Val Gly

1 5 10 15

Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Asn Val Tyr Ser Asn

20 25 30

Asn Tyr Thr Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln

35 40 45

Leu Leu Tyr Tyr Ala Ala Tyr Arg Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Lys Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Asp Val

65 70 75 80

Val Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ser Gly His Lys Asp Tyr

85 90 95

Ser Asp Asp Gly Ser Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 866

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 866

Glu Leu Asp Leu Thr Gln Thr Ala Ser Pro Val Ser Gly Ala Val Gly

1 5 10 15

Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ala Ser Asp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys

65 70 75 80

Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Ser Thr

85 90 95

Thr Gly Asn Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys

100 105 110

<210> 867

<211>  110

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibody sequence

<400> 867

Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Thr Ile Tyr Thr Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Ser Thr

85 90 95

Thr Gly Asn Gly Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 868

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 868

His Ile Ile Thr Asn Tyr

1 5

<210> 869

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 869

Asp Ala Ser

1

<210> 870

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 870

Gln Asn Tyr Leu Tyr Phe Ser Ser Gly Asp Trp Asn Val

1 5 10

<210> 871

<211> 384

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 871

gaagtgcagc tggtggagag cggcggcggt ctggtacaac cgggcggcag cctgagactg 60

agctgcgccg ctagcggctt cagcttcagc agcagctact gcatgtgctg ggtgagacaa 120

gcccccggca aggggcctgga gtgggtgagc tgcatctaca ccgacagcag cggcgccacc 180

tactacgcta gctgggccaa gggcagattc accatcagca gacacaacag caagaacacc 240

ctgtacctgc agatgaacag cctgagagcc gaggacaccg ccgtgtacta ctgcgctaga 300

ggctgggact acgaggaccc cggctacacc gacaccacct acttcagcct gtggggcaga 360

ggcaccctgg tgaccgtgag cagc 384

<210> 872

<211> 384

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 872

gaagtgcagc tggtggagag cggcggcggt ctggtacaac cgggcggcag cctgagactg 60

agctgcgccg ctagcggctt cagcttcagc agcagctact gcatgtgctg ggtgagacaa 120

gcccccggca aggggcctgga gctggtgagc tgcatctaca ccgacagcag cggcgccacc 180

tactacgcta gctgggccaa gggcagattc accatcagca gacacaacag caagaacacc 240

ctgtacctgc agatgaacag cctgagagcc gaggacaccg ccgtgtacta ctgcgctaga 300

ggctgggact acgaggaccc cggctacacc gacaccacct acttcagcct gtggggcaga 360

ggcaccctgg tgaccgtgag cagc 384

<210> 873

<211> 384

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 873

gaagtgcagc tggtggagag cggcggcggt ctggtacaac cgggcggcag cctgagactg 60

agctgcgccg ctagcggctt cagcttcagc agcagctaca gcatgagctg ggtgagacaa 120

gcccccggca aggggcctgga gtgggtgagc agcatctaca ccgacagcag cggcgccacc 180

tactacgcta gctgggccaa gggcagattc accatcagca gacacaacag caagaacacc 240

ctgtacctgc agatgaacag cctgagagcc gaggacaccg ccgtgtacta ctgcgctaga 300

ggctgggact acgaggaccc cggctacacc gacaccacct acttcagcct gtggggcaga 360

ggcaccctgg tgaccgtgag cagc 384

<210> 874

<211> 128

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 874

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Ser

20 25 30

Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Val Ser Ser Ile Tyr Thr Asp Ser Ser Gly Ala Thr Tyr Tyr Ala Ser

50 55 60

Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Gly Trp Asp Tyr Glu Asp Pro Gly Tyr Thr Asp Thr

