Monoclonal antibody or antigen-binding fragment thereof that specifically binds to gd2 (ganglioside gd2), and use thereof

Abstract

This invention relates to the fields of biotechnology and medicine, and particularly to monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 (ganglioside GD2). The invention further relates to nucleic acids encoding said antibodies, expression vectors, host cells and methods for producing said antibodies, methods for producing antibodies according to the invention, pharmaceutical compositions comprising antibodies according to the invention, pharmaceutical compositions comprising antibodies according to the invention and other therapeutically active compounds, methods for treating GD2-mediated diseases or conditions, use of antibodies or pharmaceutical compositions thereof for treating GD2-mediated diseases or conditions, and use of antibodies and other therapeutically active compounds for treating GD2-mediated diseases or conditions.

Description

[Technical Field]

[0001] This invention relates to the fields of biotechnology and medicine, and particularly to monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 (ganglioside GD2). The invention further relates to nucleic acids encoding said antibodies, expression vectors, host cells and methods for producing said antibodies, methods for producing antibodies according to the invention, pharmaceutical compositions comprising antibodies according to the invention, pharmaceutical compositions comprising antibodies according to the invention and other therapeutically active compounds, methods for treating GD2-mediated diseases or conditions, use of antibodies or pharmaceutical compositions thereof for treating GD2-mediated diseases or conditions, and use of antibodies and other therapeutically active compounds for treating GD2-mediated diseases or conditions. [Previous Technology]

[0002] GD2 is the first ganglioside proven to be an effective target antigen for cancer immunotherapy. Gangliosides are composed of glycosphingolipids and sialic acid (N-acetylenamine, Neu5Ac, or NANA), which are nine-carbon monosaccharides. Ganglioside nomenclature is based on the number and position of NANA residues. The monosaccharide is first added to ceramide to form lactosceramide, and then NANA residues are added to form the ganglioside. Each sugar is bound by a specific glycosyltransferase. GD2 has two NANA (α-2,8-sialic acid and α-2,3-sialic acid) and is derived from the precursor GD3 by adding Gal-Nac via GM2 / GD2 synthase (β1,4-N-acetylenamine transferase). The terminal penta-oligosaccharide constitutes the most specific antibody-specific epitope for GD2. The key enzyme GM2 / GD2 synthase responsible for GD2 synthesis has been successfully used as a molecular marker for minimal residual neuroblastoma in the bone marrow, with significant prognostic implications for patient survival. As described in the section on the synthetic pathway of gangliosides, the epitope neighborhood of GD2 can be clearly defined. For example, GD3 and GD1b are the most common cross-reactive gangliosides recognized by anti-GD2 antibodies. GD2-derives with a 9-O-acetyl modification on the terminal sialic acid are called O-acetyl-GD2. While most anti-GD2 antibodies cross-react with O-GD2, some do not. Anti-O-GD2 antibodies that do not cross-react with GD2 have less cross-reactivity with normal neurons. Gangliosides are found on the cell surface of the nervous system in vertebrates. Lower vertebrates such as fish and amphibians possess more polysialic gangliosides, containing 4 to 5 NANA residues, while gangliosides in higher vertebrates, including reptiles, birds, and mammals, contain only 1 to 3 NANA residues (MAYA SUZUKI et al., Disialoganglioside GD2 as a therapeutic target for human diseases, Expert Opinion on Therapeutic Targets, 2015, Vol. 15, pp. 349-362, PMID: 25604432, DOI: 10.1517 / 14728222.2014.986459). GD2 is expressed in neural stem cells, mesenchymal stem cells (MSCs), and peripheral sympathetic-adrenergic progenitor cells, and it is involved in neural differentiation and proliferation. Although the role of polysialic acid in neuronal development has been extensively studied, the exact function of gangliosides, and specifically GD2, remains unknown. After birth, GD2 expression is limited to the CNS, predominantly in neuronal cell bodies and MSCs, and at low levels in peripheral nerves and skin melanocytes.GD2 is thought to play a role in the maintenance and repair of neural tissue, which undergoes continuous and progressive degenerative changes through the regulation of complement initiation and subsequent inflammation, although the exact immune mechanisms remain unclear. It should be noted that GD2 (+) MSCs have the potential to differentiate into multiple clones, including neurons (MAYA SUZUKI et al., Disialoganglioside GD2 as a therapeutic target for human diseases, Expert Opinion on Therapeutic Targets, 2015, Vol. 15, pp. 349-362, PMID: 25604432, DOI: 10.1517 / 14728222.2014.986459). GD2 is overexpressed in various embryonal carcinomas (neuroblastoma, brain tumors, retinoblastoma, Ewing's sarcoma, rhabdomyosarcoma), bone tumors (osteosarcoma, Ewing's sarcoma), soft tissue sarcomas (leiomyosarcoma, liposarcoma, fibrosarcoma), lung cancer, melanoma, and breast cancer. Tumor monoclonal antibodies (mAbs) have demonstrated clinical efficacy and have thus become an important approach for cancer immunotherapy. Due to its limited expression in normal tissues, disialotetrahexosylganglioside GD2 expressed on neuroblastoma cells is an excellent candidate for mAb therapy. International application WO2005070967A2 discloses an antibody targeting GD2. To date, only two antibodies against GD2 have been approved worldwide for therapeutic use (dinutuximab and naxitamab). In conjunction with the above, there is a need to develop novel antagonistic antibodies that specifically bind to GD2. [Summary of the Invention]

[0003] The authors of this invention have developed an antibody that specifically binds to GD2 and has at least 80% humanization in its variable domain. The antibody exhibits high thermal stability. In one aspect, the present invention relates to isolated monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 (ganglioside GD2), said antibody or antigen-binding fragment comprising: (a) a heavy chain variable domain comprising: (i) a CDR1 having an amino acid sequence selected from GHNMN (SEQ ID NO: 1) or GKNMN (SEQ ID NO: 2), (ii) a CDR2 having the amino acid sequence AIDPFYGGTSYNQKFKG (SEQ ID NO: 3), (iii) a CDR3 having an amino acid sequence selected from GMIY (SEQ ID NO: 4), GMFY (SEQ ID NO: 5), GMYY (SEQ ID NO: 6), or GMLY (SEQ ID NO: 7); and (b) a light chain variable domain comprising: (i) a CDR1 having an amino acid sequence selected from RSSRSLVHRNGNTYLH (SEQ ID NO: 8) or RSSQNLVHRNGNTYLH (SEQ ID NO: 9), (ii) having a CDR2 selected from the following amino acid sequences: KVSNRFG (SEQ ID NO: 10) or KVNNRFS (SEQ ID NO: 11), and (iii) having a CDR3 selected from the following amino acid sequences: GQSTHVPPLT (SEQ ID NO: 12) or SQSTHVPPLS (SEQ ID NO: 13). In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising: (i) FR1 having the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGSSFT (SEQ ID NO: 42), (ii) FR2 having the amino acid sequence WVRQNIGQGLEWMG (SEQ ID NO: 43), (iii) FR3 having the amino acid sequence RVTLTVDKSISTAYMELSRLRSDDTAVYYCVS (SEQ ID NO: 44), and (iv) FR4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 45).In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain comprising: (i) FR1 having the amino acid sequence DIVMTQTPLSLSVTPGERASLSC (SEQ ID NO: 46), (ii) FR2 having an amino acid sequence selected from WYLQKPGQSPKLLIH (SEQ ID NO: 47) or WYLQKPGQSPQLLIH (SEQ ID NO: 48), (iii) FR3 having the amino acid sequence GVPDRFSGSGSGTDFTLKISRVEAEDVGVYFC (SEQ ID NO: 49), and (iv) FR4 having the amino acid sequence FGQGTKLELK (SEQ ID NO: 50). In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: a) a heavy chain variable domain comprising: (i) FR1 having the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGSSFT (SEQ ID NO: 42), (ii) FR2 having the amino acid sequence WVRQNIGQGLEWMG (SEQ ID NO: 43), (iii) FR3 having the amino acid sequence RVTLTVDKSISTAYMELSRLRSDDTAVYYCVS (SEQ ID NO: 44), and (iv) FR4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 45), and wherein b) a light chain variable domain comprising: (i) FR1 having the amino acid sequence DIVMTQTPLSLSVTPGERASLSC (SEQ ID NO: 46), and (ii) FR2 having an amino acid sequence selected from: WYLQKPGQSPKLLIH (SEQ ID NO: 45). (ii) FR3 having the amino acid sequence GVPDRFSGSGSGTDFTLKISRVEAEDVGVYFC (SEQ ID NO: 49), and (iv) FR4 having the amino acid sequence FGQGTKLELK (SEQ ID NO: 50). In some embodiments of the invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising: (i) CDR1 having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 having the amino acid sequence of SEQ ID NO: 3, and (iii) CDR3 having the amino acid sequence of SEQ ID NO: 5.In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising: (i) a CDR1 having the amino acid sequence of SEQ ID NO: 2, (ii) a CDR2 having the amino acid sequence of SEQ ID NO: 3, and (iii) a CDR3 having the amino acid sequence of SEQ ID NO: 4. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising: (i) a CDR1 having the amino acid sequence of SEQ ID NO: 9, (ii) a CDR2 having the amino acid sequence of SEQ ID NO: 11, and (iii) a CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising: (i) a CDR1 having the amino acid sequence of SEQ ID NO: 8, (ii) a CDR2 having the amino acid sequence of SEQ ID NO: 10, and (iii) a CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising an amino acid sequence having at least 98% identity with the amino acid sequence of SEQ ID NO: 17. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising an amino acid sequence selected from: SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising an amino acid sequence having at least 96% identity with the amino acid sequence of SEQ ID NO: 21. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising an amino acid sequence selected from the following: SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20 or SEQ ID NO: 21.In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain comprising an amino acid sequence having at least 98% identity with the amino acid sequence of SEQ ID NO: 17; (b) a light chain variable domain comprising an amino acid sequence having at least 96% identity with the amino acid sequence of SEQ ID NO: 21; In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain comprising an amino acid sequence selected from the following: SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17; (b) a light chain variable domain comprising an amino acid sequence selected from the following: SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20 or SEQ ID NO: 21. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16; and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 17; and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to GD2 is a full-length IgG antibody. In some embodiments of the present invention, the isolated monoclonal antibody is a full-length IgG antibody having a human IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments of the present invention, the isolated monoclonal antibody is a full-length IgG antibody having a human IgG1 isotype. In some embodiments of the invention, the isolated monoclonal antibody contains YTE mutations (M252Y, S254T, T256E) and / or K322A in the Fc fragment compared to the naturally occurring sequence of the Fc fragment. In some embodiments of the invention, the isolated monoclonal antibody comprises a heavy chain containing an amino acid sequence selected from: SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, or SEQ ID NO: 37.In some embodiments of the present invention, the isolated monoclonal antibody comprises a light chain containing an amino acid sequence selected from the following: SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41. In some embodiments of the present invention, the isolated monoclonal antibody comprises: (a) a heavy chain containing an amino acid sequence selected from the following: SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, or SEQ ID NO: 37, and (b) a light chain containing an amino acid sequence selected from the following: SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41. In some embodiments of the present invention, the isolated monoclonal antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments of the present invention, the isolated monoclonal antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 41. In one aspect, the present invention relates to isolated nucleic acids encoding any of the above-described antibodies or antigen-binding fragments thereof. In some embodiments of the present invention, the isolated nucleic acid is DNA. In one aspect, the present invention relates to expression vectors comprising any of the above-described nucleic acids. In one aspect, the present invention relates to a method for generating host cells to generate any of the above-described antibodies or antigen-binding fragments thereof, and includes transforming cells with the above-described vector. In one aspect, the present invention relates to host cells for generating any of the above-described antibodies or antigen-binding fragments thereof, the host cells comprising any of the above-described nucleic acids. In one aspect, the present invention relates to a method for generating any of the above-described antibodies or antigen-binding fragments thereof, comprising culturing the host cells in a growth medium under conditions sufficient to generate the antibody, and, if necessary, subsequently isolating and purifying the resulting antibody. In one aspect, the present invention relates to pharmaceutical compositions for treating GD2-mediated diseases or conditions, comprising, in combination with one or more pharmaceutically acceptable excipients, any of the aforementioned antibodies or antigen-binding fragments thereof in a therapeutically effective amount.In some embodiments of the pharmaceutical composition, the GD2-mediated disease or condition is selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. In one aspect, the present invention relates to a pharmaceutical composition for treating a GD2-mediated disease or condition, the pharmaceutical composition comprising any of the above-described antibodies or antigen-binding fragments thereof and at least one other therapeutically active compound. In some embodiments of the pharmaceutical composition, the GD2-mediated disease or condition is selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. In some embodiments of the pharmaceutical composition, the other therapeutically active compound is an antibody, a chemotherapeutic agent, or a hormonal agent. In some embodiments of the pharmaceutical composition, the other therapeutically active compound is an immune checkpoint inhibitor. In some embodiments of the pharmaceutical composition, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors. In some embodiments of the pharmaceutical composition, the PD-1 inhibitor is an antibody that specifically binds to PD-1. In some embodiments of the pharmaceutical composition, the antibody that specifically binds to PD-1 is selected from: prolgolimab, pembrolizumab, and nivolumab. In some embodiments of the pharmaceutical composition, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. In some embodiments of the pharmaceutical composition, the antibody that specifically binds to CTLA-4 is ipilimumab or novellimab. In some embodiments of the pharmaceutical composition, the PD-L1 inhibitor is an antibody that specifically binds to PD-L1. In some embodiments of the pharmaceutical composition, the antibody that specifically binds to PD-L1 is selected from durvalumab, avelumab, atezolizumab, and manelimab. In some embodiments of the pharmaceutical composition, other therapeutically active compounds are selected from IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from this group. In one aspect, the present invention relates to a method for inhibiting the biological activity of GD2 in a subject requiring such inhibition, comprising administering an effective amount of any of the above-described antibodies or their antigen-binding fragments, or the pharmaceutical composition thereof, to a subject requiring such treatment.In one aspect, the present invention relates to a method for treating a GD2-mediated disease or condition, comprising administering any of the aforementioned antibodies or antigen-binding fragments thereof to a subject requiring such treatment, and selected from: a) administration of at least one other therapeutically active compound, b) radiotherapy, c) hematopoietic stem cell transplantation, d) surgical treatment and, if necessary, adjuvant therapy, or e) any combination of a) to d) above. In some embodiments of the treatment method, the GD2-mediated disease or condition is selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. In some embodiments of the treatment method, the other therapeutically active compound is an antibody, a chemotherapeutic agent, or a hormonal agent. In some embodiments of the treatment method, the other therapeutically active compound is an immune checkpoint inhibitor. In some embodiments of the treatment method, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors. In some embodiments of the treatment method, the PD-1 inhibitor is an antibody that specifically binds to PD-1. In some embodiments of the treatment method, the antibody that specifically binds to PD-1 is selected from prolgolimab, pembrolizumab, and nivolumab. In some embodiments of the treatment method, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. In some embodiments of the treatment method, the antibody that specifically binds to CTLA-4 is ipilimumab or novellimab. In some embodiments of the treatment method, the PD-L1 inhibitor is an antibody that specifically binds to PD-L1. In some embodiments of the treatment method, the antibody that specifically binds to PD-L1 is selected from durvalumab, avelumab, atezolizumab, and manelimab. In some embodiments of the treatment method, other therapeutically active compounds are selected from IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from this group. In one aspect, the present invention relates to the use of the aforementioned antibody or its antigen-binding fragment, or the aforementioned pharmaceutical composition, for treating GD2-mediated diseases or conditions in subjects requiring such treatment. In another aspect, the present invention relates to the use of any of the aforementioned antibodies or their antigen-binding fragments, and at least one of the following, for treating GD2-mediated diseases or conditions: a) other therapeutically active compounds, b) radiotherapy, c) hematopoietic stem cell transplantation, or d) surgical treatment and, if necessary, adjuvant therapy.In some embodiments of the use, the GD2-mediated disease or condition is selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. In some embodiments of the use, the other therapeutically active compound is an immune checkpoint inhibitor. In some embodiments of the use, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors. In some embodiments of the use, the PD-1 inhibitor is an antibody that specifically binds to PD-1. In some embodiments of the use, the antibody that specifically binds to PD-1 is selected from: prolgolimab, pembrolizumab, nivolumab. In some embodiments of the use, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. In some embodiments of the use, the antibody that specifically binds to CTLA-4 is ipilimumab or novellimab. In some embodiments of the use, the PD-L1 inhibitor is an antibody that specifically binds to PD-L1. In some embodiments of the use, the antibody that specifically binds to PD-L1 is selected from durvalumab, avelumab, atezolizumab, and manelimab. In some embodiments of the use, other therapeutically active compounds are selected from IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from this group.

