CN116997354A - Monoclonal antibodies against LILRB1 for diagnostic and therapeutic use - Google Patents

Abstract

Provided herein are antibodies that bind to LILRB1 and uses of the antibodies in the detection and treatment of cancer and autoimmune diseases.

Description

Monoclonal antibodies against LILRB1 for diagnostic and therapeutic use

Priority ofRights statement

The present application claims priority from U.S. provisional application Ser. Nos. 63/057,601 and 63/124,516, filed on 7, 28 and 11, 2020, 12, respectively, the entire contents of both applications being hereby incorporated by reference.

Reference to sequence Listing

The present application contains a sequence listing that has been submitted via EFS-Web in ASCII format and is hereby incorporated by reference in its entirety. The ASCII text created at month 7 and 23 of 2021 is named utfh_p0370wo_st25.Txt and is 319 kilobytes in size.

Technical Field

The present disclosure relates generally to the fields of medicine, oncology, immunology, and immunooncology. More specifically, the disclosure relates to agonistic and antagonistic antibodies that bind to LILRB1 and methods of using the agonistic and antagonistic antibodies.

Background

NK cells play a key role in anti-cancer immunity, and the function of the NK cells against cancer cells can be enhanced by engaging activating receptors or blocking inhibitory receptors 1. In activating receptors, fcγriii (CD 16) plays a key role in therapeutic monoclonal antibody-induced antibody-dependent cytotoxicity (ADCC), for the treatment of hematological malignancies (rituximab for lymphoma and dacemamectin for multiple myeloma (daratumumab)) and metastatic solid cancers (cetuximab and trastuzumab) ^{2 3} . Antibodies that bind to activating receptors such as NKG2D and NKp46 have also been shown to have NK-dependent tumor immunity in preclinical studies ^{4 5} . Importantly, it has also been demonstrated that antibodies blocking inhibitory receptors on NK cells such as KIR and NKG2A can enhance the function of NK cells against cancer cells ^{6 7} . Thus, the development of antibodies targeting immune receptors on NK cells can provide a novel cancer immunotherapy strategy.

LILRB1, a receptor containing ITIM, is expressed on a variety of human immune cells. This includes all B cells, monocytes and macrophages, DCs, and NK cells and T cells sub-A group. LILRB1 ligand comprising MHC class I molecules activates LILRB1 and transduces a negative signal down-regulating immune response ⁸ . LILRB1 for patients with advanced prostate and breast cancer ⁺ NK cell percentage is significantly higher than LILRB1 in healthy donors or patients with localized cancer ⁺ Percentage of NK cells ^9-11 . Blocking LILRB1 signaling in immune cells can activate NK cells' activity against solid tumors and leukemia using in vitro models ^{10 12} And activating T cells or macrophages against solid tumors ^13-15 . However, it is not clear whether LILRB1 can be targeted to "turn on" immune cells in vivo for cancer treatment. In addition, it has also been reported that LILRB1 is expressed on some tumor cells and stimulates an immune response ^{16 17} . Thus, it is not clear that the net result of blocking LILRB1 signaling to tumor cells and immune cells is to activate or suppress an anti-tumor immune response.

Disclosure of Invention

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

In one aspect, the isolated monoclonal antibody or antigen binding fragment thereof comprises: a Heavy Chain (HC) variable region (VH) and a Light Chain (LC) variable region (VL), the VH and the VL comprising CDR sequences of clone pairs 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 antigen binding fragment thereof may be a murine antibody, a rodent antibody, a rabbit antibody, a chimeric antibody, a humanized antibody or a human antibody. The isolated monoclonal antibody or antigen-binding fragment thereof may have a VH chain and a VL chain having amino acid sequences at least 90% or 95% identical to the sequences paired with the clones of tables 6 and 8, respectively. The isolated monoclonal antibody or antigen-binding fragment thereof may have a VH chain and a VL chain encoded by nucleic acid sequences at least 80% or 90% identical to the sequences paired with the clones of tables 5 and 7, respectively. The isolated monoclonal antibody or antigen-binding fragment thereof may have a VH chain and a VL chain having amino acid sequences identical to the sequences paired with the clones of tables 6 and 8, respectively. The isolated monoclonal antibody or antigen-binding fragment thereof may have a VH chain and a VL chain encoded by nucleic acid sequences identical to the sequences paired with the clones of tables 5 and 7, respectively.

The variant may be one in which one or more of the HC-CDRs or LC-CDRs have one, two or three amino acid substitutions, additions, deletions or combinations thereof. In certain embodiments, each CDR is defined according to Kabat definition, chothia definition, a combination of Kabat definition and Chothia definition, abM definition, or contact definition of the CDR.

In certain embodiments, the isolated monoclonal antibodies described herein are chimeric, humanized or human antibodies. In certain aspects, the humanized antibody has a VH chain and a VL chain having amino acid sequences at least 90% or 95% identical to the sequences of clone pairs of Hu-176 VH-1 and Hu-176-K as shown in tables 6 and 8, respectively. In certain aspects, the VH and VL chains have amino acid sequences identical to the sequences of clone pairs of Hu-176 VH-1 and Hu-176-K as shown in tables 6 and 8, respectively. In certain aspects, the humanized antibody has a VH chain and a VL chain having amino acid sequences at least 90% or 95% identical to the sequences of clone-paired Hu-176 VH-1 (W48L) and Hu-176-K, respectively, as shown in tables 6 and 8. In certain aspects, the VH chain and the VL chain have amino acid sequences identical to the sequences of clone pairs of Hu-176 VH-1 (W48L) and Hu-176-K as shown in tables 6 and 8, respectively.

In certain aspects, the isolated monoclonal antibodies described herein comprise amino acid modifications in the IgG Fc region. In certain aspects, the IgG Fc region comprises amino acid modifications in one or more of amino acid positions 234, 235, 297 and 329. In some aspects, the IgG Fc region comprises an amino acid substitution N to a at amino acid position 297. In some aspects, the IgG Fc region comprises an amino acid substitution L at amino acid position 234 to a, an amino acid substitution L at amino acid position 235 to a, and an amino acid substitution P at amino acid position 329 to G.

In another aspect, the present disclosure provides an isolated monoclonal antibody or antigen-binding fragment thereof that competes for the same epitope with an antibody having the heavy chain CDR amino acid sequences and the light chain CDR amino acid sequences from the clone-paired tables 1 and 3. In certain embodiments, the epitope bound by the antibody or antigen binding fragment is located in the linker region between the D1 domain and the D2 domain of human LILRB 1. In certain embodiments, the disclosure provides an isolated monoclonal antibody, or antigen binding fragment thereof, wherein the monoclonal antibody, when bound to LILRB1, binds to residues Y76 and R84 of LILRB 1.

In certain embodiments, the isolated monoclonal antibodies described herein are of the IgG1 type, igG2 type, igG3 type, or IgG4 type. In certain embodiments, the antigen binding fragments described herein are recombinant ScFv (single chain fragment variable) antibodies, fab fragments, F (ab') 2 fragments, or Fv fragments.

In certain aspects, an isolated monoclonal antibody or antigen binding fragment thereof described herein is conjugated or fused to an imaging agent or a cytotoxic agent. In certain aspects, the isolated monoclonal antibodies described herein, or antigen-binding fragments thereof, are labeled with, for example, a fluorescent label, an enzymatic label, or a radiolabel.

In another aspect, a pharmaceutical composition is provided comprising an isolated monoclonal antibody or antigen-binding fragment thereof as provided herein and at least one pharmaceutically acceptable carrier.

In another aspect, there is provided an isolated nucleic acid encoding the isolated monoclonal antibody or antigen binding fragment thereof as provided herein.

In another aspect, there is provided a vector comprising the isolated nucleic acid as provided herein.

In another aspect, there is provided a host cell comprising the vector as provided herein. The host cell may be a mammalian cell. The host cell may be a CHO cell.

In another aspect, there is provided a hybridoma encoding or producing the isolated monoclonal antibody as provided herein.

In another aspect, a method of producing an antibody is provided. The method may comprise culturing the host cell as provided herein under conditions suitable for expression of the antibody and recovery of the antibody.

In another aspect, there is provided a Chimeric Antigen Receptor (CAR) protein comprising an antigen binding fragment as provided herein.

In another aspect, an isolated nucleic acid encoding a CAR protein as provided herein is provided.

In another aspect, there is provided an engineered cell comprising the isolated nucleic acid as provided herein. In certain embodiments, the cell is a T cell, NK cell, or myeloid cell.

In another aspect, there is provided a method of treating cancer in a subject or ameliorating the effects of cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof as defined herein.

The method can reduce or eradicate the tumor burden in the subject, can reduce the number of tumor cells, can reduce tumor size, can reduce tumor infiltration, can reduce tumor metastasis, can eradicate the tumor in the subject. The cancer may be a solid tumor or a hematological malignancy.

In certain embodiments, the cancer is a solid tumor comprising: adrenal gland 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, merck cell carcinoma (merkel cell cancer), nasopharyngeal cancer, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pineal tumor, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma, skin cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, and vaginal cancer.

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

In some embodiments, the cancer is a hematological malignancy comprising: acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), B-cell leukemia, blast Plasmacytoid Dendritic Cell Neoplasm (BPDCN), chronic Lymphocytic Leukemia (CLL), chronic myelomonocytic leukemia (CMML), chronic Myelogenous Leukemia (CML), pre-B acute lymphoblastic leukemia (pre-B ALL), diffuse large B-cell lymphoma (DLBCL), extranodal NK/T-cell lymphoma, hairy cell leukemia, HHV 8-associated primary exudative lymphoma, plasmablastoid lymphoma, primary CNS lymphoma, primary mediastinal large B-cell lymphoma, T-cell/tissue cell enriched B-cell lymphoma, heavy chain disease, hodgkin's lymphoma, non-Hodgkin's lymphoma, waldenstrom's lymphoma, multiple myeloma, polycythemia, and myelodysplasia.

The antibody or antigen binding fragment thereof may be administered intravenously, intraarterially, intratumorally, or subcutaneously.

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

In certain embodiments, the method may further comprise administering to the subject one or more drugs selected from the group consisting of: topoisomerase inhibitors, anthracycline topoisomerase inhibitors, anthracyclines (anthracyclines), daunorubicins (daunorubicins), nucleoside metabolism inhibitors, cytarabine, hypomethylating agents, low dose cytarabine (LDAC), combinations of daunorubicin and cytarabine, daunorubicin and cytarabine liposomes for injection,Azacytidine, (-) -and>decitabine, all-trans retinoic acid (ATRA), arsenic trioxide, histamine dihydrochloride,/-histamine dihydrochloride >Interleukin-2 (interlukin-2), aldeslukin (aldeslukin)>Gemtuzumab (gemtuzumab ozogamicin),>FLT-3 inhibitors, midostaurin (midostaurin),Clofarabine, farnesyl transferase inhibitor (farnesyl transferase inhibitor), decitabine, IDH1 inhibitor, ai Funi cloth (ivosidenib), and->IDH2 inhibitor, etanercept (enastinib), and->Smooth (SMO) inhibitors, glasegib (glasegib), arginase inhibitors, IDO inhibitors, ai Kaduo stat (epacoadostat), BCL-2 inhibitors, valnetoclax (vennetoclax), and the like>Platinum complex derivatives, oxaliplatin, kinase inhibitors, tyrosine kinase inhibitors, PI3 kinase inhibitors, BTK inhibitors, ibrutinib and/or _ for use in the treatment of cancer>Acartinib (acalabrutinib),Zanbutinib (zanubutinib), PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, LAG3 antibodies, ICOS antibodies, TIGIT antibodies, TIM3 antibodies, CD40 antibodies, 4-1BB antibodies, CD47 antibodies, SIRP1 alpha antibodies or fusion proteins, CD70 antibodies and CLL1 antibodies, CD123 antibodies, antagonists of E-selectin, antibodies that bind to tumor antigens, antibodies that bind to T cell surface markers, antibodies that bind to myeloid cells or NK cell surface markers, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, plant-derived alkaloids, hormone therapy drugs, hormone antagonists, aromatase inhibitors and P-glycoprotein inhibitors.

The isolated monoclonal antibody or antigen binding fragment thereof may include an anti-tumor agent linked thereto. The anti-neoplastic agent may be linked to the antibody through a photolabile linker. The anti-neoplastic agent may be linked to the antibody by an enzymatically cleavable linker. The antineoplastic agent may be a toxin, radioisotope, cytokine or enzyme.

In another embodiment, there is provided a method of detecting cancer cells or cancer stem cells in a sample or subject, the method comprising (a) contacting a subject or a sample from the subject with the antibody or antigen binding fragment thereof as defined herein; and (b) detecting binding of the antibody to a cancer cell or cancer stem cell in the subject or sample. The sample may be a body fluid or biopsy, or blood, bone marrow, sputum, tears, saliva, mucus, serum, urine, or stool. Detection may include immunohistochemistry, flow cytometry, immunoassays (including ELISA, RIA, etc.) or western blotting. The method may further comprise performing steps (a) and (b) a second time and determining a change in the detected level compared to the first time. The isolated monoclonal antibody or antigen binding fragment thereof may further comprise a label, such as a peptide tag, an enzyme, a magnetic particle, a chromophore, a fluorescent molecule, a chemiluminescent molecule, or a dye. The isolated monoclonal antibody or antigen binding fragment thereof may be conjugated to a liposome or nanoparticle.

In a further aspect, there is provided a method of treating or ameliorating the effects of an autoimmune disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof as defined herein. The antibody or antigen binding fragment thereof may be administered intravenously, intraarterially, intratumorally, or subcutaneously. The method may further comprise administering to the subject one or more drugs selected from the group consisting of a steroid or an NSAID. The autoimmune Disease may be Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis, reactive arthritis, undifferentiated spondyloarthropathies, juvenile spinal arthropathy, behcet's Disease, tendinitis, ulcerative colitis, crohn's Disease, irritable bowel syndrome, inflammatory bowel Disease, fibromyalgia, chronic fatigue syndrome, pain associated with systemic inflammatory diseases, systemic lupus erythematosus, sjogren's syndrome, rheumatoid arthritis, juvenile onset diabetes (also referred to as type I diabetes), crohn's Disease 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 (Hashimoto's Disease), autoimmune thyroid Disease, pernicious anaemia, gastric atrophy, chronic hepatitis, lupus hepatitis, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis, hypoparathyroidism, de-rette's syndrome (Dressler's syndrome), myasthenia gravis, eaton-Lambert syndrome (Eaton-Lambert syndrome), autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, pemphigus vulgaris, pemphigus, dermatitis herpetiformis, alopecia, scleroderma, progressive systemic sclerosis, CREST syndrome (calcaneosis, raynaud's phenomenon, oesophageal dyskinesia, digital end sclerosis and telangiectasia), adult onset diabetes (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 (Takayasu's arteritis), polymyalgia rheumatica, temporal arteritis, schistosomiasis, giant cell arteritis, eczema, lymphomatoid granulomatosis, kawasaki's disease, endophthalmitis, psoriasis, fetal erythroblastosis, eosinophilic fasciitis, schuman's syndrome (Shulman 'ssyndrome), fei Erdi's syndrome (Felty's syndrome), fuchs ciliary inflammation (Fuch's), igA nephropathy, henoch-Schonlein purpura), graft versus host disease, graft rejection, rabbit fever syndrome, suppurative arthritis, familial mediterranean fever, TNF receptor-related Periodic Syndrome (PS), musk-Wells syndrome or high IgD syndrome.

In another embodiment, provided herein is a method for increasing the immune function of NK cells of a subject, the method comprising administering to the subject an antibody or antigen-binding fragment thereof or an engineered cell as defined herein.

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

Drawings

The following drawings form a part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIGS. 1A-C: expression of LILRB1 on human peripheral blood NK cells. (FIG. 1A) PBMC were isolated from peripheral blood of buffy coats of healthy donors or patients with Multiple Myeloma (MM) or prostate cancer by density gradient centrifugation using Ficoll-Paque PLUS medium, and then stained with anti-CD 3-PE, anti-CD 56-FITC, anti-LILRB 1-APC or isotype APC antibodies. NK cell gating to SSC ^{Low and low} FSC ^{Low and low} CD56 ⁺ CD3-. LILRB1 expression on NK cells was gated according to isotype APC antibodies. Representative flow cytometry shows that LILRB1 is predominantly on CD56 ^{Dark and dark} Rather than CD56 ^Bright NK cells on expression. (fig. 1B) CD56 from healthy donors (n=12), patients with 2B or 2c stage prostate cancer (n=16) and patients with 3B or 3c stage prostate cancer (n=17) were determined by flow cytometry ^{Dark and dark} LILRB1 in NK cells ⁺ Percentage of NK cells. (fig. 1C) determination by flow cytometry of patients from healthy donors (as in fig. 1B) with newly diagnosed MM (n=10) and patients with MM with partial response or refractory disease to treatment (n=8) and treatmentLILRB1 for patients with MM with good response (cr+vgpr, n=9) ⁺ Percentage of NK cells. CR = complete remission, VGPR = very good partial remission. * P (P)<0.05；***P<0.001。

Fig. 2A-I: production and characterization of rabbit antagonistic anti-LILRB 1 mAb. (fig. 2A) left panel: k562 and K562 cells overexpressed by HLA-G1 (K562-HLA-G) were stained with an anti-HLA-G antibody (clone: MEM-G/9, ai Bokang company (Abcam)) for HLA-G expression on the surface and analyzed by flow cytometry. Right panel: k562 or K562-HLA-G was co-cultured with LILRB1 reporter cells. K562/K562-HLA-G cells were stained with DDAOSE prior to co-culture with LILRB1 reporter cells. The percentage of activated LILRB1 reporter cells (GFP) was analyzed by flow cytometry 24 hours after co-culture. (FIG. 2B) titers of antagonistic anti-LILRB 1 mAbs blocking K562-HLA-G stimulated LILRB1 reporter cell activation. LILRB1 reporter cells were co-cultured with K562-HLA-G and incubated with different concentrations of antagonistic anti-LILRB 1 mAb. (FIG. 2C) representative flow cytometry plots showing that B1-176 specifically bind LILRB 1. LILR reporter cells were incubated with 0.5 μg/mL rabbit B1-176 for 30 min at 4 ℃. The reporter cells were then incubated with anti-rabbit IgG PE antibodies (jackson laboratory (Jackson Laboratory)) and analyzed by flow cytometry. (FIG. 2D) binding specificity of B1-176 rabbit antibodies to LILRB and LILRA as determined by ELISA. (FIG. 2E) affinity for B1-176 by Octet RED 96. (FIG. 2F) screening B1-176 binding to LILRB1-Fc fusion proteins with different domain deletions by ELISA assay. (FIG. 2G) ability of B1-176 to bind to LILRB1-D1D2 Fc fusion proteins with different mutants as determined by ELISA (top panel). The two amino acids in LILRB1 (Y76 and R84) were identified as critical for binding of B1-176 (bottom panel). (FIG. 2H) detailed binding surfaces of rabbit mAbs B1-176 to LILRB1 were generated by molecular docking using Discovery Studio. (FIG. 2I) cross-reactivity of B1-176 and commercially available anti-LILRB 1 mAbs with LILR expressed on 2B4 cells, as obtained by flow cytometry.

Fig. 3A-D: anti-LILRB 1 blocks humanization of antibody 176. (FIG. 3A) the combined Kabat/IMGT/Chothia CDR-grafting strategy was used to humanize rabbit antibody 176. The heavy and light chains of rabbit antibody B1-176 are shown as Rab-176 VH, rab-176 VL, respectively. The heavy and light chains of the human antibody framework are shown as Hu IGHV3-53 x 04 and Hu IGKV1-9 x 01. Amino acids close to HCDR that differ from the original amino acids of the rabbit (shown in blue) are shown green. The heavy chain of B1-176 is humanized based on a human antibody framework, shown as Hu-176 VH-1 or Hu-176 VH-2 (W48L), with mutations marked with asterisks. The light chain of B1-176 is humanized based on a human antibody framework, shown as Hu-176 VL. (FIG. 3B) ELISA results show that the rabbit amino acid L48 (marked with an asterisk) in FR2 needs to be kept at the same position to keep the binding activity of humanized B1-176 to rabbit B1-176 the same. (FIG. 3C) molecular docking data shows that rabbit B1-176 is structurally similar to humanized Hu B1-176-N297A. (FIG. 3D) the affinity of the rabbit human chimeric anti-LILRB 1 antibody B1-176N 297A and the humanized anti-LILRB 1 antibody expressed in human IgG1 with N297A or LALALAPG mutation was determined by Octet RED96 or ELISA.

Fig. 4A-C: antagonistic LILRB1 mabs can block the activation of LILRB1 receptor cells stimulated by hematological cancers and solid tumor cell lines. (FIG. 4A) blood cancer cell lines (left panel) or solid cancer cell lines (right panel) were tested for MHC class I levels by flow cytometry using an anti-pan MHC class I antibody (clone: HP-1F7, st. KluyBiotechnology Co., ltd. (Santa Cruz Biotechnology)). Cancer cell lines (pre-stained with DDAOSE) were co-cultured with LILRB1 reporter cells to test the ability of the cancer cells to stimulate LILRB 1. Activated LILRB1 reporter cells (GFP ⁺ ) Is analyzed as a percentage of (c). (FIG. 4B) Rabbit B1-176 (left panel) and humanized Hu B1-176-N297A (right panel) can block blood cancer cell line-induced activation of LILRB1 receptor cells in a dose-dependent manner. The LILRB1 reporter cells were co-cultured with K562-HLA-G, the multiple myeloma cell line KMS27 or the pre-B leukemia cell line 697, followed by incubation with anti-LILRB 1 mAb. 24 hours after treatment, the activation of LILRB1 reporter cells was analyzed by flow cytometry. (FIG. 4C) rabbits B1-176 (left panel) and humanized Hu B1-176-N297A (right panel) were titrated to block activation of LILRB1 receptor cells by solid tumor cell lines. Will be LILRB1 reporterAs 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, followed by incubation with anti-LILRB 1 mAb. 24 hours after treatment, the activation of LILRB1 reporter cells was analyzed by flow cytometry.

Fig. 5A-F: antagonistic LILRB1 mAb can modulate the function of NKL cell lines against cancer cells in vitro. (fig. 5A) multiple myeloma cell line KMS27 was co-cultured with NKL and co-incubated with 10 μg/mL control human IgG (hIgG) or B1-176-N297A (left panel, n=3), hub 1-176-N297A (middle panel, n=3), and hub 1-176-LALAPG (right panel, n=2). After 4 hours, the cytotoxic activity of NKL on cancer cells was analyzed by flow cytometry. (FIG. 5B) multiple myeloma cell lines OPM2, RPMI8226 or acute T cell leukemia Jurkat cells were co-cultured with NKL and incubated with 10. Mu.g/mL B1-176-N297A or hIgG. n=3. (FIG. 5C) pre-B leukemia 697 cells (left panel) or Burkitt lymphoma Raji cells (right) were overexpressed with MICA (697-MICA, raji-MICA) and co-cultured with NKL. 10. Mu.g/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 MALM-3M were co-cultured with NKL and incubated with 10. Mu.g/mL B1-176-N297A or hIgG. n=3. (fig. 5F) KMS27, OPM2, RPMI8226, jurkat cells or 697/697MICA cells were co-cultured with NKL (E: T ratio = 1:1). 10 μg/mL control hIgG, B1-176-N297A (for RPMI8226, jurkat and 697/697 MICA) or HuB 1-176-N297A (for KMS27 and OPM2 treatments) was added to the cell culture. After 24 hours IFN-gamma levels in the cell culture supernatants were determined by ELISA. n=3-4, statistical significance between anti-LILRB 1 antibody and igg was analyzed. * P <0.05; * P <0.01; * P <0.001.

Fig. 6A-B: antagonistic LILRB1 mAb can increase the cytotoxic activity of primary NK cells on cancer cells in vitro. (FIG. 6A) sorting of multiple myeloma cell lines KMS27 and OPM2, pre-B leukemia cell line 697 or lymphoma cell lines Raji and Daudi cells with FACS-sorted LILRB1 isolated from PBMC of healthy donors ⁺ NK cellsCo-culturing. 10. Mu.g/mL control hIgG or B1-176N297A was added to the cell culture. n=3 except Daudi cells n=2. (fig. 6B) KMS27 cells were co-cultured with NK cells from one multiple myeloma patient (E: T ratio = 2.5:1) and incubated with 10 μg/mL control hIgG or hub 1-176-N297A. The cytotoxic activity of primary NK cells was analyzed by flow cytometry 4 hours after co-culture. n=3, P<0.001。

Fig. 7A-C: antagonistic LILRB1 mabs can increase the cytotoxic activity of NKL cells in vivo. (FIG. 7A) will be 5X 10 ⁶ CFSE stained 697 (NKL resistance) and 697MICA (NKL sensitivity) cell mixtures with 5×10 ⁷ Individual NKL cells were injected together into the abdominal cavity of NSG mice. Control hIgG or B1-176-N297A at 10mg/kg was injected retroorbital into mice. After 24 hours, peritoneal cells were harvested and stained with anti-MICA-APC antibody. The ratio of 697-MICA to 697 cells was quantified by flow cytometry and representative flow charts. The ratio of 697-MICA to 697 was used to calculate the cytotoxic activity of NKL cells in vivo. n=3-4, P <0.05. (FIG. 7B) 1X 10 ⁶ Cells overexpressing 697MICA luciferase (697 MICA-luci) and 5X 10 ⁶ Individual NKL cells were mixed and subcutaneously injected into NSG mice. A control hIgG or B1-176-N297A was administered retroorbital at 10 mg/kg. Bioluminescence imaging (BLI) was performed 48 hours later. Quantification of BLI data (total flux (p/s)) from two independent experiments showed that mice receiving B1-176-N297 showed significantly lower tumor burden compared to control hIgG treated mice, indicating that B1-176-N297 improved cytotoxic function in NKL cells. n=8-10, P<0.01. (FIG. 7C) NSG mice were sub-lethal irradiated and injected 5X 10 by tail vein on day 0 ⁵ KMS27 and 5X 10 over-expressing luciferase ⁶ Individual NKL cells. An additional 5×10 by tail vein injection on day 14 ⁶ Individual NKL cells were injected into NSG mice. Mice received 10mg/kg of control hIgG or B1-176-N297A retroorbital on day 0, day 3 and day 7, and then once a week for another month. BLI was performed on days 28 and 35. Summary BLI data shows that B1-176-N297 significantly reduced tumor progression in mice (left panel). n=4, number from one representative experimentAccording to the above. * P (P)<Statistical significance was calculated by single tail unpaired t test 0.05. Survival analysis of xenografts from multiple myeloma mice showed that B1-176-N297 treated mice significantly improved survival compared to control hIgG treated mice (right panel). n=9-10, pooled data from two representative experiments. * P: <0.001。

Fig. 8A-D: antagonistic LILRB1 mAb can modulate the function of NK92mi cell lines against cancer cells in vitro. (FIGS. 8A-C) leukemia cell lines (RS 4-11, MHHCALL2, MOLM13, THP-1, 697 MICA), solid tumor cell lines (MDA-MB-231, SW480, MALEM-3M) or multiple myeloma cell lines (RMPI 8226) were co-cultured with NK92mi and incubated with 10. Mu.g/mL control human IgG (hIgG), B1- #3 or B1-176. Four hours later, the cytotoxic activity of NKL on cancer cells was analyzed by flow cytometry. (FIG. 8D) two cases of primary leukemia cells were co-cultured with NK92mi and incubated with 10. Mu.g/mL control human IgG (hIgG) or B1- #3N 297A. Four hours later, the cytotoxic activity of NK92mi on cancer cells was analyzed by flow cytometry.

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

Fig. 10A-D: the active LILRB1 mAb can inhibit the cytotoxic activity of NK cells on cancer cells in vitro. NK92mi cells were co-cultured with 697 (FIG. 10A) or THP1 cells (FIG. 10B) and treated with anti-LILRB 1 mAb. Antagonistic B1-3 increased, whereas agonistic B1-7 inhibited the cytotoxic activity of NK92mi on 697 and THP-1 cells. (FIG. 10C) NKL cells were co-cultured with 697/697-MICA and treated with anti-LILRB 1 mAb. Antagonistic B1-3 increased, while agonistic B1-7 inhibited the cytotoxic activity of NKL on 697-MICA. (FIG. 10D) NKL cells were co-cultured with 697-MICA and treated with B1-7 (N297A, S267E) with mutations in B1-7 and Fc. The N297A mutation in Fc abrogates the activity of agonistic B1-7. The cytotoxic activity was analyzed by flow cytometry 4 hours after co-culture.

Fig. 11: the agonist LILRB1 mAb can inhibit IFN-gamma secretion by NKL cells. NKL cells were co-cultured with 697-MICA cells and treated with anti-LILRB 1 mAbs. Antagonistic B1-3 increased, whereas agonistic B1-7 inhibited IFN- γ secretion by NKL cells. 24 hours after co-cultivation, culture supernatants were collected and IFN-. Gamma.levels were determined by ELISA.

Fig. 12A-G: generation of anti-LILRB 1 mAb screen. (FIG. 12A) anti-LILRB 1 specific rabbit memory B cell isolation, in vitro culture, and cloning strategy for the generation of anti-LILRB 1 mAbs. After 14 days of incubation with rabbit CD40L feeder cells and rabbit cytokine mixtures in 96-well plates, B cell supernatants were screened for binding to LILRB1 in ELISA. The antibody heavy and light chain variable genes were then cloned into rabbit IgG expression vectors and recombinant antibodies were produced using the transient HEK293Expi-F cell expression system. (FIG. 12B) A flow chart of a screen for anti-LILRB 1 mAb. (FIG. 12C) measurement of EC of 44 anti-LILRB 1 rabbit mAbs by ELISA ₅₀ . (FIG. 12D) 12 epitope bins of 44 anti-LILRB 1 rabbit mAbs were determined using a classical sandwich epitope binning assay (Octet RED 96). (FIG. 12E) to screen for antagonistic anti-LILRB 1 antibodies, LILRB1 reporter cells were co-cultured with K562-HLA-G cells and incubated with anti-LILRB 1 mAb (10 μg/mL) for 24 hours. (fig. 12F) left panel: homology of LILRB1 to other receptors of the LILR family. The phylogenetic tree of D1-D2 coding amino acid sequences from all LILRs was generated by MEGA version 7.0 using the maximum likelihood method, except for the D1 structure selected for LILRB4 only. Right table: the specificity of the anti-LILRB 1 mAb was analyzed by Octet RED 96. (FIG. 12G) affinity of commercial anti-LILRB 1 monoclonal antibodies HP-F1 and GHI/75, analyzed by Octet RED 96.