100 105 110

Thr Tyr Phe Ser Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 875

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic antibodies

<400> 875

gacattcagc tgacacagag ccctagcttc ctgagcgcta gcgtgggcga cagagtgacc 60

atcacctgcc aagcctctca gaccatctac accaacctgg cctggtatca gcagaagccc 120

ggcaaagccc ccaagctgct gatatacgcc gctagcaccc tggcgagcgg cgtgcctagc 180

agattcagcg gcagcggcag cggcaccgag ttcaccctga ccatcagcag cctgcagccc 240

gaggacttcg ccacctacta ctgtcagagc tactacggca gcagcaccac cggcaacggc 300

ttcggcggcg gcaccaaggt ggagatcaag 330

Claims (72)

1. An isolated monoclonal antibody or an antigen-binding fragment thereof, said isolated monoclonal antibody or antigen-binding fragment thereof comprising: a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL), said VH and said VL comprising clonal-paired CDR sequences as shown in Tables 1 and 3; and variants thereof, wherein one or more of the HC-CDR and/or LC-CDR have one, two or three amino acid substitutions, additions, deletions or combinations thereof. 2. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the isolated monoclonal antibody is a mouse antibody, rodent antibody, rabbit antibody, chimeric antibody, humanized antibody or human antibody. 3. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the antigen-binding fragment is a recombinant ScFv (single-chain variable fragment) antibody, a Fab fragment, an F(ab')2 fragment, or an Fv fragment. 4. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the isolated monoclonal antibody is a human antibody. 5. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the VH chain and VL chain have amino acid sequences that are at least 90% or 95% identical to the sequences paired with the clones in Tables 6 and 8, respectively. 6. The isolated monoclonal antibody or its antigen-binding fragment according to claim 5, wherein the VH chain and VL chain have the same amino acid sequences as the clones paired in Tables 6 and 8, respectively. 7. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the VH chain and VL chain are encoded by nucleic acid sequences that are at least 80% or 90% identical to the sequences paired with the clones in Tables 5 and 7, respectively. 8. The isolated monoclonal antibody or its antigen-binding fragment according to claim 7, wherein the VH chain and VL chain are encoded by nucleic acid sequences identical to those paired with the clones in Tables 5 and 7, respectively. 9. The isolated monoclonal antibody or its antigen-binding fragment according to any one of claims 1 to 8, wherein the isolated monoclonal antibody is a humanized antibody. 10. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 9, wherein the humanized antibody has a VH chain and a VL chain, the VH chain and the VL chain having an amino acid sequence that is at least 90% or 95% identical to the clones of Hu-176 VH-1 and Hu-176-K as shown in Tables 6 and 8, respectively. 11. The isolated monoclonal antibody or its antigen-binding fragment according to claim 10, wherein the VH chain and the VL chain have the same amino acid sequences as the clones of Hu-176 VH-1 and Hu-176-K shown in Tables 6 and 8, respectively. 12. The isolated monoclonal antibody or its antigen-binding fragment according to claim 9, wherein the humanized antibody has a VH chain and a VL chain, the VH chain and the VL chain having an amino acid sequence that is at least 90% or 95% identical to the clones of Hu-176 VH-1 (W48L) and Hu-176-K as shown in Tables 6 and 8, respectively. 13. The isolated monoclonal antibody or its antigen-binding fragment according to claim 10, wherein the VH chain and the VL chain have the same amino acid sequences as the clones of Hu-176 VH-1 (W48L) and Hu-176-K shown in Tables 6 and 8, respectively. 14. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 13, comprising an IgG Fc region, said IgG Fc region comprising amino acid modifications at one or more amino acid positions of amino acid positions 234, 235, 297 and 329. 15. The isolated monoclonal antibody or its antigen-binding fragment according to claim 14, wherein the IgG Fc region includes an amino acid substitution of N for A at amino acid position 297. 