Implementation Method

[0005] Definitions and General Methods Unless otherwise defined herein, all technical and scientific terms used in conjunction with this invention have the same meaning as commonly understood by those skilled in the art. Furthermore, unless the context requires otherwise, singular terms should include plural terms, and plural terms should include singular terms. Generally, the classifications and methods of this invention concerning cell culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, organic synthetic chemistry, medical and pharmaceutical chemistry, and hybridization and chemistry of proteins and nucleic acids described herein are well known to those skilled in the art and are widely used in the field. Enzymatic reactions and purification methods are performed according to the manufacturer's guidelines, as is common in the art or as described herein. As used herein, the term "Ka" is expected to refer to the binding rate of a particular antibody-antigen interaction, while the terms "KD" or "Kd" are expected to refer to the dissociation rate of a particular antibody-antigen interaction. "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise stated, “binding affinity” refers to inherent (characteristic, true) binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its binding partner Y can generally be expressed by a dissociation constant (Kd). Preferred Kd values ​​are about 200 nM, 150 nM, 100 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, 1 nM, or less. Affinity can be measured by common methods known in the art, including those described in this specification. Low-affinity antibodies generally bind antigens slowly and tend to dissociate easily, while high-affinity antibodies generally bind antigens more quickly and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, and any of these methods can be used for the purposes of this invention. The term “koff” or “kdis” refers to the dissociation rate constant of a specific interaction between a binding molecule and an antigen. The dissociation rate constant koff can be measured using biological layer interferometry, such as with the Octet™ system. The term “kon” or “binding rate” refers to the binding rate constant. The term “dissociation rate screening” refers to screening in which candidates are examined solely based on koff values. The term “R²” refers to the coefficient of determination. The term “response” refers to the antibody-antigen binding signal. The term “in vitro” refers to a biological entity, biological process, or biological reaction occurring under artificial conditions outside the body. For example, cells grown in vitro should be understood as cells grown in an environment outside the body, such as in test tubes, culture vials, or microtiter plates. As used herein, the term “IC50” (50% inhibition concentration) refers to a concentration of agent at which the activity or response can be measured, such as the concentration at which the growth / proliferation of cells, such as tumor cells, is inhibited by 50%.The IC50 value can be calculated using appropriate dose-response curves and specialized statistical software for curve fitting. The term "ED50" (EC50) (50% effective dose / concentration) refers to the concentration of the formulation that produces a 50% biological effect (which may include cytotoxicity). As used in this specification and the following claims, unless the context otherwise requires, the words "have," "include," and "comprise," or variations thereof such as "has," "having," "includes," "including," "comprises," or "comprising," should be understood to imply inclusion of the stated whole or group of wholes, but not to exclude any other whole or group of wholes. Specific Description of Antibodies This invention relates to monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 (ganglioside GD2). The term "monoclonal antibody" or "mAb" refers to an antibody synthesized and isolated from a single population of cell clones. The antibodies of this invention are recombinant antibodies. The term "recombinant antibody" refers to an antibody expressed in a cell or cell line containing a nucleotide sequence encoding an antibody, wherein the nucleotide sequence does not bind to cells in nature. In one aspect, the present invention relates to isolated monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 (ganglioside GD2), said antibody or antigen-binding fragment comprising: (a) a heavy chain variable domain comprising: (i) a CDR1 having an amino acid sequence selected from GHNMN (SEQ ID NO: 1) or GKNMN (SEQ ID NO: 2), (ii) a CDR2 having the amino acid sequence AIDPFYGGTSYNQKFKG (SEQ ID NO: 3), (iii) a CDR3 having an amino acid sequence selected from GMIY (SEQ ID NO: 4), GMFY (SEQ ID NO: 5), GMYY (SEQ ID NO: 6), or GMLY (SEQ ID NO: 7); and (b) a light chain variable domain comprising: (i) a CDR1 having an amino acid sequence selected from RSSRSLVHRNGNTYLH (SEQ ID NO: 8) or RSSQNLVHRNGNTYLH (SEQ ID NO: 9), (ii) having a CDR2 selected from the following amino acid sequences: KVSNRFG (SEQ ID NO: 10) or KVNNRFS (SEQ ID NO: 11), and (iii) having a CDR3 selected from the following amino acid sequences: GQSTHVPPLT (SEQ ID NO: 12) or SQSTHVPPLS (SEQ ID NO: 13).The term "isolated" used in this specification to describe various antibodies refers to antibodies that have been identified and separated and / or regenerated from cells or cell cultures in which the antibody is expressed. Impurities (contaminant components) from the natural environment are materials that commonly interfere with the diagnostic or therapeutic use of peptides and may include enzymes, hormones, and other proteins or non-protein solutes. Isolated peptides are typically prepared by at least one purification step. Amplification of the GD2 gene and / or overexpression of its protein have been observed in many cancers, for example, in any disease from the following groups: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. As used in this specification, the terms "antibody" or "immunoglobulin" (Ig) include intact antibodies. The term "antibody" refers to a glycoprotein, or antigen-binding moiety, comprising at least two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each heavy chain contains a heavy chain variable region (abbreviated as VH in this specification) and a heavy chain constant region. Five types of mammalian antibody heavy chains are known, represented by Greek letters: α, δ, ε, γ, and μ. (Janeway CA, Jr. et al., Immunobiology, 5th ed., published by Garland Publishing, 2001). The types of heavy chains present define the types of antibodies; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. (Rhoades RA, Pflanzer RG, Human Physiology, 4th ed., published by Thomson Learning, 2002). The different heavy chains differ in size and composition; α and γ contain approximately 450 amino acids, while μ and ε have approximately 550 amino acids. The constant region is identical across all antibodies of the same isotype, but differs across antibodies of different isotypes. Heavy chains γ, α, and δ have a constant region consisting of three constant domains CH1, СН2, and CH3 (in a line), as well as a hinge region for increased flexibility (Woof J., Burton D., Nat Rev Immunol 4, 2004, cc. 89-99); heavy chains μ and ε have a constant region consisting of four constant domains CH1, СН2, CH3, and CH4 (Janeway CA, Jr. et al., Immunobiology, 5th ed., published by Garland Publishing, 2001). In mammals, only two types of light chains are known, represented by lambda (λ) and kappa (κ).Each light chain consists of a variable region (abbreviated as VL in this specification) and a constant region. The light chain is approximately 211 to 217 amino acids in length. Preferably, the light chain is a kappa (κ) light chain, and the constant domain CL is preferably C kappa (κ). The "antibody" according to the invention can be any class (e.g., IgA, IgD, IgE, IgG, and IgM, preferably IgG) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, preferably IgG1). The VL and VH regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are scattered among more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of an antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. As used in this specification, the terms “antigen-binding portion” or “antigen-binding fragment” (or simply “antibody portion” or “antibody fragment”) refer to one or more fragments of an antibody that retain the ability to bind specifically to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments included in the term "antigen-binding portion" of an antibody include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by disulfide bridges in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains of an antibody single arm; and (v) dAb fragments consisting of VH / VHH domains (Ward et al., (1989) Nature 341: 544-546). Furthermore, the two regions VL and VH of the Fv fragment are encoded by different genes, which can be joined using a recombinant approach using a synthetic adapter that allows them to be linked as a single protein, in which the VL and VH regions pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). It is assumed that such single-chain molecules are also included within the term "antigen-binding portion" of an antibody. Such antibody fragments are generated using conventional techniques known to those skilled in the art, and are screened in the same manner as intact antibodies.The term "variable domain" refers to the fact that certain portions of a variable domain differ significantly in sequence between antibodies. The V domain mediates antigen binding and determines the specificity of each particular antibody for its specific antigen. However, the variability is not uniformly distributed across the 110 amino acid span of the variable domain. Instead, the V region consists of invariant segments of 15–30 amino acids called framework regions (FRs), which are separated by shorter, highly variable regions called "hypervariant regions" or CDRs. The variable domains of the natural heavy and light chains each contain four FRs, largely adopting a β-sheet configuration, connected by three hypervariant regions that form loops connecting the β-sheet structure and, in some cases, constituting portions of the β-sheet structure. Hypervariable regions in each chain are tightly bound together by FRs and, together with hypervariable regions in the other chain, contribute to the formation of the antibody's antigen-binding site (see Kabat et al., Sequences of Proteins of Immunological Interest. 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Constant domains do not directly involve antibody-antigen binding but exhibit various effector functions, such as antibody involvement in antibody-dependent cytotoxicity (ADCC). According to this specification, the term "hypervariable region" refers to an amino acid residue of the antibody responsible for antigen binding. Hypervariable regions typically contain amino acid residues from the "complementarity-determining region" or "CDR" and / or residues from the "hypervariable ring." As used in this application, "Kabat numbering scheme" or "numbering according to Kabat" refers to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the variable regions of the antibody heavy and light chains (Kabat et al. Ann. NY Acad. Sci., 190:382-93 (1971); Kabat et al. Sequences of Proteins of Immunological Interest, 5th edition, US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)). The antibody of this invention that "binds" to a target antigen refers to an antibody that binds to the antigen with sufficient affinity such that it can be used as a diagnostic and / or therapeutic agent targeting proteins, cells, or tissues expressing the antigen, and exhibits slight cross-reactivity with other proteins.Depending on the analytical method—fluorescence-initiated cell sorting (FACS), radioimmunoassay (RIA), or ELISA—in such embodiments, the degree to which the antibody binds to non-target proteins is less than 10% of the degree to which the antibody binds to specific target proteins. Regarding the binding of an antibody to a target molecule, the terms "specific binding," "specific binding to," or "specific targeting" of a specific polypeptide or an epitope on a specific target polypeptide refer to binding that is significantly (measurably) different from non-specific interactions. Specific binding can be measured, for example, by comparing the binding of the molecule to that of a control molecule. For example, specific binding can be measured by competition with another molecule similar to the target (e.g., an excess of unlabeled target). In this case, if the binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled target, specific binding is indicated. As used in this specification, the term "specific binding" or the phrase "specifically binding to" or "specifically targeting" a particular polypeptide or an epitope on a particular polypeptide target can be described by examples of molecules whose targets have the following Kd: at least about 200 nM, or at least about 150 nM, or at least about 100 nM, or at least about 60 nM, or at least about 50 nM, or at least about 40 nM, or at least about 30 nM, or at least about 20 nM, or at least about 10 nM, or at least about 8 nM, or at least about 6 nM, or at least about 4 nM, or at least about 2 nM, or at least about 1 nM or greater. In one embodiment, the term "specific binding" refers to a binding in which a molecule binds to a particular polypeptide or an epitope on a particular polypeptide, while substantially not binding to any other polypeptide or epitope on a polypeptide. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising: (i) FR1 having the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGSSFT (SEQ ID NO: 42), (ii) FR2 having the amino acid sequence WVRQNIGQGLEWMG (SEQ ID NO: 43), (iii) FR3 having the amino acid sequence RVTLTVDKSISTAYMELSRLRSDDTAVYYCVS (SEQ ID NO: 44), and (iv) FR4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 45).In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain comprising: (i) FR1 having the amino acid sequence DIVMTQTPLSLSVTPGERASLSC (SEQ ID NO: 46), (ii) FR2 having an amino acid sequence selected from WYLQKPGQSPKLLIH (SEQ ID NO: 47) or WYLQKPGQSPQLLIH (SEQ ID NO: 48), (iii) FR3 having the amino acid sequence GVPDRFSGSGSGTDFTLKISRVEAEDVGVYFC (SEQ ID NO: 49), and (iv) FR4 having the amino acid sequence FGQGTKLELK (SEQ ID NO: 50). In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: a) a heavy chain variable domain comprising: (i) FR1 having the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGSSFT (SEQ ID NO: 42), (ii) FR2 having the amino acid sequence WVRQNIGQGLEWMG (SEQ ID NO: 43), (iii) FR3 having the amino acid sequence RVTLTVDKSISTAYMELSRLRSDDTAVYYCVS (SEQ ID NO: 44), and (iv) FR4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 45), and wherein b) a light chain variable domain comprising: (i) FR1 having the amino acid sequence DIVMTQTPLSLSVTPGERASLSC (SEQ ID NO: 46), and (ii) FR2 having an amino acid sequence selected from: WYLQKPGQSPKLLIH (SEQ ID NO: 45). (ii) FR3 having the amino acid sequence GVPDRFSGSGSGTDFTLKISRVEAEDVGVYFC (SEQ ID NO: 49), and (iv) FR4 having the amino acid sequence FGQGTKLELK (SEQ ID NO: 50). In some embodiments of the invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising: (i) CDR1 having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 having the amino acid sequence of SEQ ID NO: 3, and (iii) CDR3 having the amino acid sequence of SEQ ID NO: 5.In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising: (i) a CDR1 having the amino acid sequence of SEQ ID NO: 2, (ii) a CDR2 having the amino acid sequence of SEQ ID NO: 3, and (iii) a CDR3 having the amino acid sequence of SEQ ID NO: 4. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising: (i) a CDR1 having the amino acid sequence of SEQ ID NO: 9, (ii) a CDR2 having the amino acid sequence of SEQ ID NO: 11, and (iii) a CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising: (i) a CDR1 having the amino acid sequence of SEQ ID NO: 8, (ii) a CDR2 having the amino acid sequence of SEQ ID NO: 10, and (iii) a CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising an amino acid sequence having at least 98% identity with the amino acid sequence of SEQ ID NO: 17. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of: In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment includes a light chain variable domain comprising an amino acid sequence having at least 96% identity with the amino acid sequence of SEQ ID NO: 21. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain containing an amino acid sequence selected from the following: In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain containing an amino acid sequence having at least 98% identity with the amino acid sequence of SEQ ID NO: 17; (b) a light chain variable domain containing an amino acid sequence having at least 96% identity with the amino acid sequence of SEQ ID NO: 21; In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain containing an amino acid sequence selected from the following: SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17; (b) a light chain variable domain containing an amino acid sequence selected from the following: SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20 or SEQ ID NO: 21.In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16; and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments of the present invention, the isolated monoclonal antibody or its antigen-binding fragment comprises: (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 17; and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to GD2 is a full-length IgG antibody. In some embodiments of the present invention, the isolated monoclonal antibody is a full-length IgG antibody having a human IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments of the present invention, the isolated monoclonal antibody is a full-length IgG antibody having a human IgG1 isotype. In some embodiments of the invention, the isolated monoclonal antibody contains YTE mutations (M252Y, S254T, T256E) and / or K322A in the Fc fragment compared to the naturally occurring sequence of the Fc fragment. The aforementioned mutations in the Fc fragment are numbered according to the EU numbering of the amino acid chain of the antibody (Edelman, GM et al., Proc. Natl. Acad. Sci. USA 63 (1969), pp. 78-85; Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, (1991).In some embodiments of the present invention, the isolated monoclonal antibody comprises a heavy chain containing an amino acid sequence selected from the following: In some embodiments of the present invention, the isolated monoclonal antibody comprises a light chain containing an amino acid sequence selected from the following: In some embodiments of the present invention, the isolated monoclonal antibody comprises: (a) a heavy chain containing an amino acid sequence selected from the following: SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36 or SEQ ID NO: 37, and (b) a light chain containing an amino acid sequence selected from the following: SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40 or SEQ ID NO: 41. In some embodiments of the present invention, the isolated monoclonal antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments of the present invention, the isolated monoclonal antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 41. In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to GD2 is antibody 07-006. Antibody 07-006 comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 22; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 38. Antibody 07-006 comprises: (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 14; and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 18.Antibody 07-006 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 6, and (b) a light chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 10, and (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 12. Antibody 07-006 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 51, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 53, (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 56, and (b) a light chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 58, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 60, and (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 62. Antibody 07-006 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 64, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 66, (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 69, and (b) a light chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 71, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 73, and (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 75. In some embodiments of the invention, the isolated monoclonal antibody that specifically binds to GD2 is antibody 07-015. Antibody 07-015 comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 23; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39.Antibody 07-015 comprises: (a) a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 15; and (b) a light chain variable domain containing the amino acid sequence of SEQ ID NO: 19. Antibody 07-015 comprises: (a) a heavy chain variable domain containing: (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 1, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7, and (b) a light chain variable domain containing: (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 10, and (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 12. Antibody 07-015 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 52, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 53, (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 57, and (b) a light chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 58, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 60, and (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 62. Antibody 07-015 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 65, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 66, (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 70, and (b) a light chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 71, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 73, and (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 75. In some embodiments of the invention, the isolated monoclonal antibody that specifically binds to GD2 is antibody 07-016.Antibody 07-016 comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 23; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 38. Antibody 07-016 also comprises: (a) a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 15; and (b) a light chain variable domain containing the amino acid sequence of SEQ ID NO: 18. Antibody 07-016 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 1, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7, and (b) a light chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 10, and (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 12. Antibody 07-016 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 52, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 53, (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 57, and (b) a light chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 58, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 60, and (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 62. Antibody 07-016 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 65, (ii) a CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 66, (iii) a CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 70, and (b) a light chain variable domain comprising: (i) a CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 71, (ii) a CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 73, and (iii) a CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 75.In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to GD2 is antibody 07-028. Antibody 07-028 comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 23; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 40. Antibody 07-028 comprises: (a) a variable domain of the heavy chain containing the amino acid sequence of SEQ ID NO: 15; and (b) a variable domain of the light chain containing the amino acid sequence of SEQ ID NO: 20. Antibody 07-028 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 1, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7, and (b) a light chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 11, and (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 13. Antibody 07-028 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 52, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 53, (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 57, and (b) a light chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 58, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 61, and (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 63.Antibody 07-028 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 65, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 66, (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 70, and (b) a light chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 71, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 74, and (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 76. In some embodiments of the invention, the isolated monoclonal antibody that specifically binds to GD2 is antibody 07-031. Antibody 07-031 comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 24; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39. Antibody 07-031 comprises: (a) a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 16; and (b) a light chain variable domain containing the amino acid sequence of SEQ ID NO: 19. Antibody 07-031 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 4, and (b) a light chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 10, and (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 12.Antibody 07-031 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 51, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 53, (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 54, and (b) a light chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 58, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 60, and (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 62. Antibody 07-031 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 64, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 66, (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 67, and (b) a light chain variable domain comprising: (i) CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 71, (ii) CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 73, and (iii) CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 75. In some embodiments of the invention, the isolated monoclonal antibody that specifically binds to GD2 is antibody 07-041. Antibody 07-041 comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 25; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 41. Antibody 07-041 comprises: (a) a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 17; and (b) a light chain variable domain containing the amino acid sequence of SEQ ID NO: 21.Antibody 07-041 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 5, and (b) a light chain variable domain comprising: (i) a CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 9, (ii) a CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 11, and (iii) a CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 12. Antibody 07-041 comprises: (a) a heavy chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 51, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 53, (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 55, and (b) a light chain variable domain comprising: (i) CDR1 (Chothia) having the amino acid sequence of SEQ ID NO: 59, (ii) CDR2 (Chothia) having the amino acid sequence of SEQ ID NO: 61, and (iii) CDR3 (Chothia) having the amino acid sequence of SEQ ID NO: 62. Antibody 07-041 comprises: (a) a heavy chain variable domain comprising: (i) a CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 64, (ii) a CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 66, (iii) a CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 68, and (b) a light chain variable domain comprising: (i) a CDR1 (IMGT) having the amino acid sequence of SEQ ID NO: 72, (ii) a CDR2 (IMGT) having the amino acid sequence of SEQ ID NO: 74, and (iii) a CDR3 (IMGT) having the amino acid sequence of SEQ ID NO: 75. Modification of the amino acid sequence of the antibody is provided. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody are prepared by introducing appropriate nucleotide changes into the nucleic acid encoding the antibody, or by peptide synthesis. Such modifications include, for example, the deletion, and / or insertion and / or substitution of residues within the amino acid sequence of an antibody. Any combination of deletions, insertions, and substitutions may be prepared to obtain the final construct, provided that the final construct possesses the desired properties.Amino acid changes can also alter post-translational processes in antibodies, such as changing the number or position of glycosylation sites. Modification variants of the antibody amino acid sequence using amino acid substitutions are described. These variants replace at least one amino acid residue in the antibody molecule with a different residue. The most favorable sites for substitution mutagenesis include hypervariable regions or CDRs, but FR or Fc alterations are also considered. Conservative substitutions are shown under the heading "Preferred Substitutions" in Table 1. If such substitutions cause changes in biological activity, further substantial alterations can be made, indicated as "Exemplary Substitutions" in Table A, or variations described in more detail below when describing the amino acid categories, and product screening can also be performed. Table A initial residues Exemplary replacement Preferred replacement Ala (A) Val; Leu; Ile Val Arg(R) Lys; Gin; Asn Lys Asn(N) Gin; His; Asp, Lys; Arg Gin Asp(D) Glu;Asn Glu Cys(C) Ser;Ala Ser Gln(Q) Asn; Glu Asn Glu(E) Asp; Gin Asp Gly(G) Ala Ala His(H) Asn; Gin; Lys; Arg Arg Ile(I) Leu; Val; Met; Ala; Phe; leucine Leu Leu(L) Leucine; Ile; Val; Met; Ala; Phe Ile Lys(K) Arg; Gin; Asn Arg Met(M) Leu(Phe)Go Leu Phy(F) Trp_Leu_Val_Ile_Ala_Tyr Tyr Pro(P) Only Only Ser(S) Thr Thr Thr(T) Val: Ser Ser Trp(W) Tyr:Phe Tyr Tyr(Y) Trp4Phe4Thr4Ser Where Val (V) Ile_Leu_Met_Phe_Ala Leu In some embodiments of the present invention, antibodies 07-006, 07-015, 07-016, 07-028, 07-031, and 07-041 include an Fc fragment, which, compared to the naturally occurring sequence of the Fc fragment, contains a YTE mutation (M252Y, S254T, T256E) and / or K322A. In some embodiments of the present invention, antibodies 07-006, 07-015, 07-016, 07-028, 07-031, and 07-041 include an Fc fragment, which, compared to the naturally occurring sequence of the Fc fragment, contains a YTE mutation (M252Y, S254T, T256E) and K322A. In some embodiments of the present invention, antibodies 07-006, 07-015, 07-016, 07-028, 07-031, and 07-041 include an Fc fragment containing a YTE mutation (M252Y, S254T, T256E) compared to the naturally occurring sequence of the Fc fragment. In some embodiments of the present invention, antibodies 07-006, 07-015, 07-016, 07-028, 07-031, and 07-041 include an Fc fragment containing a K322A mutation compared to the naturally occurring sequence of the Fc fragment. Antibody 07-006 having both the YTE and K322A mutations comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 30; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 38. Antibody 07-015, which has the YTE and K322A mutations, comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 31; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39. Antibody 07-016, which has the YTE and K322A mutations, comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 31; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 38. Antibody 07-028, which has the YTE and K322A mutations, comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 31; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 40. Antibody 07-031 (or antibody 10-02) with the YTE and K322A mutations comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 32; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39. Antibody 07-041 (or antibody 10-08) with the YTE and K322A mutations comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 33; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 41. Antibody 07-006 with the YTE mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 322A.The heavy chain comprising (a) the amino acid sequence of SEQ ID NO: 26; and (b) the light chain comprising the amino acid sequence of SEQ ID NO: 38. Antibody 07-015 with the YTE mutation comprises: (a) the heavy chain comprising the amino acid sequence of SEQ ID NO: 27; and (b) the light chain comprising the amino acid sequence of SEQ ID NO: 39. Antibody 07-016 with the YTE mutation comprises: (a) the heavy chain comprising the amino acid sequence of SEQ ID NO: 27; and (b) the light chain comprising the amino acid sequence of SEQ ID NO: 38. Antibody 07-028 with the YTE mutation comprises: (a) the heavy chain comprising the amino acid sequence of SEQ ID NO: 27; and (b) the light chain comprising the amino acid sequence of SEQ ID NO: 40. Antibody 07-031 (or antibody 10-01) with the YTE mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 28; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39. Antibody 07-041 (or antibody 10-07) with the YTE mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 29; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 41. Antibody 07-006 with the K322A mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 34; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 38. Antibody 07-015 with the K322A mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 35; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39. Antibody 07-016 with the K322A mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 35; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 38. Antibody 07-028 with the K322A mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 35; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 40. Antibody 07-031 (or Antibody 10-03) with the K322A mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 36; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 39. Antibody 07-041 (or Antibody 10-09) with the K322A mutation comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 37; and (b) a light chain containing the amino acid sequence of SEQ ID NO: 41. In some embodiments of the present invention, the antibody according to the present invention may be a defucosylated antibody.In some embodiments of the invention, the antibody according to the invention may be a fucosylated antibody. The presence or absence of antibody fucosylation depends on the cell culture used to produce the antibody according to the invention. In some cases, antibody fragments may be used instead of whole antibodies. The small size of the fragments facilitates their rapid clearance and can facilitate better penetration into dense tumors. Various techniques have been developed for producing antibody fragments. Conventionally, these fragments are derived via proteolytic digestion of whole antibodies (see, for example, Morimoto et al., Journal of Biochemical and Biophysical Methods, 24, 1992, pp. 107-117, and Brennan et al., Science, 229, 1985, p. 81). However, these fragments can currently be produced directly from recombinant host cells. Fab, Fv, and ScFv antibody fragments can be expressed and secreted in E. coli, thus allowing for the promotion of large-scale production of these fragments. Antibody fragments can be isolated from antibody phage libraries. According to another embodiment, the Fab'-SH fragment can be directly isolated from *E. coli* and chemically coupled to form the F(ab')2 fragment (Carter et al., *Bio / Technology 10: 163-167* (1992). According to another method, the F(ab')2 fragment can be directly isolated from recombinant host cell cultures. Fab and F(ab')2 fragments with increased in vivo half-life and retention of epitope-binding receptor residues are described in US 5869046. Other techniques for generating antibody fragments will be apparent to those skilled in the art. In other embodiments, the antibody of choice is a single-chain Fv fragment (scFv) (see WO 93 / 16185; US 5571894 and US 5587458). Fv and scFv are the only species with complete binding sites, lacking constant regions; as a result, they are suitable for reducing nonspecific binding during in vivo use. scFv fusion proteins can be constructed to produce fusion of effector proteins at the N-terminus or C-terminus of the scFv (see Antibody above). Engineering (edited by Borrebaeck). The antibody fragment may also be, for example, a “linear antibody” as described in U.S. Patent 5,641,870. Nucleic acid molecules: In one aspect, the present invention relates to isolated nucleic acids encoding any of the aforementioned antibodies or antigen-binding fragments thereof that specifically bind to GD2. In any of the above embodiments, the nucleic acid molecule may be isolated. The terms “nucleic acid,” “nucleic acid sequence,” and “nucleic acid sequence” are used interchangeably in this specification.The terms "sequence", "polynucleotide", "oligonucleotide", "polynucleotide sequence" and "nucleotide sequence" refer to the exact sequence of a nucleotide, modified or unmodified, that determines a segment or region of a nucleic acid, containing or not containing non-natural nucleotides, and is a double-stranded DNA or RNA, a single-stranded DNA or RNA, or a transcript of said DNA. This should also include nucleotide sequences that are not native to the chromosomal environment of the invention, i.e., in their natural state. The sequences of the invention have been isolated and / or purified, i.e., sampled directly or indirectly, for example by copying, and their environment has been at least partially modified. Therefore, isolated nucleic acids obtained by recombinant genetics, by means of, for example, host cells, or by chemical synthesis should also be mentioned herein. Unless otherwise stated, references to nucleotide sequences encompass their complements. Therefore, references to nucleic acids having a specific sequence should be understood to encompass nucleic acids with their complementary strands and their complementary sequences. An "isolated" nucleic acid molecule is a nucleic acid molecule identified and separated from at least one nucleic acid molecule-impurity, which binds to the impurity in a natural source of antibody nucleic acid. An isolated nucleic acid molecule differs from the form or set thereof found under natural conditions. Therefore, an isolated nucleic acid molecule differs from nucleic acid molecules present in cells under natural conditions. In one aspect, the present invention relates to nucleic acid molecules comprising a nucleotide sequence encoding an amino acid sequence selected from SEQ ID NO: 1-76. The nucleic acid molecule may also comprise any combination of said nucleotide sequences. In some embodiments of the invention, the isolated nucleic acid is DNA. The nucleic acid molecule of the present invention can be isolated from any source that produces a monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2. In some embodiments, the nucleic acid molecule of the present invention may be synthetic rather than isolated. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding an amino acid sequence of the heavy chain variable domain of antibody 07-006 and comprises a nucleotide sequence having SEQ ID NO: 77. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding an amino acid sequence of the light chain variable domain of antibody 07-006 and comprises a nucleotide sequence having SEQ ID NO: 78. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 07-015, and includes the nucleotide sequence having SEQ ID NO: 79. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 07-015, and includes the nucleotide sequence having SEQ ID NO: 80. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 07-016, and includes the nucleotide sequence having SEQ ID NO: 81.In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 07-016, and includes the nucleotide sequence having SEQ ID NO: 82. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 07-028, and includes the nucleotide sequence having SEQ ID NO: 83. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 07-028, and includes the nucleotide sequence having SEQ ID NO: 84. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 07-031, and includes the nucleotide sequence having SEQ ID NO: 85. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 07-031, and includes the nucleotide sequence having SEQ ID NO: 86. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 07-041, and includes the nucleotide sequence having SEQ ID NO: 87. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 07-041, and includes the nucleotide sequence having SEQ ID NO: 88. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 10-001, and includes the nucleotide sequence having SEQ ID NO: 89. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 10-001, and includes the nucleotide sequence having SEQ ID NO: 90. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 10-002, and includes the nucleotide sequence having SEQ ID NO: 91. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 10-002, and includes the nucleotide sequence having SEQ ID NO: 92. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 10-003 and includes a nucleotide sequence having SEQ ID NO: 93. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 10-003 and includes a nucleotide sequence having SEQ ID NO: 94. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 10-007 and includes a nucleotide sequence having SEQ ID NO: 95. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 10-007 and includes a nucleotide sequence having SEQ ID NO: 95.The nucleotide sequence of SEQ ID NO: 96. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 10-008 and includes the nucleotide sequence having SEQ ID NO: 97. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 10-008 and includes the nucleotide sequence having SEQ ID NO: 98. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 10-009 and includes the nucleotide sequence having SEQ ID NO: 99. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 10-009 and includes the nucleotide sequence having SEQ ID NO: 100. Nucleic acid molecules can be used to express monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2. Vectors In one aspect, the invention relates to expression vectors comprising the above-described isolated nucleic acids. The invention relates to vectors suitable for expressing any nucleotide sequence described herein. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. In some embodiments of the invention, the vector is a plasmid, i.e., a circular double-stranded DNA fragment to which an additional DNA segment can be attached. In some embodiments of the invention, the vector is a viral vector, wherein an additional DNA segment can be attached to a viral genome. In some embodiments of the invention, the vector is capable of autonomous replication in the host cell to which it is introduced (e.g., bacterial vectors with a bacterial replication origin and attachable mammalian vectors). In further embodiments of the invention, the vector (e.g., a non-attached mammalian vector) can integrate into the host cell's genome after introduction into the host cell and thereby replicate along with the host gene. Furthermore, some vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). As described herein, the invention relates to vectors comprising nucleic acid molecules encoding any amino acid sequence (e.g., heavy chain and / or light chain binding domain sequences) that specifically binds to a monoclonal antibody or a portion thereof. The invention further relates to vectors comprising nucleic acid molecules encoding antibodies or fragments thereof.Expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAVs), plant viruses such as cauliflower mosaic virus and tobacco mosaic virus, granules, YAC, EBV-derived episomes, etc. DNA molecules can be ligated into vectors, allowing the transcriptional and translational control sequences within the vector to perform their intended functions of regulating DNA transcription and translation. The expression vector and expression control sequences can be selected to be compatible with the expression host cells used. DNA molecules that partially or completely encode a first binding domain and a second binding domain (e.g., heavy and light chain sequences, wherein the binding domain comprises both heavy and light chain sequences) can be introduced into various vectors. In one embodiment, any combination of said DNA molecules is introduced into the same expression vector. DNA molecules can be introduced into expression vectors using standard methods (e.g., ligation of antibody gene fragments and complementary restriction sites on the vector, or blunt-end ligation if no restriction site is present). In some embodiments of the invention, suitable vectors are those that include restriction sites, such that, as described above, any VH or VL sequence can be readily inserted and expressed. Polyadenylation and transcription termination can occur at natural chromosomal sites downstream of the coding region. The recombinant expression vector can also encode a signal peptide that promotes the secretion of the antibody chain from the host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is linked within the frame to the amino terminus of the immunoglobulin chain. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide derived from a non-immunoglobulin). In some embodiments of the invention, in addition to the antibody chain gene, the recombinant vector expression of the invention can also carry a regulatory sequence that controls the expression of the antibody chain gene in the host cell. Those skilled in the art will understand that the design of the expression vector, including the selection of the regulatory sequence, can depend on factors such as the selection of the host cells to be transformed, the desired protein expression level, etc. Preferred control sequences for expression in mammalian host cells include viral elements that ensure high levels of protein expression in mammalian cells, such as those derived from promoters and / or enhancers of: retroviral LTRs, cytomegaloviruses (CMV) (e.g., CMV promoters / enhancers), simian virus 40 (SV40) (e.g., SV40 promoters / enhancers), adenoviruses (e.g., major late promoter adenovirus (AdMLP)), polyomaviruses, and strong mammalian promoters, such as innate immunoglobulin promoters or actin promoters. Methods for expressing polypeptides in bacterial or fungal cells, such as yeast cells, are also well known in the art. In some embodiments of the invention, in addition to antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may also carry additional sequences, such as sequences regulating vector replication in host cells (e.g., origin of replication) and selectable marker genes. Selectable marker genes facilitate the selection of host cells in which the vector has been introduced.In some embodiments of the invention, the vector may include expression control sequences. As used herein, the term "expression control sequence" refers to a polynucleotide sequence that is essential for the expression and processing of the coding sequence to which it is linked. Expression control sequences include appropriate transcription initiation, termination, promoter, and enhancer sequences; effective RNA processing signals, such as splicing and polyadenylation signals; sequences stabilizing cytoplasmic mRNA; sequences enhancing translation efficiency (i.e., Kozak concordant sequences); sequences enhancing protein stability; and sequences enhancing protein secretion when needed. The nature of such control sequences varies depending on the host organism; in prokaryotes, such control sequences generally include a promoter and transcription termination sequence at a ribosome-binding site; in eukaryotes, such control sequences typically include a promoter and transcription termination sequence. The term "control sequence" includes at least all components whose presence is necessary for expression and processing, and may also include additional components whose presence is advantageous, such as leader sequences and fusion partner sequences. In one aspect, the invention relates to methods for generating host cells to produce any of the above-described antibodies or antigen-binding fragments thereof that specifically bind to GD2, and includes transforming cells with the above-described vector. In one aspect, the present invention relates to host cells for generating any of the aforementioned antibodies or antigen-binding fragments thereof that specifically bind to GD2, the host cells comprising any of the aforementioned nucleic acids. As used herein, the term “recombinant host cell” (or simply “host cell”) refers to a cell in which a recombinant expression vector has been introduced. The present invention relates to host cells that may include, for example, the vectors according to the invention described above. The present invention also relates to host cells comprising, for example, a nucleotide sequence encoding a binding domain of the binding molecule of the present invention, a nucleotide sequence encoding a light chain or an antigen-binding portion thereof, or both. It should be understood that “recombinant host cell” and “host cell” refer not only to a specific test cell but also to the progeny of such cells. Because modifications can occur in subsequent generations due to mutations or environmental influences, such progeny may not, in fact, be equivalent to the parent cells; however, such cells are still included within the scope of the term “host cell” as used herein. Nucleic acid molecules encoding monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 according to the present invention and vectors comprising these nucleic acid molecules can be used to transfect suitable mammalian or their cells, plant or their cells, bacterial or yeast host cells. Transformation can be achieved using any known technique for introducing polynucleotides into host cells. Methods for introducing heterologous polynucleotides into mammalian cells are well-known in the art and include dextran-mediated transfection, cationic polymer-nucleic acid complex transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, encapsulation of polynucleotides in liposomes, and direct microinjection of DNA into the nucleus. Alternatively, nucleic acid molecules can be introduced into mammalian cells using viral vectors.Mammalian cell lines used as hosts for transformation are well known in the art and include a number of available immortalized cell lines. These include, for example, Chinese hamster ovary (CHO) cells, NS0 cells, SP2 cells, HEK-293T cells, FreeStyle 293 cells (Invitrogen), NIH-3T3 cells, HeLa cells, young hamster kidney (BHK) cells, African green monkey kidney cells (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, and many other cell lines. Cell lines are selected by determining which cell lines have high expression levels and provide the necessary characteristics of the produced protein. Other cell lines that can be used are insect cell lines, such as Sf9 or Sf21 cells. When a recombinant expression vector encoding a monoclonal antibody or its antigen-binding fragment that specifically binds to GD2 is introduced into mammalian host cells, the antibody or its fragment is produced by culturing the host cells for a period of time sufficient to allow the antibody or its fragment to be expressed in the host cells, or more preferably, the antibody or its fragment is secreted into the culture medium in which the host cells are grown. Standard protein purification techniques can be used to isolate GD2-specifically binding monoclonal antibodies or their antigen-binding fragments from culture media. Plant host cells include, for example, *Nicotiana*, *Arabidopsis*, duckweed, maize, wheat, and potato. Bacterial host cells include species of *Escherichia* and *Streptomyces*. Yeast host cells include *Schizosaccharomyces pombe*, *Saccharomyces cerevisiae*, and *Pichia pastoris*. Furthermore, various known techniques can be used to enhance the production levels of GD2-specifically binding monoclonal antibodies or their antigen-binding fragments from