Fig. 13A-B: characterization of B1-176. Fusion proteins of the LILRB1 ECD mutant with the Fc of hIgG1 were generated to characterize the binding epitope of B1-176. (FIG. 13A) schematic representation of LILRB1-fc mutation. (FIG. 13B) single or multiple mutations of LILRB1 amino acids.

Fig. 14A-D: expression of LILRB1 on the cell surface. (FIG. 14A) A representative flow chart of LILRB1 expression on NKL cells. (FIG. 14B) representative flow chart shows that multiple myeloma cell lines do not express LILRB1 on the cell surface. (fig. 14C) representative flow chart shows that most malignant plasma cells of patients with MM do not express LILRB1 on the cell surface. (FIG. 14D) representative flow chart shows, pre-B ALL cell line 697, MHHCALL2, RS4; 11. RCHACV, REH; acute monocytic leukemia cell lines THP-1, MOLM13, MV4-11; and Raji cells express LILRB1 on the cell membrane, whereas T cell leukemia Jurkat cells and chronic granulocytic leukemia cell line K562 do not express LILRB1. Cells were incubated with anti-LILRB 1-APC (clone: HP-F1, e biosciences (eBioscience)) for 30 minutes on ice and analyzed by flow cytometry.

Detailed Description

LILRB1, a member of the LILR receptor family containing ITIM, plays a key role in the regulation of innate and adaptive immunity. The LILRB1 is expressed on various types of immune cells including NK cells, and acts as an immune checkpoint protein. Expression of LILRB in myelogenous suppressor cells (MDSCs) can promote tumor growth and lead to an inhibitory immune microenvironment for tumor progression and metastasis. On the other hand, activation of LILRB1 signaling using agonistic antibodies may reduce tissue inflammation and may be used for management of autoimmune diseases. Provided herein are agonistic and antagonistic human LILRB1 monoclonal antibodies having specific targeting properties for modulating LILRB1 signaling. These LILRB1 antibodies can be used to treat human diseases including cancer and autoimmune diseases.

I. Aspects of the present disclosure

LILRB1 is expressed on T cells and NK cell subsets. LILRB1 is mainly used in CD56 from healthy donors and patients with different malignancies ^{Dark and dark} NK cells on expression. In addition, LILRB1 from peripheral blood of patients with Multiple Myeloma (MM) suffering from persistent disease during treatment ⁺ The percentage of NK cells is significantly higher than LILRB1 from healthy donors or patients with minimal disease or complete response ⁺ Percentage of NK. LILRB1 in peripheral blood of patients with advanced prostate cancer (stages 3B and 3C) ⁺ The percentage of NK cells was also significantly higher than LILRB1 of healthy donors ⁺ NK cellsIs a percentage of (c). These results are consistent with previous studies, indicating a correlation with CD56 ^Bright Peripheral blood CD56 compared to NK cells ^{Dark and dark} Higher levels of LILRB1 in NK cells ⁴⁰ . Other previous studies also reported that LILRB1 of NK cells in peripheral blood of patients with metastatic prostate and breast cancer compared to NK cells from healthy donors or patients with localized cancer ⁺ NK cell percentage was significantly higher ^{9 10} . Previous studies have also reported circulating CD8 ⁺ There is a strong correlation between the percentage of LILRB1T cells and the risk of recurrence of non-myogenic invasive bladder cancer ⁴¹ . In conclusion, the expression of LILRB1 on NK cells and T cells has prognostic value. Although the exact mechanism of the LILRB1 polymorphism in human NK cells is unknown, the expression of LILRB1 on NK cells is related to specific haplotypes and polymorphic regulatory regions ⁴² . LILRB1 from certain patients with cancer ⁺ The increase in NK cells is well documented. NK cells up-regulate LILRB1 expression when cultured in vitro with cancer cells ⁹ . HLA-G and soluble HLA-G are reported to up-regulate 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 labeled with CD57 or several KIRs have high LILRB1 expression and poor proliferation potency ⁴⁴ . Mass circulation CD57 ⁺ NK cells are associated with resistance to HER 2-specific therapeutic antibodies in patients with primary breast cancer ⁴⁵ This may explain the LILRB1 of patients with cancer who have an adverse response to treatment ⁺ The cause of increased NK cells.

Importantly, blocking LILRB1 with antagonistic monoclonal antibodies increases NK cell immune function against multiple myeloma cells in vitro and in vivo. In early studies, heidenreich and colleagues reported that blocking LILRB1 on NK92 cell lines did not increase their cytotoxic activity against multiple myeloma cell lines ⁴⁶ . This difference may be related to the use of NK92 cell lines, which NK92 cell lines may be more cytotoxic than the NKL cell lines and primary NK cells used hereinActivity(s) ⁴⁷ . Ligands for MHC class I, LILRB1, are strongly expressed in late MM cell lines, where expression levels are directly related to clinical staging of the disease ⁴⁸ 。 ⁴⁶ The cell line RPMI8226 and other MM cell lines used in the study of (a) express high levels of MHC class I molecules at the cell surface and have a powerful ability to activate LILRB1 reporter cells. These data indicate that MM cells may become resistant to NK cells by activating LILRB1 on NK cells by conjugation to MHC class I molecules expressed by MM cells.

NK cell function depends on the balance of various activation and inhibition signals in the cell. Targeting multiple immune receptors can optimize NK cell function on cancer cells. The combination of LILRB1 blocks the synergistic action of activation of the NKG2D receptor (via its ligand MICA) to increase the cytotoxic function of NK cells. These results are consistent with previous reports, indicating that overexpression of HLA-G on MICA-expressing M8 melanoma cell lines blocks the cytotoxic activity of NKL cells on cancer cell lines by activating LILRB1 ⁴⁹ . Several methods are being developed for increasing the surface abundance of MICA on cancer cells ^{4 19} . Other studies reported the combined effects of LILRB1 blockade and KIR blockade or ADCC-induced mabs in vitro ^{10 12} . Adoptively transferred allo-haplotype identical NK cells are considered to have improved function due to mismatch of MHC class I molecules and KIR ^{1 50} . Since LILRB1 may still be activated on these allogeneic NK cells, there may be a combined effect of LILRB1 blocking and adoptive transfer of allogeneic NK cells.

Interestingly, it has been reported that LILRB1 on cancer cells such as transformed B-lymphoid cancer cells and MGUS cells may activate an immune response ^{16 17} . LILRB1 is expressed on pre-B leukemia cells and burkitt lymphoma Raji cells. However, administration of anti-LILRB 1 blocking antibodies increased the function of NK cells on LILRB1 positive cell line 697 cells and Raji cells, consistent with previous reports that LILRB1 blocking increased the cytotoxic activity of NK cells on pre-B-ALL ¹² . These results indicate that the immunostimulatory function of LILRB1 may be environmentally dependentA kind of electronic device. Due to significantly higher expression of LILRB1 on NK cells of patients with persistent disease after treatment, LILRB1 blockade may increase NK cell function in patients with persistent MM. However, the level of LILRB1 expression on myeloma cells and NK cells should be monitored before and during anti-LILRB 1 antibody treatment. To minimize the risk of modulating the LILRB1 receptor on myeloma cells, anti-LILRB 1 antibody treatment should prioritize those patients with high LILRB1 expression levels on NK cells and no LILRB1 expression on myeloma cells.

In summary, blocking LILRB1 by antagonistic antibodies has the potential as an immunotherapeutic approach for treating patients with various types of cancers, particularly those with high LILRB1 level expression on NK cells.

Monoclonal antibodies and their production

Monoclonal antibodies described herein can be prepared using standard methods, followed by screening, characterization, and functional assessment. The variable region may be sequenced and then subcloned into a human expression vector to produce a chimeric antibody gene, which is then expressed and purified. These chimeric antibodies can be tested for antigen binding, signaling blockade, and xenograft experiments. Monoclonal antibodies described herein can also be prepared using phage display methods, wherein a large library of phage-displayed human scFv is panned against the target protein. The human scFv selected to specifically bind to the target protein can be sequenced and then subcloned into a human expression vector to produce the desired human antibody.

A. General procedure

It will be appreciated that monoclonal antibodies that bind to LILRB1 will have several applications. These applications include the generation of diagnostic kits for the detection and diagnosis of cancer and for cancer therapies. In these contexts, such antibodies may be associated with a diagnostic or therapeutic agent that is used as a capture or competitor in a competitive assay, or that is used alone without the addition of additional reagents. Antibodies may be mutated or modified, as discussed further below. Methods for preparing and characterizing Antibodies are well known in the art (see, e.g., antibodies: laboratory Manual (A Laboratory Manual), cold spring harbor laboratory (Cold Spring Harbor Laboratory), 1988; U.S. Pat. No. 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 for immunization may vary. Thus, it is often desirable to enhance the host immune system, as may be achieved by coupling a peptide or polypeptide immunogen to a carrier. Exemplary and preferred carriers are Keyhole Limpet Hemocyanin (KLH) and Bovine Serum Albumin (BSA). Other albumins such as ovalbumin, mouse serum albumin or rabbit serum albumin may also be used as carriers. Methods for conjugating polypeptides to carrier proteins are well known in the art and include glutaraldehyde, m-maleimidobenzoyl-N-hydroxysuccinimide ester, carbodiimide and double nitrided benzidine. As is well known in the art, the immunogenicity of a particular immunogenic composition may be enhanced by the use of a non-specific stimulator of the immune response, known as an adjuvant. Exemplary and preferred adjuvants include complete Freund's adjuvant (a non-specific stimulator of the immune response containing killed Mycobacterium tuberculosis (Mycobacterium tuberculosis)), incomplete Freund's adjuvant, and aluminum hydroxide adjuvant.

The amount of the immunogenic composition used to produce polyclonal antibodies varies depending on the nature of the immunogen and the animal used for immunization. A variety of 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 various points after immunization. A second booster injection may also be administered. The procedure of boosting and titer determination is repeated until the appropriate titer is achieved. When a desired level of immunogenicity is obtained, the immunized animal can be bled and serum isolated and stored, and/or the animal can be used to produce mabs.

After immunization, somatic cells, particularly B lymphocytes (B cells), with potential for antibody production are selected for the MAb generation protocol. These cells may be obtained from biopsied spleen or lymph nodes, or from circulating blood. Antibody-producing B lymphocytes from the immunized animal are then fused with cells of an immortal myeloma cell, typically one of the same species as the animal or human/mouse chimeric cells being immunized. Myeloma cell lines suitable for use in hybridoma-producing fusion procedures preferably do not produce antibodies, have high fusion efficiency and lack enzymes, so that they cannot then be grown in certain selective media that only support the growth of the desired fusion cells (hybridomas). Any of a variety of myeloma cells may be used, as known to those skilled in the art (Goding, pages 65-66, 1986; campbell, pages 75-83, 1984).

Methods for generating hybrids of antibody-producing spleen or lymph node cells and myeloma cells typically involve mixing somatic cells with myeloma cells in a ratio of 2:1, but the ratio may vary from about 20:1 to about 1:1, respectively, in the presence of one or more agents (chemical or electrical) that promote cell membrane fusion. Kohler and Milstein (1975; 1976) describe fusion methods using Sendai virus, and Gefter et al (1977) describe fusion methods using polyethylene glycol (PEG), such as 37% (v/v) PEG. The use of electrokinetic fusion methods is also suitable (Goding, pages 71-74, 1986). Fusion procedures typically produce viable hybrids at low frequencies, about 1×10 ^-6 To 1X 10 ^-8 . However, this does not pose a problem because by culturing in selective medium, the viable fusion hybrids differentiate from the parental, infused cells (particularly the infused myeloma cells that would normally continue to divide indefinitely). The selective medium is typically a medium containing agents that block de novo synthesis of nucleotides in the tissue culture medium. Exemplary and preferred agents are aminopterin (aminopterin), methotrexate (methotrexate), and azaserine. Aminopterin and methotrexate block de novo synthesis of purines and pyrimidines, whereas azaserine blocks only purine synthesis And (3) forming the finished product. In the case of aminopterin or methotrexate, the medium is supplemented with hypoxanthine and thymidine as a source of nucleotides (HAT medium). In the case of diazoserine, the medium is supplemented with hypoxanthine. If the B cell source is an Epstein-Barr virus (EBV) transformed human B cell line, ouabain (ouabain) is added to eliminate EBV transformed lines that are not fused with myeloma.

The preferred selection medium is HAT or HAT with ouabain. Only cells that are able to manipulate the nucleotide salvage pathway survive in HAT medium. Myeloma cells are defective in key enzymes of salvage pathways, such as hypoxanthine phosphoribosyl transferase (HPRT), and therefore cannot survive. B cells can operate this pathway, but have a limited lifetime in culture and typically die in about two weeks. Thus, the only cells that can survive in the selective medium are those hybrids formed by myeloma and B cells. When the B cell source for fusion is an EBV transformed B cell line, as herein, ouabain is also used for drug selection of hybrids, since EBV transformed B cells are readily killed by drugs, and the myeloma partner used is selected to be resistant to ouabain.

Culturing provides a population of hybridomas from which to select a particular hybridoma. Typically, hybridoma selection is performed by culturing cells in microtiter plates by monoclonal dilution, followed by testing individual clone supernatants (after about two to three weeks) for the desired reactivity. The assay should be sensitive, simple and rapid, such as radioimmunoassays, enzyme immunoassays, cytotoxicity assays, plaque assays, spot-immune binding assays, and the like. 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 be propagated indefinitely to provide mabs. Cell lines can be used to perform MAb generation in two basic ways. Samples of hybridomas can be injected (typically into the peritoneal cavity) into animals (e.g., mice). Optionally, the animals are sensitized with a hydrocarbon, particularly an oil such as pristane (tetramethylpentadecane), prior to injection. When human hybridomas are used in this manner, immunocompromised mice, such as SCID mice, are preferably injected to prevent tumor rejection. The injected animals produce tumors that secrete specific monoclonal antibodies produced by the fused cell hybrids. Body fluids of animals 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 the MAbs are naturally secreted into the medium from which they can be readily obtained in high concentrations. Alternatively, human hybridoma cell lines may be used in vitro to produce immunoglobulins in the cell supernatant. The cell line may be adapted to be grown in serum-free medium to optimize the ability to recover high purity human monoclonal immunoglobulins.

If desired, the MAb produced by either means can be further purified using filtration, centrifugation, and various chromatographic methods such as FPLC or affinity chromatography. Monoclonal antibody fragments of the present disclosure can be obtained from purified monoclonal antibodies by methods that include digestion with enzymes such as pepsin or papain and/or cleavage of disulfide bonds by chemical reduction. Alternatively, monoclonal antibody fragments encompassed by the present disclosure may be synthesized using an automated peptide synthesizer.

It is also contemplated that molecular cloning methods may be used to generate the monoclonal. For this purpose, RNA can be isolated from hybridoma cell lines and antibody genes obtained by RT-PCR and cloned into immunoglobulin expression vectors. Alternatively, combinatorial immunoglobulin phagemid libraries are prepared from RNA isolated from cell lines and phagemids expressing the appropriate antibodies are selected by panning using viral antigens. The advantage of this approach over conventional hybridoma technology is that about 10 can be generated and screened in a single round ⁴ Double antibodies, and new specificities are generated by the combination of H and L chains, further increasing the chance of finding appropriate antibodies.

More recently, additional methods for producing mabs have been developed, such as scFv phage display (see CM Hammers and JR Stanley, antibody phage display: techniques and applications (Antibody phage display: technique and applications, journal of dermatological research (J Invest Dermatol) (2014) 134:e17). Typically, a panel of human mabs that bind to a target protein (e.g., human LILRB 1) is produced by panning through a large number of different human scFv phage-displayed antibody libraries.

To generate a library of human scFv phage-displayed antibodies, RNA is extracted from selected cell sources, such as peripheral blood mononuclear cells. The RNA is then reverse transcribed into cDNA for PCR of the VH and VL chains of the encoded antibody. Specific primer sets specific for different VH and VL chain region gene families allow amplification of all transcribed rearranged variable regions within a given immunoglobulin lineage, reflecting all antibody specificities for a particular individual.

VH and VL PCR products representing antibody lineages were ligated into phage display vectors engineered to express VH and VL as scFv fused to pIII minor capsid proteins of filamentous phage originally derived from escherichia coli (e.coli) of M13 phage. This results in a library of phages, each of which expresses an scFv on its surface and carries a vector with the corresponding nucleotide sequence therein.

The library is then screened against phage through which the expressed surface scFv binds to the target antigen by a technique called biopanning. Briefly, target proteins are coated on a solid phase for incubation with phage libraries. After washing and elution, the antigen-enriched phage is recovered and used for the next round of phage panning. After at least three rounds of phage panning, individual bacterial colonies were picked for phage ELISA and other functional/genetic analysis.

Positive hits to scFv regions were sequenced and the positive hits were converted to fully human IgG heavy and light chain constructs for producing mabs of interest using the methods disclosed above. For example, the transfection reagent PEI was used to co-transfect IgG expression plasmids into Expi293 cells. After 7 days of expression, the supernatant was harvested and the antibodies were purified by affinity chromatography using protein a resin.

Other U.S. patents, each incorporated herein by reference, that teach the production of antibodies useful in the present disclosure include U.S. Pat. nos. 5,565,332 that describe the use of combinatorial methods to produce chimeric antibodies; U.S. Pat. nos. 4,816,567 describing recombinant immunoglobulin preparations; and U.S. patent 4,867,973 describing antibody therapeutic conjugates.

B. Antibodies of the disclosure

Antibodies to lilrb1

In the first case, an antibody or antigen binding fragment thereof according to the present disclosure may be defined by its binding specificity, in which case the binding specificity is for LILRB1. One skilled in the art can determine whether such antibodies fall within the scope of the claims by assessing the binding specificity/affinity of a given antibody using techniques well known to those skilled in the art.

In one aspect, antibodies and antigen binding fragments that specifically bind to LILRB1 are provided. In some embodiments, such antibodies, when bound to LILRB1, modulate the activation of LILRB1. In certain embodiments, the antibody or antigen binding fragment activates LILRB1 upon binding to LILRB1. In certain embodiments, the antibody or antigen binding fragment inhibits activation of LILRB1 upon binding to LILRB1. In certain embodiments, the antibody or antigen binding fragment may specifically interfere with, block or reduce the interaction between LILRB1 and its binding partner when bound to LILRB1. In certain embodiments, the antibodies 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 binding of human LILRB1 to an MHC class I molecule, 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 antibody or antigen binding fragment has a Kd of less than (more tightly bound to) 10 ^-6 、10 ^-7 、10 ^-8 、10 ^-9 、10 ^-10 、10 ^-11 、10 ^-12 、10 ^-13 M. In some embodiments, the antibody or antigen binding fragment has an IC50 of less than 10uM, 10uM to 1uM, 1000nM to 100nM, 100nM to 10nM, a fragment for blocking binding of MHC class I molecules such as HLA-G to LILRB1,10nM to 1nM, 1000pM to 500pM, 500pM to 200pM, less than 200pM, 200pM to 150pM, 200pM to 100pM, 100pM to 10pM, 10pM to 1pM.

In some embodiments, provided herein are antibodies or antigen binding fragments having the CDRs of the clone-paired set forth in table 1 and table 3.

In certain embodiments, an antibody may be defined by the variable sequence of the antibody, including additional "framework" regions. Antibodies are characterized by the heavy and light chain amino acid sequences of the clone pairs from tables 6 and 8. Furthermore, antibody sequences may differ from these sequences, particularly in regions other than CDRs. For example, amino acids may differ from those listed above by a given percentage, e.g., 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 for conservative substitutions (discussed below). Each of the foregoing applies to the amino acid sequences of tables 6 and 8. In another embodiment, the antibody derivatives of the present disclosure include VL and VH domains having up to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more conservative or non-conservative amino acid substitutions while still exhibiting the desired binding and functional properties.

Although the antibodies of the present disclosure are produced as IgG, it may be useful to modify the constant regions to alter their function. The constant region of an antibody typically mediates binding of the antibody to host tissues or factors, including different cells of the immune system (e.g., effector cells) and the first component of the classical complement system (Clq). Thus, the term "antibody" includes intact immunoglobulins of the IgA, igG, igE, igD, igM type (as well as subtypes thereof), in which the light chain of the immunoglobulin may be of the kappa or lambda type. Within the light and heavy chains, the variable and constant regions are linked by a 35"j" region of about 12 or more amino acids, wherein the heavy chain further includes a "D" region of about 10 more amino acids. See generally, basic immunology (Fundamental Immunology), chapter 7 (Paul, W.edit., 2 nd edition, new York, raven Press (N.Y.) (1989)).

The disclosure further includes nucleic acids that hybridize to nucleic acids encoding the antibodies disclosed herein. Typically, the nucleic acid hybridizes under medium or high stringency conditions with a nucleic acid encoding an antibody disclosed herein and also encoding an antibody that retains the ability to specifically bind to LILRB 1. A first nucleic acid molecule is "hybridizable" to a second nucleic acid molecule when a single-stranded form of the first nucleic acid molecule can be annealed to the second nucleic acid molecule under conditions of appropriate temperature and solution ionic strength (see Sambrook et al, molecular cloning: A laboratory Manual (Molecular Cloning: A Laboratory Manual), 3 rd edition, cold spring harbor Press (Cold Spring Harbor Press, cold Spring Harbor, N.Y.) 2001). The conditions of temperature and ionic strength determine the "stringency" of hybridization. Typical medium stringency hybridization conditions are 40% formamide with 5X or 6X SSC and 0.1% SDS at 42 ℃. The high stringency hybridization conditions are 50% formamide, 5X or 6X SSC (0.15M NaC1 and 0.015M sodium citrate), at 42 ℃, or optionally at higher temperatures (e.g., 57 ℃, 59 ℃, 60 ℃, 62 ℃, 63 ℃, 65 ℃, or 68 ℃). Hybridization requires that the two nucleic acids contain complementary sequences, but is dependent on the stringency of the hybridization and mismatches between bases are possible. The appropriate stringency 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 two nucleotide sequences, the higher the stringency with which nucleic acids can hybridize. For hybrids greater than 100 nucleotides in length, an equation for calculating the melting temperature has been developed (see Sambrook et al, supra). For hybridization with shorter nucleic acids (e.g., oligonucleotides), the location of the mismatch becomes more important and the length of the oligonucleotide determines its specificity (see Sambrook et al, supra).

TABLE 1 amino acid sequence of LILRB1 (B1) mAb heavy chain CDR

TABLE 2 nucleic acid sequences of LILRB1 (B1) mAb heavy chain CDRs

TABLE 3 amino acid sequence of LILRB1 (B1) mAb light chain CDR

TABLE 4 nucleic acid sequences of LILRB1 (B1) mAb CDRs

TABLE 5 LILRB1 mAb heavy chain variable region nucleotide sequence

TABLE 6 LILRB1 mAb heavy chain variable region amino acid sequence

TABLE 7 LILRB1 mAb light chain variable region nucleotide sequence

TABLE 8 LILRB1 mAb light chain variable region amino acid sequence

2. Exemplary epitope and competitor antigen binding proteins

In another aspect, the disclosure provides epitopes to which anti-LILRB 1 antibodies bind. In some embodiments, epitopes bound by antibodies described herein are useful. In certain embodiments, the epitopes provided herein can be used to isolate antibodies or antigen binding proteins that bind to LILRB 1. In certain embodiments, the epitopes provided herein can be used to generate antibodies or antigen binding proteins that bind to LILRB 1. In certain embodiments, an epitope or a sequence comprising an epitope provided herein may be used as an immunogen to produce an antibody or antigen binding protein that binds to LILRB 1. In certain embodiments, the epitopes described herein or sequences comprising the epitopes described herein may be used to interfere with the biological activity of LILRB 1.

In some embodiments, antibodies or antigen binding fragments thereof that bind to any of the epitopes are particularly useful. In some embodiments, the epitope provided herein modulates the biological activity of LILRB1 when bound by an antibody. In some embodiments, the epitope provided herein activates LILRB1 when bound by an antibody. In some embodiments, the epitope provided herein inhibits activation of LILRB1 when bound by an antibody. In some embodiments, the epitopes provided herein block the interaction between LILRB1 and its binding partner when bound by an antibody.

In some embodiments, domains/regions containing residues that are in contact with or buried by an antibody can be identified by mutating specific residues in LILRB1 and determining whether the antibody can bind to the mutated LILRB1 protein. By performing a number of individual mutations, residues that play a direct role in binding or are close enough to the antibody that the mutation can affect binding between the antibody and antigen can be identified. From knowledge of these amino acids, it is possible to elucidate antigen domains or regions containing residues that are in contact with antigen binding proteins or are covered by antibodies. Such domains may include binding epitopes of antigen binding proteins.

In another aspect, the present disclosure provides antigen binding proteins that compete for specific binding to LILRB1 with one of the exemplified antibodies or antigen binding fragments that bind to an epitope described herein. Such antigen binding proteins may also bind to the same epitope or overlapping epitope as one of the antibodies or antigen binding fragments exemplified herein. Antigen binding proteins that compete with or bind to the same epitope as the exemplified antibodies are expected to show similar functional properties. Exemplary antibodies include those described above, including those having the heavy and light chain variable regions and CDRs included in tables 1 and 3, the heavy and light chains shown in tables 6 and 8, and the heavy and light chain coding regions shown in tables 5 and 7.

C. Engineering of antibody sequences

In various embodiments, engineering the sequences of the identified antibodies may be selected for various reasons, such as improved expression, improved cross-reactivity, or reduced off-target binding. The following is a general discussion of the related art of antibody engineering.

The hybridomas can be cultured, and then the cells are lysed and total RNA extracted. Random hexamers can be used with RT to generate cDNA copies of RNA, and then PCR is performed using a multiplex of PCR primers that are expected to amplify all human variable gene sequences. The PCR product can be cloned into pGEM-T Easy vector and then sequenced by automated DNA sequencing using standard vector primers. Binding and neutralization assays can be performed using antibodies collected from hybridoma supernatants and purified by FPLC using protein G columns. Recombinant full length IgG antibodies can be produced by subcloning heavy and light chain Fv DNA from a cloning vector into an IgG plasmid vector, transfecting into 293Freestyle cells or CHO cells, and collecting purified antibodies from 293 or CHO cell supernatants.

The rapid availability of antibodies produced during the same host cell and cell culture process as the final cGMP production process makes it possible to reduce the duration of the process development program. The Lonsha company (Lonza) developed a general method for rapid production of small amounts (up to 50 g) of antibodies in CHO cells using pooled transfectants grown in CDACF medium. Although somewhat slower than a truly transient system, advantages include higher product concentrations and use of the same host and process as the production cell line. Growth and productivity examples of GS-CHO pools expressing model antibodies in disposable bioreactors: in a disposable bag bioreactor culture (5L working volume) operating in fed-batch mode, a concentration of 2g/L of harvested antibody was reached within 9 weeks of transfection.

Antibody molecules will include fragments (e.g., F (ab') ₂ ) Or single chain immunoglobulins which may be produced, for example, recombinantly. Such antibody derivatives are monovalent. In one embodiment, such fragments may be combined with each other, or with other antibody fragments or receptor ligands to form a "chimeric" binding molecule. Importantly, such chimeric molecules may contain substituents that are capable of binding to different epitopes of the same molecule.

1. Antigen binding modifications

In related embodiments, the antibody is a derivative of the disclosed antibody, e.g., an antibody comprising CDR sequences that are identical to CDR sequences in the disclosed antibody (e.g., a chimeric antibody or a CDR-grafted antibody). Alternatively, it may be desirable to make modifications, such as introducing conservative changes into the antibody molecule. In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydrophilic amino acid index in conferring interactive biological functions on proteins is generally understood in the art (Kyte and Doolittle, 1982). It is understood that the relatively hydrophilic nature of the amino acids contributes to the secondary structure of the resulting protein, which in turn defines the interaction of the protein with other molecules, e.g., enzymes, substrates, receptors, DNA, antibodies, antigens, etc.

It will also be appreciated in the art that substitution of similar amino acids can be effectively made based on hydrophilicity. U.S. Pat. No. 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 of the protein, correlates with the biological properties of the protein. As detailed in U.S. Pat. No. 4,554,101, amino acid residues have been assigned the following hydrophilicity values: basic amino acid: arginine (+3.0), lysine (+3.0), and histidine (-0.5); acidic amino acid: 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), glutamine (+0.2), and threonine (-0.4); sulfur-containing amino acid: 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 will be appreciated that an amino acid may be substituted for another amino acid having similar hydrophilicity and produce a biologically or immunologically modified protein. In such a change, substitution of an amino acid having a hydrophilicity value within ±2 is preferable, substitution of an amino acid having a hydrophilicity value within ±1 is particularly preferable, and substitution of an amino acid having a hydrophilicity value within ±0.5 is more particularly preferable.

As outlined above, amino acid substitutions are generally based on the relative similarity of amino acid side chain substituents, e.g., their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take into account the various above features are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

Isoform modifications are also contemplated by the present disclosure. By modifying the Fc region to have different isoforms, different functions may be achieved. For example, instead of IgG ₁ Can increase antibody-dependent cytotoxicity, shift to class a can improve tissue distribution, and shift to class M can improve valency.

The modified antibodies may be prepared by any technique known to those skilled in the art, including expression by standard molecular biology techniques or chemical synthesis of polypeptides. Methods for recombinant expression are discussed elsewhere in this document.