16. The isolated monoclonal antibody or its antigen-binding fragment according to claim 14, wherein the IgG Fc region includes an amino acid substitution at amino acid position 234 where L is changed to A, an amino acid substitution at amino acid position 235 where L is changed to A, and an amino acid substitution at amino acid position 329 where P is changed to G. 17. The isolated monoclonal antibody or its antigen-binding fragment according to any one of claims 1 to 16, wherein the antibody is a chimeric antibody. 18. The isolated monoclonal antibody or its antigen-binding fragment according to any one of claims 1 to 16, wherein the isolated monoclonal antibody or its antigen-binding fragment induces activation of LILRB1. 19. The isolated monoclonal antibody or its antigen-binding fragment according to any one of claims 1 to 16, wherein the isolated monoclonal antibody or its antigen-binding fragment inhibits the activation of LILRB1. 20. An isolated monoclonal antibody or an antigen-binding fragment thereof, said isolated monoclonal antibody or an antigen-binding fragment thereof competing with an isolated monoclonal antibody or an antigen-binding fragment thereof according to any one of claims 1 to 19 for binding to the same epitope. 21. An isolated monoclonal antibody or an antigen-binding fragment thereof, said isolated monoclonal antibody or an antigen-binding fragment thereof binding to an epitope on LILRB1 recognized by an antibody according to any one of claims 1 to 20. 22. An isolated monoclonal antibody or an antigen-binding fragment thereof, wherein when bound to LILRB1, the monoclonal antibody binds to residues Y76 and R84 of LILRB1. 23. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 22, wherein the antibody or fragment thereof is conjugated or fused with an imaging agent or a cytotoxic agent. 24. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 22, wherein the antibody or fragment thereof is labeled. 25. The isolated monoclonal antibody or its antigen-binding fragment according to claim 24, wherein the labeling is fluorescent labeling, enzyme-catalyzed labeling or radioactive labeling. 26. A pharmaceutical composition comprising an isolated monoclonal antibody or an antigen-binding fragment thereof according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier. 27. An isolated nucleic acid encoding an isolated monoclonal antibody according to any one of claims 1 to 22. 28. A vector comprising the isolated nucleic acid according to claim 27. 29. A host cell comprising the vector according to claim 28. 30. The host cell of claim 29, wherein the host cell is a mammalian cell. 31. The host cell according to claim 29, wherein the host cell is a CHO cell. 32. A hybridoma or engineered cell that encodes and/or produces an isolated monoclonal antibody according to any one of claims 1 to 22. 33. A method for producing an antibody, the method comprising culturing a host cell according to claim 29 under conditions suitable for expressing the antibody and recovering the antibody. 34. A chimeric antigen receptor (CAR) protein comprising an antigen-binding fragment according to any one of claims 1 to 22. 35. An isolated nucleic acid encoding the CAR protein according to claim 34. 36. A vector comprising the isolated nucleic acid according to claim 35. 37. An engineered cell comprising the isolated nucleic acid according to claim 35. 38. The engineered cell of claim 37, wherein the cell is a T cell, NK cell, or macrophage. 39. A method of treating a subject's cancer or improving the effect of treating a subject's cancer, the method comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 22 or engineered cells according to claim 37 or 38. 40. The method of claim 39, wherein the method reduces or eradicates the tumor burden of the subject. 41. The method of claim 39, wherein the method reduces the number of tumor cells. 42. The method of claim 39, wherein the method reduces tumor size. 43. The method of claim 39, wherein the method reduces or prevents tumor metastasis. 44. The method of claim 39, wherein the method eradicates the tumor of the subject. 45. The method of claim 39, wherein the subject's NK cells have been identified as expressing LILRB1. 46. The method of claim 45, wherein the subject's NK cells have been identified as expressing an increased level of LILRB1 relative to a reference level. 