production cell lines. For example, the glutamine synthase gene expression system (GS system) is a common method used to enhance expression under certain conditions. Compared to each other, GD2-specifically binding monoclonal antibodies or their antigen-binding fragments from various cell lines are likely to have different glycosylation profiles. However, monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 and are encoded by the nucleic acid molecules described herein, or that contain the amino acid sequences provided herein, are part of this invention, regardless of the glycosylation of the binding molecule, and generally regardless of the presence or absence of post-translational modifications. The host cell mentioned above does not refer to a host cell derived from a human embryo. The host cell mentioned above does not refer to a host cell derived by modifying the genetic integrity of human germline cells. Methods for obtaining antibodiesIn one aspect, the present invention relates to a method for obtaining an antibody or antigen-binding fragment thereof that specifically binds to GD2, comprising culturing host cells in a growth medium under conditions sufficient to produce said antibody or fragment thereof, and, if necessary, subsequently isolating and purifying the obtained antibody or fragment thereof. The present invention relates to a method for obtaining a monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2 according to the present invention. One embodiment of the invention relates to a method for producing a monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2 as defined herein, comprising producing a recombinant host cell capable of expressing a monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2, culturing said host cell under conditions suitable for the expression / production of a monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2, and isolating the obtained monoclonal antibody or fragment thereof that specifically binds to GD2. A monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2 produced by such expression in such recombinant host cells is referred herein as a “recombinant monoclonal antibody that specifically binds to GD2” or “antigen-binding fragment of a recombinant monoclonal antibody that specifically binds to GD2”. The invention also relates to progeny from such host cells. Another aspect of the present invention is a pharmaceutical composition comprising a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to GD2 as an active ingredient (or as the sole active ingredient). In one aspect, the present invention relates to a pharmaceutical composition for treating a disease or condition mediated by GD2, comprising any of the aforementioned antibodies or antigen-binding fragments thereof in combination with one or more pharmaceutically acceptable excipients to a therapeutically effective amount."Pharmaceutical composition" refers to a composition comprising the antibody of the present invention and at least one component selected from: pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, adjuvants, dispensing agents and sensing agents, delivery agents, such as preservatives, stabilizers, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, thickeners, sweeteners, flavoring agents, aroma agents, antibacterial agents, fungicides, lubricants, and extended delivery control agents, the selection and appropriate proportions of which depend on the type and route of administration and the dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragacanth gum, and mixtures thereof. Protection against microbial action can be provided by various antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and similar compounds. The composition may also contain isotonic agents, such as sugars, polyols, sodium chloride, etc. The prolongation of the composition's effect can be achieved by agents that slow down the absorption of the active ingredient, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents, and delivery agents are water, ethanol, polyols and mixtures thereof, natural oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, etc. Examples of disintegrants and dispensing agents are starch, alginate and its salts, silicates, etc. Examples of lubricants are magnesium stearate, sodium dodecyl sulfate, talc, and high molecular weight polyethylene glycol. Pharmaceutical compositions for oral, sublingual, transdermal, intraocular, intravenous, subcutaneous, topical, or rectal administration of the active ingredient, alone or in combination with another active compound, can be administered to humans and animals in standard dosage forms within mixtures having conventional drug carriers. Suitable standard forms of administration include oral forms, such as tablets, gelatin capsules, pills, powders, granules, chewing gum, and oral solutions or suspensions; sublingual and buccal administration forms; aerosols; implants; and topical, percutaneous, subcutaneous, intramuscular, intravenous, intranasal, or intraocular administration forms and rectal administration forms. The terms "excipient" or "adjuvant" are used herein to describe any component other than the antibodies of the present invention. These are substances of inorganic or organic nature used in the production / manufacturing of pharmaceuticals to impart the necessary physicochemical properties to the pharmaceutical product. In some embodiments, the composition is intended to improve, prevent, or treat conditions that may be related to GD2. The term "GD2-mediated disease or condition" refers to any disease or condition directly or indirectly related to GD2, including the cause, development, progression, persistence, or pathology of the disease or condition."Treatment," "treating," and "treatment" refer to methods of alleviating or eliminating at least one of a biological condition and / or its accompanying symptoms. As used herein, "alleviating" a disease, symptom, or condition means reducing the severity and / or frequency of the symptoms of the disease, symptom, or condition. Further, references to "treatment" herein include references to curative, palliative, and preventative treatments. In one aspect, the subject or patient of treatment is a mammal, preferably a human subject. The subject can be male or female of any age. The term "symptom" means any condition that would benefit from treatment with the compounds of the present invention. This includes chronic and acute symptoms or diseases, including those pathological conditions that make mammals susceptible to the symptoms discussed. "Therapeuticly effective amount" means the amount of therapeutic agent to be administered during treatment, said amount alleviating, to some extent, one or more symptoms of the disease to be treated. In some embodiments of the pharmaceutical compositions of the present invention, the diseases or conditions mediated by GD2 are selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. The pharmaceutical compositions of the present invention and their preparation methods will undoubtedly be apparent to those skilled in the art. The pharmaceutical compositions should preferably be manufactured in accordance with GMP (Good Manufacturing Practice) requirements. The compositions may contain buffer components, tensile agents, stabilizers, and solubilizers. The prolongation of the composition can be achieved by agents that slow the absorption of the active pharmaceutical ingredient, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents, and delivery agents include water, ethanol, polyols and mixtures thereof, oils, and organic esters for injection. Any method recognized in the art for administering peptides, proteins, or antibodies can be suitably used for monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 according to the present invention. The term "pharmaceutically acceptable" refers to one or more compatible liquid or solid components suitable for administration in mammals, preferably humans. The terms "buffer solution," "buffer component," and "buffer" refer to a solution that is resistant to pH changes by the action of its acid-base conjugated component and allows the antibody product specifically binding to GD2 to resist pH changes. Generally, pharmaceutical compositions preferably have a pH in the range of 4.0 to 8.0. Examples of buffer solutions used include, but are not limited to, buffer solutions containing acetate, phosphate, citrate, histidine, succinate, etc. As used herein, the terms "tonic agent," "osmotic agent," or "osmotic agent" refer to an excipient that can increase the osmotic pressure of a liquid antibody preparation. An "isotonic" drug is a drug having an osmotic pressure equivalent to that of human blood. Isotonic drugs typically have an osmotic pressure of about 250 to 350.Osmotic pressure of mOsm / kg. Isotonic agents used include, but are not limited to, polyols, sugars and sucrose, amino acids, and metal salts such as sodium chloride. "Stabilizer" refers to an excipient, or a mixture of two or more excipients, that provides physical and / or chemical stability to the surfactant. Stabilizers can be amino acids, such as, but not limited to, arginine, histidine, glycine, lysine, glutamine, and proline; surfactants, such as, but not limited to, polysorbate 20 (trade name: Tween 20), polysorbate 80 (trade name: Tween 80), polyethylene glycol and its copolymers (trade names: poloxamer, prolind), and sodium dodecyl sulfate (SDS); antioxidants, such as, but not limited to, methionine, acetylcysteine, ascorbic acid, monothioglycerol, and sulfites; and chelating agents, such as, but not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium citrate. The pharmaceutical compositions according to the invention are stable compositions. A pharmaceutical composition is “stable” if the active agent retains its physical and / or chemical stability and / or biological activity during a specified storage period at a specified storage temperature, such as 2-8°C. Preferably, the active agent retains both physical and chemical stability, as well as biological activity. The storage period is adjusted based on the results of stability tests under accelerated or natural aging conditions. The pharmaceutical compositions according to the invention can be manufactured, packaged, or widely marketed in the form of a single unit dose or multiple single unit doses in off-the-shelf formulations. As used herein, the term “single unit dose” refers to a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject, or a convenient portion of such a dose, such as half or one-third of such a dose. The pharmaceutical compositions according to the invention are generally suitable for parenteral administration as sterile formulations, intended to be administered in the human body by means of injection, infusion, and implantation bypassing the gastrointestinal tract, through ruptures in the skin and mucosal barriers. In particular, parenteral administration is considered, including subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intrasynovial, percutaneous injection or infusion, and renal dialysis infusion techniques. Intratumoral delivery, such as intratumoral injection, is also possible. Regional perfusion is also considered. Preferred embodiments include intravenous and subcutaneous routes. Any method recognized in the art for administering peptides or proteins can be suitably used for antibodies or antigen-binding fragments thereof that specifically bind to GD2 according to the present invention. Injectable formulations can be prepared, packaged, or marketed in unit dose form (without limitation), for example in ampoules, vials, plastic containers, pre-filled syringes, and automated injection devices. Formulations for parenteral administration include, in particular, suspensions, solutions, emulsions in oily or aqueous matrices, pastes, etc.In another embodiment, the present invention provides compositions for parenteral administration comprising a pharmaceutical composition provided in dry (i.e., powder or granules) form for reconstitution by a suitable matrix (e.g., sterile pyrogen-free water) prior to administration. Such pharmaceutical formulations can be prepared, for example, by lyophilization, a process known in the art as freeze-drying, and involves freezing the product followed by solvent removal from the frozen material. Antibodies or antigen-binding fragments thereof that specifically bind to GD2 according to the present invention can also be administered intranasally or by inhalation from an inhaler (e.g., a pressurized aerosol container, pump, jet, nebulizer, or nebulizer) with or without a suitable propellant, or as nasal drops or sprays, either alone or as a mixture of suitable pharmaceutically acceptable excipients. Pharmaceutical formulations for parenteral administration can be formulated for immediate release or modified release. Modified release pharmaceutical formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. In one aspect, the present invention relates to pharmaceutical compositions for treating GD2-mediated diseases or conditions, the pharmaceutical composition comprising any of the aforementioned antibodies or antigen-binding fragments thereof and at least one other therapeutically active compound. In some embodiments of the pharmaceutical compositions of the present invention, the other therapeutically active compound is an antibody, a chemotherapeutic agent, or a hormonal agent. In some embodiments of the pharmaceutical compositions of the present invention, the other therapeutically active compound is an immune checkpoint inhibitor. In some embodiments of the pharmaceutical compositions of the present invention, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors. In some embodiments of the pharmaceutical compositions of the present invention, the PD-1 inhibitor is an antibody that specifically binds to PD-1. In some embodiments of the pharmaceutical compositions of the present invention, the antibody that specifically binds to PD-1 is selected from prolgolimab, pembrolizumab, and nivolumab. In some embodiments of the pharmaceutical compositions of the present invention, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. In some embodiments of the pharmaceutical compositions of the present invention, the antibody that specifically binds to CTLA-4 is ipilimumab or novellimab. In some embodiments of the pharmaceutical compositions of the present invention, the PD-L1 inhibitor is an antibody that specifically binds to PD-L1. In some embodiments of the pharmaceutical compositions of the present invention, the antibody that specifically binds to PD-L1 is selected from: durvalumab, avelumab, atezolizumab, and manelimab. In some embodiments of the pharmaceutical compositions of the present invention, other therapeutically active compounds are selected from: IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from this group. Therapeutic use of monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2: In one aspect, antibodies or antigen-binding fragments that specifically bind to GD2 are used to treat conditions mediated by GD2 activity.In one aspect, the subject or patient being treated is a mammal, preferably a human subject. The subject can be male or female of any age. In the case of tumors (e.g., cancer), a therapeutically effective amount of an antibody or fragment thereof (e.g., an antibody or fragment thereof that specifically binds to GITR) can reduce the number of cancer cells; reduce the size of the initial tumor; inhibit (i.e., to some extent slow down and preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with the condition to some extent. The antibody or fragment thereof can, to some extent, prevent the growth of and / or kill existing cancer cells, and it can be cell growth inhibitory and / or cytotoxic. For cancer treatment, for example, in vivo efficacy can be measured by evaluating survival, time to progression (TTP), tumor response rate (RR) to treatment, duration of response, and / or quality of life. This document relates to the use or method of using an antibody or antigen-binding fragment thereof that specifically binds to GD2, together with one or more other therapeutic agents, which is intended to refer to, mention, and include: 1) such combinations of an antibody or antigen-binding fragment thereof that specifically binds to GD2 and a therapeutic agent are administered simultaneously to a patient requiring treatment, wherein such components are formulated together into a single dosage form, which releases the components to the patient at substantially the same time; 2) such combinations of an antibody or antigen-binding fragment thereof that specifically binds to GD2 and a therapeutic agent are administered simultaneously to a patient requiring treatment, wherein such components are formulated separately into separate dosage forms, which are taken by the patient at substantially the same time, and subsequently, the components are released to the patient at substantially the same time. 3) Such combinations of GD2-specific antibodies or their antigen-binding fragments and therapeutic agents are sequentially administered to a patient requiring treatment, wherein such components are formulated separately into separate dosage forms, which are taken by the patient at consecutive times, wherein there is a significant time interval between each administration, and the components are subsequently released to the patient at substantially different times; and 4) Such combinations of GD2-specific antibodies or their antigen-binding fragments and therapeutic agents are sequentially administered to a patient requiring treatment, wherein such components are formulated together into a single dosage form, which releases the components in a controlled manner, and subsequently they are released to the patient simultaneously, consecutively, or jointly at the same and / or different times, wherein each component can be administered via the same or different routes. GD2-specific antibodies or their antigen-binding fragments can be administered as a stand-alone therapy without further therapeutic treatment. In one aspect, the present invention relates to a method for inhibiting the biological activity of GD2 in a subject requiring such inhibition, comprising administering an effective amount of any of the aforementioned antibodies or their antigen-binding fragments.In one aspect, the present invention relates to a method for treating a GD2-mediated disease or condition, comprising administering to a subject requiring such treatment a therapeutically effective amount of any of the aforementioned antibodies or antigen-binding fragments thereof, or the pharmaceutical composition thereof. In another aspect, the present invention relates to a method for treating a GD2-mediated disease or condition, comprising administering to a subject requiring such treatment any of the aforementioned antibodies or antigen-binding fragments thereof, selected from: a) administration of at least one other therapeutically active compound, b) radiotherapy, c) hematopoietic stem cell transplantation, d) surgical treatment and, if necessary, adjuvant therapy, or e) any combination of a) to d) above. In some embodiments of the treatment method, the GD2-mediated disease or condition is selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. In some implementations of the treatment method, other therapeutically active compounds are antibodies, chemotherapeutic agents, or hormonal agents. "Chemotherapy agents" are chemical compounds that can be used in the treatment of malignant tumors. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, indomethacin, and piperosulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylene melamine, triethylenephosphamide, triethylene thiophosphamide, and trimethylmelamine; acetogenins (e.g., blatazine and blatazineone); and δ-9-tetrahydrocannabinol (drocannabinol).MARINOL®; β-lappazone; lappaol; colchicine; betulinic acid; camptothecin (including synthetic analogues topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetaminophen, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolaxin, calcexin, and bizexin); podophyllotoxin; podophyllic acid; teniposide; noctifluides (e.g., noctifluides 1 and noctifluides 8); dolastatin; docalmicin (including synthetic analogues...) Analogs (KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, naphthiamethoxam, chlorphosphatidylcholine, estradiol, ifosfamide, methyl chloroethylamine, oxynitric acid, melphalan, neonitric acid mustard, benzyl mustard cholesterol, prednisolone, trofenoxam, uracil mustard; nitrosourea, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ramustine; antibiotics, such as enediyne antibiotics (e.g., galicarmycin, galicarmycin γ). II and galicillin ω II (see, for example, Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); danendomycin, including danendomycin A; epomycin; and new carcinogen chromophores and associated chromogens of endothelial antibiotics), aclarubicin, actinomycin D, amiodarone, diazoserine, bleomycin, actinomycin C, carabicin, erythromycin, carcinomamycin, chromomycin, daunorubicin, detoxin, 6-diazo-5-oxo-L-leucine, doxorubicin (including ADRIAMYCIN® morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrole-doxorubicin, doxorubicin HCl liposome injection (DOXOL®), doxorubicin liposome TLC)D-99 (MYOCETCA®) and peglylated doxorubicin liposomes (CAELYX® and deoxydoxorubicin), epirubicin, isorubicin, idarubicin, ephedrine, mitomycin C, mycophenolic acid, nopramine, olivomycin, pepromycin, pofibromycin, puromycin, triamcinolone acetonide, rodorubicin, streptomycin, strepzotocin, tuberculin, ubenmex, fenestrated statin, zorubicin; antimetabolites, such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilone, and 5-fluorouracil (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thiouracil. Imidacloprid, thioguanine; pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyflurane, enoxabin, fluorouridine; antiadrenergics, such as aminoglutethimide, mitotane, trelostan; folic acid supplements, such as folinic acid; acetylglucuronide; aldoxyphosphatidylcholine; aminolevulinic acid; enturacil; acridine; bestrabucil; pyrazinamide Group; Idatrix; Desphosphonium; Demecoxine; Desaccharin; Eflunomide; Elimethicone; Etogluconol; Gallium nitrate; Hydroxyurea; Lentinan; Clonidamine; Maytansine alkaloids, such as maytansine and anthraquinone; Mitoguanidine; Mitoantrone; Mogutarol; Nitropropamide; Pentostatin; Methamidomus acid; Pirarubicin; Loxoantrone; 2-Ethylpyrazine; Procarbazine; PSK® Polysaccharide Complex (JHS Natural) Products, Eugene, OR); Razosen; Rhizomycin; Sisofir; Germ spiroamine; Alternaria solanilic acid; Triaminoquinone; 2,2',2”-Trichlorotriethylamine; Trichothecene (e.g., T-2 toxin, Verrucin A, Bacitracin A, and Serpentin); Urethroids; Dacarbazine; Mannomustine; Dibromomannitol; Dibromoeusol; Piperobromide; Gacytosine; Cytarabine (“Ara-C”); Thioteguanidine; Taxane-like substances, such as paclitaxel (TAXOL®), albumin-modified paclitaxel nanoparticles (ABRAXANE®), and docetaxel (TAX). OTERE®; chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum-based agents such as cisplatin, oxaliplatin, and carboplatin; vinca alkaloids that prevent tubulin polymerization to form microtubules, including vinca alkaloids (VELBAN®), vinblastine (ONCOVIN®), vindesine (ELDISINE®), FILDESIN®, and vinorelbine (NAVELBINE®); etoposide (VP-16); ifosfamide; mitoxantrone; methyltetrahydrofolate; noscholine; idatraxa; donomycin; methotrexate; ibandronate; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid, including bexarotin (TARGRETIN®); bisphosphonates, such as clodronates (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronic acid (ZOMETA®), alendronate (FOSAMAJX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL). ®); Trasatabine (1,3-dioxolane cytosine analog); Antisense oligonucleotides, such as those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); Vaccines, such as THERATOPE® vaccine and gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN® vaccine, and VAXID® vaccine; Topoisomerase 1 inhibitors (e.g., LURTOTECAN®); rmRH (e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (Pfizer); pirivacin, COX-2 inhibitors (e.g., celecoxib or etoricoxib), protein body inhibitors (e.g., PS341); bortezomib (VELCADE®); CCI-779; tepifenab (811577); orafenib, ABT510; Bcl-2 inhibitors, such as olimosen sodium (GENASENSE®); picosenoside; EGFR inhibitors (see definition below); tyrosine kinase inhibitors (see definition below); and any pharmaceutically acceptable salts, acids, or derivatives thereof; and combinations of two or more thereof, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for treatment regimens of oxaliplatin (ELOXATINTM) in combination with 5-FU and folate.Hormonal agents are reagents that regulate or inhibit the effects of hormones on tumors. Examples of such agents include antiestrogens with mixed agonist / antagonist profiles, including tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), edoxifene, droloxifene, raloxifene (EVTSTA®), trivoxifen, raloxifene, and selective estrogen receptor modulators (SERMs), such as SERM3; pure antiestrogens without agonist properties, such as fulvestrant (FASLODEX®) and EM800 (these agents can block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER conversion rate, and / or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors, such as formestan and exemestan (AROMASIN®), and nonsteroidal aromatase inhibitors, such as anastrozole (AREVIIDE). X®, letrozole (FEMARA®), and aminoglutethimide, and other aromatase inhibitors including vortexilazole (RIVISOR®), megestrol acetate (MEGASE®), fastrozole, and imidazole; luteinizing hormone-releasing hormone agonists, including leuprorelin (LUPRON® and ELIGARD®), goserelin, buserelin, and triptorelin; sex steroids, including progestins such as megestrol acetate and medroxyprogesterone acetate; estrogens such as diethylstilbestrol and prednisolone; and androgens / retinoin-like substances such as flumethrin; all-trans retinoic acid and fenvitamin A; onasone; antiprogestins; estrogen receptor downregulators (ERDs); antiandrogens such as flutamide, niglutethimide, and bicalutamide; testrolide; and any pharmaceutically acceptable salts, acids, or derivatives of the above; and combinations of two or more of the above. In some embodiments of the treatment, other