Fc region modification

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 attached to the antibody) or modified to alter its glycosylation to again alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of residues in the Fc region is that of the EU index of Kabat. Antibodies disclosed herein also include antibodies having a modified (or blocked) Fc region to provide altered effector function. See, for example, U.S. Pat. nos. 5,624,821; WO2003/086310; WO2005/120571; WO2006/0057702. Such modifications may be used to enhance or inhibit various responses of the immune system, potentially having beneficial effects on diagnosis and therapy. Alterations in the Fc region include amino acid changes (substitutions, deletions and insertions), glycosylation or deglycosylation, and the addition of multiple fcs. The change in Fc can also alter the half-life of the antibody in the therapeutic antibody, thereby achieving a lower dosing frequency and thus increasing convenience and reducing use of materials. This mutation reportedly eliminates the heterogeneity of disulfide bonds between the heavy chains of 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. Such a method is further described in U.S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of CH1 is altered, for example, to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody. In another embodiment, the antibody is modified to increase its biological half-life. Various methods are possible. For example, one or more of the following mutations may be introduced: T252L, T254S, T F as described in U.S. patent 6,277,375. Alternatively, to increase the biological half-life, the antibody may be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from both loops of the CH2 domain of the Fc region of IgG, as described in U.S. Pat. nos. 5,869,046 and 6,121,022. In still other embodiments, the Fc region is altered by substitution of at least one amino acid residue with a different amino acid residue to alter the effector function of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320, and 322 may be substituted with different amino acid residues such that the antibody has altered affinity for the effector ligand, but retains the antigen binding capacity of the parent antibody. The affinity altered effector ligand may be, for example, an Fc receptor or the C1 component of complement. Such a method is described in further detail in U.S. Pat. nos. 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 alter the ability of the antibody to fix complement. Such a 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 increase or decrease the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and/or to increase or decrease the affinity of the antibody for fcγ receptors: 238. 239, 243, 248, 249, 252, 254, 255, 256, 258, 264, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 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. Such a method is further described in PCT publication WO 00/42072. Furthermore, binding sites for fcγr1, fcγrii, fcγriii and FcRn on human IgG1 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 fcyriii. In addition, the following combination mutants are shown to improve fcyriii binding: T256A/S298A, S A/E333A, S A/K224A and S298A/E333A/K334A.

In one embodiment, the Fc region is modified to reduce the ability of the antibody to mediate effector functions and/or to increase anti-inflammatory properties by modifying residues 243 and 264. In one embodiment, the Fc region of an 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 the antibody to mediate effector functions and/or to increase anti-inflammatory properties by modifying residues 243, 264, 267 and 328.

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

In one embodiment, the Fc region is modified to eliminate the ability of the antibody to mediate effector functions by modifying residue 297 to alanine (N234A).

In yet another embodiment, the antibody comprises a specific glycosylation pattern. For example, deglycosylated antibodies can be prepared (i.e., antibodies lack glycosylation). The glycosylation pattern of an antibody can be altered, for example, to increase the affinity or avidity of the antibody for an antigen. Such modification may be accomplished, for example, by altering one or more of the glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions may be made which result in removal of one or more of the variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such deglycosylation may increase the affinity or avidity of the antibody for the antigen. See, for example, U.S. Pat. nos. 5,714,350 and 6,350,861.

Antibodies can also be prepared in which the glycosylation pattern includes a hypofucosylated or afucosylated glycan, such as a hypofucosylated antibody or afucosylated antibody, in which the amount of fucosyl residues in the glycan is reduced. Antibodies may also include glycans with increased amounts of bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC capacity of antibodies. Such modification may be accomplished, for example, by expressing the antibody in a host cell, wherein the glycosylation pathway is genetically engineered to produce glycoproteins having a particular glycosylation pattern. These cells have been described in the art and can be used as host cells in which the recombinant antibodies of the invention are expressed to thereby produce antibodies with altered glycosylation. For example, cell lines Ms704, ms705 and Ms709 lack the fucosyltransferase gene FUT8 (α (1, 6) -fucosyltransferase), such that antibodies expressed in the Ms704, ms705 and Ms709 cell lines lack fucose on their carbohydrates. Ms704, ms705 and Ms709 FUT 8-/-cell lines were generated by targeted disruption of the FUT8 gene in CHO/DG44 cells using two alternative vectors (see U.S. patent publication No. 20040110704). For example, EP 1 176 195 describes cell lines with functionally disrupted FUT8 genes encoding fucosyltransferases such that antibodies expressed in such cell lines exhibit low fucosylation by reducing or eliminating alpha-1, 6 linkage associated enzymes. EP 1 176 195 also describes cell lines with low enzymatic activity for the addition of fucose to N-acetylglucosamine, with or without enzymatic activity, which is bound to the Fc region of antibodies, such as the rat myeloma cell line YB2/0 (ATCC CRL 1662). PCT publication WO 03/035835 describes a variant CHO cell line, lec13 cells, which has a reduced capacity to link fucose to Asn (297) linked carbohydrates, also 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 (Lemna) (us patent 7,632,983). Methods for producing antibodies in plant systems are disclosed in U.S. Pat. nos. 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-acetylglucosaminyl transferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structure, which results in increased ADCC activity of the antibodies.

Alternatively, fucosidase may be used to cleave fucosyl residues of an antibody, e.g., fucosidase α -L-fucosidase removes fucosyl residues from an antibody. Antibodies disclosed herein further include antibodies produced in lower eukaryotic host cells, particularly fungal host cells, such as yeast and filamentous fungi, that have been genetically engineered to produce glycoproteins having mammalian or human-like glycosylation patterns. A particular advantage of these genetically modified host cells compared to the mammalian cell lines currently in use is the ability to control the glycosylation profile of glycoproteins produced in the cells so that compositions of glycoproteins can be produced in which the particular N-glycan structure predominates (see, e.g., U.S. Pat. nos. 7,029,872 and 7,449,308). These genetically modified host cells have been used to produce antibodies having predominantly specific N-glycan structures.

In addition, since fungi such as yeasts or filamentous fungi lack the ability to produce fucosylated glycoproteins, antibodies produced in such cells will lack fucose unless the cells are further modified to include an enzymatic pathway for the production of fucosylated glycoproteins (see, e.g., PCT publication WO 2008112092). In particular embodiments, the antibodies disclosed herein further include those produced in lower eukaryotic host cells, and include fucosylated and nonfucosylated hybrid and complex N-glycans, including bisected and multi-antennary 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 particular embodiments, the antibody compositions provided herein may include an antibody having at least one hybrid N-glycan selected from the group consisting of: glcNAcMan5GlcNAc2; galGlcNAcMan5GlcNAc2 and nanagalmacman 5GlcNAc2. In a particular aspect, the hybrid N-glycans are the predominant N-glycan species in the composition. In further aspects, a hybrid N-glycan is a particular N-glycan species that includes about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99% or 100% of the hybrid N-glycan in the composition.

In a particular embodiment, the antibody compositions provided herein comprise 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-glycans are the predominant N-glycan species in the composition. In further aspects, the complex N-glycans are specific N-glycan species that comprise about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99% or 100% of complex N-glycans in the composition. In a particular embodiment, the N-glycans are fucosylated. Typically, fucose is linked to GlcNAc at the reducing end of the N-glycan through a 1, 3-linkage; linked to GlcNAc at the reducing end of the N-glycan through a 1, 6-linkage; a Gal linkage at the non-reducing end of the N-glycan through an alpha 1, 2-linkage; a GlcNac linkage through an alpha 1, 3-linkage to the non-reducing end of the N-glycan; or through a α1, 4-linkage to GlcNAc at the non-reducing end of the N-glycan.

Thus, in a particular aspect of the glycoprotein composition described above, the glycoform is an α1, 3-linkage or an α1, 6-linkage fucose to produce a glycoform 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); fucose in the alpha 1, 3-bond or alpha 1, 4-bond to produce a glycoform selected from the group consisting of: glcNAc (Fuc) Man5GlcNAc2, glcNAc (Fuc) Man3GlcNAc2, glcNAc2 (Fuc 1-2) Man3GlcNAc2, galGlcNAc2 (Fuc 1-2) Man3GlcNAc2, gal2GlcNAc2 (Fuc 1-2) Man3GlcNAc2, NANAGal2GlcNAc2 (Fuc 1-2) Man3GlcNAc2, and NANA2Gal2GlcNAc2 (Fuc 1-2) Man3GlcNAc2; or in alpha 1, 2-linked fucose to produce glycoforms selected from the group consisting of: gal (Fuc) GlcNAc2Man3GlcNAc2, gal2 (Fuc 1-2) GlcNAc2Man3GlcNAc2, NANANAGal 2 (Fuc 1-2) GlcNAc2Man3GlcNAc2 and NANA2Gal2 (Fuc 1-2) GlcNAc2Man3GlcNAc2.

In a further aspect, the antibodies include high mannose N-glycans, including, but not limited to, man8GlcNAc2, man7GlcNAc2, man6GlcNAc2, man5GlcNAc2, man4GlcNAc2, or N-glycans composed of Man3GlcNAc 2N-glycan structures. In the above further aspects, the complex N-glycans further comprise fucosylated and nonfucosylated bisected and multi-antenna species. As used herein, the terms "N-glycan" and "glycoform" are used interchangeably and refer to N-linked oligosaccharides, e.g., oligosaccharides that are linked to an asparagine residue of a polypeptide by an asparagine-N-acetylglucosamine linkage. The N-linked glycoprotein contains N-acetylglucosamine residues linked to the amide nitrogen of an asparagine residue in the protein.

D. Single chain antibody

Single chain variable fragments (scFv) are fusions of the variable regions of the heavy and light chains of immunoglobulins, joined together by short (usually serine, glycine) linkers. Such chimeric molecules retain the original immunoglobulin specificity despite the removal of the constant region and the introduction of the linker peptide. Such modifications typically leave the specificity unchanged. These molecules have historically been produced to facilitate phage display, where expression of the antigen binding domain as a single peptide is convenient. Alternatively, scFv may be produced directly from subcloned heavy and light chains derived from hybridomas. Single chain variable fragments lack the constant Fc region found in whole antibody molecules and thus lack the common binding sites (e.g., protein a/G) for purifying antibodies. These fragments can generally be purified/immobilized using protein L because protein L interacts with the variable region of the kappa light chain.

Flexible linkers typically include amino acid residues that promote helix and turn angles, such as alanine, serine, and glycine. However, other residues may also play a role. Tang et al (1996) used phage display as a means of rapidly selecting single chain antibody (scFv) custom linkers from a library of protein linkers. Random linker libraries were constructed in which the genes for the heavy and light chain variable domains were linked by a segment encoding an 18 amino acid polypeptide of the variable composition. scFv library (about 5×10) ⁶ Individual different members) are displayed on filamentous phage and affinity selected with hapten. The population of selected variants exhibited a significant increase in binding activity, but retained considerable sequence diversity. Screening 1054 individualThe variants then produce a catalytically active scFv that is efficiently produced in soluble form. Sequence analysis revealed that the sequence in the linker was at V _H Conserved prolines in the two residues after the C-terminus, as well as large amounts of arginine and prolines at other positions, are the only common features of the selected tethers.

Recombinant antibodies of the present disclosure may also relate to sequences or portions that allow dimerization or multimerization of the receptor. Such sequences include IgA-derived sequences that allow binding to J-chains to form multimers. Another multimerization domain is the Gal4 dimerization domain. In other embodiments, the chain may be modified with an agent, such as biotin/avidin, which allows for a combination of the two antibodies.

In separate embodiments, single chain antibodies may be produced by linking the acceptor light and heavy chains using non-peptide linkers or chemical units. Typically, the light and heavy chains will be produced, purified in different cells, and then joined together in an appropriate manner (i.e., the N-terminus of the heavy chain is joined to the C-terminus of the light chain by an appropriate chemical bridge).

The crosslinking reagent serves to form a molecular bridge that connects the functional groups of two different molecules, such as a stabilizer and a coagulant. However, it is contemplated that dimers or multimers of the same analog or heteromeric complexes comprising different analogs may be produced. To link two different compounds in a stepwise manner, heterobifunctional cross-linking agents can be used to eliminate unwanted homopolymer formation.

Exemplary heterobifunctional crosslinkers include 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.). The cross-linking agent can react with lysine residues of one protein (e.g., the selected antibody or fragment) via primary amine reactive groups, and the cross-linking agent that has been linked to the first protein reacts with cysteine residues (free thiol) of other proteins (e.g., the selection agent) via thiol reactive groups.

Preferably a cross-linking agent with reasonable stability in blood is used. Many types of disulfide bond containing linkers are known to be successful in conjugating targeting agents and therapeutic/prophylactic agents. Linkers containing sterically hindered disulfide bonds may provide greater stability in vivo, preventing release of the targeting peptide prior to reaching the site of action. Thus, these linkers are a set of linkers.

Another crosslinking agent is SMPT, which is a difunctional crosslinking agent that includes disulfide bonds "sterically hindered" by adjacent benzene rings and methyl groups. It is believed that the steric hindrance of the disulfide bond serves to protect the bond from thiol anions such as glutathione that may be present in tissue and blood and thereby helps prevent the decoupling of the conjugate prior to delivery of the attached agent to the target site.

Like many other known crosslinking agents, SMPT crosslinking agents have the ability to crosslink functional groups such as SH of cysteine or primary amines (e.g., epsilon amino groups of lysine). Another possible type of crosslinking agent includes heterobifunctional photoactive phenyl azides containing cleavable disulfide linkages, such as sulfosuccinimidyl-2- (p-azidosalicylamino) ethyl-1, 3' -dithiopropionate. The N-hydroxy-succinimidyl group reacts with a primary amino group and the phenylazide (upon photolysis) reacts non-selectively with any amino acid residue.

In addition to sterically hindered cross-linkers, non-sterically hindered linkers may be used in accordance with the disclosure herein. Other useful cross-linking agents that are not considered to include or produce protected disulfides include SATA, SPDP, and 2-iminothiolane (Wawrzynczak and Thorpe, 1987). The use of such cross-linking agents is well known in the art. Another embodiment relates to the use of flexible joints.

U.S. patent 4,680,338 describes bifunctional linkers useful for producing conjugates of ligands with amine-containing polymers and/or proteins, particularly for forming antibody conjugates with chelators, drugs, enzymes, detectable labels, and the like. Us patent 5,141,648 and 5,563,250 disclose cleavable conjugates containing labile bonds that are cleavable under various mild conditions. This linker is particularly useful because the agent of interest can be directly bonded to the linker, wherein cleavage results in release of the active agent. Specific uses include the addition of free amino groups or free sulfhydryl groups to proteins, such as antibodies or drugs.

U.S. patent 5,856,456 provides peptide linkers for linking polypeptide components to make fusion proteins, such as single chain antibodies. The linker is up to about 50 amino acids in length, including at least one occurrence of a 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 aminooxy-containing linkers useful in a variety of immunodiagnostic and isolation techniques.

E. Purification

In certain embodiments, the antibodies of the disclosure may be purified. As used herein, the term "purified" is intended to refer to a composition that can be separated from other components, wherein the protein is purified to any degree relative to its naturally available state. Thus, a purified protein is also referred to as a protein that is not affected by the environment in which it may naturally occur. When the term "substantially purified" is used, this designation will refer to a composition wherein the 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, a rough classification of the cellular environment into polypeptide and non-polypeptide fractions. After separation of the polypeptide from other proteins, chromatographic and electrophoretic techniques can be used to further purify the polypeptide of interest to achieve partial or complete purification (or purification to homogeneity). An analytical method particularly suitable for the preparation of pure peptides is ion exchange chromatography, exclusion chromatography; polyacrylamide gel electrophoresis; isoelectric focusing. Other methods for protein purification include precipitation with ammonium sulfate, PEG, antibodies, etc., or by thermal denaturation followed by centrifugation; gel filtration, reverse phase, hydroxyapatite and affinity chromatography; and combinations of such and other techniques.

In purifying antibodies of the present disclosure, it may be desirable to express the polypeptide in a prokaryotic or eukaryotic expression system and extract the protein using denaturing conditions. The polypeptide may be purified from other cellular components using an affinity column that binds to the labeled portion of the polypeptide. As is well known in the art, it is believed that the order in which the different purification steps are performed may be altered, or that certain steps may 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 portion of the antibody (i.e., protein a). Alternatively, the antigen may be used to simultaneously purify and select the appropriate antibody. Such methods typically utilize a selective agent bound to a carrier, such as a column, filter or bead. The antibody binds to the support, the contaminants are removed (e.g., washed away), and the antibody is released by application of conditions (salt, heat, etc.).

In view of the present disclosure, one of ordinary skill in the art will be able to employ various methods for quantifying the degree of purification of a protein or peptide. These methods include, for example, determining the specific activity of the active fraction or assessing the amount of polypeptide in the fraction by SDS/PAGE analysis. Another method for assessing the purity of the fractions is to calculate the specific activity of the fractions to compare said specific activity with the specific activity of the initial extract and thus calculate the purity. Of course, the actual unit used to represent the amount of activity will depend on the particular assay technique chosen after purification and whether the expressed protein or peptide exhibits detectable activity.

It is known that migration of polypeptides can vary with different conditions of SDS/PAGE, sometimes significantly (Capaldi et al, 1977). It will thus be appreciated that under different electrophoretic conditions, the apparent molecular weight of the purified or partially purified expression product may be different.

III.LILRB1 related diseases

LILRB1, a member of the LILR receptor family containing ITIM, plays a key role in the regulation of innate and adaptive immunity. The LILRB1 is expressed on various types of immune cells including NK cells, and acts as an immune checkpoint protein. Expression of LILRB in myelogenous suppressor cells (MDSCs) can promote tumor growth and lead to an inhibitory immune microenvironment for tumor progression and metastasis. On the other hand, activation of LILRB1 signaling using agonistic antibodies may reduce tissue inflammation and may be used for management of autoimmune diseases. Provided herein are agonistic and antagonistic human LILRB1 monoclonal antibodies having specific targeting properties for modulating LILRB1 signaling. These LILRB1 antibodies can be used to treat human diseases including cancer, autoimmune diseases, and inflammatory disorders.

Although hyperproliferative diseases may be associated with any disease that causes the cells to begin to multiply uncontrolled, a typical example is cancer.

Examples of cancers can be generally classified as solid tumors and hematological malignancies. Solid tumors include, but are not limited to, adrenal cancer, bile duct cancer, bone cancer, brain cancer (e.g., astrocytoma, brain stem glioma, craniopharyngeal tumor, ependymoma, angioblastoma, medulloblastoma, meningioma, oligodendroglioma, spinal shaft tumor), 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 bronchogenic carcinoma, non-small cell lung cancer (squamous/non-squamous), broncheoalveolar lung cancer, papillary adenocarcinoma), mesothelioma, melanoma, merck cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, carcinoma, pineal tumor, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma (including cartilage, ewing's sarcoma, ewing' sarcoma (including sarcoma, fibrosarcoma, sarcoma, carcinoma of the skin, sarcomas including the skin, sarcomas such as carcinoma, carcinoma of the skin, carcinoma of the human skin, carcinoma of the skin, such as the skin, carcinoma of the skin, carcinoma of the human skin, etc.).

Hematological malignancies include, but are not limited to, blast-like dendritic cell neoplasms (BPDCN), heavy chain diseases, leukemias (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 myelomonocytic leukemia or M4 AML, acute monocytic leukemia or M5 AML), B-cell leukemia, chronic Lymphocytic Leukemia (CLL), chronic myelomonocytic leukemia (CMML), chronic Myelogenous Leukemia (CML), pre-B acute lymphocytic leukemia (pre-B ALL), diffuse large B-cell lymphoma (DLBCL), extranodal NK/T-cell lymphoma, hairy cell leukemia, HHV 8-associated primary exudative lymphoma, plasmablone lymphoma, primary CNS lymphoma, primary mediastinal large B-cell lymphoma, T-cell-enriched B-cell lymphoma), lymphomas (including, but not limited to hodgkin's lymphoma, non-hodgkin's lymphoma, lymphomatosis), myelomas, multiple Myeloma (MDS), myelodysplasia (dysmyelomas), and myelomas (lymphomas).

Immunotherapy holds great promise for achieving long-lasting antitumor effects. Immune checkpoint PD-1 and CTLA-4 blocking 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, are present in TME in even greater numbers than T cells. In fact, monocyte-derived macrophages are the most abundant population of immune cells in tumor tissue. Although these innate cells have the ability to kill tumor cells and initiate or reactivate T cells, they become dysfunctional in TMEs and become MDSCs and tumor-associated macrophages (TAMs) that support tumor development and inhibit immune monitoring and attack. MDSCs, including monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs), represent heterogeneous populations of immature myeloid cells that fail to terminally differentiate. TAMs are a mixed macrophage population in TMEs. TAMs are anti-inflammatory and are associated with poor prognosis. MDSCs and TAMs are defined by their immunosuppressive function, despite their phenotypic plasticity. Removal, reprogramming or blocking the transport of these immunosuppressive monocytes is becoming an attractive therapeutic strategy for anticancer.

LILRB1 is expressed on MDSC and TAM in TME. Therapeutic blockade of LILRB1 has the potential to reactivate or enhance an anti-tumor immune response in patients presenting with a disease that is unresponsive/recurrent to T cell checkpoint inhibitors.

LILRB1 expression on myeloid cells can regulate systems involved in autoimmune and inflammatory diseases. Therapeutic activation or agonism 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, it is a viral disease with autoimmune components), 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-dermatitis herpetiformis, chronic Fatigue Immune Dysfunction Syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, condensed collectin, crest syndrome, crohn's disease, degoss disease, juvenile dermatomyositis, lupus, primary mixed cryoglobulinemia fibromyalgia-fibromyositis, graves' disease, grignard-Barlich syndrome, hashimoto thyroiditis, idiopathic pulmonary fibrosis, idiopathic Thrombocytopenic Purpura (ITP), igA nephropathy, insulin dependent diabetes mellitus, juvenile chronic arthritis (Style's disease), juvenile rheumatoid arthritis, meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyadenopathy, polymyositis and dermatomyositis, idiopathic agaropectinemia, idiopathic biliary cirrhosis, psoriasis, psoriatic arthritis, raynaud's phenomenon, lyter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, systemic scleroderma, progressive Systemic Sclerosis (PSS), systemic Sclerosis (SS), sjogren's syndrome, stiff person syndrome, systemic Lupus Erythematosus (SLE), takayasu's arteritis, temporal arteritis/giant cell arteritis, inflammatory Bowel Disease (IBD), ulcerative colitis, coanda disease, intestinal mucosa inflammation, consumption diseases associated with colitis, uveitis, vitiligo and wegener's granulomatosis, alzheimer's disease, asthma, atopic allergy, 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 infection, autoimmune diabetes and the like. Inflammatory disorders include, for example, chronic and acute inflammatory disorders.

Treatment of disease

A. Formulation and administration

The present disclosure provides pharmaceutical compositions comprising an anti-LILRB antibody and an antigen for producing the antibody. Such compositions comprise a prophylactically or therapeutically effective amount of an antibody or fragment thereof, and a pharmaceutically acceptable carrier. In particular embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is a specific carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be employed 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, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

The composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like. Oral formulations may include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable agents are described in Remington's pharmaceutical sciences (Remington's Pharmaceutical Sciences). Such compositions will contain a prophylactically or therapeutically effective amount of the antibody or fragment thereof, preferably in purified form, together with a suitable amount of carrier, so as to provide a form for appropriate administration to a patient. The formulation should be suitable for the mode of administration, which may be oral, intravenous, intra-arterial, intra-buccal, intranasal, nebulized, bronchial inhalation, or delivery by mechanical ventilation.

As described herein, the antibodies of the present disclosure may be formulated for parenteral administration, e.g., formulated for injection by intradermal, intravenous, intraarterial, intramuscular, subcutaneous, intratumoral, or even intraperitoneal routes. Alternatively, the antibodies may be administered directly to the mucosa by a topical route, for example by nasal drops, inhalation or by nebulizer. Pharmaceutically acceptable salts include acid salts, and the 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, and the like. Salts formed from the free carboxyl groups may also be derived from inorganic bases (e.g., sodium, potassium, ammonium, calcium or ferric hydroxides) and organic bases (e.g., isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine (procaine), and the like).

Passive transfer of antibodies, known as artificially obtained passive immunization, will typically involve the use of intravenous injection. The antibody may be in the form of human or animal plasma or serum, as a mixed human immunoglobulin for intravenous (IVIG) or Intramuscular (IG), as high titers of human IVIG or IG from immunized or from disease-recovering donors, and as monoclonal antibodies (mabs). Such immunization generally lasts only for a short period of time and there is also a potential risk of hypersensitivity and serum sickness, especially of non-human origin. However, passive immunization provides immediate protection. The antibodies will be formulated in a carrier suitable for injection (i.e., sterile and injectable).

Typically, the components of the compositions of the present disclosure are provided separately or mixed together in unit dosage form, e.g., as a dry lyophilized powder or anhydrous concentrate in a hermetically sealed container, such as an ampoule or generally a sachet, indicating the amount of active agent. In administering the composition by infusion, it may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. When the composition is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.

The compositions of the present disclosure may be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, and the like, and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

B. Cell therapy

In another aspect, the disclosure provides an immune cell expressing a Chimeric Antigen Receptor (CAR). In some embodiments, the CAR comprises an antigen binding fragment provided herein. In one embodiment, the CAR protein comprises, from N-terminus to C-terminus: leader peptide, anti-LILRB 1 heavy chain variable domain, linker domain, anti-LILRB 1 light chain variable domain, human IgG1-CH2-CH3 domain, spacer region, CD28 transmembrane domain, 4-1BB intracellular co-stimulatory signaling and CD3 zeta intracellular T cell signaling domain.

Also provided are methods for immunotherapy comprising administering an effective amount of an immune cell of the present disclosure. In one embodiment, the medical disease or disorder is treated by transferring a population of immune cells that elicit an immune response. In certain embodiments of the present disclosure, the cancer or infection is treated by transferring a population of immune cells that elicit an immune response. Provided herein are methods for treating or delaying progression of cancer in an individual, the methods comprising administering to the individual an effective amount of antigen-specific cell therapy.

The immune cells may be T cells (e.g., regulatory T cells, cd4+ T cells, cd8+ T cells, or gamma-delta T cells), NK cells, constant NK cells, NKT cells, or macrophages. Also provided herein are methods of generating and engineering immune cells, and methods of using and administering cells for adoptive cell therapy, in which case the cells may be autologous or allogeneic. Thus, immune cells can be used as immunotherapies, such as targeting cancer cells.

Immune cells may be isolated from a subject, particularly a human subject. Immune cells may be obtained from healthy human subjects, healthy volunteers or healthy donors. Immune cells may be obtained from a subject of interest, such as a subject suspected of having a particular disease or condition, a subject suspected of having a susceptibility to a particular disease or condition, or a subject being treated for a particular disease or condition. Immune cells may be collected from any location where immune cells are present in a subject, including but not limited to blood, cord blood, spleen, thymus, lymph nodes, and bone marrow. The isolated immune cells may be used directly or the isolated immune cells may be stored for a period of time, such as by freezing.

Immune cells may be enriched/purified from any tissue in which the immune cells are located, including, but not limited to, blood (including blood collected from a blood bank or umbilical cord blood bank), spleen, bone marrow, tissue removed and/or exposed during surgery, and tissue obtained by biopsy procedures. The tissue/organ from which the immune cells are enriched, isolated and/or purified may be isolated from both living and non-living subjects, wherein the non-living subjects are organ donors. In certain embodiments, the 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 inhibition. In particular aspects, immune cells are isolated from pooled blood, particularly pooled cord blood, to enhance immunomodulation. Pooled blood may be from 2 or more sources, such as 3, 4, 5, 6, 7, 8, 9, 10 or more sources (e.g., donor subjects).

The population of immune cells may be obtained from a subject in need of therapy or suffering from a disease associated with reduced immune cell activity. Thus, the cells will be autologous to the subject in need of therapy. Alternatively, the immune cell population may be obtained from a donor, preferably a histocompatibility matched donor. The immune cell population may be collected from peripheral blood, cord blood, bone marrow, spleen, or any other organ/tissue in which immune cells are present in the subject or donor. Immune cells may be isolated from a group of subjects and/or donors, such as from pooled cord blood.

When the population of immune cells 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 the cells can be introduced into the subject. Allogeneic donor cells may or may not be compatible with Human Leukocyte Antigens (HLA). In order to be compatible with the subject, the allogeneic cells may 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 for cancer antigens. In certain embodiments, NK cells are engineered to express a TCR. NK cells can be further engineered to express CARs. Multiple CARs and/or TCRs, such as for different antigens, may be added to a single cell type, such as a T cell or NK cell.

Suitable modification methods are known in the art. See, e.g., sambrook et al, supra; and Ausubel et al, current guidelines for molecular biology experiments (Current Protocols in Molecular Biology), green publication society (Greene Publishing Associates) and John Wiley father-son company (John Wiley & Sons), new York, 1994. For example, cells can be transduced to express T Cell Receptors (TCRs) that are antigen specific for cancer antigens using transduction techniques described in heimskerk et al (2008) and Johnson et al (2009).

In some embodiments, the cells include one or more nucleic acids encoding one or more antigen receptors introduced by genetic engineering, as well as genetically engineered products of such nucleic acids. In some embodiments, the nucleic acid is heterologous, i.e., is not normally present in the cell or in a sample obtained from the cell, such as a sample obtained from another organism or cell, e.g., it is not normally found in the engineered cell and/or an organism from which such cell is derived. In some embodiments, the nucleic acid is not naturally occurring, such as a nucleic acid not found in nature (e.g., chimeric).

C. Combination therapy

It may also be desirable to provide combination therapies using the antibodies of the present disclosure in combination with additional anti-cancer therapies. These therapies will be provided in a combined amount effective to reduce one or more disease parameters. This process may involve contacting the cell/subject with two agents/therapies simultaneously, e.g., using a single composition or pharmacological formulation comprising both agents, or by contacting the cell/subject with two different compositions or formulations simultaneously, wherein one composition comprises an antibody and the other composition comprises the other agent.

Alternatively, the antibodies may be spaced minutes to weeks before or after other treatments. It is generally ensured that no significant period of time is exceeded between each delivery time, so that the therapy will still be able to exert an advantageous combined effect on the cells/subject. In such cases, it is contemplated that the cells are contacted in two ways within about 12 to 24 hours of each other, within about 6 to 12 hours of each other, or only within a delay time of about 12 hours. In some cases, it may be desirable to significantly extend the treatment period; however, wherein several 10 (2, 3, 4, 5, 6 or 7) days to several (1, 2, 3, 4, 5, 6, 7 or 8) weeks of time are required between respective administrations.