47. The method of claim 39, wherein the cancer is a solid cancer. 48. The method of claim 47, wherein the solid cancer is selected from the group consisting of: adrenal cancer, bile duct cancer, bone cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, esophageal cancer, eye cancer, gastric cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, melanoma, Merkel cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pineal tumor, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma, skin cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, and vaginal cancer. 49. The method of claim 39, wherein the target is a monocyte, macrophage, dendritic cell, neutrophil and other myeloid cells, myeloid-derived suppressor cells and tumor-associated macrophages. 50. The method of claim 39, wherein the cancer is a malignant hematologic malignancy. 51. The method of claim 50, wherein the hematologic malignancy is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell leukemia, chronic lymphocytic leukemia (CLL), blastic plasmacytoid dendritic cell vegetations (BPDCN), chronic myeloid monocytic leukemia (CMML), chronic myeloid leukemia (CML), pre-B acute lymphoblastic leukemia (pre-B ALL), diffuse large B-cell leukemia, etc. Large cell lymphoma (DLBCL), extranodal NK/T cell lymphoma, hairy cell leukemia, heavy chain disease, HHV8-associated primary exudative lymphoma, plasmablastic lymphoma, primary CNS lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histocyte-rich B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, multiple myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative vegetations, and polycythemia vera. 52. The method of claim 51, wherein the subject's myeloma cells have been identified as not expressing LILRB1. 53. The method of claim 39, wherein the antibody or its antigen-binding fragment is administered intravenously, intra-arterially, intratumorally, or subcutaneously. 54. The method of claim 39, further comprising administering to the subject one or more drugs selected from the group consisting of: topoisomerase inhibitors, anthracycline topoisomerase inhibitors, anthracycline, daunorubicin, nucleoside metabolism inhibitors, cytarabine, hypomethylating agents, low-dose cytarabine (LDAC), combinations of daunorubicin and cytarabine, liposomes of daunorubicin and cytarabine for injection, azacytidine, decitabine, all-trans retinoic acid (ATRA), arsenic, arsenic trioxide, histamine dihydrochloride, interleukin-2, aldehyde-interleukin, gemtuzumab, FLT-3 inhibitors, midostaurin, clofarabine, farnesyltransferase inhibitors, decitabine, IDH1 inhibitors, evanixib, IDH2 inhibitors, etanercept, smoothing agent (SMO) inhibitors, graziab, arginase inhibitors, IDO inhibitors, icardolstat, BC L-2 inhibitors, venetotok, platinum complex derivatives, oxaliplatin, kinase inhibitors, tyrosine kinase inhibitors, PI3 kinase inhibitors, BTK inhibitors, ibrutinib, acalatinib, zanubrutinib, PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, LAG3 antibodies, ICOS antibodies, TIGIT antibodies, TIM3 antibodies, CD40 antibodies, 4-1BB antibodies, CD47 antibodies, SIRP1α antibodies or fusion proteins, CD70 and CLL1 antibodies, CD123 antibodies, E-selectin antagonists, antibodies binding to tumor antigens, antibodies binding to T cell surface markers, antibodies binding to myeloid or NK cell surface markers, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, hormone therapy drugs, hormone antagonists, aromatase inhibitors, and P-glycoprotein inhibitors. 55. The method according to any one of claims 39 to 54, wherein the isolated monoclonal antibody or its antigen-binding fragment further comprises an antitumor drug linked thereto. 56. The method of claim 55, wherein the antitumor drug is linked to the antibody via a photostable connector. 57. The method of claim 55, wherein the antitumor drug is linked to the antibody via an enzymatically cleaved linker. 58. The method of claim 55, wherein the antitumor drug is a toxin, a radioactive isotope, a cytokine, or an enzyme. 59. A method for detecting cancer cells or cancer stem cells in a sample or subject, the method comprising: (a) Contacting a subject or a sample from said subject with an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 25; and (b) Detect the binding of the antibody to cancer cells or cancer stem cells in the subject or sample. 