therapeutically active compounds are immune checkpoint inhibitors. The term "immune checkpoint inhibitor" (or "checkpoint inhibitor") refers to a compound that inhibits the activity of immune checkpoints. Inhibition includes functional reduction and complete blockade. Examples of inhibitory checkpoint molecules include B7-H3, B7-H4, BTLA, CTLA-4, KIR, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, TIGIT, and VISTA. In some embodiments of the invention, the immune checkpoint inhibitor is an antibody that specifically recognizes an immune checkpoint protein. Many immune checkpoint inhibitors are known, and alternative immune checkpoint inhibitors similar to these known immune checkpoint protein inhibitors may be developed in the near future. Immune checkpoint inhibitors include, but are not limited to, peptides, antibodies, nucleic acid molecules, and low molecular weight compounds. In some embodiments of the treatment method, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors. In some embodiments of the treatment method, the PD-1 inhibitor is an antibody that specifically binds to PD-1.In some embodiments of the present invention, the PD-1 inhibitor is an antibody that specifically binds to PD-1. Examples of antibodies that specifically bind to PD-1 include pembrolizumab, nivolumab, prolgolimab, toripalimab, cimiprimab, sintilimab, and others. The most preferred antibodies are prolgolimab, pembrolizumab, and nivolumab. In some embodiments of the treatment method, the antibody that specifically binds to PD-1 is selected from prolgolimab, pembrolizumab, and nivolumab. In some embodiments of the treatment method, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. In some embodiments of the present invention, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. Examples of antibodies that specifically bind to CTLA4 include ipilimumab, trimemumab, zefulimab, norelimumab, and others. The most preferred antibodies are ipilimumab or norelimumab. In some embodiments of the treatment method, the antibody that specifically binds to CTLA-4 is ipilimumab or novellimab. In some embodiments of the treatment method, the PD-L1 inhibitor is an antibody that specifically binds to PD-L1. In some embodiments of the treatment method, the antibody that specifically binds to PD-L1 is selected from durvalumab, avelumab, atezolizumab, and manelimab. In some embodiments of the treatment method, other therapeutically active compounds are selected from IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from this group. In one aspect, the present invention relates to the use of the above-described antibodies or their antigen-binding fragments, or the above-described pharmaceutical compositions, for treating GD2-mediated diseases or conditions in subjects requiring such treatment. In one aspect, the present invention relates to the use of any of the above-described antibodies or their antigen-binding fragments, and at least one of the following groups, for treating GD2-mediated diseases or conditions: a) other therapeutically active compounds, b) radiotherapy, c) hematopoietic stem cell transplantation, or d) surgical treatment and, if necessary, adjuvant therapy. In some embodiments of the use, the GD2-mediated diseases or conditions are selected from: brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma. In some embodiments of the use, the other therapeutically active compound is an immune checkpoint inhibitor. In some embodiments of the use, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors. In some embodiments of the use, the PD-1 inhibitor is an antibody that specifically binds to PD-1.In some embodiments of the use, the antibody that specifically binds to PD-1 is selected from: prolgolimab, pembrolizumab, nivolumab. In some embodiments of the use, the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4. In some embodiments of the use, the antibody that specifically binds to CTLA-4 is ipilimumab or novellimab. In some embodiments of the use, the PD-L1 inhibitor is an antibody that specifically binds to PD-L1. In some embodiments of the use, the antibody that specifically binds to PD-L1 is selected from: durvalumab, avelumab, atezolizumab, manelimab. In some embodiments of the use, other therapeutically active compounds are selected from: IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from this group. Dosage and route of administration: The monoclonal antibody or its antigen-binding fragment that specifically binds to GD2 according to the present invention will be administered in an amount effective in treating the condition in question, i.e., at the dose and duration required to achieve the desired result. The effective therapeutic dose can vary depending on factors such as the specific condition to be treated, the patient's age, sex, and weight, and whether the monoclonal antibody or its antigen-binding fragment that specifically binds to GD2 is administered as a standalone treatment or in combination with one or more other drugs or treatments. Dosing regimens can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several separate doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. Formulating parenteral compositions in unit dosage forms is particularly advantageous for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose for a patient / subject to be treated; each unit contains a predetermined amount of the active compound, calculated to produce the desired therapeutic effect when bound to a desired drug carrier. The specifications of the unit dosage forms of the present invention are generally determined by and directly depend on the following factors: (a) the unique characteristics of the therapeutic agent and the specific therapeutic or preventative effect to be achieved, and (b) the inherent limitations in the field of formulating such active compounds for treating sensitive subjects. Therefore, based on the disclosure provided herein, those skilled in the art will understand that dosages and dosing regimens can be adjusted according to methods well-known in the therapeutic field. That is, the maximum tolerable dose can be readily determined, as can the effective amount to provide a detectable therapeutic effect to the patient, and the time required for administering each agent to provide a detectable therapeutic effect to the patient. Therefore, although certain dosages and administration regimens are illustrated herein, these examples are by no means limited to the dosages and administration regimens that can be provided to patients in the practice of embodiments of the invention.It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include a single dose or multiple doses. Furthermore, it should be understood that for any particular subject, the specific dosage regimen should be adjusted over time based on individual needs and the judgment of the medical professional administering or supervising the administration of the composition, and the dosage ranges set forth in this specification are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. Moreover, the administration regimen of the compositions of the present invention can be based on various factors, including the type of disease, the patient's age, weight, sex, medical condition, severity of the condition, route of administration, and the specific monoclonal antibody or its antigen-binding fragment that specifically binds to GD2 used. Therefore, dosage regimens can be widely varied but can be conventionally determined using standard methods. For example, the dosage can be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects, such as toxic effects or laboratory values. Therefore, the present invention covers intra-patient dose escalation determined by those skilled in the art. Methods for determining appropriate dosages and regimens are well known in the art and will be understood by those skilled in the art once the concepts disclosed herein are provided. Examples of suitable administration methods are provided above. The appropriate dose of the monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2 according to the present invention is considered to be in the range of 0.1-200 mg / kg, preferably 0.1-100 mg / kg, including about 0.5-50 mg / kg, for example about 1-20 mg / kg. The monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2 may be administered, for example, at a dose of at least 0.25 mg / kg, for example at least 0.5 mg / kg, including at least 1 mg / kg, for example at least 1.5 mg / kg, for example at least 2 mg / kg, for example at least 3 mg / kg, including at least 4 mg / kg, for example at least 5 mg / kg; and for example up to 50 mg / kg, including up to 30 mg / kg, for example up to 20 mg / kg, including up to 15 mg / kg. It is usually repeated at appropriate time intervals, for example once a week, once every two weeks, once every three weeks, or once every four weeks, and continued for a duration deemed appropriate by the attending physician. In some cases, the attending physician may increase or decrease the dose as necessary. Diagnostic uses of antibodies that specifically bind to GD2The GD2-specifically binding monoclonal antibody or its antigen-binding fragment according to the present invention is also used for diagnostic purposes (e.g., in vitro, ex vivo). For example, the GD2-specifically binding monoclonal antibody or its antigen-binding fragment according to the present invention can be used to detect or measure GD2 levels in samples obtained from patients (e.g., tissue samples or body fluid samples, such as inflammatory exudates, blood, serum, intestinal fluid, saliva, or urine). Suitable methods for detection and measurement include immunoassays, such as flow cytometry, enzyme-linked immunosorbent assay (ELISA), chemiluminescence assay, radioimmunoassay, and immunohistochemistry. Examples are provided below to better understand the invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. All publications, patents, and patent applications referenced in this specification are incorporated herein by reference. Although the foregoing invention has been described in somewhat detail by way of illustration and example for purposes of clarity, it will be apparent to those skilled in the art, based on the teachings of the present invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended embodiments. Materials and general methods General information on the nucleotide sequences of the light and heavy chains of human immunoglobulins is given in the following: Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991). The amino acids in the antibody chain are numbered according to EU codes (Edelman, GM et al., Proc. Natl. Acad. Sci. USA 63 (1969) 78-85; Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, (1991). Recombinant DNA techniques, as described in Sambrook, J. et al., Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, use standard methods to manipulate DNA. Molecular biology reagents are used according to the manufacturer's protocol. Gene synthesis prepares the desired gene segment from oligonucleotides prepared by chemical synthesis. Flanking is 300-1400 single restriction sites.A bp-long gene segment is assembled via annealing and oligonucleotide ligation, including PCR amplification, and subsequently cloned via restriction sites. The DNA sequence of the subcloned gene fragment is confirmed by DNA sequencing. DNA sequencing is performed using Sanger sequencing. Unipro's UGENE Suite version 1.29 and SnapGene Viewer are used for sequence creation, plotting, analysis, annotation, and description for DNA and protein sequence analysis and sequence data management. The expression vector is a variant of the expression plasmid intended for expression in prokaryotic cells (E. coli) and transient expression in eukaryotic cells (e.g., CHO cells) for the expression of the antibody described in the application materials. In addition to the antibody expression cassette, the vector contains: an origin of replication that allows the plasmid to replicate in E. coli, and a gene conferring resistance to various antibiotics (e.g., ampicillin, kanamycin) in E. coli. The fusion gene containing the antibody chain, as described below, is generated by PCR and / or gene synthesis and assembled using known recombination methods and techniques by ligating the corresponding nucleic acid segments, for example, using unique restriction sites in the corresponding vector. The nucleic acid sequence of the subcloned gene is verified by DNA sequencing. For transient transfection, a larger quantity of plasmids was prepared using plasmid preparations derived from transformed *E. coli* cultures. Example 1: Selection of Anti-GD2 Antibody Sequence. Anti-GD2 antibody molecules were generated using structural data obtained on a computer-generated chip. Scaffolding on the computer-generated chip was performed using the internal algorithm of JSC “Biocad”. The PrepWizard tool from Schrodinger Suite 2017-2 was used for structure preparation. Folding was then performed using the Prime tool from Schrodinger Suite 2017-2. A sequential modification method involving the amino acid composition of variable domains was applied. The antibodies were optimized on the computer-generated chip to generate antibody candidates for further research, indicated in Table 1. Table 1. Antibody Candidates for Further Research Antibody name targeting GD2 07-001 07-002 07-003 07-004 07-005 07-006 07-007 07-008 07-009 07-010 07-011 07-012 07-013 07-014 07-015 07-016 07-017 07-019 07-028 07-029 07-030 07-031 07-032 07-033 07-041 07-042 07-043 07-044 Six lead antibodies were selected from Table 1 as follows: 07-006, 07-015, 07-016, 07-028, 07-031, and 07-041; these antibodies surprisingly showed the best parameters (see Examples below). Example 2: Identity / Humanization Analysis of Light / Heavy Chain Variable Fragments of Anti-GD2 Antibodies 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. Table 2 shows the identity analysis of the heavy chain variable fragments of anti-GD2 antibodies 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. Table 2. Percentage of Identity in Antibody VH Percentage of identity in VH 07-006 07-015 07-016 07-028 07-031 07-041 07-006 100 98 98 98 99 99 07-015 98 100 100 100 98 98 07-016 98 100 100 100 98 98 07-028 98 100 100 100 98 98 07-031 99 98 98 98 100 99 07-041 99 98 98 98 99 100 Therefore, the anti-GD2 heavy chain variable fragments according to the present invention have at least 98% identity with each other. Table 3 shows the humanization analysis of the heavy chain variable fragments of anti-GD2 antibodies 07-006, 07-015, 07-016, 07-028, 07-031 or 07-041. Table 3. Degree of humanization of antibody VH VH Humanization Level 07-006 0.806 07-015 0.806 07-016 0.806 07-028 0.806 07-031 0.806 07-041 0.806 Therefore, the heavy chain variable fragment of the anti-GD2 antibody according to the present invention has a humanization degree of more than 80%. Table 4 shows the identity analysis of the light chain variable fragments of anti-GD2 antibodies 07-006, 07-015, 07-016, 07-028, 07-031 or 07-041. Table 4. Percentage of identity in antibody VL Same in VL Sex percentage 07-006 07-015 07-016 07-028 07-031 07-041 07-006 100 99 100 96 99 96 07-015 99 100 99 96 100 96 07-016 100 99 100 96 99 96 07-028 96 96 96 100 96 96 07-031 99 100 99 96 100 96 07-041 96 96 96 96 96 100 Therefore, the variable light chain fragments of the anti-GD2 antibody according to the present invention share at least 96% identity with each other. Table 5 shows the humanization analysis of the variable light chain fragments of anti-GD2 antibodies 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. Table 5. Degree of VL Humanization Humanization level of antibody VL 07-006 0.8 07-015 0.81 07-016 0.8 07-028 0.8 07-031 0.81 07-041 0.8 Therefore, the candidate anti-GD2 light chain variable fragments according to the present invention have a humanization degree of more than 80%. Example 3: Production of sequences of anti-GD2 antibodies 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. Genes of heavy / light chain variable domains for antibodies against GD2 selected according to the present invention were synthesized de novo: 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. For this purpose, we synthesized 55-60 bp oligonucleotides, each oligonucleotide forming a completely overlapping gene sequence. Two rounds of PCR were used to assemble each gene, resulting in fragments of 339 bp each. The fusion of the heavy chain variable domain gene with the Fc fragment of human IgG1, the light chain variable domain, and CK was performed using known recombination methods and processes, such as by ligating appropriate nucleic acid segments using SOE-PCR (overlap extension splicing), and by using PCR and / or gene synthesis and assembly. Heavy and light chain genes for antibodies against GD2 selected according to the present invention were cloned into PEE plasmids for the production of protein in the form of IgG1 in mammalian cells: 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. The cloned nucleic acid sequences were verified by DNA sequencing. The required quantities of the resulting plasmids (Figures 2 and 3) were produced in *E. coli* cells and purified using a commercial plasmid DNA isolation kit from Qiagen. The resulting gene constructs were transferred for transient protein production in CHO cell lines. Example 4. Modification of the Fc heavy chain constant domain of GD2 antibodies 07-006, 07-015, 07-016, 07-028, 07-031, or 07-041. To generate antibodies with improved properties, the Fc heavy chain constant domain was modified by introducing point mutations M252Y, S254T, T256 (YTE), and / or K322A. The YTE mutation set enabled prolonged pharmacokinetics, while the introduction of the K322A mutation reduced the complement-dependent cytotoxicity of the resulting antibodies. Additionally, due to expression in the CHO-1g6-Fut8 cell line, the Fc portion of the antibody is defucosylated, thus leading to increased antibody-dependent cytotoxicity. The resulting antibodies are shown in Table 6. Table 6. Variants of antibodies against GD2 according to the present invention. Initial antibody name without modifications to the Fc fragment The Fc fragment contains mutations M252Y, S254T, and T256E. (YTE) antibody name The name of an antibody with the K322A mutation in the Fc fragment. Antibody names containing mutations M252Y, S254T, T256E (YTE) + K322A in the Fc fragment. 07-006 07-006 + YTE 07-006 + K322A 07-006 + YTE + K322A 07-015 07-015 + YTE 07-015 + K322A 07-015 + YTE + K322A 07-016 07-016 + YTE 07-016 + K322A 07-016 + YTE + K322A 07-028 07-028 + YTE 07-028 + K322A 07-028+ YTE+ K322A 07-031 10-001 10-003 10-002 07-041 10-007 10-009 10-008 Assembly of the genetic construct involved the fusion of a heavy chain variable domain gene and the Fc of human IgG1, with a point mutation pre-introduced within the Fc. The substituted heavy chain gene was cloned into the pEE plasmid for the production of protein in the form of IgG1 along with the already produced light chain construct in the CHO-1g6-Fut8 cell line. The cloned nucleic acid sequence was verified by DNA sequencing. The required quantities of the resulting plasmid (Figures 2 and 3) were cultured in *E. coli* cells and purified using a Qiagen kit. The resulting genetic construct was transferred for transient protein production in the CHO-1g6-Fut8 cell line. Example 5: Production, isolation, and purification of an antibody against GD2 from a suspension culture of mammalian cells. Full-length antibody was produced in CHO cell growth medium, and a defucosylated form of full-length antibody was produced in CHO-1g6-Fut8 cell growth medium. After transfection of cells with the expression vector, feed-on batch culture was performed for 7 days in serum-free medium. The secretion of the antibody under discussion was monitored using a Pall ForteBio Octet RED96 system for molecular interaction analysis on a protein A biosensor. After culturing, cell cultures were centrifuged at 2000 g for 20 min and filtered through a 0.22 µm sieve. The target protein was isolated from the culture medium by affinity chromatography using a HiTrap rProtein A FF column on an Akta Pure 25 chromatography system. The culture medium was applied to the HiTrap rProtein A FF column; the column was then washed with PBS, and the protein was eluted with 0.1 M glycine buffer (pH 3); the protein solution was then neutralized by adding 1 M Tris-HCl рН8 at a 1 / 5 v / v ratio. The protein was then transferred to PBS (pH 7.4) by dialysis; the resulting solution was then filtered (0.22 μm). The product was stored at -70 °C. The purity of the obtained protein solution was assessed by SDS gel electrophoresis (Figure 4). Example 6: Kinetic study of the affinity of the GD2 antibody for ganglioside GD2 using a Forte Bio OctetRed96. The binding of the antibody to GD2 was assessed by biomembrane interferometry on an OctetRed96 (Pall) instrument. An AR2G sensor was coated with ganglioside GD2. The sensor with immobilized GD2 was then immersed in wells containing the antibody. After the antibody and ganglioside were bound, the sensor was immersed in working solution for the subsequent dissociation phase. After subtracting the reference signal, the obtained sensor map was analyzed using Octet Data Analysis software (version 8.2) according to standard procedures and using a 1:1 interaction model. The KD of the aGD2 antibody according to the present invention is shown in Table 7.Table 7. Dissociation constants of antibodies against GD2. Antibody name KD, M 07-006 7,58E-10 07-015 4,49E-10 07-016 7,03E-10 07-028 6,13E-10 07-031 10,6E-10 07-041 8,41E-10 10-008 7,56 E-10 Therefore, all tested anti-GD2 antibodies bound specifically to ganglioside GD2 with high affinity (Table 7). Example 7: Thermal stability analysis of antibodies against GD2. Antibodies were heated in PBS at pH 7.4 using an amplifier in a plastic tube at 50°C for 48 hours, followed by a transition to +4°C. After the program was completed, the samples were analyzed before and after heating using analytical gel chromatography on a TSK Gel G3000 SWxl column. The target peak areas of the samples before and after heating were compared. A change of less than 5% in the monomer peak area after 48 hours of heating indicated the stability of the product and its potential for long-term storage (Table 8). Table 8. Peak area ratio on the antibody product chromatograms before and after heating. Antibody name % Peak ratio Σ aggregate, % monomer,% Σ fragment, % 07-006 Before heating 1.49 96.06 2.46 After heating 1.30 94.81 3.88 07-015 Before heating 1.81 95.64 2.55 After heating 1.58 91.46 6.95 07-016 Before heating 1.11 96.85 2.04 After heating 1.14 92.32 6.54 07-028 Before heating 1.41 96.50 2.08 After heating 1.39 93.21 5.41 07-031 Before heating 0.72 89.95 9.33 After heating 0.65 89.68 9.67 07-041 Before heating 0.86 97.50 1.64 After heating 1.03 95.68 3.29 10-008 Before heating 0.34 98.17 1.49 After heating 0.65 96.12 3.23 Therefore, all tested anti-GD2 antibodies showed high thermal stability (Table 8). Example 8 Determination of antibody-dependent cytotoxicity of antibodies against GD2 We used a reporter cell line based on the Jurkat cell line; SK-N-BE(2) as the target cell, which stably expresses surface CD16 and contains a gene encoding firefly luciferase under the control of the NFAT promoter. Jurkat-NFAT-Luc-CD16 cells were cultured at 37°C and 5% CO2 on RPMI-1640 medium (10% FBS, 10 μg / ml gentamicin, 2 mM L-glutamine, 0.3 μg / ml puromycin and 200 μg / ml hygromycin); SK-N-BE(2) were cultured under the same conditions on DMEM / F12 medium (10% FBS, 10 mcg / ml gentamicin and 2 mM L-glutamine). 25,000 Jurkat-NFAT-Luc-CD16 effector cells and 25,000 SK-N-BE(2) target cells, along with an antibody dilution at a concentration shown in the figure, were introduced into each well of a 96-well culture plate at 50 µl volumes. Spots without antibody served as negative controls. The plates were incubated at 37°C and 5% CO2 for 4 hours; thereafter, the luminescence intensity in the wells was measured using luciferase substrate (JSC BIOCAD) on a Spark plate reader (Tecan), and data processing and plotting were performed using SigmaPlot 14.0 software. The EC50 values ​​of the anti-GD2 antibody samples are shown in Table 9. Table 9. EC50 values ​​of anti-GD2 antibody samples Antibody name EC50 (ng / ml) 07-001 3.2 07-002 3.6 07-003 2.2±1.3 07-004 4.5 07-005 2.8 07-006 1.3±0.6 07-007 5.3 07-008 4 07-009 2.7±1.7 07-010 3.6 07-011 1.8 07-012 1.3±0.9 07-013 1 07-014 1 07-015 1.1 07-016 1 07-017 1.4 07-019 0.7 07-028 0.7 07-029 1.3 07-030 2.6 07-031 8.5±2.6 07-032 10.3 07-033 1.1 07-041 4.1±3.9 07-042 2.4 07-043 1.6 07-044 2.2 07-041-dFuc (a defucosylated variant of 07-041) 0.9±0.3 10-007 0.7±0.2 10-008 1±0.7 10-009 0.6±0.1 10-010 13.6±0.7 10-011 19.8±9.3 10-012 3.3±1.6 Figure 5 shows that antibody 10-008 exhibits antibody-dependent cytotoxicity in the assay using the Jurkat-NFAT-Luc-CD16 cell line. Example 9: Analysis of Complement-Dependent Cytotoxicity. The SK-N-BE (2) (human neuroblastoma) cell line was used as the target cell for the analysis. Cells were grown in DMEM medium supplemented with 10% bovine serum. To perform the analysis, a cell suspension of 1 x 10⁶ cells / ml was prepared in DMEM medium supplemented with 0.1% bovine serum albumin, and multiple dilutions of the antibody candidate were prepared. 50 µl of antibody dilution, 50 µl of cell suspension, and 50 µl of freshly isolated human serum from a healthy donor were added to each well of a 96-well plate. The plate was incubated at 37°C and 5% CO₂ for 3 hours. After incubation, 15 µl of “Alamar Blue” live dye (Invitrogen) was added to all wells, and the plate was incubated at 37°C and 5% CO₂ for 18 hours. The plate was agitated on an orbital oscillator for 10–20 minutes at room temperature. Fluorescence readings were obtained using a TECAN Spark plate reader. The detected fluorescence signal was proportional to the number of viable cells. Excel and SigmaPlot 14.0 software were used for data processing and plotting. Antibodies 07-041dFuc (a defucosylated variant of 07-041), 10-007, 10-008, and 10-009 were tested to induce target cell death in the presence of human serum. Antibodies 10-008 and 10-009 showed a reduced effect compared to other antibodies (see Figure 6). [Simplified Explanation of the Diagram]