It is also contemplated that more than one administration of an anti-LILRB 1 antibody or other therapy would be desirable. Various combinations may be employed, where the antibody is "a" and the other therapy is "B", as exemplified 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 are contemplated. In order to kill cells, inhibit cell growth, inhibit metastasis, inhibit angiogenesis, or otherwise reverse or reduce the malignant phenotype of tumor cells, a target cell or site may be contacted with an antibody and at least one other therapy using the methods and compositions of the invention. These therapies will be provided in a combined amount effective to kill or inhibit proliferation of the cancer cells. This process may involve contacting the cells/sites/subjects with the agent/therapy simultaneously.

Specific agents contemplated for use in combination therapy with the antibodies of the present disclosure include chemotherapy and hematopoietic stem cell transplantation. Chemotherapy may include cytarabine (ara-C) and anthracycline (most commonly daunorubicin), high dose arabinoside alone, all-trans retinoic acid (ATRA) in addition to induction chemotherapy, anthracyclines, histamine dihydrochloride (cplene) and interleukin 2 (Proleukin) usually after completion of consolidation therapy, gemtuzumab ozogamicin (gemtuzumab ozogamicin) (Mylotarg), clofarabine and targeted therapies such as kinase inhibitors, inhibitors of farnesyl transferase, decitabine and MDR1 (multidrug resistance protein) or arsenic trioxide or recurrent Acute Promyelocytic Leukemia (APL) in patients with recurrent AML over 60 years of age who are candidates for high dose chemotherapy.

In certain embodiments, the agent of the combination therapy is one or more drugs selected from the group consisting of: topoisomerase inhibitor, anthracycline, daunorubicin (daunorubicin), nucleoside metabolism inhibitor, cytarabine (cytarabine), hypomethylation agent, low dose cytarabine (LDAC), combination of daunorubicin and cytarabine, daunorubicin for injection and cytarabine liposome, Azacytidine, (-) -and>decitabine, all-trans retinoic acid (ATRA), arsenic trioxide, histamine dihydrochloride,/-for>Interleukin-2, aldesleukin,>getuzumab ozogamicin, < - > and->FLT-3 inhibitors, midostaurin, < >>Clofarabine, farnesyl transferase inhibitor, decitabine, IDH1 inhibitor, ai Funi cloth (ivosidenib),IDH2 inhibitors, etanercept (enastinib), and->Smoothing (SMO) inhibitors, glagil (glasdegib), arginase inhibitors, IDO inhibitors, ai Kaduo stava (epacoadostat), BCL-2 inhibitors, valnematode,>platinum complex derivatives, oxaliplatin, kinase inhibitors, tyrosine kinase inhibitors, PI3 kinase inhibitors, BTK inhibitors, ibrutinib (ibrutinib), and->Acartinib (acalabrutinib),Zanbutinib (zanubutinib), PD-1 antibodies, PD-L1 antibodies, CTLA-4 antibodies, LAG3 antibodies, ICOS antibodies, TIGIT antibodies, TIM3 antibodies, CD40 antibodies, 4-1BB antibodies, CD47 antibodies, SIRP1 alpha antibodies or fusion proteins, CD70 antibodies and CLL1 antibodies, CD123 antibodies, antagonists of E-selectin, antibodies that bind to tumor antigens, antibodies that bind to T cell surface markers, antibodies that bind to myeloid cells or NK cell surface markers, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, plant-derived alkaloids, hormone therapy drugs, hormone antagonists, aromatase inhibitors and P-glycoprotein inhibitors.

V. antibody conjugates

The antibodies of the present disclosure can be linked to at least one agent to form an antibody conjugate. To enhance the efficacy of an antibody molecule as a diagnostic or therapeutic agent, it is common to link or covalently bind or complex at least one desired molecule or moiety. Such a molecule or moiety may be, but is not limited to, at least one effector or reporter molecule. Effector molecules include molecules having a desired activity, such as cytotoxic activity. Non-limiting examples of effector molecules that have been linked to antibodies include toxins, antineoplastic agents, therapeutic enzymes, radionuclides, antiviral agents, chelators, cytokines, growth factors, and oligonucleotides or polynucleotides. In contrast, a reporter is defined as any moiety that can be detected using an assay. Non-limiting examples of reporter molecules that have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, photoaffinity molecules, colored particles or ligands, such as biotin.

Antibody-drug conjugates have become a breakthrough method for developing cancer therapies. Antibody-drug conjugates (ADCs) include monoclonal antibodies (mabs) covalently linked to cell killing drugs. This approach combines the high specificity of a MAb against its antigen target with a highly potent cytotoxic drug, resulting in "armed" MAb that delivers a payload (drug) to tumor cells with enriched antigen levels. Targeted delivery of drugs can also minimize their exposure in normal tissues Dew, thereby reducing toxicity and increasing therapeutic index. FDA vs two ADC drugs: 2011(Bentuximab (brentuximab vedotin)) and +.2013>Approval of either trastuzumab maytansinoid (trastuzumab emtansine) or T-DM1 validated the method. Currently, more than 30 ADC candidate drugs are in various stages of the clinical trial for cancer treatment (Leal et al, 2014). As antibody engineering and linker-payload optimization become more mature, the discovery and development of new ADCs is increasingly dependent on the identification and validation of new targets suitable for this approach and the generation of targeted mabs. Two criteria for ADC targets are up-regulated/high level expression in tumor cells and robust internalization.

The antibody conjugates are also preferably used as diagnostic agents. Antibody diagnostics are generally divided into two classes, one for in vitro diagnostics, such as various immunoassays, and another for in vivo diagnostic protocols, commonly referred to as "antibody-directed imaging. Many suitable imaging agents are known in the art, as well as methods of their attachment to antibodies (see, e.g., U.S. Pat. nos. 5,021,236, 4,938,948 and 4,472,509). The imaging moiety used may be paramagnetic ions, radioisotopes, 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), iron (II), 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 for therapeutic and/or diagnostic applications, astatine may be mentioned ²¹¹ 、 ¹⁴ Carbon (C), ⁵¹ Chromium (Cr), ³⁶ Chlorine (Cl), ⁵⁷ Cobalt (Co), ⁵⁸ Cobalt, copper ⁶⁷ 、 ¹⁵² Eu, ga ⁶⁷ 、 ³ Hydrogen, iodine ¹²³ Iodine ¹²⁵ Iodine ¹³¹ Indium (indium) ¹¹¹ 、 ⁵⁹ Iron (Fe), ³² Phosphorus, rhenium ¹⁸⁶ Rhenium (Re) ¹⁸⁸ 、 ⁷⁵ Selenium (Se), ³⁵ Sulfur, technetium ^99m And/or yttrium ⁹⁰ 。 ¹²⁵ I is generally preferred for use in certain embodiments, and technetium ^99m And/or indium ¹¹¹ It is also generally preferred because of its low energy and suitability for long range detection. The radiolabeled monoclonal antibodies of the present disclosure may be produced according to methods well known in the art. For example, monoclonal antibodies can be iodinated by contacting with sodium and/or potassium iodide, a chemical oxidizing agent such as sodium hypochlorite, or an enzymatic oxidizing agent such as lactoperoxidase. Technetium can be used by ligand exchange procedures ^99m Monoclonal antibodies according to the present disclosure are labeled, for example, by reducing pertechnetate with a stannous solution, chelating the reduced technetium onto a Sephadex column (Sephadex column), and applying the antibodies to this column. Alternatively, direct labelling techniques may be used, for example by incubating pertechnetate, e.g.SNCl ₂ Buffer solutions such as sodium potassium phthalate solutions, and antibodies. The intermediate functional group commonly used to bind a radioisotope present as a metal ion to an antibody is diethylenetriamine pentaacetic acid (DTPA) or ethylenediamine tetraacetic acid (EDTA).

Fluorescent labels contemplated for use as conjugates include Alexa 350, alexa 430, AMCA, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, cascading blue, cy3, cy5,6-FAM, fluorescein isothiocyanate, HEX, 6-JOE, oreg green 488, oreg green 500, oreg green 514, pacific blue, REG, rhodamine green, rhodamine red, renal contrast agent (Renographin), ROX, TAMRA, TET, tetramethyl rhodamine, and/or Texas red.

Another type of antibody conjugate contemplated in the present disclosure is an antibody conjugate intended primarily for use in vitro, wherein the antibody is linked to a secondary binding ligand and/or an enzyme (enzyme tag) that will produce 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 and streptavidin compounds. The use of such markers is well known to those skilled in the art and is described, for example, in U.S. Pat. nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149 and 4,366,241.

Yet another known method of site-specific attachment of a molecule to an antibody involves the reaction of the antibody with a hapten-based affinity tag. Essentially, hapten-based affinity tags react with amino acids in the antigen binding site, thereby disrupting this site and blocking specific antigen reactions. However, this may not be advantageous as it results in the antibody conjugate losing antigen binding.

Molecules containing azido groups can also be used to form covalent bonds with proteins via reactive aza-ene intermediates generated by low intensity uv light (Potter and Haley, 1983). Specifically, 2-and 8-azido analogs of purine nucleotides have been used as site-directed optical probes to identify nucleotide binding proteins in crude cell extracts (Owens and Haley,1987; athereton et al, 1985). 2-and 8-azido nucleotides 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 binding agents.

Several methods for linking or conjugating antibodies to their conjugate moieties are known in the art. Some ligation methods involve the use of metal chelate complexes using, for example, organic chelators such as diethylenetriamine pentaacetic acid (DTPA); ethylene triamine tetraacetic acid; n-chloro-p-toluenesulfonamide; and/or tetrachloro-3 alpha-6 alpha-diphenylglycoluril-3 linked to antibodies (U.S. Pat. nos. 4,472,509 and 4,938,948). Monoclonal antibodies may also be reacted with enzymes in the presence of coupling agents such as glutaraldehyde or periodate. Conjugates with fluorescein markers are prepared in the presence of these coupling agents or by reaction with isothiocyanates. In us patent 4,938,948, imaging of breast tumors is achieved using monoclonal antibodies, and the detectable imaging moiety is conjugated to the antibody using a linker such as methylparaben or N-succinimidyl-3- (4-hydroxyphenyl) propionate.

In other embodiments, it is contemplated that the immunoglobulin is derivatized by selectively introducing sulfhydryl groups in the Fc region of the immunoglobulin using reaction conditions that do not alter the binding site of the antibody. Antibody conjugates produced according to this method are disclosed to exhibit improved longevity, specificity, and sensitivity (U.S. patent 5,196,066, which is incorporated herein by reference). Site-specific ligation of effectors or reporter molecules has also been disclosed in the literature (O' Shannessy et al, 1987), wherein the reporter or effector molecule is conjugated to carbohydrate residues in the Fc region. This approach is reported to produce antibodies that are currently in clinical evaluation with diagnostic and therapeutic promise.

VI immunoassay method

In still further embodiments, the present disclosure relates to an immunoassay method for binding, purifying, removing, quantifying, and generally otherwise detecting LILRB-associated cancers. While such methods may be applied in a traditional sense, another use would be quality control and monitoring of vaccines and other virus stocks, wherein antibodies according to the present disclosure can be used to assess the amount or integrity (i.e., long term stability) of H1 antigen in a virus. Alternatively, the method may be used to screen various antibodies to obtain a suitable/desired response profile.

Some immunodetection methods include enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), immunoradiometric assays, fluoroimmunoassay, chemiluminescent assays, bioluminescent assays, and western blots, to name a few. In particular, competitive assays for detecting and quantifying LILRB are also provided. The steps of various useful immunoassays have been described in the scientific literature, such as Doolittle and Ben-Zeev (1999); gulbis and Galand (1993); de Jager et al (1993) and Nakamura et al (1987). Generally, the immunological binding method comprises obtaining a sample suspected of containing a LILRB-associated cancer, and contacting the sample with a primary antibody according to the present disclosure, as the case may be, under conditions effective to allow formation of an immune complex.

These methods include methods for detecting or purifying LILRB or LILRB-associated cancer cells from a sample. The antibodies will preferably be attached to a solid support, such as in the form of a column matrix, and a sample suspected of containing LILRB-associated cancer cells is applied to the immobilized antibodies. Unwanted components will be washed out of the column, LILRB expressing cells are immunocomplexed with the immobilized antibodies, which are then collected by removing the organisms or antigens from the column.

The 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 will be obtained, and the sample will be contacted with an antibody that binds to LILRB or a component thereof, followed by detecting the amount of immune complex formed under specific conditions and quantifying it. In terms of antigen detection, the biological sample analyzed may be any sample suspected of containing LILRB-associated cancer, such as a tissue slice or specimen, homogenized tissue extract, biological fluid including blood and serum, or secretions such as feces or urine.

Contacting the selected biological sample with the antibody under effective conditions and for a period of time sufficient to allow formation of an immune complex (primary immune complex) typically requires only the addition of an antibody composition to the sample and incubating the mixture for a period of time sufficient for the antibody to form an immune complex with, i.e., bind to, LILRB. After this time, the sample-antibody composition, such as a tissue section, ELISA plate, dot blot, or western blot, will typically be washed to remove any non-specifically bound antibody species, thereby detecting only those antibodies that specifically bind within the primary immune complex.

In general, detection of immune complex formation is well known in the art and can be accomplished by applying a number of methods. These methods are generally based on the detection of labels or markers such as any of those radioactive, fluorescent, biological and enzymatic tags. Patents relating to the use of such labels include U.S. Pat. nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149 and 4,366,241. Of course, additional advantages may be found by using secondary binding ligands such as secondary antibodies and/or biotin/avidin ligand binding arrangements, as known in the art.

The antibody itself used in the detection may be linked to a detectable label, wherein this label may then simply be detected, whereby the amount of primary immune complex in the composition may be determined. Alternatively, the first antibody bound within the primary immune complex may be detected by a second binding ligand having binding affinity for the antibody. In these cases, the second binding ligand may be linked to a detectable label. The second binding ligand is itself typically an antibody, and thus may be referred to as a "secondary" antibody. The primary immune complex is contacted with a labeled secondary binding ligand or antibody under effective conditions and for a period of time sufficient to allow formation of the secondary immune complex. The secondary immune complex is then typically washed to remove any non-specifically bound labeled secondary antibodies or ligands, and the remaining label in the secondary immune complex is then detected.

An additional method involves detecting the primary immune complex by a two-step method. As described above, a second binding ligand, such as an antibody having binding affinity for the antibody, is used to form a secondary immune complex. After washing, the secondary immune complex is contacted with a third binding ligand or antibody having binding affinity for the second antibody again under effective conditions for a period of time sufficient to allow the formation of an immune complex (tertiary immune complex). The third ligand or antibody is linked to a detectable label, allowing detection of the tertiary immune complex thus formed. This system may provide signal amplification if desired.

One immunoassay method uses two different antibodies. The first biotinylated antibody is used to detect the target antigen and then the second antibody is used to detect biotin attached to the complexed biotin. In the method, the sample to be detected is first incubated in a solution containing the first step antibody. If the target antigen is present, some of the antibodies bind to the antigen to form biotinylated antibody/antigen complexes. The antibody/antigen complex is then amplified by incubation in successive solutions of streptavidin (or avidin), biotinylated DNA and/or complementary biotinylated DNA, with each step adding additional biotin sites to the antibody/antigen complex. The amplification step is repeated until the appropriate level of amplification is reached, at which point the sample is incubated in a solution containing the second step anti-biotin antibody. This second step antibody is labeled, for example with an enzyme that can be used to detect the presence of the antibody/antigen complex by histology using a chromogenic substrate. By suitable amplification, macroscopic conjugates can be produced.

Another known immunoassay method utilizes an immuno-PCR (polymerase chain reaction) method. The PCR method is similar to the Cantor method until incubated with biotinylated DNA, however, instead of using multiple rounds of streptavidin and biotinylated DNA incubation, 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 to perform a PCR reaction with the appropriate primers and appropriate controls. At least in theory, the tremendous amplification capacity and specificity of PCR can be used to detect individual antigen molecules.

A.ELISA

In the simplest and direct sense of an immunoassay, 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 such techniques, and western blotting, dot blotting, FACS analysis, etc. may also be used.

In one exemplary ELISA, antibodies of the present disclosure are immobilized onto a selected surface exhibiting protein affinity, such as a well in a polystyrene microtiter plate. Then, a test composition suspected of containing LILRB-associated cancer cells is added to the well. After binding and washing to remove non-specifically bound immune complexes, bound antigen can be detected. Detection may be achieved by the addition of another anti-LILRB antibody linked to a detectable label. This type of ELISA is a simple "sandwich ELISA". Detection may also be achieved by adding a second anti-LILRB 1 antibody followed by a third antibody having binding affinity for the second antibody, wherein the third antibody is linked to a detectable label.

In another exemplary ELISA, a sample suspected of containing LILRB 1-associated cancer cells is immobilized onto the well surface and then contacted with an anti-LILRB 1 antibody of the present disclosure. After binding and washing to remove non-specifically bound immune complexes, bound anti-LILRB 1 antibodies were detected. In the case where the original anti-LILRB 1 antibody is linked to a detectable label, the immune complex can be detected directly. Likewise, the immune complex may be detected using a second antibody having binding affinity to the first anti-LILRB 1 antibody, wherein the second antibody is linked to a detectable label.

Regardless of the format employed, ELISA has certain common features 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 with a solution of the antigen or antibody overnight or for a specified period of time. The wells of the plate will then be washed to remove incompletely adsorbed material. Any remaining available surface of the wells is then "coated" with a non-specific protein that is antigen neutral to the test antisera. These non-specific proteins include Bovine Serum Albumin (BSA), casein or milk powder solutions. The coating allows blocking of non-specific adsorption sites on the immobilized surface and thus reduces the background caused by non-specific binding of antisera to the surface.

In ELISA, it may be more customary to use secondary or tertiary detection means than direct procedures. Thus, after binding of proteins or antibodies to the wells, coating with non-reactive material to reduce background, and washing to remove unbound material, the immobilized surface is contacted with the biological sample to be tested under conditions effective to allow formation of immune complexes (antigen/antibody). Detection of the immunocomplexes then requires a labeled secondary binding partner or antibody, and a secondary binding partner or antibody that binds to the labeled tertiary or tertiary binding partner.

By "under conditions effective to permit formation of immune complexes (antigen/antibody)" is meant that the conditions preferably include dilution of 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 non-specific background.

"suitable" conditions also mean that the temperature or period of incubation is sufficient for effective binding. The incubation step is typically about 1 to 2 to 4 hours or so, preferably about 25 to 27 ℃, or may be about 4 ℃ or so overnight.

After all incubation steps in ELISA, the contacted surfaces were washed to remove non-composite material. Preferred washing procedures include washing with solutions such as PBS/Tween or borate buffers. After formation of specific immune complexes between the test sample and the initially bound material and subsequent washing, the presence of even minute amounts of immune complexes can be determined.

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

After incubation with the labeled antibody and after washing to remove unbound material, e.g. by washing with e.g. urea or bromocresol purple or 2,2' -azido-bis- (3-ethyl-benzothiazoline-6-sulfonic Acid) (ABTS) or H with peroxidase as enzyme label ₂ O ₂ Incubation with chromogenic substrate to quantify the amount of label. Quantification is then achieved by measuring the degree of color produced, for example, using a visible spectrum spectrophotometer.

B. Western blot

Western blotting (alternatively, western 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 according to the length of the polypeptide (denaturing conditions) or the 3-D structure of the protein (native/non-denaturing conditions). The protein is then transferred to a membrane (typically nitrocellulose or PVDF) where it is probed (detected) using antibodies specific for the target protein.

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

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

To enable the protein to be detected by antibodies, the protein is moved from within the gel onto a membrane made of nitrocellulose or polyvinylidene difluoride (PVDF). The membrane was placed on top of the gel and a stack of filter papers was placed on top of the gel. The entire stack is placed in a buffer solution that moves on the paper by capillary action, thereby moving the proteins with the buffer solution. Another method for transferring proteins is called electroblotting and uses an electric current to pull the proteins from the gel into PVDF or nitrocellulose membranes. The protein moves from within the gel onto the membrane while maintaining the organization of the protein within the gel. Due to this blotting procedure, the proteins were exposed on a thin surface layer for detection (see below). Both membranes were chosen for their non-specific protein binding properties (i.e., binding to all proteins is equally good). Protein binding is based on hydrophobic interactions, as well as charged interactions between the membrane and the protein. Nitrocellulose membranes are cheaper than PVDF, but are more fragile and do not withstand repeated probing well. The uniformity and overall effectiveness of protein transfer from the gel to the membrane can be checked by staining the membrane with coomassie brilliant blue (Coomassie Brilliant Blue) or Ponceau S dye. Once transferred, the protein is detected using a labeled primary antibody or unlabeled primary antibody, followed by indirect detection using a labeled protein a or secondary labeled antibody that binds to the Fc region of the primary antibody.

C. Immunohistochemistry

The antibodies of the present disclosure may also be used in combination with freshly frozen and/or formalin-fixed, paraffin-embedded tissue blocks prepared for Immunohistochemical (IHC) studies. Methods for preparing tissue pieces from these particle 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; abbond et al, 1990; allred et al, 1990).

Briefly, frozen sections can be prepared by: rehydrating 50ng of frozen "crushed" tissue in Phosphate Buffered Saline (PBS) in small plastic capsules at room temperature; granulating the granules by centrifugation; re-suspending the particles in a viscous embedding medium (OCT); turning the capsules and/or re-granulating by centrifugation; quick-freezing in isopentane at-70deg.C; a freezing cylinder for cutting plastic capsules and/or removing tissue; fixing the tissue cylinder on a chuck of a slicer of a constant cooling box; and/or cutting from 25 to 50 serial sections from the capsule. Alternatively, the entire frozen tissue sample may be used for serial slice cutting.

Permanent sections can be prepared by a similar method involving rehydrating a 50mg sample in a plastic microcentrifuge tube; granulating; resuspended in 10% formalin for 4 hours fixation; washing/granulating; resuspended in warmed 2.5% agar; granulating; cooling in ice water to harden the agar; removing the tissue/agar block from the tube; infiltration and/or embedding of the blocks in paraffin; and/or cutting up to 50 consecutive permanent slices. Also, the entire tissue sample may be replaced.

D. Immunoassay kit

In still further embodiments, the present disclosure relates to an immunoassay kit for use with the immunoassay methods described above. Since antibodies can be used to detect LILRB-associated cancer cells, the antibodies can be included in a kit. Thus, the immunoassay kit will comprise in a suitable container means a primary antibody that binds to LILRB, and optionally an immunoassay reagent.

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

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

The kit may further comprise an appropriate aliquot of the LILRB composition, either labeled or unlabeled, which may be used to prepare a standard curve for the detection assay. The kit may contain the antibody-labeled conjugate in a fully conjugated form, in an intermediate form, or as a separate moiety conjugated by the user of the kit. The components of the kit may be packaged in aqueous medium or lyophilized form.

The container means of the kit typically comprises at least one vial, test tube, flask, bottle, syringe or other container means in which the antibody may be placed, or preferably suitably aliquoted. The kits of the present disclosure will also typically include a means for containing antibodies, antigens, and any other reagent containers in a tightly closed manner for commercial sale. Such containers may include injection or blow molded plastic containers that retain the desired vials therein.

E. Flow cytometry and FACS

Antibodies of the present disclosure may also be used in flow cytometry or FACS. Flow cytometry is a laser or impedance-based technique used in many detection assays, including cell counting, cell sorting, biomarker detection, and protein engineering. The techniques suspend cells in a fluid stream and pass the cells through an electronic detection device, allowing for multi-parameter analysis of physical and chemical properties of up to thousands of particles per second at the same time. Flow cytometry is commonly used to diagnose conditions, particularly hematological cancers, but there are many other applications in basic research, clinical practice, and clinical trials.

Fluorescence Activated Cell Sorting (FACS) is a special type of cytometry. Fluorescence activated cell sorting provides a method for sorting heterogeneous mixtures 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. In general, the technology relates to a cell suspension that is centered in a narrow, fast-flowing liquid stream. The fluid flow is arranged such that there is a substantial separation between the cells relative to their diameter. The vibration mechanism breaks the cell stream into individual droplets. Just prior to the stream breaking up into droplets, the 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 flow breaks up into droplets. Immediately prior to measuring fluorescence intensity, a charge is placed on the ring and when the droplet breaks apart from the stream, the opposite charge is trapped on the droplet. The charged droplets then fall through an electrostatic deflection system that transfers the droplets into a container based on their charge.

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

VII kit

In various aspects of 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 embodiments are provided. The kit may comprise one or more sealed vials containing any of the pharmaceutical compositions of the present embodiments. Kits can include, for example, at least one LILRB1 antibody or LILRB 1-specific CAR construct, as well as reagents for preparing, formulating, and/or administering the components of an embodiment or performing one or more steps of the methods of the invention. In some embodiments, the kit may further comprise a suitable container, which is a container that will not react with components of the kit, such as an eppendorf tube (eppendorf tube), assay plate, syringe, bottle, or tube. The container may be made of a sterilizable material such as plastic or glass.

The kit may further comprise instructions summarizing the procedural steps of the methods described herein and will follow substantially the same procedures as described herein or known to one of ordinary skill in the art. The instruction information may be in a computer readable medium containing machine readable instructions that when executed using a computer result in the display of a real or virtual program that delivers a pharmaceutically effective amount of the therapeutic agent.

VIII definition of

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application, as claimed. In the present application, the use of the singular includes the plural unless specifically stated otherwise. In the present application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "include" and other forms of use such as "include" and "include" are not limiting. Furthermore, unless specifically stated otherwise, terms such as "element" or "component" encompass both elements and components comprising one unit as well as elements and components comprising more than one subunit. Furthermore, the use of the term "portion" may include a portion of a portion or the entire portion.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "about" as used herein, when referring to measurable values such as amount, duration, etc., is intended to encompass a maximum of + -10% variation of the indicated value. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weight, reaction conditions), and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the disclosed subject matter. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The term "antibody" refers to a complete immunoglobulin of any isotype or fragment thereof that can compete with the complete 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 typically comprise at least two full length heavy chains and two full length light chains, but in some cases may comprise fewer chains, such as an antibody naturally occurring in the camelidae, which may comprise only heavy chains. The antibodies may be derived from only a single source, or may be "chimeric", i.e., different portions of the antibodies may be derived from two different antibodies, as described further below. Antigen binding proteins, antibodies or binding fragments may be produced in hybridomas by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term "antibody" includes derivatives, variants, fragments and muteins thereof, except antibodies comprising two full length heavy chains and two full length light chains, examples of which are described below. Furthermore, unless expressly excluded, antibodies include monoclonal antibodies, bispecific antibodies, minibodies, 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, respectively. In some embodiments, the term also encompasses peptibodies.

Naturally occurring antibody structural units typically comprise tetramers. Each such tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one full length "light" chain (in certain embodiments, about 25 kDa) and one full length "heavy" chain (in certain embodiments, about 50kDa to 70 kDa). The amino-terminal portion of each chain typically includes a variable region of about 100 to 110 or more amino acids that is typically responsible for antigen recognition. The carboxy-terminal portion of each chain typically defines a constant region that may be responsible for effector function. Human light chains are generally classified as kappa and lambda light chains. Heavy chains are generally classified as μ, δ, γ, α or ε, and the isotypes of antibodies 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 classified into subclasses, including but not limited to IgA1 and IgA2. In full length light and heavy chains, the variable and constant regions are typically joined by a "J" region having about 12 or more amino acids, with the heavy chain also including a "D" region having more than about 10 amino acids. See, e.g., basic immunology, chapter 7 (Paul, W.edit, 2 nd edition, rainbow Press (1989) of New York), which 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 the amino terminus of about 120 to 130 amino acids in the heavy chain and the amino terminus of about 100 to 110 amino acids in the light chain. In certain embodiments, the variable regions of different antibodies differ greatly in amino acid sequence, even in antibodies of the same species. The variable region of an antibody generally determines the specificity of a particular antibody for its target.

The variable regions typically exhibit the same general structure of relatively conserved Framework Regions (FR) connected by three hypervariable regions (also known as complementarity determining regions or CDRs). CDRs from both chains of each pair are typically aligned by a framework region that can bind to a particular epitope. From N-terminal to C-terminal, both the light chain variable region and the heavy chain variable region typically include domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain generally conforms to the definition of the Kabat sequence (Kabat Sequences of Proteins of Immunological Interest) of proteins of immunological interest (national institutes of health of Besseda, malyland (National Institutes of Health, bethesda, md.) (1987 and 1991)), chothia and Lesk, journal of molecular biology (J. Mol. Biol.), 196:901-917 (1987) or Chothia et al, nature, 342:878-883 (1989).

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

In certain embodiments, the explicit delineation of CDRs and the identification of residues comprising the antibody binding site is accomplished by resolving the structure of the antibody and/or resolving the structure of the antibody-ligand complex. In certain embodiments, this may be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various analytical methods may be employed to identify or mimic CDR regions. Examples of such methods include, but are not limited to, kabat definition, chothia definition, abM definition, and contact definition.

Kabat definition is a standard for numbering residues in antibodies and is commonly used to identify CDR regions. See, e.g., johnson and Wu, nucleic Acids Res., 28:214-8 (2000). The Chothia definition is similar to the Kabat definition, but the Chothia definition considers the location of certain structural loop regions. See, e.g., chothia et al, journal of molecular biology, 196:901-17 (1986); chothia et al, nature 342:877-83 (1989). AbM defines an integrated suite (integrated suite) of computer programs that model antibody structures produced by the oxford molecular group (Oxford Molecular Group). See, for example, martin et al, proc. Natl. Acad. Sci. USA (Proc Natl Acad Sci (USA)), 86:9268-9272 (1989); "AbM ^TM Computer program for modeling antibody variable regions (AbM ^TM A Computer Program for Modeling Variable Regions of Antibodies) ", oxford molecular limited, UK; oxford Molecular, ltd.). AbM definition the tertiary structure of antibodies from primary sequences was modeled using a combination of knowledge databases and ab initio methods, such as those described in the following documents: samulla et al, "from the head of protein Structure prediction using combinatorial layering methods (Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach)", protein, structure, function and genetics (PROTEINS, structure, function and Genetics), journal of Proc.3:194-198 (1999). The contact definition is based on an analysis of the complex crystal structure available. See, e.g., macCallum et al, J.Molec.Biol.5:732-45 (1996).