60. The method of claim 59, wherein the sample is a body fluid or a biopsy. 61. The method of claim 59, wherein the sample is blood, bone marrow, sputum, tears, saliva, mucus, serum, urine, or feces. 62. The method of claim 59, wherein the detection includes immunohistochemistry, flow cytometry, immunoassay (including ELISA, RIA, etc.) or Western blotting. 63. The method of claim 59, further comprising: performing steps (a) and (b) a second time; and determining the change in detection level compared to the first time. 64. The method of claim 59, wherein the isolated monoclonal antibody or its antigen-binding fragment further comprises a label. 65. The method of claim 64, wherein the label is a peptide tag, enzyme, magnetic particle, chromophore, fluorescent molecule, chemiluminescent molecule, or dye. 66. The method according to any one of claims 39 to 65, wherein the isolated monoclonal antibody or its antigen-binding fragment is conjugated to liposomes or nanoparticles. 67. A method for treating an autoimmune disease in a subject or for improving an autoimmune disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 22 or engineered cells according to claim 37 or 38. 68. The method of claim 67, wherein the target is a monocyte, macrophage, dendritic cell, neutrophil, and/or other myeloid cell. 69. The method of claim 67, wherein the antibody or its antigen-binding fragment is administered intravenously, intra-arterially, intratumorally, or subcutaneously. 70. The method of claim 67, further comprising administering to the subject one or more drugs selected from the group consisting of steroids or NSAIDs. 71. The method of claim 67, wherein the autoimmune disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis, reactive arthritis, undifferentiated spondyloarthropathy, juvenile spondyloarthropathy, Behcet's disease, tendonitis, ulcerative colitis, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, fibromyalgia, chronic fatigue syndrome, pain symptoms associated with systemic inflammatory diseases, systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, or juvenile epoch-forming diabetes mellitus. Also known as type 1 diabetes, Wegener's granulomatosis, polymyositis, dermatomyositis, inclusion body myositis, multiple endocrine failure, Schmidt's syndrome, autoimmune uveitis, Addison's disease, Graves' disease, Hashimoto's thyroiditis, autoimmune thyroid disease, pernicious anemia, gastric atrophy, chronic hepatitis, lupus hepatitis, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis, hypoparathyroidism, Deslese syndrome, myasthenia gravis, Eaton-Lambert syndrome, autoimmune thrombocytopenic purpura, hemolytic anemia, pemphigus vulgaris, etc. Herpes, herpetic dermatitis, alopecia, scleroderma, progressive systemic sclerosis, CREST syndrome (calcification, Raynaud's phenomenon, esophageal motility disorder, finger sclerosis and telangiectasia), adult-onset diabetes mellitus (also known as type II diabetes), mixed connective tissue disease, polyarteritis nodosa, systemic necrotizing vasculitis, glomerulonephritis, atopic dermatitis, atopic rhinitis, Goodpassch syndrome, Chagas disease, sarcoidosis, rheumatic fever, asthma, antiphospholipid syndrome, erythema multiforme, Cushing's syndrome, autoimmune chronic active hepatitis, allergic diseases, allergic encephalomyelitis, transfusion reaction Leprosy, malaria, leishmaniasis, trypanosomiasis, Goran's arteritis, polymyalgia rheumatica, temporal arteritis, schistosomiasis, giant cell arteritis, eczema, lymphomatoid granulomatosis, Kawasaki disease, endophthalmitis, psoriasis, fetal erythroblastosis, eosinophilic fasciitis, Shulman syndrome, Felty's syndrome, Fuchs' cyclitis, IgA nephropathy, Henlein-Schönlein purpura, graft-versus-host disease, transplant rejection, tularemia, periodic fever syndrome, septic arthritis, familial Mediterranean fever, TNF receptor-associated periodic syndrome (TRAPS), Mueller-Weil syndrome, or high IgD syndrome. 72. A method for enhancing the immune function of NK cells in a subject, the method comprising administering to the subject an antibody or antigen-binding fragment thereof according to any one of claims 1 to 22 or engineered cells according to claim 37 or 38.