[0004] [Figure 1] shows the structure of the Fab fragment complexed with the GD2 target. [Figure 2] is a vector map of the heavy chain genetic sequence carrying the anti-GD2 antibody. [Figure 3] is a vector map of the light chain genetic sequence carrying the anti-GD2 antibody. Regarding Figures 2-3: name definition CMV promoter Eukaryotic CMV promoter TPL adenovirus 5'-untranslated triple leader sequence E_MLP Enhancer elements of the adenovirus major late promoter Intron receptors receptor site Kozak sequence GCCGCCACC Precursor IgK Mouse IgK signaling precursor peptide Anti-GD2_VH Heavy chain variable domain gene of aGD2 antibody. Anti-GD2_VH can refer to the heavy chain variable domain of the aGD2 antibody according to the present invention, for example, the antibody is selected from antibodies against GD2: 07-006, 07-015, 07-016, 07-028, 07-031 or 07-041. Anti-GD2_VL Light chain variable domain gene of aGD2 antibody. Anti-GD2_VL can refer to the light chain variable domain of the aGD2 antibody according to the present invention, for example, the antibody is selected from antibodies against GD2: 07-006, 07-015, 07-016, 07-028, 07-031 or 07-041. HumIgG1 CK CK (κ) light chain constant domain gene HumIgG1 HC HC heavy chain constant domain gene. HumIgG1HC can refer to both unmodified variants and variants with point mutations in the antibody Fc fragment, wherein the point mutations are selected from: M252Y, S254T, T256 (YTE), K322A or YTE + K322A Poly-A signal Polyadenylation signaling EBV Eukaryotic Origin (OriP) The eukaryotic origin of EB virus replication pUC starting point Prokaryotic cladding starting point AmpR A β-lactamase gene conferring resistance to ampicillin was introduced. This enables the selection of *E. coli* cell cultures. STOP stop codon START start codon [Figure 4] is an electrophoresis diagram of the 10-008 candidate by gradient gel 4-20% SDS-PAGE under reducing and non-reducing conditions. 1. Molecular weight marker; 2. 10-008 1 μg under non-reducing conditions; 3. 10-008 1 μg under reducing conditions. [Figure 5] is a graph showing the presence of antibody-dependent cytotoxicity of antibody 10-008 in the assay using SK-N-BE(2) target cells. Spots without antibody were used as negative controls. [Figure 6] is a graph showing complement-dependent cytotoxicity of the antibody against GD2 according to the present invention in the assay using SK-N-BE(2) target cells. The graph shows the fluorescence level of the live dye (used to indicate the number of live cells) relative to the antibody concentration after the addition of human serum. EC50 values ​​were obtained in SigmaPlot 14.0 software based on a logistic model. [Sequence List]