Conventionally, CDR regions in the heavy chain are commonly referred to as H1, H2, and H3, and are numbered sequentially in the direction from the amino terminus to the carboxy terminus. CDR regions in the light chain are commonly referred to as L1, L2 and L3 and are numbered sequentially in the direction from the amino terminus to the carboxy terminus.

The term "light chain" includes full length light chains and fragments thereof having sufficient variable region sequences to confer binding specificity. The full length light chain includes a variable region domain VL and a constant region domain CL. The variable region domain of the light chain is located at the amino terminus of the polypeptide. Light chains include kappa chains and lambda chains.

The term "heavy chain" includes full length heavy chains and fragments thereof having sufficient variable region sequences to confer binding specificity. The full length heavy chain includes 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 carboxy terminus, with CH3 closest to the carboxy terminus of the polypeptide. The heavy chain may be of any isotype including IgG (including IgG1, igG2, igG3 and IgG4 subtypes), igA (including IgA1 and IgA2 subtypes), igM and IgE.

"back mutation" is a mutation introduced in the nucleotide sequence encoding a humanized antibody that results in an amino acid corresponding to an amino acid in a parent antibody (e.g., a donor antibody, such as a rabbit antibody). Certain framework residues from the parent antibody may be retained during humanization of the antibodies of the invention in order 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 from a mouse. For example, back mutations change a human framework residue to a parent murine residue. Examples of framework residues that can be back mutated include, but are not limited to, canonical residues, interfacial stacking residues, unusual parent residues near the binding site, residues in the "vernier zone" (forming a platform on which the CDRs are stored) (Foote and Winter,1992, J. Mol. Biol. 224, 487-499), and those near CDR H3.

Bispecific or bifunctional antibodies are typically artificial hybrid antibodies having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods, including but not limited to fusion hybridomas or linked Fab' fragments. See, e.g., songsivilai et al, clinical and experimental immunology (Clin. Exp. Immunol.), 79:315-321 (1990); kostelny et al, J.Immunol.148:1547-1553 (1992).

The term "antigen" refers to a substance capable of inducing an adaptive immune response. In particular, antigens are substances that serve as targets for adaptive immune response receptors. Typically, an antigen is a molecule that binds to an antigen-specific receptor but is not itself capable of inducing an immune response in vivo. Antigens are typically proteins and polysaccharides, and less commonly also lipids. Suitable antigens include, but are not limited to, bacterial moieties (capsids, capsules, cell walls, flagella, pili, and toxins), viruses, and other microorganisms. Antigens also include tumor antigens, e.g., antigens resulting from mutations in tumors. Antigens, as used herein, also include immunogens and haptens.

As used herein, "antigen binding protein" ("ABP") means any protein that binds to a particular target antigen. In the present application, the specific target antigen is LILRB protein or a fragment thereof. "antigen binding proteins" include, but are not limited to, antibodies and antigen binding fragments thereof. A peptibody is another example of an antigen binding protein.

As used herein, the term "antigen binding fragment" refers to a portion of a protein that is capable of specifically binding to an antigen. In certain 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 comprise the complete native antibody structure. In certain embodiments, the antigen binding fragment is derived not from an antibody but from a receptor. Examples of antigen binding fragments include, but are not limited to, bifunctional antibodies, fab ', F (ab') ₂ Fv fragment, disulfide stabilized Fv fragment (dsFv), (dsFv) ₂ Bispecific dsFv (dsFv-dsFv'), disulfide stabilized diabodies (ds diabodies), single chain antibody molecules (scFv), scFv dimers (bivalent diabodies), multispecific antibodies, single domain antibodies (sdabs), camelized or nanobodies, domain antibodiesAnd bivalent domain antibodies. In certain embodiments, the antigen binding fragment is capable of binding to the same antigen to which the parent antibody binds. In certain embodiments, an antigen binding fragment may include one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies. In certain embodiments, the antigen binding fragment is derived from a receptor and contains one or more mutations. In certain embodiments, the antigen binding fragment does not bind to the natural ligand of the receptor from which the antigen binding fragment is derived.

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

"Fab ' fragments" include a light chain and a portion of a heavy chain such that an interchain disulfide bond can be formed between the two heavy chains of two Fab ' fragments to form F (ab ') ₂ A molecule, a portion of which contains a VH domain and a CH1 domain and also contains a region between the CH1 domain and the CH2 domain.

“F(ab') ₂ The fragment "contains two light chains and two heavy chains, such that an interchain disulfide bond is formed between the two heavy chains, which contain a portion of the constant region located between the CH1 domain and the CH2 domain. Thus, F (ab') ₂ Fragments are made up of two Fab' fragments held together by disulfide bonds located between the two heavy chains.

The "Fc" region includes two heavy chain fragments, including the CH1 domain and the CH2 domain of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

"Fv region" includes variable regions from both the heavy and light chains but lacks constant regions.

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

"domain antibodies" are immunologically functional immunoglobulin fragments that contain only the variable region of a heavy chain or the variable region of a light chain. In some cases, two or more VH regions are covalently linked to a peptide linker to produce a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.

A "bivalent antigen binding protein" or "bivalent antibody" includes two antigen binding sites. In some cases, the two binding sites have the same antigen specificity. The divalent antigen binding proteins and divalent antibodies may be bispecific, see below. In certain embodiments, bivalent antibodies other than "multispecific" or "multifunctional" antibodies are generally understood to have each of their binding sites identical.

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

A "bispecific", "bispecific" or "bifunctional" antigen-binding protein or antibody is a hybrid antigen-binding protein or antibody having two different antigen-binding sites, respectively. 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, fusion of hybridomas or ligation of Fab' fragments. See, e.g., songsivilai and Lachmann,1990, clinical and laboratory immunology 79:315-321; kostelny et al, 1992, J.Immunol.148:1547-1553. The two binding sites of the bispecific antigen binding protein or antibody will bind to two different 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). As used herein, unless otherwise indicated, "binding affinity" refers to an intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibodies and antigens). The affinity of a molecule X for its partner Y can generally be expressed by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies typically bind to antigen slowly and tend to dissociate easily, while high affinity antibodies typically bind to antigen faster and tend to remain bound longer. A variety of methods for measuring binding affinity are known in the art, any of which may be used for the purposes of the present invention. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An antibody that "specifically binds" or is "specific for" a particular polypeptide or epitope on a particular polypeptide is an antibody that binds to the particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. For example, the LILRB 1-specific antibodies of the invention are specific for LILRB 1. In some embodiments, the dissociation constant (Kd) of an antibody that binds to LILRB1 is +.100 nM, +.10 nM, +.1 nM, +.0.1 nM, +.0.01 nM or+.0.001 nM (e.g., 10nM ^-8 M or less, e.g. 10 ^-8 M to 10 ^-13 M, e.g. 10 ^-9 M to 10 ^-13 M). As used herein, dissociation constant Kd refers to the ratio of dissociation rate to association rate (k _off /k _on ) The ratio may be determined using any conventional method known in the art, including but not limited to surface plasmon resonance, microphoresis, HPLC-MS methods, and flow cytometry (e.g., FACS) methods. In certain embodiments, the Kd value can be suitably determined by using flow cytometry.

The term "compete" when used in the context of antigen binding proteins (e.g., antibodies or antigen binding fragments thereof) that compete for the same epitope means competition between antigen binding proteins as determined by assays in which the antigen binding protein (e.g., antibody or antigen binding fragment thereof) being tested prevents or inhibits (e.g., reduces) specific binding of a reference antigen binding protein (e.g., ligand or reference antibody) to a common antigen (e.g., LILRB or fragment thereof). Multiple types of competitive binding assays can be used to determine whether one antigen binding protein competes with another antigen binding protein, for example: solid phase direct or indirect Radioimmunoassay (RIA), solid phase direct or indirect Enzyme Immunoassay (EIA), sandwich competition assay (see, e.g., stahli et al, 1983, methods of enzymology (Methods in Enzymology) 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., kirkland et al, 1986, journal of immunology 137:3614-3619), solid phase direct labeling assay, solid phase direct labeling sandwich assay (see, e.g., harlow and Lane,1988, antibodies: laboratory Manual, cold spring harbor Press); RIA is directly labeled using a 1-125 labeled solid phase (see, e.g., morel et al, 1988, molecular immunology (molecular. Immunol.)) 25:7-15; solid phase direct biotin-avidin EIA (see, e.g., cheung et al, 1990, virology 176: 546-552); and direct labelling of RIA (Moldenhauer et al, 1990, J. Immunol.) (Scand. J. Immunol.) 32:77-82. Typically, such assays involve the use of purified antigens bound to a solid surface or cells carrying any of these, unlabeled test antigen binding proteins and labeled reference antigen binding proteins. Competitive inhibition is measured by determining the amount of label bound to a solid surface or cell in the presence of the test antigen binding protein. Typically, the test antigen binding protein is present in excess. Antigen binding proteins identified by competition assays (competing 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 an adjacent epitope that is sufficiently close to the epitope bound by the reference antigen binding protein to be sterically hindered. The examples herein provide additional detailed information about methods for determining competitive binding. Typically, when the competing antigen binding protein is present in excess, it will inhibit (e.g., reduce) specific binding of the reference antigen binding protein to the co-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 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 to which an antibody binds. The epitope may be a linear epitope or a conformational epitope. Linear epitopes are formed by contiguous amino acid sequences of antigens and interact with antibodies based on their primary structure. Conformational epitopes, on the other hand, consist of discrete segments of the amino acid sequence of the antigen and are based on the interaction of the 3D structure of the antigen with the antibody. Typically, an epitope is about five or six amino acids in length. Two antibodies may bind to the same epitope within an antigen if they exhibit competitive binding to the antigen.

As used herein, a "cell" may be prokaryotic or eukaryotic. Prokaryotic cells include, for example, bacteria. Eukaryotic cells include, for example, fungi, plant cells, and animal cells. Types of animal cells (e.g., mammalian cells or human cells) include, for example, cells from the circulatory/immune system or organs, e.g., 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 lobular neutrophils (hypersegmented neutrophil)), monocytes or macrophages, erythrocytes (e.g., reticulocytes), mast cells, platelets or megakaryocytes, and dendritic cells; cells from endocrine systems or organs, such as thyroid cells (e.g., thyroid epithelial cells, follicular cells), parathyroid cells (e.g., parathyroid main cells, eosinophils), adrenal cells (e.g., pheochromocytes), and pineal somatic cells (e.g., pineal gland cells); cells from the nervous system or organs, such as glioblasts (e.g., astrocytes and oligodendrocytes), microglia, large cell neurosecretory cells, astrocytes, burt's cells, and pituitary cells (e.g., gonadotrophin cells, adrenocorticotropic hormone cells, thyroid stimulating hormone cells, growth stimulating hormone cells, and lactogenic hormone cells); cells from the respiratory system or organs, for example, lung cells (type I and type II lung cells), clara cells (clara cells), goblet cells and alveolar macrophages; cells from the circulatory system or organ (e.g., cardiomyocytes and pericytes); cells from the digestive system or organs, for example, gastric mucosa primary cells, parietal cells, goblet cells, paneth cells (paneth cells), G cells, D cells, ECL cells, I cells, K cells, S cells, enteroendocrine cells, enteropheochromocytes, APUD cells, and hepatocytes (e.g., hepatocytes and Kupffer cells); cells from the skin system or organ, such as bone cells (e.g., osteoblasts, bone cells and osteoclasts), tooth cells (e.g., odontoblasts and amenorrhea cells), cartilage cells (e.g., chondroblasts and chondrocytes), skin/hair cells (e.g., hair cells, keratinocytes and melanocytes (nevi cells), muscle cells (e.g., muscle cells), adipocytes, fibroblasts and tendon cells, cells from the urinary system or organ (e.g., podocytes, peribulbar cells, mesangial cells, extrabulbar cells, perivascular cells and focal cells), and cells from the germ system or organ (e.g., sperm, sertoli cells), leigh cells (leydig cells), ova, oocytes), cells may be normal, healthy cells, or diseased or unhealthy cells (e.g., cancer cells), further including fertilized ova or stem cells of mammals including embryonic stem cells, fetal cells, multipotent stem cells, stem cells that are induced to be pluripotent stem cells, stem cells that are pluripotent cells that are stem cells that are capable of being differentiated (35, stem cells that are capable of being committed to be committed to multiple cell types, stem cells that are capable of being differentiated, any of the stem cells may be induced by somatic cells. Stem cells may also include cancer stem cells. The mammalian cells may be rodent cells, e.g., mouse cells, rat cells, hamster cells. The mammalian cells may be rabbit cells, for example, rabbit cells. The mammalian cells may also be primate cells, e.g. human cells.

The term "chimeric antigen receptor" or "CAR" as used herein 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 or signaling (e.g., T cell signaling or T cell activation domain) that activates immune cells (e.g., T cells or NK cells) (see, e.g., kershaw et al, supra, eshhar et al, proc. Natl. Acad. Sci. USA, 90 (2): 720-724 (1993) and Sadelain et al, current immunology view (curr. Opin. Immunol.)) 21 (2): 215-223 (2009)). The CAR is capable of redirecting immune cell specificity and reactivity to a selected target in a non-MHC-restricted manner using the antigen binding properties of monoclonal antibodies. non-MHC-restricted antigen recognition enables CAR-expressing immune cells to recognize antigen independent of antigen processing, bypassing the primary mechanism of tumor escape. In addition, when expressed in T cells, the CAR advantageously does not dimerize with endogenous T Cell Receptor (TCR) alpha and beta chains.

The term "host cell" means 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 a gene of interest. The term includes progeny of a parent cell, whether or not the progeny are identical in morphology or genetic constitution to the original parent cell, as long as the gene of interest is present.

The term "identity" refers to the relationship between sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. "percent identity" means the percentage of identical residues between amino acids or nucleotides in a comparison molecule and is calculated based on the size of the smallest molecule in the compared molecule. For these calculations, the gaps (if any) in the alignment are preferably accounted for by 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 polypeptides include those described in the following documents: calculated molecular biology (Computational Molecular Biology) (Lesk, a.m. edit), 1988, new york: oxford university press (New York: oxford University Press); bioinformatics and genome project (Biocomputing Informatics and Genome Projects) (Smith, d.w. editions), 1993, new york: academic Press (New York: academic Press); computer analysis of sequence data (Computer Analysis of Sequence Data), section I, (Griffin, a.m. and Griffin, h.g. editions), 1994, new jersey: humana Press (New Jersey: humana Press); von Heinje, g.,1987, sequence analysis in molecular biology (Sequence Analysis in Molecular Biology), new york: academic press; sequence analysis primer (Sequence Analysis Primer) (Gribskov, m. And Devereux, j. Edit), 1991, new york: rice Stoken Press (New York: M.Stockton Press); and Carilo et al, 1988, journal of applied math, J.Appli.Math., J.Industrial and applied math.J., 48:1073.

In calculating the percent identity, the sequences being compared are typically aligned in a manner that maximizes the match between the sequences. One example of a computer program that may be used to determine percent identity is the GCG program package, which includes GAP (Devereux et al, 1984, nucleic acids research 12:387; university of Madison, wis.) computer group of genetics, genetics Computer Group, university of Wisconsin. The computer algorithm GAP is used to align two polypeptides or polynucleotides for which percent sequence identity is to be determined. Sequences are aligned to achieve a best match of their corresponding amino acids or nucleotides ("match range", as determined by the algorithm). Gap opening penalties (which are calculated as 3 x average diagonal, where "average diagonal" is the average of the diagonals of the comparison matrix used; the "diagonal" is the score or number assigned to each perfect amino acid match by a particular comparison matrix) and gap extension penalties (which are typically 1/10 times the gap opening penalty) are used with the algorithm, such as PAM 250 or BLOSUM 62. In certain embodiments, a standard comparison matrix (see, e.g., dayhoff et al, 1978, protein sequence and structure atlas (Atlas of Protein Sequence and Structure), content of PAM 250 comparison matrix in 5:345-352; henikoff et al, 1992, proc. Natl. Acad. Sci. U.S. 89:10915-10919) is also used by the algorithm.

Examples of parameters that can be used to determine the percent identity of a polypeptide or nucleotide sequence using the GAP program can be found in: needleman et al, 1970, journal of molecular biology 48:443-453.

Some alignment schemes for aligning two amino acid sequences may result in only a short region of the two sequences matching, and this small alignment region may have very high sequence identity, although there is no significant relationship between the two full-length sequences. Thus, if desired, the selected alignment method (GAP program) may be adjusted to produce an alignment of at least 50 or other numbers of consecutive amino acids across the target polypeptide.

As used herein, the term "linked" refers to association by intramolecular interactions, such as covalent, metallic and/or ionic bonds, or intermolecular interactions, such as hydrogen bonding or noncovalent bonding.

The leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB 1) 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 found in the gene cluster of chromosome region 19q13.4. The encoded proteins belong to the subfamily B of LIR receptors containing 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 MHC class I molecules on antigen presenting cells and transduces negative signals that inhibit stimulation of an immune response. The receptors are thought to control inflammatory responses and cytotoxicity to help focus immune responses and limit autoreactivity.

The term "operably connected" refers to an arrangement of elements wherein the components so described are configured to perform their commonly employed functions. Thus, a given signal peptide operably linked to a polypeptide directs the secretion of the polypeptide from a cell. In the case of a promoter, a promoter operably linked to a coding sequence will direct the expression of the coding sequence. The promoter or other control element need not be contiguous with the coding sequence, so long as the promoter or other control element functions to direct its expression. For example, an intermediate untranslated but still transcribed sequence may be present between the promoter sequence and the coding sequence, and the promoter sequence may still be considered "operably linked" to the coding sequence.

The term "polynucleotide" or "nucleic acid" includes both single-stranded nucleotide polymers and double-stranded nucleotide polymers. The nucleotides comprising the polynucleotide may be ribonucleotides or deoxyribonucleotides or a modified form of either nucleotide type. Such modifications include base modifications such as bromouracil nucleosides and inosine derivatives, ribose modifications such as 2',3' -dideoxyribose and internucleotide linkage modifications such as phosphorothioates, phosphorodithioates, phosphoroselenos, phosphorodiselenos, phosphorothioate (phosphoanilothioate), phosphoroanilide (phosphosporanildate) and phosphoramidate.

The term "polypeptide" or "protein" means a macromolecule having the amino acid sequence of a native protein, i.e., a protein produced by naturally occurring and non-recombinant cells; or the protein is produced by a genetically engineered or recombinant cell and includes a molecule having the amino acid sequence of the native protein or a molecule having one or more amino acid deletions, additions and/or substitutions of the native sequence. The term also includes amino acid polymers in which one or more amino acids are chemical analogs and polymers corresponding to naturally occurring amino acids. The terms "polypeptide" and "protein" specifically encompass LILRB antigen binding proteins, antibodies, or sequences with deletions, additions and/or substitutions of one or more amino acids of the antigen binding protein. The term "polypeptide fragment" refers to a polypeptide having an amino terminal deletion, a carboxy terminal deletion, and/or an internal deletion as compared to the full-length native protein. Such fragments may also contain modified amino acids as compared to the native protein. In certain embodiments, the fragment is about five to 500 amino acids in length. For example, a fragment may be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids in length. Useful polypeptide fragments include immunologically functional 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 heavy and/or light chains, a portion of an antibody chain or its variable region comprising only two CDRs, and the like.

Pharmaceutically acceptable carriers useful in the present invention are conventional. Martin, lemington's pharmaceutical sciences, mark Publishing Co., iston, pa., 15 th 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 particular mode of administration employed. For example, parenteral formulations typically comprise injectable fluids including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol and the like as vehicles. For solid compositions (e.g., in powder, pill, tablet, or capsule form), conventional non-toxic solid carriers may include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to the biologically neutral carrier, the pharmaceutical composition to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives and pH buffering agents and the like, for example, sodium acetate or sorbitan 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 prenatal and postnatal forms. In many embodiments, the subject is a human. The subject may be a patient, which refers to a person presented to a medical provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient. The subject may or may not have a disease or condition, but may or may not exhibit symptoms of the disease or condition.

As used herein, the term "therapeutically effective amount" or "effective dose" refers to a dose or concentration of a drug effective to treat a disease or condition. For example, with respect to the use of the monoclonal antibodies or antigen-binding fragments thereof disclosed herein to treat cancer, a therapeutically effective amount is a dose or concentration of monoclonal antibodies or antigen-binding fragments thereof that is capable of reducing tumor volume, eradicating all or part of a tumor, inhibiting or slowing tumor growth or infiltration of cancer cells into other organs, inhibiting growth or proliferation of cells that mediate a cancerous condition, inhibiting or slowing metastasis of tumor cells, ameliorating any symptoms or markers associated with a tumor or cancerous condition, preventing or slowing the progression of a tumor or cancerous condition, or some combination thereof.

As used herein, "treating" or "treatment" of a condition includes preventing or alleviating the condition, slowing the onset or rate of progression of the condition, reducing the risk of developing the condition, preventing or delaying the progression of symptoms associated with the condition, alleviating or ending symptoms associated with the condition, producing complete or partial regression of the condition, curing the condition, or some combination thereof.

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

As used herein, "substantially free" with respect to a specified component is used herein to mean that the specified component is not deliberately formulated into a composition and/or is present as a contaminant or in trace amounts only. Thus, the total amount of the specified components resulting from any unintended contamination of the composition is well below 0.05%, preferably below 0.01%. Most preferred are compositions in which the amount of the specified component is not detectable using standard analytical methods.

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

IX. embodiment

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 materials and methods

Female NOD-SCID IL2 Rgamma-Null (NSG) mice, 6-8 weeks old (weighing about 20 g) purchased from the southwest medical center of the university of Texas (UT southwest) animal core facility. Mice were housed in pathogen free (SPF) rooms with 12 hours light/dark cycle, controlled room temperature, and ad libitum feeding and drinking. Mice were randomly assigned to each treatment group for the experiment.

The cell line and the original sample, expi293F (catalog No. a 14528) were obtained from life technologies company (Life Technologies) (Carlsbad). Hematological cancer cell line 697, MHH-CALL-2, OPM2 was purchased from DSMZ (Braunschweig, germany). KMS27, KMS26, KMS12PE and KMS20 were purchased from the japan health science foundation (Japan Health Sciences Foundation) health science research resource library (Health Sciences Research Resources Bank, HSRRB). Previously described LILRB1 reporter cells ¹⁸ . All other cell lines were purchased from ATCC unless otherwise noted. Hematologic cancer cell lines were maintained supplemented with 10% heat inactivationRPMI 1640 of FBS (Sigma Aldrich), R10. In addition to the maintenance of H460 and H1299 in R10, the solid tumor cell lines were maintained in DMEM with 10% heat-inactivated FBS. Culturing NKL cells as described previously ¹⁹ . All cell culture media were supplemented with +1% penicillin and streptomycin.

Peripheral Blood Mononuclear Cells (PBMCs) were isolated from the buffy coat of healthy donors (interstate blood bank) by gradient centrifugation using Ficoll medium (general life sciences). To isolate LILRB1 positive NK cells, PBMCs were incubated with anti-human CD56 microbeads (Miltenyi Biotech) and isolated using an autopacs Pro isolation system. The isolated CD56 is then used in the following pair ⁺ Cells were stained: anti-CD 3-PE (clone: HIT3a, bioLegend), anti-CD 56-FITC (clone: TULY56, e biosciences), anti-LILRB 1-APC (clone: HP-F1, eBioscience) or mouse IgG1 kappa isotype control-APC (eBioscience). Sorting LILRB1 using FACSAria I system ⁺ NK cells (CD 56) ⁺ CD3 ^- ). Sorted LILRB1 ⁺ NK cells were maintained in the same medium as NKL cells for 2-3 days. Cancer patient samples were obtained from the southwest medical center (UTSW) of the university of texas and from a hematological malignancy tissue bank of UTSW. Patient NK cells were isolated using the same protocol except that the autopacs isolated NK cells were cultured, activated and used for cytotoxicity assays without FACS.

anti-LILRB 1 monoclonal antibodies (mabs) were generated. Two New Zealand white rabbits were immunized subcutaneously with 0.5mg of recombinant human LILRB1 protein (unlabeled ECD, sino Biological). Four booster immunizations were given at three week intervals after the primary immunization. Serum anti-LILRB 1 titers were assessed by an indirect enzyme-linked immunosorbent assay (ELISA). Individual LILRB1 positive memory B cells enriched using antigen pulldown were cultured in 96-well plates for 14 days, and the culture supernatant was analyzed for binding of antibodies to LILRB1 by ELISA. Antibody variable region genes were cloned from those positive B cells and sequenced.

Expression and purification of mAb. Using an Expifectamine ^TM 293 turnThe heavy and light chain expression constructs were co-transfected into HEK293 cells using a staining kit (catalog number: A14528, ji Boke company (Gibco)) to produce full length IgG in human embryonic kidney Expi293F cells. After fed-batch culture for 7 days, culture supernatants were collected and antibodies were purified by affinity chromatography using protein A resin (catalog number: 10-2001-XM, repligen Co., ltd.).

Epitope binning and affinity measurement using biological layer interferometry. Classical sandwich epitope binning experiments were performed on an 8-channel Octet RED96 system. First, a baseline was established in kinetic buffer (catalog No. 18-1105, fudi biosystems (ForteBio)) for 3 minutes. The antibody (30. Mu.g/mL) was then captured by a protein A biosensor (catalog number 18-5010, fudi Biol.) 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 soaking the biosensor in kinetic buffer for 10 seconds. The biosensor was exposed to recombinant LILRB1 (25. Mu.g/mL) for 4 minutes, then incubated with secondary antibody (40. Mu.g/mL). The surface was regenerated in 100mM glycine (pH 2.6) for 45 seconds. The competitive binding of the antibody pairs was assessed. The additional binding signal observed for the secondary antibody indicates an unoccupied epitope (non-competitor). The lack of secondary antibody binding (blocked by primary antibody binding) suggests that both antibodies compete for similar epitopes (competitors).

For antibody affinity measurements, antibodies (analyte, 30 μg/mL) were loaded onto protein G biosensors (catalog No. 18-5082, fudi biosystems) for 4 minutes. 20 seconds after a short baseline in kinetic buffer, the loaded biosensor was exposed to a solution of recombinant LILRB1 in a range of concentrations (0-500 nM). After background subtraction, the data were fitted to a 1:1 binding model to extract the association sum rate (k _on ) Dissociation rate (k) _off ). Using the ratio k _off /k _on KD was calculated. The kinetic constants of the Octet RED96 system ranged between 1mM and 10pM. Thus, affinities above 10pM will be shown as KD<10pM. All experiments were performed with shaking at 1,000 rpm. All raw data used the fudi biology company Octet data analysis software 9.0.

Ig-like C2-type domains (D) including the D1, D2, D3, D4 domains of LILRB1 were cloned for expression by performing PCR. The motif between D4 and the transmembrane domain is defined as the stem region or junction region. Different mutant uses of LILRB1The lightning site-directed mutagenesis kit (Agilent, catalog number 210519) was generated using the LILRB1 wild-type DNA construct as a template. LILRB ECD, LILRB1 mutant and different domains were cloned by Fc fusion in the expression vector and Fc portion of human IgG 1. Expression and purification of the LILRB Fc fusion protein was performed using the same procedure as the antibodies described above.

LILRB1 recombinant protein (50 ng/well, 100. Mu.L/well) was coated on Corning 96-well ELISA plates at 37℃for 4 hours. The plates were blocked with 5% skim milk at 37 ℃ for 2 hours. After washing with PBST, 100 μl of serial dilutions of anti-LILRB 1 antibody were added and incubated at 37 ℃ for 60 minutes. Subsequently, the plates were washed 5 times with PBST and incubated with anti-rabbit or anti-human F (ab') 2HRP conjugated antibodies (jackson immunoresearch company (Jackson ImmunoResearch inc.), catalog nos. 111-036-003 and 109-036-003) for 30 minutes. The plate was again washed 5 additional times with PBST, then the immune response was developed with TMB substrate (sigma, cat# T0440) and was read by adding 2M H before the plate was read at 450nm ₂ SO ₄ And (5) terminating.

anti-LILRB 1 rabbit antibodies were humanized by CDR grafting into a human germline matched framework. Briefly, CDRs in rabbit antibody heavy and light chains are defined by a combination of three online programs: kabat, IMGT, and Paratome. The parental rabbit mAb and the most homologous human germline sequences were aligned and residues were identified in a mutation lineage guide assay that were not known to be structurally critical or that did not undergo changes during the in vivo maturation process and were humanized. DNA sequences encoding humanized VK and VH (GENEWIZ) were synthesized and human IgG signal peptide and Kozak sequences were engineered at the 5' end of the VK and VH sequences. The humanized VK and VH fragments were then cloned into fusion with the intact human constant region.

HLA-G-1cDNA with Signal peptide mutant ²³ Cloning into the pLentiLox3.7-PuroR plasmid. As previously described, lentiviral plasmids pLentiLox3.7-luciferase-Puror, pLentiLox3.7-HLA-G-Puror and pLVX-MICA-ZsGreen plasmids were used for overexpression of target proteins in cell lines ²⁴ . Infected cells that overexpress luciferase or HLA-G were enriched by selection with 1. Mu.g/mL puromycin. MICA positive cells were enriched three times by FACS (clone: 6D4, hundred organisms). According to previous reports, LILRB2-5 reporter cells and LILRA1-6 reporter cells were made from retroviral infection ^{18 25} 。

Carboxyfluorescein succinimidyl ester (CFSE, semer Fei's technology Co., thermo Fisher Scientific)) labeled Propionibacterium Iodide (PI) staining of target cells in combination with 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 FACS Calibur. Cell lysis was calculated by the percentage of PI positive leukemia cells in total leukemia cells. Spontaneous cell death in the absence of NK cells was less than 5% and was subtracted from total killing in the absence of NK cells.