[0006] <![CDATA[ <110> BIOCAD Joint Stock Company of the Russian Federation <![CDATA[ <120> Monoclonal antibodies or antigen-binding fragments thereof that specifically bind to GD2 (ganglioside GD2) and their uses <![CDATA[ <140> 111 111 114]]> <![CDATA[ <140> 2022-03-24 <![CDATA[ <150> RU 2021107773]]> <![CDATA[ <151> 2021-03-24 <![CDATA[ <160> 100]]> <![CDATA[ <170> BiSSAP 1.3.6 <![CDATA[ <210> 1]]> <![CDATA[ <211> 5]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR1 (Kabat) of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028. <![CDATA[ <400> 1]]> Gly His Asn Met Asn 1 5 <![CDATA[ <210> 2]]> <![CDATA[ <211> 5]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR1 (Kabat) of the heavy chain variable domain of antibodies 07-006, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 2]]> Gly Lys Asn Met Asn 1 5 <![CDATA[ <210> 3]]> <![CDATA[ <211> 17]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> AntibodyThe amino acid sequences CDR2 (Kabat) of the heavy chain variable domains of 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009 <![CDATA[ <400> 3]]> Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[ <210> 4]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Kabat) of the heavy chain variable domain of antibodies 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 4]]> Gly Met Ile Tyr 1 <![CDATA[ <210> 5]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Kabat) of the heavy chain variable domain of antibodies 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 5]]> Gly Met Phe Tyr 1 <![CDATA[ <210> 6]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Kabat) of the heavy chain variable domain of antibody 07-006 <![CDATA[ <400> 6]]> Gly Met Tyr Tyr 1 <![CDATA[ <210> 7]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028(Kabat)]]> <![CDATA[ <400> 7]]> Gly Met Leu Tyr 1 <![CDATA[ <210> 8]]> <![CDATA[ <211> 16]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR1 (Kabat) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 8]]> Arg Ser Ser Arg Ser Leu Val His Arg Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[ <210> 9]]> <![CDATA[ <211> 16]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences CDR1 (Kabat) of the light chain variable domain of antibodies 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 9]]> Arg Ser Ser Gln Asn Leu Val His Arg Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[ <210> 10]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (Kabat) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 10]]> Lys Val Ser Asn Arg Phe Gly 1 5 <![CDATA[ <210> 11]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223>The amino acid sequence CDR2 (Kabat) of the light chain variable domain of antibodies 07-028, 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 11]]> Lys Val Asn Asn Arg Phe Ser 1 5 <![CDATA[ <210> 12]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Kabat) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 12]]> Gly Gln Ser Thr His Val Pro Pro Leu Thr 1 5 10 <![CDATA[ <210> 13]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Kabat) of the light chain variable domain of antibody 07-028 <![CDATA[ <400> 13]]> Ser Gln Ser Thr His Val Pro Pro Leu Ser 1 5 10 <![CDATA[ <210> 14]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> [Amino acid sequence of the variable domain of the heavy chain of antibody 07-006] <![CDATA[ <400> 14]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile GlyGln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser <![CDATA[ <210> 15]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Amino acid sequences of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028 <![CDATA[ <400> 15]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly His 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Leu Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser 100 105 110 Ser <![CDATA[ <210> 16]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences of the variable domains of the heavy chain of antibodies 07-031, 10-001, 10-02, and 10-003. <![CDATA[ <400> 16]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Ile Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser <![CDATA[ <210> 17]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences of the variable domains of the heavy chain of antibodies 07-041, 10-007, 10-08, and 10-009. <![CDATA[ <400> 17]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro GlyAla 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 100 105 110 Ser <![CDATA[ <210> 18]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Amino acid sequences of the light chain variable domains of antibodies 07-006 and 07-016 <![CDATA[ <400> 18]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Arg Ser Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile His Lys Val Ser Asn Arg Phe Gly Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 7075 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Gly Gln Ser 85 90 95 Thr His Val Pro Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys <![CDATA[ <210> 19]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences of the variable domains of the light chain of antibodies 07-015, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 19]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Arg Ser Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile His Lys Val Ser Asn Arg Phe Gly Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Gly Gln Ser 85 90 95 Thr His Val Pro Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys <![CDATA[ <210> 20]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223>[Amino acid sequence of the variable domain of the light chain of antibody 07-028] <![CDATA[ <400> 20]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Arg Ser Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile His Lys Val Asn Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Pro Pro Leu Ser Phe Gly Gln Gly Thr LysLeu Glu Leu 100 105 110 Lys <![CDATA[ <210> 21]]> <![CDATA[ <211> 113]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences of the variable domains of the light chain of antibodies 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 21]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Gln Asn Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu IleHis Lys Val Asn Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Gly Gln Ser 85 90 95 Thr His Val Pro Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys <![CDATA[<210> 22]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequence of the Heavy Chain of Antibody 07-006]]> <![CDATA[<400> 22]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser ValPhe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile GluLys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 23]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibodies 07-015, 07-016, 07-028]]> <![CDATA[<400> 23]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly His 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser TyrAsn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Leu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val LysPhe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 24]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 07-031]]> <![CDATA[<400>24]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Ile Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val GluPro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe SerCys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 25]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> ]]> Artificial sequence <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 07-041]]> <![CDATA[<400> 25]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Phe Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser GlyAla Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu ValLys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 26]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequence of the Heavy Chain of Antibody 07-006 + YTE]]> <![CDATA[<400> 26]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 ValSer Gly Met Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu HisGln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 27]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chains of antibodies 07-015 + YTE, 07-016 + YTE and 07-028 + YTE]]> <![CDATA[<400> 27]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly His 20 2530 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Leu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro LysPro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 28]]> <![CDATA[<211>443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 10-001]]> <![CDATA[<400> 28]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Ile Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser SerSer Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp SerAsp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 29]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 10-007]]> <![CDATA[<400> 29]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Phe Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 LysSer Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 GlyGln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 30]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequence of the Heavy Chain of Antibody 07-006 + YTE + K322A]]> <![CDATA[<400> 30]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val ThrLeu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val GluVal His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 31]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 07-015 + YTE + K322A, 07-016 + YTE + K322A and 07-028 + YTE + K322A]]><![CDATA[<400> 31]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly His 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Leu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 32]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 10-002]]> <![CDATA[<400> 32]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Ile Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val SerTrp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser LeuThr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 33]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequence of the Heavy Chain of Antibody 10-008]]> <![CDATA[<400> 33]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 8590 95 Val Ser Gly Met Phe Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 34]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequence of the Heavy Chain of Antibody 07 - 006 + K322A]]> <![CDATA[<400> 34]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn MetAsn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys AspThr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 35]]> <![CDATA[<211> 443]]><![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequences of the Heavy Chains of Antibodies 07-015 + K322A, 07-016 + K322A, and 07-028 + K322A]]> <![CDATA[<400> 35]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly His 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Leu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser SerVal Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys ThrThr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 36]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino Acid Sequence of the Heavy Chain of Antibody 10 - 003]]> <![CDATA[<400> 36]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Ile Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu AlaPro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile SerLys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 37]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the heavy chain of antibody 10-009]]> <![CDATA[<400> 37]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Lys 20 25 30 Asn Met Asn Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Asp Pro Phe Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys GlyArg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gly Met Phe Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 115 120 125 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 180 185 190 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val AspGly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser 305 310 315 320 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 38]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the light chain of antibodies 07-006 and 07-016]]> <![CDATA[<400> 38]]> Asp Ile Val Met Thr GlnThr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Arg Ser Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile His Lys Val Ser Asn Arg Phe Gly Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Gly Gln Ser 85 90 95 Thr His Val Pro Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly GluCys 210 215 220 <![CDATA[ <210> 39]]> <![CDATA[ <211> 220]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences of the light chains of antibodies 07-015, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 39]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Arg Ser Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile His Lys Val Ser Asn Arg Phe Gly Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Gly Gln Ser 85 90 95 Thr His Val Pro Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val ThrGlu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <![CDATA[<210> 40]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the light chain of antibody 07-028]]> <![CDATA[<400> 40]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Arg Ser Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile His Lys Val Asn Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Pro Pro Leu Ser Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <![CDATA[<210> 41]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Amino acid sequence of the light chain of antibodies 07-041, 10-007, 10-008, 10-009]]> <![CDATA[<400> 41]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys Arg Ser Ser Gln Asn Leu Val His Arg 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile His Lys Val Asn Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 775 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Gly Gln Ser 85 90 95 Thr His Val Pro Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <![CDATA[ <210> 42]]> <![CDATA[ <211> 30]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence FR1 (Kabat) of the heavy chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 42]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 510 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr 20 25 30 <![CDATA[ <210> 43]]> <![CDATA[ <211> 14]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence FR2 (Kabat) of the heavy chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 43]]> Trp Val Arg Gln Asn Ile Gly Gln Gly Leu Glu Trp Met Gly 1 5 10 <![CDATA[ <210> 44]]> <![CDATA[ <211> 32]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence FR3 (Kabat) of the heavy chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 44]]> Arg Val Thr Leu Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Val Ser 20 25 30 <![CDATA[ <210> 45]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223>The amino acid sequence FR4 (Kabat) of the heavy chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 45]]> Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <![CDATA[ <210> 46]]> <![CDATA[ <211> 23]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence FR1 (Kabat) of the light chain variable domain of antibodies 07-006, 07-15, 007-16, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 46]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Arg Ala Ser Leu Ser Cys 20 <![CDATA[ <210> 47]]> <![CDATA[ <211> 15]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence FR2 (Kabat) of the light chain variable domain of antibodies 07-006, 07-016, 07-028, 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 47]]> Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile His 1 5 10 15 <![CDATA[ <210> 48]]> <![CDATA[ <211> 15]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223>The amino acid sequence FR2 (Kabat) of the variable domain of the light chain of antibodies 07-015, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 48]]> Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile His 1 5 10 15 <![CDATA[ <210> 49]]> <![CDATA[ <211> 32]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequences of the variable domain of the light chain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009]]>FR3 (Kabat) <![CDATA[ <400> 49]]> Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys 20 25 30 <![CDATA[ <210> 50]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence FR4 (Kabat) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 50]]> Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys 1 5 10 <![CDATA[ <210> 51]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223>The amino acid sequence CDR1 (Chothia) of the heavy chain variable domain of antibodies 07-006, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 51]]> Gly Ser Ser Phe Thr Gly Lys 1 5 <![CDATA[ <210> 52]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR1 (Chothia) of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028. <![CDATA[ <400> 52]]> Gly Ser Ser Phe Thr Gly His 1 5 <![CDATA[ <210> 53]]> <![CDATA[ <211> 6]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (Chothia) of the heavy chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 53]]> Asp Pro Phe Tyr Gly Gly 1 5 <![CDATA[ <210> 54]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Chothi]]>a) of the heavy chain variable domain of antibodies 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 54]]> Gly Met Ile Tyr 1 <![CDATA[ <210> 55]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]><![CDATA[ <223> The amino acid sequence CDR3 (Chothia) of the heavy chain variable domain of antibodies 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 55]]> Gly Met Phe Tyr 1 <![CDATA[ <210> 56]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Chothia) of the heavy chain variable domain of antibody 07-006 <![CDATA[ <400> 56]]> Gly Met Tyr Tyr 1 <![CDATA[ <210> 57]]> <![CDATA[ <211> 4]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Chothia) of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028 <![CDATA[ <400> 57]]> Gly Met Leu Tyr 1 <![CDATA[ <210> 58]]> <![CDATA[ <211> 13]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 10-001, 10-002, and 10-003 is C]]>DR1 (Chothia). <![CDATA[ <400> 58]]> Arg Ser Leu Val His Arg Asn Gly Asn Thr Tyr Leu His 1 5 10 <![CDATA[ <210> 59]]> <![CDATA[ <211> 13]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR1 (Chothia) of the light chain variable domain of antibodies 07-041, 10-007, 10-008, and 10-009.<![CDATA[ <400> 59]]> Gln Asn Leu Val His Arg Asn Gly Asn Thr Tyr Leu His 1 5 10 <![CDATA[ <210> 60]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (Chothia) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 60]]> Lys Val Ser Asn Arg Phe Gly 1 5 <![CDATA[ <210> 61]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (Chothia) of the light chain variable domain of antibodies 07-028, 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 61]]> Lys Val Asn Asn Arg Phe Ser 1 5 <![CDATA[ <210> 62]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (Chothia) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 62]]> Gly Gln Ser Thr His Val Pro Pro Leu Thr 1 5 10 <![CDATA[ <210> 63]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[<223 >The amino acid sequence CDR3 (Chothia) of the light chain variable domain of antibody 07-028 <![CDATA[ <400> 63]]> Ser Gln Ser Thr His Val Pro Pro Leu Ser 1 5 10 <![CDATA[ <210> 64]]> <![CDATA[<21]]> 1> 8]]>br / > <![CDATA[ <212> PRT]]>br / > <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]>br / > <![CDATA[ <223> The amino acid sequence CDR1 (IMGT) of the heavy chain variable domain of antibodies 07-006, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 64]]>br / > <![CDATA[Gly Ser Ser Phe Thr Gly Lys Asn 1 5 <![CDATA[ <210> 65]]> <![CDATA[ <211> 8]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR1 (IMGT) of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028 <![CDATA[ <400> 65]]> Gly Ser Ser Phe Thr Gly His Asn 1 5 <![CDATA[ <210> 66]]> <![CDATA[ <211> 8]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (IMGT) of the heavy chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 66]]> Ile Asp Pro Phe Tyr Gly Gly Thr 1 5 <![CDATA[ <210> 67]]> <![CDATA[ <211> 6]]> <![CDATA[ <212> PRT]]><![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Amino acid sequences of the heavy chain variable domain of antibodies 07-031, 10-001, 10-002, and 10-003: CDR3 (IMGT) <![CDATA[ <400> 67]]> Val Ser Gly Met Ile Tyr 1 5 <![CDATA[ <210> 68]]> <![CDATA[ <211> 6]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (IMGT) of the heavy chain variable domain of antibodies 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 68]]> Val Ser Gly Met Phe Tyr 1 5 <![CDATA[ <210> 69]]> <![CDATA[ <211> 6]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (IMGT) of the heavy chain variable domain of antibody 07-006 <![CDATA[ <400> 69]]> Val Ser Gly Met Tyr Tyr 1 5 <![CDATA[ <210> 70]]> <![CDATA[ <211> 6]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR3 (IMGT) of the heavy chain variable domain of antibodies 07-015, 07-016, and 07-028 <![CDATA[ <400> 70]]> Val Ser Gly Met Leu Tyr 1 5 <![CDATA[ <210> 71]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[<223 >The amino acid sequence CDR1 (IMGT) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-028, 07-031, 10-001, 10-002, and 10-003. <![CDATA[ <400> 71]]> Arg Ser Leu Val His Arg Asn Gly Asn Thr Tyr 1 5 10 <![CDATA[ <210> 72]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[<22]]> 3> The amino acid sequence CDR1 (IMGT) of the light chain variable domain of antibodies 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 72]]>br / > <![CDATA[Gln Asn Leu Val His Arg Asn Gly Asn Thr Tyr 1 5 10 <![CDATA[ <210> 73]]> <![CDATA[ <211> 3]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence of the variable domain of the light chain of antibodies 07-006, 07-015, 07-016, 07-031, 10-001, 10-002, and 10-003 is CDR2 (IMGT). <![CDATA[ <400> 73]]> Lys Val Ser 1 <![CDATA[ <210> 74]]> <![CDATA[ <211> 3]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (IMGT) of the variable domain of the light chain of antibodies 07-028, 07-041, 10-007, 10-008, and 10-009. <![CDATA[ <400> 74]]> Lys Val Asn 1 <![CDATA[ <210> 75]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]><![CDATA[ <223> The amino acid sequence CDR3 (IMGT) of the light chain variable domain of antibodies 07-006, 07-015, 07-016, 07-31, 07-041, 10-001, 10-002, 10-003, 10-007, 10-008, and 10-009. <![CDATA[ <400> 75]]> Gly Gln Ser Thr His Val Pro Pro Leu Thr 1 5 10 <![CDATA[ <210> 76]]> <![CDATA[ <211> 10]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> The amino acid sequence CDR2 (IMGT) of the light chain variable domain of antibody 07-028 <![CDATA[ <400> 76]]> Ser Gln Ser Thr His Val Pro Pro Leu Ser 1 5 10 <![CDATA[ <210> 77]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 07-006 <![CDATA[ <400> 77]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 tactactggg gtcagggcac tctggtgaca gtgtcgagt 339 <![CDATA[<210 >78]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the light chain variable domain of antibody 07-006 <![CDATA[ <400> 78]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaa 339 <![CDATA[ <210> 79]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 07-015 <![CDATA[ <400> 79]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggcacaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctctaccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtggggatg 300 ctgtactggg gtcagggcac tctggtgaca gtgtcgagt 339 <![CDATA[ <210> 80]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the light chain variable domain of antibody 07-015 <![CDATA[ <400> 80]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccacaa ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaa 339 <![CDATA[ <210> 81]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 07-016 <![CDATA[ <400> 81]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggcacaaca tgaattgggtccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtggggatg 300 ctgtactggg gtcagggcac tctggtgaca gtgtcgagt 339 <![CDATA[ <210> 82]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the light chain variable domain of antibody 07-016 <![CDATA[ <400> 82]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaa 339 <![CDATA[ <210> 83]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 07-028<![CDATA[<400> 83]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggcacaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 ctgtactggg gtcagggcac tctggtgaca gtgtcgagt 339 <![CDATA[<210> ]]>84 <![CDATA[<211> 339]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 07-028]]> <![CDATA[<400> 84]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtaaa caatagattc 180 tccggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgct ctcaaagtac acacgttcca 300 cccctatctt ttggacaagg gaccaagtta gaactgaaa 339<![CDATA[ <210> 85]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 07-031 <![CDATA[ <400> 85]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 atctactggg gtcagggcac tctggtgaca gtgtcgagt 339 <![CDATA[ <210> 86]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the light chain variable domain of antibody 07-031 <![CDATA[ <400> 86]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccacaa ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggtacagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaa 339 <![CDATA[ <210> 87]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 07-041 <![CDATA[ <400> 87]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 ttctactggg gtcagggcac tctggtgaca gtgtcgagt 339 <![CDATA[ <210> 88]]> <![CDATA[ <211> 339]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the light chain variable domain of antibody 07-041 <![CDATA[ <400> 88]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaca gaacctggtt caccggaatggcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtaaa caatagattc 180 tccggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaa 339 <![CDATA[<210> 89]]> <![CDATA[<211> 1329]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of antibody 10-001]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 atctactggg gtcagggcac tctggtgaca gtgtcgagtg ctagcaccaa gggcccatcg  360 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgtggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720 ccaaaaccca aggacaccct ctacatcacc cgggagcctg aggtcacatg cgtggtggtg 780 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 960 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggacgagc tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaaaagcctctccctgtcc 1320 ccgggtaaa 1329 <![CDATA[<210> 90]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 10-001]]> <![CDATA[<400> 90]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccacaa ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 <![CDATA[<210> 91]]><![CDATA[<211> 1329]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 10-002]]> <![CDATA[<400> 91]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 atctactggg gtcagggcac tctggtgaca gtgtcgagtg ctagcaccaa gggcccatcg 360 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720ccaaaaccca aggacaccct ctacatcacc cgggagcctg aggtcacatg cgtggtggtg 780 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg cgcggtctcc 960 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggacgagc tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaaaagcct ctccctgtcc 1320 ccgggtaaa 1329 <![CDATA[<210> 92]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 10-002]]> <![CDATA[<400> 92]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggttcaccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccacaa ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 <![CDATA[<210> 93]]> <![CDATA[<211> 1329]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 10-003]]> <![CDATA[<400> 93]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagggattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 atctactggg gtcagggcac tctggtgaca gtgtcgagtg ctagcaccaa gggcccatcg 360 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 780 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg cgcggtctcc 960 aacaaagccc tcccagcccccatcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggacgagc tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaaaagcct ctccctgtcc 1320 ccgggtaaa 1329 <![CDATA[<210> 94]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 10-003]]> <![CDATA[<400> 94]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaag gtccctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccacaa ctcctcatcc acaaagtatc caatagattc 180 ggcggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaac gtacggtggctgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 <![CDATA[ <210> 95]]> <![CDATA[ <211> 1329]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Nucleic acid sequence encoding the amino acid sequence of the heavy chain variable domain of antibody 10-007 <![CDATA[ <400> 95]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 ttctactggg gtcagggcac tctggtgaca gtgtcgagtg ctagcaccaa gggcccatcg 360 gtcttccccc tggcaccctc ctccaagagcacctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720 ccaaaaccca aggacaccct ctacatcacc cgggagcctg aggtcacatg cgtggtggtg 780 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 960 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggacgagc tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctata gcaagctcac cgtggacaag agcaggtggcagcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaaaagcct ctccctgtcc 1320 ccgggtaaa 1329 <![CDATA[<210> 96]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 10-007]]> <![CDATA[<400> 96]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaca gaacctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtaaa caatagattc 180 tccggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcacccatcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 <![CDATA[<210> 97]]> <![CDATA[<211> 1329]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 10-008]]> <![CDATA[<400> 97]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60 tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 ttctactggg gtcagggcac tctggtgaca gtgtcgagtg ctagcaccaa gggcccatcg 360 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaagt ggacaagaga gttgagccca aatcttgtga caaaactcac660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720 ccaaaaccca aggacaccct ctacatcacc cgggagcctg aggtcacatg cgtggtggtg 780 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg cgcggtctcc 960 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggacgagc tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaaaagcct ctccctgtcc 1320 ccgggtaaa 1329 <![CDATA[<210> 98]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 10-008]]> <![CDATA[<400> 98]]> gatatcgtga tgacacaaaccccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaca gaacctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtaaa caatagattc 180 tccggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcg gccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc y600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 <![CDATA[<210> 99]]> <![CDATA[<211> 1329]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 10-009]]> <![CDATA[<400> 99]]> caggtacaac tcgtacaatc tggggccgaa gtgaagaaac caggcgcttc cgttaaggtg 60tcctgcaaag ccagcgggag ctcgttcaca gggaagaaca tgaattgggt ccgacagaac 120 attggacagg gattagaatg gatgggcgct atagatccct tctatggagg cacatcctac 180 aaccagaaat tcaagggccg cgttaccctc acagtcgata agtctatctc taccgcatac 240 atggaactgt cccgcttacg gtcggatgat acagcagtgt actattgtgt tagtgggatg 300 ttctactggg gtcagggcac tctggtgaca gtgtcgagtg ctagcaccaa gggcccatcg 360 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 780 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900 gtcctcaccgtcctgcacca ggactggctg aatggcaagg agtacaagtg cgcggtctcc 960 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggacgagc tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaaaagcct ctccctgtcc 1320 ccgggtaaa 1329 <![CDATA[<210> 100]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 10-009]]> <![CDATA[<400> 100]]> gatatcgtga tgacacaaac cccattgagc ctgtccgtga cgccaggaga gcgcgctagt 60 ttaagttgtc ggagttcaca gaacctggtt caccggaatg gcaataccta cttgcactgg 120 tacttgcaga aacctgggca gtcgccaaag ctcctcatcc acaaagtaaa caatagattc 180 tccggcgtgc cagatagatt ctctggctct ggttctggta cagattttac tctgaagatt 240 tctcgggtgg aggccgagga cgtaggggtg tacttctgcggccaaagtac acacgttcca 300 cccctaacct ttggacaagg gaccaagtta gaactgaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660