Cytokine measurement will be 5X 10 total ⁴ Individual NKL cells and 5×10 cells ⁴ Individual cancer cells were co-cultured in U-bottom 96-well plates for 24 hours. IFN-. Gamma.release was detected in culture supernatants by ELISA (BAOCHINE) according to the manufacturer's manual.

In vivo killing assay will total 5X 10 ⁶ (CFSE) labeled 697 (NKL resistance) and 697-MICA (NKL sensitivity) cells were mixed and combined with 5X 10 cells ⁷ The NKL combinations were injected Intraperitoneally (IP) into NSG mice. Retroorbital administration of anti-LILRB 1 antibody (10 mg/kg) or control human IgG (hIgG). After 24 hours, cells from the mouse peritoneal cavity were harvested and stained with anti-MICA antibodies and analyzed by FACS Calibur1 (BD Biosciences). The in vivo cytotoxic activity of NKL was calculated as follows:

NK = 697-MICA/697 ratio in mice receiving 697, 697-MICA cells and NKL cells.

CN = ratio of 697-MICA/697 in mice receiving 697 and 697-MICA cells.

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

The in vivo cytotoxic activity of NKL cells on 697-MICA was also tested subcutaneously in NSG mice. Will total 1 x 10 ⁶ 697-MICA (697 MICA-luci) cells expressing luciferase with 5X 10 ⁶ Individual NKL cells were mixed and injected subcutaneously (sc) into mice. Each mouse was retroorbital administered an anti-LILRB 1 antibody (10 mg/kg) or a control hIgG. Bioluminescence imaging (BLI) was performed 48 hours later to monitor 697-MICA cells remaining in the mice.

NSG mice of 6-8 weeks of age were sub-lethally irradiated with 200cGy X-rays on day-1. On day 0, 5×10 mice were given each by tail vein injection ⁵ Individual KMS27-luci and 5×10 ⁶ Individual NKL cells. anti-LILRB 1 antibody (10 mg/kg) or control igg was administered retroorbital on day 0, day 3 and day 7, then once a week for one month. An additional 5X 10 injection was made on day 14 ⁶ Individual NKL cells. A total of 10,000iu of human IL2 was administered to each mouse by IP injection every other day. BLI was evaluated on days 28 and 35.

Data are presented as mean ± SE (standard deviation). Statistical significance between the two groups was calculated by the two-tailed unpaired t-test, unless otherwise noted. The Kaplan-meyer survival curve (Kaplan-Meier survival curve) was analyzed using a log rank test. If p <0.05, the difference is considered statistically significant.

Antibody Structure modeling 176Fv antibody Structure modeling was performed using DiscoverySoftware 2017R2 (DS). The homologous template structure that identifies the optimal hit predicted by the framework template protocol is selected. These structures serve as input structures, which form the basis for the construction of chimeric antibody Fab structures by the model antibody framework protocol. Model antibody loop building methods use Hidden Markov Models (HMMs) to identify templates and model CDRs. This method is used to reconstruct the CDR loop. Finally, the use of the CHARMM force field subjects the 176Fv homology model to energy minimization. In this way, a minimum energy structure was developed for docking and further analysis.

The structure of LILBR1 (PDB ID:5 KNM) was retrieved from the Protein Database (PDB) and subjected to energy minimization by structural preparation using the CHARMM force field. Rigid body interfacing of 176 and LILRB1 is performed using the ZDock algorithm, as described (Chen and Weng, 2002). Next, hierarchical clusters with different docking poses are generated according to antibody positions. Gestures were rescored using a ZRank scoring function based on electrostatics, van der Waals, and desolvation energy terms.

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

The purpose of using RDock is to identify residues at the antibody-antigen interface and calculate 176 the binding energy between the antibody and LILBR 1. Interaction analysis was performed using DS and PyMOL. The nonpolar interaction energy is calculated by a computational interaction energy protocol implemented in the DS. Complexes of LILBR1 with higher binding affinity between Tyr-76 and Arg-84 and 176Fv are believed to exhibit a favorable docking conformation.

The structure of h176 is predicted using DS. Docking of LILRB1-D1D2 with h176 Fab was performed using the ZDOCKpro module of the weight II package. The generic protocol for running ZDOCK includes two sequential computational steps, described as geometric search in ZDOCK and energy search in RDOCK, respectively. The crystal structure of LILRB1-D1D2 was obtained from the PDB database. RDOCK is used to improve the optimal ZDOCK pose. Gestures with high scores in both ZDOCK and RDOCK are 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 is an exception, for which the D1 domain was analyzed. Accession numbers for 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, Q6PI 73. D1 region is defined as position 27 to position 115 and D2 is defined as position 116 to position 221. Multiplex alignment was performed on all D1D2 sequences using ClustalX (version 2.1). MEGA (version 7.0) was used to generate phylogenetic trees.

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

The function of the LILRB family of immunosuppressive receptors and the immune activating receptor NKG2D in cancer progression has been characterized ^1-8 . To investigate whether LILRB1 can be a molecular target for cancer immunotherapy, LILRB1 expression on NK cells of patients with cancer was determined and compared to LILRB1 expression of healthy donors. LILRB1 is mainly found on CD56 from healthy donors and patients with cancer ^{Dark and dark} NK cells other than CD56 ^Bright NK cells were expressed (FIG. 1A). CD56 from peripheral blood of patients with prostate cancer or Multiple Myeloma (MM) was evaluated ^{Dark and dark} Percentage of NK cells expressing LILRB1 among NK cells. LILRB1 ⁺ NK cells (CD 56) ^{Dark and dark} NK) the percentage in the blood of patients with advanced prostate cancer (3B and 3 c) was significantly higher than in healthy donor blood (fig. 1B, table 9). In addition, LILRB1 from NK cells of peripheral blood of MM patients with persistent disease during treatment ⁺ NK cells (CD 56) ^{Dark and dark} In NK) is higher than from healthy donors or patientsLILRB1 in patients with mild to complete response ⁺ Percentage of NK cells (fig. 1C, table 10). These results indicate that LILRB1 ⁺ The percentage of NK cells is significantly higher in patients with advanced cancer or poor prognosis, and LILRB1 may be a molecular target for immunotherapy of these patients.

TABLE 9 pre-treatment clinical Properties of patients with prostate cancer

TABLE 10 response of patients with multiple myeloma to treatment

Example 3 production and characterization of antagonistic and agonistic monoclonal antibodies against LILRB1

To assess the therapeutic potential of anti-LILRB 1 mabs in activating NK cells, a panel of anti-LILRB 1 mabs was generated by screening individual memory B clones, cloning antibody genes, and assessing blocking activity of recombinant mabs (fig. 12A-B) ^32-34 . A total of 229 anti-LILRB 1 specific single B cell clones were generated from 384 LILRB 1B cell culture wells and evaluated by ELISA (table 11). Wherein 174 single B cell clones were identified that produced mAbs that bound to LILRB1, which LILRB1 was expressed on the cell surface of LILRB1 NFAT-GFP reporter cells (Table 12), expressing GFP when the cell surface LILRB1 was crosslinked ¹⁸ . Sixty binders were selected for further cloning and expression, 44 of which were found to have a low nanomolar rangeEC50 around (0.05-3 nM) (fig. 12C). The estimated EC50 based on the antibody concentration titration binding curve is provided in table 13. To group 44 mabs according to binding epitope, a classical sandwich epitope binning assay was performed using Octet RED96 and twelve epitope bins were identified for these 44 homobinders (fig. 12D).

TABLE 11 mAb binding in supernatant of 229B cell clones determined by ELISA

Table 12.229 binding of mAb to LILRB1 on the cell surface of reporter cells in B cell clone supernatants. The anti-mAb in the supernatant was immobilized by protein a coated cell culture plates. 96-well cell culture plates were coated with 5. Mu.g/mL of protein A in Phosphate Buffered Saline (PBS) at 37℃for 2 hours. After washing 3 times with PBS, the plates were incubated with 229B cell clone supernatants overnight at 4 ℃. LILRB1 reporter cells were cultured in plates for 24 hours. The percentage of GFP reporter cells was analyzed by flow cytometry.

TABLE 13 EC estimated based on antibody concentration titration binding curves ₅₀

mAb	EC 50 (ng/mL)	mAb	EC 50 (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-LILRB 1 mabs, LILRB1 receptor cells were co-cultured with K562 cells (K562-HLA-G) that overexpressed HLA-G1 (MHC class I molecule with highest affinity for LILRB 1) (fig. 2A). The LILRB1 reporter cells were activated by K562-HLA-G cells, but not by the parental K562 cells (MHC class I negative) (fig. 2A). All antibodies were screened using this reporter gene assay. Antibodies in bin 1, bin 7, bin 8 and bin 9 showed antagonistic effects (fig. 12E). Antibodies in bin 2, bin 3, bin 4, bin 5, bin 6, bin 10, bin 11 and bin 12 showed agonistic effects (fig. 12D-E). The cross-binding of B1-176 and other commercial anti-LILRB 1 was analyzed by flow cytometry (fig. 2I).

Among agonistic antibodies, the antibody from bin 1 showed the strongest blocking efficacy (fig. 2B). By evaluation of flow cytometry (FIG. 2C), ELISA (FIG. 2D) and Octet RED96 (FIG. 12F; table 14), B1-176 in bin 1 showed specific binding to LILRB 1. B1-176 showed high affinity for LILRB1 with KD values of about 10pM (FIG. 2E), significantly higher than the affinity of the two commercial anti-LILRB 1 monoclonal antibodies HP-F1 and GHI/75 (FIG. 12G). Thus, B1-176 was selected to further evaluate its binding epitope and modulate NK cell activation function.

TABLE 14 measurement of binding affinity of LILRB1 monoclonal antibodies using an Octet 96Red instrument

mAb	KD(M)	kon (1/millisecond)	kdis (1/second)	Complete R2
					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 epitope was determined. Upon evaluation by ELISA (FIG. 2F), B1-176 showed the D1D2 region (FIG. 13A) that specifically binds to LILRB1, but not to other domains. A series of amino acid mutations were made in the D1D2 region of LILRB1 to determine the critical amino acids for B1-176 binding (FIG. 13B). Two amino acids (R84 and Y76; positions 107 and 99 corresponding to SEQ ID NO:1, respectively) were found to contribute to LILRB1 interaction with B1-176 (FIG. 2G). Molecular docking of B1-176 was performed using Discovery Studio 2017. The most likely binding model was determined based on the PDB structure of the LILRB 1D 1D2 region (PDBID: 1 UFU) and the modeled structure of B1-176 using two key amino acids R84 and Y76. In this model, the long HCDR3 of B1-176 is inserted into a narrow ligand-binding pocket on the LILRB 1D 1 domain. Arg-84 of LILRB1 can interact with Tyr-102, glu-103 and Asp-109 from the HCDR3 loop through hydrogen bonding and electrostatic interactions. Tyr-76 of LILRB1 may form hydrogen bonds with Asp-104 from HCDR3 (FIG. 2H).

EXAMPLE 4 humanization of Rabbit anti-LILRB 1 mAb

To minimize immunogenicity of B1-176 for clinical applications, B1-176 was humanized and molecular engineered to optimize antibody sequences. Kabat/IMGR/Pa in the heavy and light chains of B1-176 were identified as previously describedRatome combination CDR ²⁰ . The CDR sequences herein are shown to be as short as HCDR and LCDR. Human germline IGHV3-53 x 04 and IGKV1-9 x 01 are selected as frameworks. Heavy chain Hu-176 VH-1 and light chain Hu-176 VL are generated by CDR grafting. However, antibodies with humanized heavy chain sequence VH-1 showed reduced binding to LILRB1 (fig. 3B). Mutation evaluation after multiple rounds of single back mutation in VH-1 showed that amino acid L48 in FR2 was important for restoring binding activity (fig. 3A and 3B). Molecular docking showed that humanized and rabbit B1-176 Fab had a similar stacked structure (fig. 3C).

Considering the broad expression of LILRB1 on normal immune cells, rabbit B1-176 was expressed as human IgG1 with the N297A mutation (B1-176-N297A), and humanized B1-176 was expressed as human IgG1 with the N297A mutation (hub 1-176-N297A) or with the L234A, L235A and P329G mutations (hub 1-176-lapg) to eliminate Fc-mediated immune effector functions ^{35 36} . All B1-176 with Fc mutants maintained strong affinity for LILRB1 (fig. 3D).

Example 5-antagonistic anti-LILRB 1 mAb blocked activation of LILRB1 reporter cells by cancer cells

Cancer cell lines that activated LILRB1 were identified by co-culturing cancer cells with LILRB1 reporter cells (fig. 4A). Flow cytometry was used to evaluate the expression of MHC class I molecules (antibody clone: HP-1F7, santa Cruz), i.e., ligands for LILRB1, on the cell surface of blood and solid cancer cell lines (FIG. 4A). Most cancer cell lines express MHC class I molecules and stimulate activation of LILRB1 reporter cells. Except for K562, DLD1 and Daudi cells, they do not express MHC class I molecules on their cell surfaces. Thus, the ability of cancer cells to activate LILRB1 reporter cells is positively correlated with their MHC class I expression levels. B1-176 and Hu B1-176-N297A blocked activation of LILRB1 reporter cells 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 alpha 3 domain of MHC class I ³⁷ . This may explain why antagonistic anti-LILRB 1 antibodies were screened from K562-HLA-G cellsThe activation of LILRB1 by other cancer cell lines can be blocked.

Example 6 in vitro function of antagonistic anti-LILRB 1 mAbs on NK cells

The NK cell line NKL was used to evaluate the in vitro efficacy of anti-LILRB 1 mAbs. NKL cells express high levels of LILRB1 on the surface (fig. 14A). Treatment with different versions of anti-LILRB 1 mAb: B1-176-N297A, huB 1-176-N297A and HuB 1-176-LALALAPG increased the cytotoxic activity of NKL cells on the MM cell line KMS27 at similar levels (FIG. 5A). The anti-LILRB 1 antibody also increased the cytotoxic activity of NKL on other MM cell lines OPM2 and RPMI8226 and T cell leukemia cell line Jurkat (fig. 5B). By flow cytometry, LILRB1 was found to be expressed on the cell surface of certain leukemia and lymphoma cell lines, such as 697 and Raji cells, but not on MM cell lines, jurkat cells, or most malignant plasma cells of patients with MM (fig. 14B-D). These results indicate that antagonistic anti-LILRB 1 antibodies increase the natural cytotoxic activity of NKL cells on MM cell lines, as the N297A mutation on Fc or LALAPG would abrogate the ADCC function of the antibodies. Interestingly, even when treated with anti-LILRB 1 antibodies, pre-B cell leukemia cell line 697 and burkitt lymphoma cell line Raji were resistant to NKL cytotoxicity (fig. 5C). Previous studies reported that MHC class I chain-related gene AB (MICA/B), a ligand for NK cell activating receptor NKG2D, was expressed on NK-sensitive Acute Lymphoblastic Leukemia (ALL) cells, but absent on NK-resistant ALL cells ³⁸ . To sensitize 697 cells and Raji, MICA was overexpressed on 697 and Raji cells. As expected, MICA on the surface of cancer cells stimulated the cytotoxic activity of NKL cells on these cells, and anti-LILRB 1 antibodies further increased the cytotoxic activity of NKL cells (fig. 5C-D). These results indicate that LILRB1 blocking and NKG2D activation synergistically increase the cytotoxic activity of NKL cells. In addition to hematologic cancer cells, anti-LILRB 1 antibodies also stimulated NKL cells to kill solid tumor cancer cell lines, such as breast cancer cell line MDA-MB-231 and melanoma cell line MALME-3M (fig. 5E).

NK cells can also increase the response of other immune cells to cancer cells by secreting cytokines. The anti-LILRB 1 antibody increased IFN- γ secretion by T cell leukemia Jurkat cells and MM cell lines RPMI8226, OPM2 cells and KMS27 stimulated NKL cells (fig. 5F). The anti-LILRB 1 antibody increased 697-MICA without increasing 697-induced IFN- γ secretion by NKL cells. This result indicated that LILRB1 blocking and NKG2D activation co-stimulated IFN- γ from NKL cells (fig. 5F). The function of antagonistic anti-LILRB 1 antibodies was also confirmed by using another NK cell line NK92 m. Antagonistic anti-LILRB 1 antibodies increased 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).

In addition, the function of anti-LILRB 1 antibodies was confirmed using primary NK cells. Primary NK cells from healthy donor buffy coat were isolated and enriched for LILRB1 by FACS ⁺ NK cells. anti-LILRB 1 antibodies increased primary LILRB1 from healthy donors ⁺ Cytotoxic activity of NK cells on multiple myeloma cell lines (KMS 27 and OPM 2), 697 cells or Raji cells, but did not increase the cytotoxic activity on Daudi cells that do not express the LILRB1 ligand MHC class I (fig. 6A). Since NK cells also express MHC class I, this result suggests that MHC class I or cis MHC class I on neighboring NK cells does not inhibit the cytotoxic activity of NK cells on cancer cells. Here 697 and Raji cells are sensitive to the cytotoxic activity of primary NK cells, probably because the cytotoxic activity of primary NK cells is stronger than that of NKL cells. One previous publication also reported that activated primary NK cells showed stronger cytotoxic activity than NKL cells, probably due to relatively high levels of cytotoxic receptors and NK94 on primary NK cells ³⁹ . NK cells were also isolated in peripheral blood of a patient with MM, about 80% of which were positive for LILRB1, and used for cytotoxicity assays. The anti-LILRB 1 mAb increased the cytotoxic activity of patient NK cells on MM cell line KMS27 (fig. 6B).

EXAMPLE 7 in vivo function of antagonistic anti-LILRB 1 mAbs on NK cells

NSG mice were used to test the in vivo function of anti-LILRB 1 antibodies. The NKL resistant 697 cells and NKL sensitive 697MICA mixture were injected into the abdominal cavity of NSG mice along with NKL cells. After 24 hours, the ratio 697-MICA/697 was analyzed and calculated as the cytotoxic activity of NKL cells in vivo (fig. 7A). These results indicate that anti-LILRB 1 antibodies increased the cytotoxic activity of NKL cells on 697-MICA cells in vivo. The cytotoxic activity of NKL cells was also tested in vivo by subcutaneously injecting a 697-MICA cell mixture over-expressed by NKL and luciferase into NSG mice. After 48 hours, bioluminescence imaging (BLI) showed a significant decrease in tumor burden in mice receiving anti-LILRB 1 antibodies compared to control igg treated mice (fig. 7B). In summary, anti-LILRB 1 antibodies can improve the in vivo cytotoxic function of NKL cells.

The efficacy of anti-LILRB 1 antibodies in preventing the development of multiple myeloma was further evaluated in xenograft mouse models. NSG mice were implanted with KMS27 cells and NKL cells via their tail veins and administered control IgG or anti-LILRB 1 antibodies, with cancer progression monitored by BLI. Mice receiving NKL cells and anti-LILRB 1 antibodies had significantly lower disease burden and longer survival times than mice receiving NKL cells and control IgG or mice receiving Phosphate Buffered Saline (PBS) alone (fig. 7C). Taken together, these results indicate that antagonistic anti-LILRB 1 antibodies can enhance the function of NKL cells in inhibiting multiple myeloma development in vivo.

Example 8-in vitro function of agonistic anti-LILRB 1 mAb

B1-7 and B1-41 were chosen to determine the function of agonistic LILRB 1. B1-7 and B1-41 showed agonistic function on 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 have Fc receptors, this result suggests that the agonistic LILRB1 mAb only functions when Fc binds to Fc receptors in the environment. To confirm this, N297A or S267E was introduced into the Fc of the agonistic LILRB1 mAb to eliminate or enhance Fc binding to Fc receptors, respectively. The results show that N297A was eliminated, while S267E enhanced B1-7 and B1-41 induced activation of LILRB1 reporter cells (FIG. 9). These results indicate that the agonistic effect against LILRB1 is Fc dependent. The agonistic LILRB1 mAb inhibited the cytotoxic activity of NK92mi (fig. 10A-B) and NKL (fig. 10C) cells on cancer cells in vitro. The N297A mutation in Fc abrogated the activity of agonistic B1-7 (FIG. 10D). The agonistic LILRB1 mAb also inhibited IFN- γ secretion by NKL cells (fig. 11).

**********

In accordance with the present disclosure, all methods disclosed and claimed herein can be made and executed without undue experimentation. Although the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Reference to the literature

To the extent that the following references provide exemplary procedures or other details supplementary to those set forth herein, they are expressly incorporated herein by reference.

Chen R, weng ZP. used shape complementation, desolvation and electrostatic docking of unbound Proteins (Docking unbound Proteins using shape complementarity, desolvation, and electrostatics) & Proteins (Proteins) & 2002;47:281-94.

Chen R, li L, weng zp.zdock: an initial phase protein docking algorithm (ZDOCK: animal-stage protein-docking algorithm) & protein 2003;52:80-87.

Guillerey C, huntington ND, smyth MJ. target natural killer cells in cancer immunotherapy (Targeting natural killer cells in cancer immunotherapy) & natural immunology (Nat Immunol) 2016;17:1025-36.Doi:10.1038/ni.3518

Weiner LM, surana R, wang S. Monoclonal antibody: a general platform for cancer immunotherapy (Monoclonal antibodies: versatile platforms for cancer immunotherapy) & Nature immunology 2010;10:317-27.Doi:10.1038/nri2744

De Weers M, tai YT, van der Veer MS et al Dai Mabs are novel therapeutic human CD38 monoclonal antibodies that induce killing of multiple myeloma and other hematological tumors (Daratumumab, a novel therapeutic human CD monoclonal antibody, induces killing of multiple myeloma and other hematological tumors) & journal of immunology 2011;186:1840-48. Doi:10.4049/jimmimunol.1003032

4.Ferrari de Andrade L, tay RE, pan D et al Antibody mediated MICA and MICB shedding inhibition promotes NK cell driven tumor immunity (anti-body-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity) & Science 2018;359:1537-42.Doi:10.1126/science. Aao0505

Multifunctional natural killer Cell adaptors targeting NKp46 by gauthier L, morel a, anceriz N et al trigger protective tumor immunity (Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity) & cells 2019;177:1701-13e16.Doi:10.1016/j.cell.2019.04.041

Preclinical characterization of a novel anti-KIR receptor therapeutic antibody that enhances natural killer-mediated tumor cell killing (Preclinical characterization of 1-7F9,a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells) & Blood (Blood) 2009;114:2667-77.doi:10.1182/blood-2009-02-206532

Andre P, denis C, soulas C et al Anti-NKG2A mAb is a checkpoint inhibitor that promotes Anti-tumor immunity by releasing T cells and NK cells (Anti-NKG 2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells) & cell & lt 2018;175:1731-43.Doi:10.1016/j.cell.2018.10.014

Human inhibitory leukocyte immunoglobulin-like receptor of kang X, kim J, deng M, et al: immune checkpoint proteins and tumor maintenance factors (Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors) & Cell Cycle 2016;15:25-40.Doi:10.1080/15384101.2015.1121324

Inherent and tumor-driven immune tolerance in the prostate microenvironment of pasro C, graves G, guerin M et al impairs natural killer cell antitumor activity (Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity) & Cancer research (Cancer Res) & 2016;76:2153-65.Doi:10.1158/0008-5472.CAN-15-1965

Overexpression of CD85j in roberti MP, juli EP, rocca YS et al TNBC patients inhibited cetuximab-mediated NK cell ADCC, but could be restored by CD85j functional blockade (Overexpression of CD, j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD, 85jfunctional blockade), "journal of immunology in europe (European journal of immunology)," 2015;45:1560-69.doi:10.1002/eji.201445353

Human breast cancer cells of mamesser E, sylvain a, thibull ML, etc. enhance self tolerance by promoting evasion of NK cell anti-tumor immunity (Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity) & journal of clinical research (The Journal of clinical investigation) & 2011;121:3609-22.Doi:10.1172/JCI45816

Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blast by killer cell immunoglobulin-like receptor negative natural killer cells after Godal R, bachanova V, gleason M et al NKG2A and LIR-1 blocking (Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG A and LIR-1 blocking): journal of the American society of blood and bone marrow transplantation (Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation) 2010;16:612-21.Doi:10.1016/j. Bbmt.2010.01.019

Lesport E, baudhuin J, sousa S et al inhibit human V gamma 9V delta 2T cell antitumor Activity by HLA-G: effects on cancer immunotherapy (Inhibition of human V gamma v delta 2t-cell antitumoral activity through HLA-G: implications for immunotherapy of cancer) & cell and molecular life sciences (Cell Mol Life Sci) & 2011;68:3385-99.Doi:10.1007/s00018-011-0632-7

Kim A, han CJ, driver I et al LILRB1 blocking enhanced bispecific T cell adaptor antibody-induced tumor cell killing of effector CD8 (+) T Cells (LILRB 1 Blockade Enhances Bispecific T Cell Engager Antibody-Induced Tumor Cell Killing by Effector CD (+) T Cells) & journal of immunology 2019;4:1076-87. Doi:10.4049/jimmimunol.1801472

Engagement of the inhibitory receptor LILRB1 by barker AA, weiskopf K, kao KS et al with MHC class I inhibits macrophages and is a target for cancer immunotherapy (Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy) & nature immunology 2018;19:76-84.Doi:10.1038/s41590-017-0004-z

harlyC,PeyratM-a,netzersetalup-regulatedthecytolyticfunctionofhumanvδ2—γδtlymphocytesbyengagementofilt2expressedbytumortargetcells(up-regulationofcytolyticfunctionsofhumanVδ2—γδTlymphocytesthroughengagementofILT2expressedbytumortargetcells)&blood2011; 117:2864-73.doi:10.1182/blood-2010-09-309781

Loss of immune checkpoints CD85j/LILRB1 on lozano E, diaz T, mena MP, et al, human malignant plasma cells, resulted in immune escape of multiple myeloma (Loss of the Immune Checkpoint CD j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma) & journal of immunology 2018;200:2581-91. Doi:10.4049/jimmimunol.1701622

Efficient leukocyte Ig-like receptor signaling and crystal structure of Sheoishi M, kuroki K, ose T et al disulfide-linked HLA-G dimer (Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer) 2006;281:10439-47.doi:10.1074/jbc.m512305200

Zou YZ, luo WG, guo J et al enhanced NK cell mediated anti-leukemia cytotoxicity (NK cell-mediated anti-nti-leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti-CD20 scfv chimeric protein) using NKG2D ligand MICA and anti-CD20 scfv chimeric proteins; 48:1750-63.doi:10.1002/eji.201847550

Gui X, deng M, song H et al reverse T cell inhibition and block AML progression by Disrupting LILRB4/APOE interactions with potent humanized antibodies (disuppting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development) & cancer immunology study (Cancer Immunol Res) & 2019; 1244-57.Doi:10.1158/2326-6066.CIR-19-0036

The crystal structure and ligand binding properties of the D1D2region of the Chapman TL, heikema AP, west AP, jr. Et al inhibitory receptor LIR-1 (ILT 2) (Crystal structure and ligand binding properties of the D D2region of the inhibitory receptor LIR-1 (ILT 2)). Immunity (Immunity) 2000;13:727-36.Doi:10.1016/s1074-7613 (00) 00071-6

Monoclonal antibodies (Efficient generation of monoclonal antibodies from single rhesus macaque antibody secreting cells) were efficiently produced by meng W, li L, xiong W et al from single rhesus antibody secreting cells (MAb 2015;7:707-18.Doi:10.1080/19420862.2015.1051440

Navarro F, llano M, bellon T et al ILT2 (LIR 1) and CD94/NKG2A NK cell receptors recognize HLA-G1 and HLA-E molecules, respectively, co-expressed on target cells (The ILT2 (LIR 1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells) 1999 in European journal of immunology; 29:277-83. Doi:10.1002/(SICI) 1521-4141 (199901) 29:01 < 277 AID-IMMU 277- CO 0.0; 2-4

The ITIM-containing receptor LAIR1 of Kang X, lu Z, cui C et al is critical for The development of acute myelogenous leukemia (The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development) & Nature cell biology (Nature cell biology) & 2015;17:665-77.Doi:10.1038/ncb3158

Motifs in deng M, lu ZG, zheng JK et al LILRB2 are critical for Angptl2 binding and activation (a motif in LILRB2 critical for Angptl2 binding and activation) & blood 2014;124:924-35.Doi:10.1182/blood-2014-01-549162

Dumitriu IE, mohr W, kolowos W et al 5,6-carboxyfluorescein diacetate succinimidyl ester labeled apoptosis and necrosis and detergent treated cells can be tracked in complex cell samples (5, 6-carboxyfluorescein diacetate succinimidyl ester-labeled apoptotic and necrotic as well as detergent-treated cells can be traced in composite cell samples) & analytical biochemistry (Analytical biochemistry) & 2001;299:247-52.doi:10.1006/abio.2001.5415

Aktas E, kucuksezer UC, bilgic S et al, relationship of CD107a expression to cytotoxic activity (Relationship between CD107a expression and cytotoxic activity) & cytology (Cellular immunology) & 2009;254:149-54.Doi:10.1016/j. Cellim. 2008.08.007

Schonberg K, hejazi M, uhrberg M. Protocols for analysis of NK cell effector functions by multiparameter flow cytometry cloning (Protocol for the clonal analysis ofNK cell effector functions by multi-parameter flow cytometry) & Methods of molecular biology (Biol) 2012;903:381-92.Doi:10.1007/978-1-61779-937-2_26

Zheng J, umikawa M, cui C et al inhibitory receptors bind ANGPTL and support hematopoietic stem cells and leukemia development (Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development) & nature 2012;485:656-60. Doi:10.1038/aperture 11095

LILRB4 signal-mediated T cell inhibition and tumor infiltration (LILRB 4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration) in deng M, guil X, kimj et al human leukemia cells, nature 2018;562:605-09.Doi:10.1038/s41586-018-0615-z

A novel Anti-LILRB 4CAR-T cell (anodel Anti-LILRB 4CAR-T Cell for the Treatment of Monocytic AML) for use in the treatment of monocyte AML by john S, chen H, deng M et al, molecular therapy (Mol ter) 2018;26:2487-95.Doi:10.1016/j. Ymthe.2018.08.001

The pentameric complex of human virus glycoprotein H such as free DC, tang Q, tang AM is the main target for effective neutralization of human cytomegalovirus vaccine (Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine) & ltu.s.national academy of sciences (academy of sciences) 2013;110:E4997-05.doi:10.1073/pnas.1316517110

Seeber S, ros F, thorey I et al uses rabbit B cells from peripheral blood to generate a robust high throughput platform of functional recombinant monoclonal antibodies (ARobust High Throughput Platform to Generate Functional Recombinant Monoclonal Antibodies Using Rabbit B Cells from Peripheral Blood) & lture science library: complex (Plos One) 2014;9:e86184.doi:ARTN e8618410.1371/journ.fine.008684

Humanized anti-VEGF rabbit monoclonal antibodies to yu Y, lee P, ke Y, etc. inhibit angiogenesis and block tumor growth in xenograft models (Ahumanized anti-VEGF rabbit monoclonal antibody inhibits angiogenesis and blocks tumor growth in xenograft models) & ltwbr/& gtpublic science library: synthesis 2010; 5:e9072.doi:10.1371/journ.pon.0009072

Isolation and characterization of IgG1 with asymmetric Fc glycosylation by ha S, ou Y, vlasak J et al (Isolation and characterization of IgG1 with asymmetrical Fc glycosylation) & Glycobiology (2011); 21:1087-96.doi:10.1093/glycob/cwr047

Effect attenuation substitution to maintain antibody stability and reduce toxicity in mice by lo M, kim HS, tolg RK et al (effect-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice) & journal of biochemistry 2017;292:3900-08.doi:10.1074/jbc.m116.767749

Chapman TL, heikeman AP, bjorkman PJ. inhibitory receptor LIR-1uses common binding interactions to recognize MHC class I molecules and viral homologs UL18 (The inhibitory receptor LIR-1uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18) & immunology 1999;11:603-13.Doi:10.1016/s1074-7613 (00) 80135-1

Resistance mechanisms to natural killer cell mediated cytotoxicity in romanski a, bug, becker S et al acute lymphoblastic leukemia (Mechanisms of resistance to natural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia) & experimental hematology (Exp hemalo) 2005;33:344-52.Doi:10.1016/j. Exphem.2004.11.006

Gross C, schmidt-Wolf IGH, nagaraj S, et al, human heat shock protein 70 reactivity correlated with an increase in cell surface density of CD94/CD56 on primary natural killer cells (Heat shock protein-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells), "chaperone for cell stress (Cell Stress Chaperon)," 2003;8:348-60.Doi:10.1379/1466-1268 (2003) 008< 0348:Hspra >2.0.Co;2

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 of CD56bright and CD56 dark NK cells (solid HLA-G campens CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD bright and CD56dim NK cells); 118:5840-50.Doi:10.1182/blood-2011-05-352393

41.Desgrandchamps F, leMaoult J, goujon A et al predict non-myogenic invasive bladder cancer recurrence by measuring checkpoint HLAG receptor ILT2 on peripheral CD8 (+) T cells (Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG's receptor ILT2 on peripheral CD8 (+) T cells) & lt 2018 & gttumor target; 9:33160-69.doi:10.18632/oncotargete.26036

Yu K, davidson CE, burshtyn dn. Lilrb1 Intron 1has a polymorphic regulatory region (LILRB 1 Intron 1Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1) that enhances NK cell transcription and recruits YY1, journal of immunology 2020;204:3030-41. Doi:10.4049/jimmimunol.2000164

LeMaoult J, zafaranlo K, le Danff C et al HLA-G upregulates ILT2, ILT3, ILT4 and KIR2DL4 (HLA-G up-regulatory ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells) in antigen presenting cells, NK cells and T cells: official publication of the American society for laboratory biology (FASEB journ: official publication of the Federation of American Societies for Experimental Biology) 2005;19:662-4. Doi:10.1096/fj.04-1617. 1617fje

The expression patterns of Bjorkstrom NK, riese P, heuts F et al NKG2A, KIR and CD57 define the CD56 dark NK cell differentiation process separated from NK cell education (Expression patterns of NKG A, KIR, and CD57 define a process of CD dim NK-cell differentiation uncoupled from NK-cell differentiation) & blood 2010;116:3853-64.doi:10.1182/blood-2010-04-281675

Resistance of human circulating CD57 (+) NK cells such as munthaell a, servitja S, cabo M, etc. to HER2-specific therapeutic antibodies in HER2 (+) primary breast cancer (High Numbers of Circulating CD (+) NK Cells Associate with Resistance to HER-Specific Therapeutic Antibodies in HER2 (+) Primary Breast Cancer), "cancer immunology research" 2019; 1280-92.Doi:10.1158/2326-6066.CIR-18-0896

Effects of Heidenreich S, zu Eulenburg C, hildebrandt Y, et al, on the cytotoxicity of multiple myeloma by the NK cell receptor LIR-1 (ILT-2/CD 85j/LILRB 1) (Impact of the NK cell receptor LIR-1 (ILT-2/CD 85j/LILRB 1) on cytotoxicity against multiple myeloma) Clinical and developmental immunology (Clinical & developmental immunology) 2012;2012:652130.doi:10.1155/2012/652130

Suck G, odensahl M, nowakowska P et al NK-92: an 'off-the-shelf treatment' (NK-92: an 'off-the-shelf therapeutic' for adoptive natural killer cell-based cancer immunotherapy) for natural killer cell-based adoptive cancer immunotherapy (Cancer Immunol Immun) 2016;65:485-92.Doi:10.1007/s00262-015-1761-x

Carbone E, neri P, mesuraca M et al HLAI class, NKG2D and natural cytotoxic receptor regulate natural killer cell recognition of multiple myeloma cells (HLAclass 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

MICA trigger signals from tumor lysis of human NK cells by menier C, riteau B, carosela ED et al are counteracted by HLA-G1 mediated inhibitory signals (MICAtriggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal) & international journal of Cancer (Int J Cancer) & 2002;100:63-70.Doi:10.1002/ijc.10460

Successful adoptive transfer and in vivo expansion of Miller JS, soignier Y, panoskltsis-Mortari A et al human single-fold identity NK cells in patients with cancer (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 listing

<110> Board of university of Texas system Board (The University of Texas System)

<120> monoclonal antibodies against LILRB1 for diagnostic and therapeutic use

<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> patent In version 3.5

<210> 1

<211> 650

<212> PRT

<213> Homo sapiens (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 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 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 sequences

<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 sequences

<400> 3

Ile Tyr Asn Gly Asp Glu Ile

1 5

<210> 4

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<400> 7

Ala Arg Ser Tyr Tyr Met

1 5

<210> 8

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 9

Ile Tyr Ser Gly Asp Gly Asp

1 5

<210> 10

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 12

Ile Asp Thr Gly Ala Ser Ile

1 5

<210> 13

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 17

Gly Phe Ser Ser Ser Ser Ser Ala Tyr

1 5

<210> 18

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 19

Ala Arg Asn Thr 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 sequences

<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 sequences

<400> 21

Ile Asp Thr Ser Ser Gly Asn

1 5

<210> 22

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 30

Met Ser Thr Ala Ser Ala Asn

1 5

<210> 31

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 33

Ile Tyr Gly Asp Ser Ile Ala

1 5

<210> 34

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 57

Ile Tyr Ser Gly Ser Gly Ser

1 5

<210> 58

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 60

Ile Val Leu Ser Asn Gly Asn

1 5

<210> 61

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 72

Val Ala Thr Gly Ser Gly Thr

1 5

<210> 73

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 78

Ile Ala Thr Gly Thr Gly Ser

1 5

<210> 79

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 87

Val Ala Ser Asp Ser Ser Arg

1 5

<210> 88

<211> 21

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 93

Ile Phe Thr Ser Ser Gly Thr Thr

1 5

<210> 94

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 96

Met Arg Ile Asn Asp Arg Ser

1 5

<210> 97

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 99

Ile Val Thr Val Asn Asn Lys

1 5

<210> 100

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 102

Ile Asn Ile Gly Gly Thr Asn

1 5

<210> 103

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 111

Ser Thr Ala Ser Arg Asn Ile

1 5

<210> 112

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 120

Ile Val Thr Val Asn Asn Lys

1 5

<210> 121

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 129

Ile Tyr Thr Gly Asp Asp Asp

1 5

<210> 130

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 132

Ile Tyr Ala Gly Ser Thr Asn

1 5

<210> 133

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<400> 136

Ala Gly Ser Gly Ser Gly 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 sequences

<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 sequences

<400> 138

Ile Tyr Ala Ala Gly Asp Asp

1 5

<210> 139

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 150

Ile Gly Lys Ser Gly Thr Thr

1 5

<210> 151

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 162

Ile Val Thr Val Asn Asn Lys

1 5

<210> 163

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 167

cagaacattt acagctac 18

<210> 168

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 168

aaggcatcc 9

<210> 169

<211> 60

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 169

gcgagagctg tctatagtga tggtggtgct ggttatcctt atatgtatgg catggacctc 60

<210> 170

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 170

cagagtcttt ataatgcgaa cgac 24

<210> 171

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 171

tgggcatcc 9

<210> 172

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 172

gcgagatcat attatatg 18

<210> 173

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 173

cagagcattt acaggtac 18

<210> 174

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 174

tatggatcc 9

<210> 175

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 175

gcgagggctc tggatagtca ttattcttcc tttgacttg 39

<210> 176

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 176

cagagtgttt atggtaacaa ccgc 24

<210> 177

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 177

ctggcatcc 9

<210> 178

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 178

gcgaggggtt tttcgatgtt taagttg 27

<210> 179

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 179

cagaacattg tcagtaat 18

<210> 180

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 180

tatgcatcc 9

<210> 181

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 181

gcgagtactc ctaatagtct aggttacgac tta 33

<210> 182

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 182

cagagcattt acaactac 18

<210> 183

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 183

gatgtatcc 9

<210> 184

<211> 57

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 184

gcgagaaata cttatgattg gaatggttat atttatggcc cgtgttattt tggcttg 57

<210> 185

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 185

cagagtgttt ataataacaa caac 24

<210> 186

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 186

tctgcatcc 9

<210> 187

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 187

gcgagaggtt tttctatgtt taagttg 27

<210> 188

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 188

cagaacattt acaacaat 18

<210> 189

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 189

tatgcatcc 9

<210> 190

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 190

gcgagcacta cgactaatgt tttcggttac gactta 36

<210> 191

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 191

cagactattg gtagctac 18

<210> 192

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 192

gaagcatcc 9

<210> 193

<211> 57

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 193

aggggatata gttatggtga tactggatat gctgatgcta ttcttacctt ggacttg 57

<210> 194

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 194

gagaccatta gtaataga 18

<210> 195

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 195

tctgcatcc 9

<210> 196

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 196

gcgaaatccc atggtggtga tggtggttat ggggttgtat ta 42

<210> 197

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 197

cagagcatta gtagttac 18

<210> 198

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 198

aaggcatcc 9

<210> 199

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 199

gcgagagatc gaaatggtgg ttctggtgct tatggttggg acttg 45

<210> 200

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 200

cagagcatta gtgattac 18

<210> 201

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 201

agggcatcc 9

<210> 202

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 202

gcgagagata gtggtaatta taattgggac ttg 33

<210> 203

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 203

cagagcattg gcaatgca 18

<210> 204

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 204

aaggcatcc 9

<210> 205

<211> 48

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 205

gcgaggtccc catatgatga tggttatggt ggtttcactt ttaattta 48

<210> 206

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 206

cagaacattt ataataac 18

<210> 207

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 207

ggtccatcc 9

<210> 208

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 208

gcgagatcga ctagtggtag ttatggtgcg ggtttgggct tg 42

<210> 209

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 209

cagagtattg gtagtaga 18

<210> 210

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 210

gaagcatcc 9

<210> 211

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 211

gcgagagata ctgctgctta ttacgccttt agctta 36

<210> 212

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 212

catatcatta ctaactac 18

<210> 213

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 213

gatgcatcg 9

<210> 214

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 214

gcgaggggtg ttaatgatta tggttgggcc cttaagttg 39

<210> 215

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 215

ccgagcatta gtacttac 18

<210> 216

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 216

agggcatcc 9

<210> 217

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 217

gcgaccaata cggatagtag taggtcttat tataatttg 39

<210> 218

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 218

cagagtattg gtagtggtaa t 21

<210> 219

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 219

ctggcatcc 9

<210> 220

<211> 60

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 220

agaggatccg gtgctagcac caatggtgtt tggtgggtaa tgggagacgg catggacctc 60

<210> 221

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 221

cagattgttg ctaacggccg c 21

<210> 222

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 222

gctacatcc 9

<210> 223

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 223

gggagattgg attatcgtgt tatttatgcc tttaatttg 39

<210> 224

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 224

gaggacattg ataggtat 18

<210> 225

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 225

gatgcatcc 9

<210> 226

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 226

gcgagagagc gctatcctgg tgctttttca agtggattgg atctc 45

<210> 227

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 227

catatcatta ctaactac 18

<210> 228

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 228

gatgcatcg 9

<210> 229

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 229

gcgagagcga cttatgctta tgctggtgct ggggacttg 39

<210> 230

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 230

gagagcattg gcagtgca 18

<210> 231

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 231

tctgcatcc 9

<210> 232

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 232

gcgaccaata cggatagtag taggtcttat tataatttg 39

<210> 233

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 233

cagagcattt acaactac 18

<210> 234

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 234

tctgcatcc 9

<210> 235

<211> 51

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 235

gcgcgaagat atgctgcttt tcttacttat ggtagtgggg cttttgatcc c 51

<210> 236

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 236

ctgaacatta atagttgg 18

<210> 237

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 237

tatacatcc 9

<210> 238

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 238

gcgagaattg gtgcttttta ttcctttaga tta 33

<210> 239

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 239

gaggacattt atagcaat 18

<210> 240

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 240

ggtgcaacc 9

<210> 241

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 241

gcgagccgaa atggtggtgc gcctgatggt ttgaacttg 39

<210> 242

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 242

gaggatattt atagtaat 18

<210> 243

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 243

aaggcatcc 9

<210> 244

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 244

gcgagaggtg gtggttattg gtcttttagt ttg 33

<210> 245

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 245

cagagtgttt ataataagaa ctac 24

<210> 246

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 246

tatgcttcc 9

<210> 247

<211> 57

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 247

ggagattggg attatgctga tgctgctggt tattatgttg cgagaggttt taacttg 57

<210> 248

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 248

cagagcatta gtagttac 18

<210> 249

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 249

aaggcatcc 9

<210> 250

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 250

agagatttcg ttagttattt gaatttg 27

<210> 251

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 251

cagagcatta gttactac 18

<210> 252

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 252

aaggcatcc 9

<210> 253

<211> 63

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 253

gcgagaggat ccggtgctag taccaatggt gtttggtggg taatgggaga cggcatggac 60

ctc 63

<210> 254

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 254

cagagtatta gtagtagcta c 21

<210> 255

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 255

tctgcgtcc 9

<210> 256

<211> 48

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 256

tgtgcgagat ctagtaatag ttatggtaat tatggtgttt ctaacttg 48

<210> 257

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 257

cagagtgttt atagtaacaa ctgg 24

<210> 258

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 258

aaggcatcc 9

<210> 259

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 259

agagatatct attcctacgg catggacctc 30

<210> 260

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 260

cagactattt ataataacaa aaat 24

<210> 261

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 261

caggcatcc 9

<210> 262

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 262

gcgagaatcg ctactggtac taatgttgat gacttc 36

<210> 263

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 263

gagaacattt atagctac 18

<210> 264

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 264

tctgcatcc 9

<210> 265

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 265

gcgagatggc ggacttttgg cttg 24

<210> 266

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 266

cagaccgttc ataataatca atgg 24

<210> 267

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 267

gatgcatcc 9

<210> 268

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 268

gcgagatcat atattactga tcgtatttat gattacgact tt 42

<210> 269

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 269

caaagtgttg ataacaacaa acaa 24

<210> 270

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 270

tctgcatcc 9

<210> 271

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 271

gggagagtaa ttgatggtgc ttgtggttat gacttg 36

<210> 272

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 272

gagaccatta gtaataga 18

<210> 273

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 273

tctgcatcc 9

<210> 274

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 274

gcgagggata ctcggagtag taattattat tttaatttg 39

<210> 275

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 275

cagaccattt ataccaat 18

<210> 276

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 276

gctgcatcc 9

<210> 277

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 277

gcgaaatccc atggtggtga tggtggttat ggggttgtgt ta 42

<210> 278

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 278

gataatgttt atagtaataa ctac 24

<210> 279

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 279

tatgcggcc 9

<210> 280

<211> 57

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 280

gcgagggggt gggattacga ggatcctggt tatactgata ctacctactt ttccttg 57

<210> 281

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 281

gataatgttt atagtaataa ctac 24

<210> 282

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 282

tatgcggcc 9

<210> 283

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 283

gcgagaggtg gtactagtta ccgccttgat ttg 33

<210> 284

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 284

gaggatatta gtagtaat 18

<210> 285

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 285

ggtgcatcc 9

<210> 286

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 286

acgagatggc ggacttttgg cttg 24

<210> 287

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 287

cagagcatta gcaatgaa 18

<210> 288

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 288

ctggcatcc 9

<210> 289

<211> 51

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 289

gccagagatc ttgttactgg ttatgctact tatggttatg gatttatctt a 51

<210> 290

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 290

caaagtgttt acaataacaa ccaa 24

<210> 291

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 291

ggtgcatcc 9

<210> 292

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 292

gcgagagttg gtggttactg gacttttgac ttg 33

<210> 293

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 293

cagagtattg gtagctat 18

<210> 294

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 294

tatgcttcc 9

<210> 295

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 295

gcgagaggac tcactattgg tactgctgag ttgtacttc 39

<210> 296

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 296

cagaacattt acagcaat 18

<210> 297

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 297

tctgcatcc 9

<210> 298

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 298

gcgagagatt tcgttagtta tttgaatttg 30

<210> 299

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 299

cagagcattg gtagctac 18

<210> 300

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 300

aaggcatcc 9

<210> 301

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 301

gcgggaagtg ggagtggtta ttattattac tacggcatgg atctc 45

<210> 302

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 302

gaggacattg ataggtat 18

<210> 303

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 303

agggcatcc 9

<210> 304

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 304

gcgagagatc aggctgacag ttatgccttt ggtttg 36

<210> 305

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 305

cagagcatta gtagttac 18

<210> 306

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 306

aaggcttcc 9

<210> 307

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 307

gcgaggggtt tttcgatgtt taagttg 27

<210> 308

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 308

cagaccattt ataccaat 18

<210> 309

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 309

gctgcatcc 9

<210> 310

<211> 57

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 310

gcgagggggt gggattacga ggatcctggt tatactgata ctacctactt ttccttg 57

<210> 311

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 311

gagagtgttt atggtaacaa ccgt 24

<210> 312

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 312

caggcttcc 9

<210> 313

<211> 60

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 313

agaggatccg gtgctgctac taatggtgtt tggtgggtga tgggagacgg catggacctc 60

<210> 314

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 314

cagagcatta ccaatgca 18

<210> 315

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 315

agggcatcc 9

<210> 316

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 316

gccagggcag gtgctagtag gagtatttat tatgacttg 39

<210> 317

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 317

cagagcatta gtagtagcta c 21

<210> 318

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 318

tctgcatcc 9

<210> 319

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 319

gcgaaatctt ataattataa tggtttaggc ttg 33

<210> 320

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 320

cagagcattg gtagtaat 18

<210> 321

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 321

aaggcatcc 9

<210> 322

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 322

gcgagatcat ataatagtgc tagtagtggt tattattggg acttg 45

<210> 323

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 323

gagaatgttt atagtaataa ctac 24

<210> 324

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 324

tatgcggcc 9

<210> 325

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 325

agagatatct attcctacgg catggacctc 30

<210> 326

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 326

cagagcattg ctagcgac 18

<210> 327

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 327

gctgcatcc 9

<210> 328

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 328

gcgagatggc ggacttttgg cttg 24

<210> 329

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 329

ggattctcct tcagtagcag ctactgt 27

<210> 330

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 330

atttatactg atagtagtgg tgccact 27

<210> 331

<211> 57

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 331

gcgagggggt gggattacga ggatcctggt tatactgata ctacctactt ttccttg 57

<210> 332

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 332

Gln Asn Ile Tyr Ser Tyr

1 5

<210> 333

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 333

Lys Ala Ser

1

<210> 334

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 336

Trp Ala Ser

1

<210> 337

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 338

Gln Ser Ile Tyr Arg Tyr

1 5

<210> 339

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 339

Tyr Gly Ser

1

<210> 340

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 340

Gln Thr Thr 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 sequences

<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 sequences

<400> 342

Leu Ala Ser

1

<210> 343

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 344

Gln Asn Ile Val Ser Asn

1 5

<210> 345

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 345

Tyr Ala Ser

1

<210> 346

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 347

Gln Ser Ile Tyr Asn Tyr

1 5

<210> 348

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 348

Asp Val Ser

1

<210> 349

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 351

Ser Ala Ser

1

<210> 352

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 353

Gln Asn Ile Tyr Asn Asn

1 5

<210> 354

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 354

Tyr Ala Ser

1

<210> 355

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 356

Gln Thr Ile Gly Ser Tyr

1 5

<210> 357

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 357

Glu Ala Ser

1

<210> 358

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 359

Glu Thr Ile Ser Asn Arg

1 5

<210> 360

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 360

Ser Ala Ser

1

<210> 361

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 362

Gln Ser Ile Ser Ser Tyr

1 5

<210> 363

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 363

Lys Ala Ser

1

<210> 364

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 364

Gln Ser 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 sequences

<400> 365

Gln Ser Ile Ser Asp Tyr

1 5

<210> 366

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 366

Arg Ala Ser

1

<210> 367

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 368

Gln Ser Ile Gly Asn Ala

1 5

<210> 369

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 369

Lys Ala Ser

1

<210> 370

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 371

Gln Asn Ile Tyr Asn Asn

1 5

<210> 372

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 372

Gly Pro Ser

1

<210> 373

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 374

Gln Ser Ile Gly Ser Arg

1 5

<210> 375

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 375

Glu Ala Ser

1

<210> 376

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 377

Pro Ser Ile Ser Thr Tyr

1 5

<210> 378

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 378

Arg Ala Ser

1

<210> 379

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 380

Gln Ser Ile Gly Ser Gly Asn

1 5

<210> 381

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 381

Leu Ala Ser

1

<210> 382

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 382

Gln Tyr Thr 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 sequences

<400> 383

Gln Ile Val Ala Asn Gly Arg

1 5

<210> 384

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 384

Ala Thr Ser

1

<210> 385

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 386

Glu Asp Ile Asp Arg Tyr

1 5

<210> 387

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 387

Asp Ala Ser

1

<210> 388

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 389

His Ile Ile Thr Asn Tyr

1 5

<210> 390

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 390

Asp Ala Ser

1

<210> 391

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 392

Glu Ser Ile Gly Ser Ala

1 5

<210> 393

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 393

Ser Ala Ser

1

<210> 394

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 395

Gln Ser Ile Tyr Asn Tyr

1 5

<210> 396

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 396

Ser Ala Ser

1

<210> 397

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 398

Leu Asn Ile Asn Ser Trp

1 5

<210> 399

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 399

Tyr Thr Ser

1

<210> 400

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 400

Gln Thr Thr Tyr Phe Gly Thr Asn Gly Gly Gly

1 5 10

<210> 401

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 401

Glu Asp Ile Tyr Ser Asn

1 5

<210> 402

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 402

Gly Ala Thr

1

<210> 403

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 405

Tyr Ala Ser

1

<210> 406

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 407

Gln Ser Ile Ser Ser Tyr

1 5

<210> 408

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 408

Lys Ala Ser

1

<210> 409

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 410

Gln Ser Ile Ser Tyr Tyr

1 5

<210> 411

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 411

Lys Ala Ser

1

<210> 412

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 413

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210> 414

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 414

Ser Ala Ser

1

<210> 415

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 417

Lys Ala Ser

1

<210> 418

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 420

Gln Ala Ser

1

<210> 421

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 422

Glu Asn Ile Tyr Ser Tyr

1 5

<210> 423

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 423

Ser Ala Ser

1

<210> 424

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 426

Asp Ala Ser

1

<210> 427

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 429

Ser Ala Ser

1

<210> 430

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 430

Ala Gly 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 sequences

<400> 431

Glu Thr Ile Ser Asn Arg

1 5

<210> 432

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 432

Ser Ala Ser

1

<210> 433

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 434

Gln Thr Ile Tyr Thr Asn

1 5

<210> 435

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 435

Ala Ala Ser

1

<210> 436

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 438

Tyr Ala Ala

1

<210> 439

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 441

Tyr Ala Ala

1

<210> 442

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 443

Glu Asp Ile Ser Ser Asn

1 5

<210> 444

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 444

Gly Ala Ser

1

<210> 445

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 446

Gln Ser Ile Ser Asn Glu

1 5

<210> 447

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 447

Leu Ala Ser

1

<210> 448

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 450

Gly Ala Ser

1

<210> 451

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 452

Gln Ser Ile Gly Ser Tyr

1 5

<210> 453

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 453

Tyr Ala Ser

1

<210> 454

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 455

Gln Asn Ile Tyr Ser Asn

1 5

<210> 456

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 456

Ser Ala Ser

1

<210> 457

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 458

Gln Ser Ile Gly Ser Tyr

1 5

<210> 459

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 459

Lys Ala Ser

1

<210> 460

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 461

Glu Asp Ile Asp Arg Tyr

1 5

<210> 462

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 462

Arg Ala Ser

1

<210> 463

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 464

Gln Ser Ile Ser Ser Tyr

1 5

<210> 465

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 465

Lys Ala Ser

1

<210> 466

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 467

Gln Thr Ile Tyr Thr Asn

1 5

<210> 468

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 468

Ala Ala Ser

1

<210> 469

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 471

Gln Ala Ser

1

<210> 472

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 473

Gln Ser Ile Thr Asn Ala

1 5

<210> 474

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 474

Arg Ala Ser

1

<210> 475

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 476

Gln Ser Ile Ser Ser Ser Tyr

1 5

<210> 477

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 477

Ser Ala Ser

1

<210> 478

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 479

Gln Ser Ile Gly Ser Asn

1 5

<210> 480

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 480

Lys Ala Ser

1

<210> 481

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 483

Tyr Ala Ala

1

<210> 484

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 485

Gln Ser Ile Ala Ser Asp

1 5

<210> 486

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 486

Ala Ala Ser

1

<210> 487

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 488

cagaacattt acagctac 18

<210> 489

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 489

aaggcatcc 9

<210> 490

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 490

caaaccaatt attttagtag tactagtcat tttggtgttt ttact 45

<210> 491

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 491

cagagtcttt ataatgcgaa cgac 24

<210> 492

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 492

tgggcatcc 9

<210> 493

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 493

ctaggcgaat ttagttgcag tagttttgat tgtcatgtt 39

<210> 494

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 494

cagagcattt acaggtac 18

<210> 495

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 495

tatggatcc 9

<210> 496

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 496

caaaccactt atgatgatta tcataatggt tgggct 36

<210> 497

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 497

cagagtgttt atggtaacaa ccgc 24

<210> 498

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 498

ctggcatcc 9

<210> 499

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 499

gcaggcggtt atgctgggaa tttcaatgct 30

<210> 500

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 500

cagaacattg tcagtaat 18

<210> 501

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 501

tatgcatcc 9

<210> 502

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 502

caaaacaatg ctggtattta tggtaattat ggtcatggt 39

<210> 503

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 503

cagagcattt acaactac 18

<210> 504

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 504

gatgtatcc 9

<210> 505

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 505

caaagttatt atggtaatac tgtttctttt act 33

<210> 506

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 506

cagagtgttt ataataacaa caac 24

<210> 507

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 507

tctgcatcc 9

<210> 508

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 508

gcaggcggtt atacttacaa tatcaatatt 30

<210> 509

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 509

cagaacattt acaacaat 18

<210> 510

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 510

tatgcatcc 9

<210> 511

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 511

caaaacaatg ctggtattta tggtggttat ggtcatggt 39

<210> 512

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 512

cagactattg gtagctac 18

<210> 513

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 513

gaagcatcc 9

<210> 514

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 514

caaagcaatt attatcgtgc tggtggtaat tatggtggag ct 42

<210> 515

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 515

gagaccatta gtaataga 18

<210> 516

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 516

tctgcatcc 9

<210> 517

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 517

caaagtattc gtagtagtag tggtattgtt catccgaata ct 42

<210> 518

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 518

cagagcatta gtagttac 18

<210> 519

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 519

aaggcatcc 9

<210> 520

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 520

caaagctatt actatattag tgctactgtt gataatact 39

<210> 521

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 521

cagagcatta gtgattac 18

<210> 522

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 522

agggcatcc 9

<210> 523

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 523

caaagtaatt attatggtag tcagggttgt act 33

<210> 524

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 524

cagagcattg gcaatgca 18

<210> 525

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 525

aaggcatcc 9

<210> 526

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 526

caaaactatt attatagtaa tactaatagt 30

<210> 527

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 527

cagaacattt ataataac 18

<210> 528

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 528

ggtccatcc 9

<210> 529

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 529

caaagtgatg attggatgag tatcagtcct gatattgtt 39

<210> 530

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 530

cagagtattg gtagtaga 18

<210> 531

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 531

gaagcatcc 9

<210> 532

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 532

caatgtactt attatgaaag tagtagtggt ggtggt 36

<210> 533

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 533

catatcatta ctaactac 18

<210> 534

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 534

gatgcatcg 9

<210> 535

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 535

caaaactatc tttattttag tagtggtgat tggaatgtt 39

<210> 536

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 536

ccgagcatta gtacttac 18

<210> 537

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 537

agggcatcc 9

<210> 538

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 538

caaaacaatt accatagtgg tagtagtaat ggtggtggtg ttgct 45

<210> 539

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 539

cagagtattg gtagtggtaa t 21

<210> 540

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 540

ctggcatcc 9

<210> 541

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 541

caatatactt attatggtac tacttatgat aatgct 36

<210> 542

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 542

cagattgttg ctaacggccg c 21

<210> 543

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 543

gctacatcc 9

<210> 544

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 544

caaggcgctt atagtagtgg ggatgttcgg act 33

<210> 545

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 545

gaggacattg ataggtat 18

<210> 546

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 546

gatgcatcc 9

<210> 547

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 547

caaagctatg ataatagtga taataatggt 30

<210> 548

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 548

catatcatta ctaactac 18

<210> 549

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 549

gatgcatcg 9

<210> 550

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 550

caaaactatc tttattttag tagtggtgat tggaatgtt 39

<210> 551

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 551

gagagcattg gcagtgca 18

<210> 552

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 552

tctgcatcc 9

<210> 553

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 553

caaagttatt atggaagtgg tacgactgct ttagatact 39

<210> 554

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 554

cagagcattt acaactac 18

<210> 555

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 555

tctgcatcc 9

<210> 556

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 556

caaaacaatt atggtattgg tagtaattat ggtcctggt 39

<210> 557

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 557

ctgaacatta atagttgg 18

<210> 558

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 558

tatacatcc 9

<210> 559

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 559

caaaccacat attttggtac taatggtggt ggt 33

<210> 560

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 560

gaggacattt atagcaat 18

<210> 561

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 561

ggtgcaacc 9

<210> 562

<211> 27

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 562

caggccgaaa gtaatgatgt ttgggct 27

<210> 563

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 563

gaggatattt atagtaat 18

<210> 564

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 564

aaggcatcc 9

<210> 565

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 565

cagactactt attggactac tactgatgat aatcct 36

<210> 566

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 566

cagagtgttt ataataagaa ctac 24

<210> 567

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 567

tatgcttcc 9

<210> 568

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 568

gcagcttata aaggtgttag tgatgatggt atttct 36

<210> 569

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 569

cagagcatta gtagttac 18

<210> 570

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 570

aaggcatcc 9

<210> 571

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 571

caaaacaatt atcatagtgg tagtagtaat ggtggtggtt ttgct 45

<210> 572

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 572

cagagcatta gttactac 18

<210> 573

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 573

aaggcatcc 9

<210> 574

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 574

caaagcactt atggtaggga taataatgat ctttttttcg ct 42

<210> 575

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 575

cagagtatta gtagtagcta c 21

<210> 576

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 576

tctgcgtcc 9

<210> 577

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 577

caaagcactt atattagtag tagtaagtat ggtgctgtt 39

<210> 578

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 578

cagagtgttt atagtaacaa ctgg 24

<210> 579

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 579

aaggcatcc 9

<210> 580

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 580

gcaggcgggt atagtggtga tctttatgct 30

<210> 581

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 581

cagactattt ataataacaa aaat 24

<210> 582

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 582

caggcatcc 9

<210> 583

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 583

caaggcgaat ttagttgtag tagtggtgat tgtactact 39

<210> 584

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 584

gagaacattt atagctac 18

<210> 585

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 585

tctgcatcc 9

<210> 586

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 586

caatatagta attttagggt gaatgatcct agtgtt 36

<210> 587

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 587

cagaccgttc ataataatca atgg 24

<210> 588

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 588

gatgcatcc 9

<210> 589

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 589

caaggcggtt atagttatgg tgatgtgtat ggt 33

<210> 590

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 590

caaagtgttg ataacaacaa acaa 24

<210> 591

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 591

tctgcatcc 9

<210> 592

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 592

gcaggctatt attatagtgg tagtgccact gatgcgtggg ct 42

<210> 593

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 593

gagaccatta gtaataga 18

<210> 594

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 594

tctgcatcc 9

<210> 595

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 595

caaagtattc gtagtagtag tggtgttgtg catccaaata ct 42

<210> 596

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 596

cagaccattt ataccaat 18

<210> 597

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 597

gctgcatcc 9

<210> 598

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 598

caaagctatt atggtagtag tactactggt aatggt 36

<210> 599

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 599

gataatgttt atagtaataa ctac 24

<210> 600

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 600

tatgcggcc 9

<210> 601

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 601

tcaggccata aagattatag tgatgatggt agtact 36

<210> 602

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 602

gataatgttt atagtaataa ctac 24

<210> 603

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 603

tatgcggcc 9

<210> 604

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 604

tcaggccata aagattatag tgatgatggt agtact 36

<210> 605

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 605

gaggatatta gtagtaat 18

<210> 606

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 606

ggtgcatcc 9

<210> 607

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 607

caaggcgctt attatggtag tagttatggt 30

<210> 608

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 608

cagagcatta gcaatgaa 18

<210> 609

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 609

ctggcatcc 9

<210> 610

<211> 42

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 610

caaagtcatt attatggtgg tagtagtgat tatggatggg ct 42

<210> 611

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 611

caaagtgttt acaataacaa ccaa 24

<210> 612

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 612

ggtgcatcc 9

<210> 613

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 613

caaggcgctg ttagtagtga ttactatcct 30

<210> 614

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 614

cagagtattg gtagctat 18

<210> 615

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 615

tatgcttcc 9

<210> 616

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 616

caaagtaatc gtcttagtag tagtgacgtt aatgct 36

<210> 617

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 617

cagaacattt acagcaat 18

<210> 618

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 618

tctgcatcc 9

<210> 619

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 619

caaagctatt attatactgc tagtgctgat actact 36

<210> 620

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 620

cagagcattg gtagctac 18

<210> 621

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 621

aaggcatcc 9

<210> 622

<211> 30

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 622

caatatacta gttatagtag tggtggggct 30

<210> 623

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 623

gaggacattg ataggtat 18

<210> 624

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 624

agggcatcc 9

<210> 625

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 625

caaggcgatt ttattggtag tagttatggc gttgct 36

<210> 626

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 626

cagagcatta gtagttac 18

<210> 627

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 627

aaggcttcc 9

<210> 628

<211> 45

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 628

caaaacaatt atcatagtgg tagtagtaat ggtggtggtt ttgct 45

<210> 629

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 629

cagaccattt ataccaat 18

<210> 630

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 630

gctgcatcc 9

<210> 631

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 631

caaagctatt atggtagtag tactactggt aatggt 36

<210> 632

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 632

gagagtgttt atggtaacaa ccgt 24

<210> 633

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 633

caggcttcc 9

<210> 634

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 634

gcaggacata aaggaactac taatgatggg aatgat 36

<210> 635

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 635

cagagcatta ccaatgca 18

<210> 636

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 636

agggcatcc 9

<210> 637

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 637

caatgtagtt attatggtag tacttatttt gggagtcct 39

<210> 638

<211> 21

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 638

cagagcatta gtagtagcta c 21

<210> 639

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 639

tctgcatcc 9

<210> 640

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 640

caaagcactt atattagtag tagtaattat ggtgctgct 39

<210> 641

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 641

cagagcattg gtagtaat 18

<210> 642

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 642

aaggcatcc 9

<210> 643

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 643

caaaacaata attattggag taatggtaac cat 33

<210> 644

<211> 24

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 644

gagaatgttt atagtaataa ctac 24

<210> 645

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 645

tatgcggcc 9

<210> 646

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 646

tcaggccata aagattatag tgatgatggt agtact 36

<210> 647

<211> 18

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 647

cagagcattg ctagcgac 18

<210> 648

<211> 9

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 648

gctgcatcc 9

<210> 649

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 649

caaagctatt atggtagtag tactactggt aatggt 36

<210> 650

<211> 375

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 gagggctctg 300

gatagtcatt attcttcctt tgacttgtgg ggcccaggca ccctggtcac catctcttca 360

<210> 653

<211> 345

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 ccgtgttatt ttggcttgtg gggcccaggc 360

accctggtca ccatctcctc a 381

<210> 656

<211> 345

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<400> 657

gagcagtcgg tggaggagtc cgggggaggc ctggtcaagc ctgagggatc cctgacactc 60

acctgcaaag cctctggatt ggacttcagt agcagctatt ggagctgctg ggtccgccag 120

actccaggga gggggctgga gtggatcgga tgcattgatg ttgggagtag 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 sequences

<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 attcttacct tggacttgtg gggcccaggc 360

accctggtca ccgtctcttc a 381

<210> 659

<211> 369

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 664

cagtcgctgg aggagtccgg gggagacctg gtccagcctg agggatccct gacactcacc 60

tgcacagctt ctggattctc cttcagtatc aacttataca tgtgctgggt ccgccaggct 120

ccagggaagg ggctggagtg gatcgcatgc atttatggta ataataatgc 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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 668

cagtcgttgg aggagtccgg gggaggcctg gtcaagcctg gggcttccct 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 gtgggagatt ggattatcgt 300

gttatttatg cctttaattt gtggggccca ggcaccctgg tcaccatctc ctca 354

<210> 669

<211> 366

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 agggcaccct ggtcaccgtc 360

tcttca 366

<210> 670

<211> 360

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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

tatgcttatg ctggtgctgg ggacttgtgg ggcccaggca ccctggtcac cgtctcttca 360

<210> 671

<211> 363

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 atttctgtgc gagccgaaat 300

ggtggtgcgc ctgatggttt gaacttgtgg ggcccaggca ccctggtcac catctcttca 360

<210> 675

<211> 354

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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

gttagttatt tgaatttgtg gggcccaggc accctggtca ccgtctcttc a 351

<210> 678

<211> 381

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<400> 682

caggagcagc tggtggagtc cgggggaggc ctggtaacgc ctggaggatc cctgacactc 60

acctgcacag cctctggatt ctccttcagt agcaagcaat acatttcctg 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 sequences

<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 atttctgtgc gagatcatat 300

attactgatc gtatttatga ttacgacttt tggggcccag gcaccctggt caccatctct 360

tca 363

<210> 684

<211> 357

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<400> 686

gagtccgagg gaggcctggt 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 sequences

<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 sequences

<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 sequences

<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

cttgttactg 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 sequences

<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 sequences

<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

gttagttatt tgaatttgtg gggcccaggc accctggtca ccgtctcctc a 351

<210> 693

<211> 366

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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

agtggttatt attattacta cggcatggat ctctggggcc cagggaccct cgtcaccatc 360

tcctca 366

<210> 694

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 atttttgtgc gagagatcag 300

gctgacagtt atgcctttgg tttgtggggc ccaggcacac tggtcaccat ctcctcag 358

<210> 695

<211> 348

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 gaggggtttt 300

tcgatgttta agttgtgggg cccaggcacc ctggtcacca tctcttca 348

<210> 696

<211> 378

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 sequences

<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 gaaatcttat 300

aattataatg gtttaggctt gtggggccca ggcaccctgg tcaccgtctc ctca 354

<210> 700

<211> 367

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 ttattgggac ttgtggggcc caggcaccct ggtcaccgtc 360

tcttcag 367

<210> 701

<211> 354

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 701

gagcagtcgg tggaggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cctctggaat cgacttcagt agcggcgcct ggatatgctg ggtccgccag 120

gctccaggga aggggctgga gttgatcgca tgcattttta ctactagtgg 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 sequences

<400> 702

caggagcagc tggtggagtc cgggggaggc ctggtccagc ctgagggatc cctgacactc 60

acctgcacag cttctggatt ctccttcagt agcaggcaat acatttcctg 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 sequences

<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 sequences

<400> 704

Gln Ser Leu Glu Glu 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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 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 sequences

<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 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 sequences

<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 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 sequences

<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 sequences

<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 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 sequences

<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 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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 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 sequences

<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 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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 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 sequences

<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 Thr Ser Val Thr Leu Gln Met

65 70 75 80

Thr Thr Leu Thr Ala Ala Asp Thr Ala Thr 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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<400> 749

Gln Ser Leu Lys Glu 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 sequences

<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 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 sequences

<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 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 sequences

<400> 752

Gln Ser Val Glu Glu 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 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 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 sequences

<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 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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 acacagttca ctctcagcat cagcgacgtg 240

cagtgtgacg atgctgccac ttactactgt ctaggcgaat ttagttgcag tagttttgat 300

tgtcatgttt tcggcggagg gaccgaggtg gtggtcaaa 339

<210> 762

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 attatcataa tggttgggct 300

ttcggcggag ggaccaatgt ggaaatcaac 330

<210> 763

<211> 330

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 763

gagctcgatc tgacccagac tccatcgtcc gtgtctgcag ctgtgggagg cacagtcacc 60

atcagttgcc aggccagtca gagtgtttat ggtaacaacc gcttagcctg gtatcatcag 120

aaaccaggac agcctcccaa acgcctgatc tatctggcat ccactctgga ttctggggtc 180

ccatcacggt tcaaaggcgc tggatctggg acacagttca ctctcaccat cagcgacctg 240

gagtgtgacg atgctgccac ttactactgt gcaggcggtt atgctgggaa tttcaatgct 300

ttcggcggag ggaccgaggt ggaaatcaaa 330

<210> 764

<211> 333

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 764

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtgggagg 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 sequences

<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 sequences

<400> 766

gagctcgtga tgacccagac tccatcgtcc gtgtctgcag ctgtgggagg cacagtcacc 60

atcagttgcc aggccagtca gagtgtttat aataacaaca acttagcctg gtatcagcag 120

aaaccagggc agcctcccaa acgcctgatc tattctgcat ccactctgga ttctggggtc 180

ccatcgcggt tcagcggcag tggatctggg acacagttca 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 sequences

<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 sequences

<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 sequences

<400> 769

gagctcgatc tgacccagac tccattctcc gtgtctgcag ctgtgggagg 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 sequences

<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 sequences

<400> 771

gagctcgatc tgacccagac tccaacctcc gtgtctgcag ctgtgggagg 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 sequences

<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 sequences

<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 sequences

<400> 774

gagctcgtga tgacccagac accatcatcc tcgtctgcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca gagtattggt agtagattcg cctggtatca gcagaaacca 120

gggcagcgtc ccaagctcct gatctatgaa gcatccaaac tgccatctgg ggtcccatcg 180

cggttcaaag gcagtggatc tgggacagag ttcacgctca ccatcagcga cctggagtgt 240

gccgatgctg ccatttatta ctgtcaatgt acttattatg aaagtagtag tggtggtggt 300

ttcggcggag ggaccgaggt ggtggtcaaa 330

<210> 775

<211> 333

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 775

gagctcgtgc 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 tatctttatt ttagtagtgg 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 sequences

<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 sequences

<400> 778

gagctcgtgc tgacccagac tccagcctcc gtgtctgcgg ctgtgggagg cacagtcacc 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 sequences

<400> 779

gagctcgatc tgacccagac tccatcccca gtgtctgcag ctgtgggagg 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 sequences

<400> 780

gagctcgtgc tgacccagac accatcctcc gtgtctgcag ctgtgggagg cacagtcacc 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 sequences

<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 tatctttatt ttagtagtgg tgattggaat 300

gttttcggcg gagggaccga ggtggtggtc aaa 333

<210> 782

<211> 333

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 782

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtgggagg 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 sequences

<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 sequences

<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 sequences

<400> 785

gagctcgtga tgacccagac accatcctcc gtggaggcag ctgtgggagg 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 sequences

<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 sequences

<400> 787

gagctcgatc tgacccagac tccatcatcc tcgtctgcag ctgtgggagg cacagtcacc 60

atcaattgcc aggccagtca gagtgtttat aataagaact acttatcctg gtttcagcag 120

aaaccagggc agcctcccaa gctcctgatc tattatgctt ccactctggc atctggggtc 180

ccatcgcggt tcaaaggcag tggatctggg acagagttca 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 sequences

<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 sequences

<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 sequences

<400> 790

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtgggagg 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 sequences

<400> 791

gagctcgtga tgacccagac tgcatcgccc gtgtctgcag ctgtgggagg cacagtcacc 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 sequences

<400> 792

gagctcgata tgacccagac tccatctccc gtgtctgcag ctgtgggagg ctcagtcacc 60

atcagttgcc aggccagtca gactatttat aataacaaaa atttggcctg gtatcagcag 120

aaaccagggc aacctcccaa gctcctgatc taccaggcat ccaaactggc atctggggtc 180

tcatcgcggt tcagtggcag tggatctggg acacagttca 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 sequences

<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 sequences

<400> 794

gagctcgatc tgacccagac tccagcctcc gtgtctgcag ctgtgggagg 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 sequences

<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 acacagttca ctctcaccat cagcgacctg 240

gagtgtgacg atgctgccac ttactactgt gcaggctatt attatagtgg tagtgccact 300

gatgcgtggg ctttcggcgg agcgaccgag gtggaaatca ac 342

<210> 796

<211> 336

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<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 sequences

<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 sequences

<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 acagagttca 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 sequences

<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 acagagttca 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 sequences

<400> 800

gagctcgtga tgacccagac accagcctcc gtgtctgcag ctgtgggagg cacagtcacc 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 sequences

<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 sequences

<400> 802

gagctcgata tgacccagac tccatcttcc acgtctgcag ctgtgggagg cacagtcacc 60

atcaagtgcc aggccagtca aagtgtttac aataacaacc aattatcctg gtttcagcag 120

aaaccagggc agcctcccaa acgcctgatc tatggtgcat ccactctgga atctggggtc 180

ccatcgcggt tcagcggcag tggatctggg acacagttca 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 sequences

<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 sequences

<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 sequences

<400> 805

gagctcgtgc tgacccagac tccatcctcc gtggaggcag ctgtgggagg 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 sequences

<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 sequences

<400> 807

gagctcgtga tgacccagac tccagcctct gtgtctgaac ctgtgggagg 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 sequences

<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 acacagttca ctctcaccat cagcgatgtg 240

gtgtgtgacg atgctgccac ttactactgt gcaggacata aaggaactac taatgatggg 300

aatgatttcg gcggagggac cgaggtggaa atcaaa 336

<210> 809

<211> 333

<212> DNA

<213> artificial sequence

<220>

<223> synthetic antibody sequences

<400> 809

gagctcgata tgacccagac tccagcctcc gtgtctgcag ctgtgggagg 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 sequences

<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 sequences

<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 sequences

<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 acagagttca 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 Cys Gln Tyr Thr 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 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 sequences

<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 sequences

<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 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 Ala Cys Gln Thr Thr 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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 Ile Ser 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 Ile Ser 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 sequences

<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 sequences

<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 sequences

<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 sequences

<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 agggcctgga 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 agggcctgga 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 agggcctgga 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 antigen-binding fragment thereof, comprising: a Heavy Chain (HC) variable region (VH) and a Light Chain (LC) variable region (VL), the VH and the VL comprising CDR sequences of clone pairs as shown in tables 1 and 3; and variants thereof, wherein one or more of the HC-CDRs and/or LC-CDRs have one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

2. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1, wherein the isolated monoclonal antibody is a murine antibody, a rodent antibody, a rabbit antibody, a chimeric antibody, a humanized antibody, or a human antibody.

3. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1, wherein the antigen-binding fragment is a recombinant ScFv (single chain fragment variable) antibody, fab fragment, F (ab') 2 fragment, or Fv fragment.

4. The isolated monoclonal antibody or antigen binding fragment thereof according to claim 1, wherein the isolated monoclonal antibody is a human antibody.

5. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1, wherein the VH chain and VL chain have amino acid sequences at least 90% or 95% identical to the sequences paired with the clones of tables 6 and 8, respectively.

6. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 5, wherein the VH and VL chains have amino acid sequences identical to the sequences of clone pairs of tables 6 and 8, respectively.

7. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1, wherein the VH and VL chains are encoded by nucleic acid sequences at least 80% or 90% identical to sequences paired with clones of tables 5 and 7, respectively.

8. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 7, wherein the VH and VL chains are encoded by nucleic acid sequences identical to sequences paired with clones of tables 5 and 7, respectively.

9. The isolated monoclonal antibody or antigen binding fragment thereof according to any one of claims 1-8, 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 having amino acid sequences at least 90% or 95% identical to the sequences of clone pairs of Hu-176 VH-1 and Hu-176-K as shown in tables 6 and 8, respectively.

11. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 10, wherein the VH chain and the VL chain have amino acid sequences identical to the sequences of clone-paired Hu-176 VH-1 and Hu-176-K as shown in tables 6 and 8, respectively.

12. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 9, wherein the humanized antibody has VH and VL chains having amino acid sequences at least 90% or 95% identical to the sequences of clone pairs of Hu-176 VH-1 (W48L) and Hu-176-K as shown in tables 6 and 8, respectively.

13. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 10, wherein the VH chain and the VL chain have amino acid sequences identical to the sequences of clone-paired Hu-176 VH-1 (W48L) and Hu-176-K as shown in tables 6 and 8, respectively.

14. The isolated monoclonal antibody or antigen binding fragment thereof according to any one of claims 1-13, comprising an IgG Fc region comprising amino acid modifications in one or more of amino acid positions 234, 235, 297 and 329.

15. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 14, wherein the IgG Fc region comprises an amino acid substitution N to a at amino acid position 297.

16. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 14, wherein the IgG Fc region comprises an amino acid substitution L at amino acid position 234 to a, an amino acid substitution L at amino acid position 235 to a, and an amino acid substitution P at amino acid position 329 to G.

17. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-16, wherein the antibody is a chimeric antibody.

18. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-16, which induces activation of LILRB 1.

19. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-16, which inhibits the activation of LILRB 1.

20. An isolated monoclonal antibody or antigen-binding fragment thereof that competes for binding to the same epitope with an isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-19.

21. An isolated monoclonal antibody or antigen-binding fragment thereof that binds to an epitope on LILRB1 that is recognized by the antibody of any one of claims 1 to 20.

22. An isolated monoclonal antibody, or antigen binding fragment thereof, wherein the monoclonal antibody, when bound to LILRB1, binds to residues Y76 and R84 of LILRB 1.

23. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-22, wherein the antibody or fragment thereof is conjugated or fused to an imaging agent or a cytotoxic agent.

24. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-22, wherein the antibody or fragment thereof is labeled.

25. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 24, wherein the label is a fluorescent label, an enzymatic label, or a radioactive label.

26. A pharmaceutical composition comprising the isolated monoclonal antibody or antigen-binding fragment thereof of any one of claims 1-25 and a pharmaceutically acceptable carrier.

27. An isolated nucleic acid encoding the isolated monoclonal antibody of any one of claims 1-22.

28. A vector comprising the isolated nucleic acid of claim 27.

29. A host cell comprising the vector of claim 28.

30. The host cell of claim 29, wherein the host cell is a mammalian cell.

31. The host cell of claim 29, wherein the host cell is a CHO cell.

32. A hybridoma or engineered cell encoding and/or producing the isolated monoclonal antibody of any one of claims 1 to 22.

33. A method of producing an antibody, the method comprising culturing the host cell of claim 29 under conditions suitable for expression of the antibody and recovering the antibody.

34. A Chimeric Antigen Receptor (CAR) protein comprising the antigen-binding fragment of any one of claims 1 to 22.

35. An isolated nucleic acid encoding the CAR protein of claim 34.

36. A vector comprising the isolated nucleic acid of claim 35.

37. An engineered cell comprising the isolated nucleic acid of 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 cancer in a subject or ameliorating the effects of cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-22 or an engineered cell according to claim 37 or 38.

40. The method of claim 39, wherein the method reduces or eradicates tumor burden in 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 NK cells of the subject have been identified as expressing LILRB1.

46. The method of claim 45, wherein NK cells of the subject have been identified as expressing increased levels 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 gland 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, merck cell carcinoma, nasopharyngeal cancer, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pineal tumor, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma, skin cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, and vaginal cancer.

49. The method of claim 39, wherein monocytes, macrophages, dendritic cells, neutrophils and other myeloid cells, myeloid-derived suppressor cells and tumor-associated macrophages are targeted.

50. The method of claim 39, wherein the cancer is a hematological malignancy.

51. The method of claim 50, wherein the hematological malignancy is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), B-cell leukemia, chronic Lymphocytic Leukemia (CLL), plasmacytoid dendritic cell neoplasm (BPDCN), chronic myelomonocytic leukemia (CMML), chronic Myelogenous Leukemia (CML), pre-B acute lymphoblastic leukemia (pre-B ALL), diffuse large B-cell lymphoma (DLBCL), extranodal NK/T-cell lymphoma, hairy cell leukemia, heavy chain disease, HHV 8-associated primary exudative lymphoma, plasmablastoid lymphoma, primary CNS lymphoma, primary mediastinal large B-cell lymphoma, T-cell/tissue cell enriched B-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, fahrenheit macroglobulinemia, multiple Myeloma (MM), myelodysplastic syndrome (MDS), myeloproliferative neoplasm, 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 antigen-binding fragment thereof is administered intravenously, intraarterially, 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, anthracyclines, daunorubicins, nucleoside metabolic inhibitors, cytarabine, hypomethylating agents, low dose cytarabine (LDAC), combination of daunorubicin and cytarabine, daunorubicin and cytarabine liposomes for injection, and pharmaceutical compositions containing them,Azacytidine, (-) -and>decitabine, all-trans retinoic acid (ATRA), arsenic trioxide, histamine dihydrochloride,/-for>Interleukin-2, aldesleukin,Gemtuzumab and>FLT-3 inhibitors, midostaurin, < >>Clofarabine, farnesyl transferase inhibitor, decitabine, IDH1 inhibitor, ai Funi cloth, < >>IDH2 inhibitors, etanercept, < >>Smoothing (SMO) inhibitors, glagil, arginase inhibitors, IDO inhibitors, ai Kaduo stat, BCL-2 inhibitors, valnemulin,/-for >Platinum complex derivatives, oxaliplatin, kinase inhibitors, tyrosine kinase inhibitors, PI3 kinase inhibitors, BTK inhibitors, ibrutinib,/u>Acartinib,/i>Zanbutinib, PD-1 antibody, PD-L1 antibody, CTLA-4 antibody, LAG3 antibody, ICOS antibody, TIGIT antibody, TIM3 antibody, CD40 antibody, 4-1BB antibody, CD47 antibody, SIRP1 alpha antibody or fusion protein, CD70 antibody and CLL1 antibody, CD123 antibody, antagonist of E-selectin, antibody binding to tumor antigen, antibody binding to T cell surface marker, antibody binding to myeloid cell or NK cell surface marker, alkylating agent, nitrosourea agent, antimetabolite, antitumor antibiotic, plant-derived alkaloid, hormone therapy drug, hormone antagonist, aromatase inhibitor and P-glycoprotein inhibitor.

55. The method of any one of claims 39-54, wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises an anti-tumor drug linked thereto.

56. The method of claim 55, wherein the anti-tumor agent is linked to the antibody through a photolabile linker.

57. The method of claim 55, wherein the anti-tumor drug is linked to the antibody by an enzymatic cleavage linker.

58. The method of claim 55, wherein the anti-tumor drug is a toxin, radioisotope, cytokine or enzyme.

59. A method of detecting cancer cells or cancer stem cells in a sample or subject, the method comprising:

(a) Contacting a subject or a sample from the subject with the antibody or antigen-binding fragment thereof of any one of claims 1 to 25; and

(b) Detecting binding of the antibody to a cancer cell or cancer stem cell in the subject or sample.

60. The method of claim 59, wherein the sample is a body fluid or biopsy.

61. The method of claim 59, wherein the sample is blood, bone marrow, sputum, tears, saliva, mucous, serum, urine, or stool.

62. The method of claim 59, wherein detecting comprises immunohistochemistry, flow cytometry, immunoassays (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 a change in the detected level compared to the first time.

64. The method of claim 59, wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a label.

65. The method of claim 64, wherein the label is a peptide tag, an enzyme, a magnetic particle, a chromophore, a fluorescent molecule, a chemiluminescent molecule, or a dye.

66. The method of any one of claims 39 to 65, wherein the isolated monoclonal antibody or antigen-binding fragment thereof is conjugated to a liposome or nanoparticle.

67. A method of treating or ameliorating the effects of an autoimmune disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-22 or an engineered cell according to claim 37 or 38.

68. The method of claim 67, wherein monocytes, macrophages, dendritic cells, neutrophils and/or other myeloid cells are targeted.

69. The method of claim 67, wherein the antibody or antigen-binding fragment thereof is administered intravenously, intraarterially, 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 a steroid or an NSAID.

71. The method of claim 67, wherein the step of, wherein the autoimmune disease is green-barre syndrome, chronic inflammatory demyelinating polyneuropathy, ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis, reactive arthritis, undifferentiated spondyloarthropathies, juvenile spinal arthropathy, behcet's disease, tendinitis, ulcerative colitis, crohn's disease, irritable bowel syndrome, inflammatory bowel disease, fibromyalgia, chronic fatigue syndrome, pain conditions associated with systemic inflammatory diseases, systemic lupus erythematosus, sjogren's syndrome, rheumatoid arthritis, juvenile onset diabetes (also known as type I diabetes), wegener's granulomatosis, polymyositis, dermatomyositis, inclusion body myositis, multiple endocrine failure, schmitt 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, de-reshler's syndrome, myasthenia gravis, eaton-lambert syndrome, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, pemphigus vulgaris, pemphigus, dermatitis herpetiformis, alopecia, scleroderma, progressive systemic sclerosis, CREST syndrome (calcanesis, raynaud's phenomenon, esophageal dyskinesia, digital end sclerosis and telangiectasia), adult onset diabetes (also known as type II diabetes), mixed connective tissue disease, polyarteritis nodosa, systemic necrotizing vasculitis, glomerulonephritis, atopic dermatitis, atopic rhinitis, goodpasture's syndrome, chagas's disease, sarcoidosis, rheumatic fever, asthma, antiphospholipid syndrome, erythema multiforme, cushing's syndrome, autoimmune chronic active hepatitis, allergic disease, allergic encephalomyelitis, transfusion reactions, leprosy, malaria, leishmaniasis, trypanosomiasis, gao's arteritis, polymyalgia rheumatica, temporal arteritis, schistosomiasis, giant cell arteritis, eczema, lymphomatoid granulomatosis, kawasaki's disease, endophthalmitis, psoriasis, fetal erythropoiesis, eosinophilic fasciitis, schuman's syndrome, fei Erdi's syndrome, fukes's cyclositis, igA nephropathy, henryi Shu Ershi purpura, anti-host disease, TRAP, graft rejection, thermal disease, periodic fever syndrome, geodesis, familial inflammation, moire's disease, moso-related sea-state syndrome, TNF-related syndrome or Duofr's syndrome.

72. A method for increasing the immune function of NK cells of a subject, the method comprising administering to the subject the antibody or antigen-binding fragment thereof of any one of claims 1 to 22 or the engineered cell of claim 37 or 38.