Claims

1. An isolated monoclonal antibody or antigen-binding fragment thereof that specifically binds to GD2 (ganglioside GD2), comprising: (a) a heavy chain variable domain comprising: (i) a CDR1 having an amino acid sequence of SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence of SEQ ID NO: 3, and (iii) a CDR3 having an amino acid sequence of SEQ ID NO: 5; and (b) a light chain variable domain comprising: (i) a CDR1 having an amino acid sequence of SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence of SEQ ID NO: 11, and (iii) a CDR3 having an amino acid sequence of SEQ ID NO:

12.

2. The isolated monoclonal antibody or its antigen-binding fragment as claimed in claim 1, wherein: (a) The heavy chain variable domain contains the amino acid sequence of SEQ ID NO: 17; and (b) the light chain variable domain contains the amino acid sequence of SEQ ID NO:

21.

3. The isolated monoclonal antibody or its antigen-binding fragment as requested in claim 1, wherein the antibody that specifically binds to GD2 is a full-length IgG antibody.

4. The isolated monoclonal antibody or its antigen-binding fragment as claimed in claim 3, wherein the full-length IgG antibody belongs to the human IgG1, IgG2, IgG3 or IgG4 isotype.

5. The isolated monoclonal antibody or its antigen-binding fragment as claimed in claim 4, wherein the full-length IgG antibody belongs to the human IgG1 isotype.

6. The isolated monoclonal antibody or its antigen-binding fragment as claimed in claim 1, comprising: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 33, and (b) a light chain containing the amino acid sequence of SEQ ID NO:

41.

7. An isolated nucleic acid encoding an isolated monoclonal antibody or an antigen-binding fragment thereof as described in any one of claims 1-6.

8. The isolated nucleic acid as claimed in claim 7, wherein the nucleic acid is DNA.

9. An expression vector comprising isolated nucleic acid as claimed in any one of claims 7-8.

10. A method for obtaining host cells to obtain an isolated monoclonal antibody or an antigen-binding fragment thereof as claimed in any one of claims 1-6, comprising cell transformation via an expression vector as claimed in claim 9.

11. A host cell for obtaining an isolated monoclonal antibody or an antigen-binding fragment thereof as claimed in any one of claims 1-6, comprising an isolated nucleic acid as claimed in any one of claims 7-8.

12. A method for obtaining an isolated monoclonal antibody or an antigen-binding fragment thereof as claimed in any one of claims 1-6, comprising culturing host cells as claimed in claim 11 in a growth medium under conditions sufficient to produce said monoclonal antibody, and, if necessary, subsequently isolating and purifying the obtained monoclonal antibody.

13. A pharmaceutical composition for treating a disease or condition mediated by GD2, comprising a therapeutically effective amount of an isolated monoclonal antibody or an antigen-binding fragment thereof, as claimed in any one of claims 1-6, in combination with one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition of claim 13, wherein the disease or condition mediated by GD2 is selected from brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma.

15. A pharmaceutical composition for treating a disease or condition mediated by GD2, comprising an isolated monoclonal antibody or an antigen-binding fragment thereof as claimed in any one of claims 1-6 and at least one other therapeutically active compound.

16. The pharmaceutical composition of claim 15, wherein the disease or condition mediated by GD2 is selected from brain tumors, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, astrocytoma, melanoma, B-cell lymphoma, small cell lung cancer, renal cell carcinoma, desmoplastic small round cell fibroma, osteosarcoma, Ewing's sarcoma, breast cancer, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, or soft tissue sarcoma.

17. A pharmaceutical composition of any one of claims 15-16, wherein the other therapeutically active compound is an antibody, a chemotherapeutic agent, or a hormonal agent.

18. A pharmaceutical composition of any one of claims 15-16, wherein the other therapeutically active compound is an immune checkpoint inhibitor.

19. The pharmaceutical composition of claim 18, wherein the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors.

20. The pharmaceutical composition of claim 19, wherein the PD-1 inhibitor is an antibody that specifically binds to PD-1.

21. The pharmaceutical composition of claim 20, wherein the antibody that specifically binds to PD-1 is selected from prolgolimab, pembrolizumab, or nivoluma.

22. The pharmaceutical composition of claim 19, wherein the CTLA-4 inhibitor is an antibody that specifically binds to CTLA-4.

23. The pharmaceutical composition of claim 22, wherein the antibody that specifically binds to CTLA-4 is ipilimumab or nurulimab.

24. The pharmaceutical composition of claim 19, wherein the PD-L1 inhibitor is an antibody that specifically binds to PD-L1.

25. The pharmaceutical composition of claim 24, wherein the antibody that specifically binds to PD-L1 is selected from durvalumab, avelumab, atezolizumab, or manelimab.

26. A pharmaceutical composition of any one of claims 15-16, wherein the other therapeutically active compound is selected from IL-2, GM-CSF, isotretinoin, one or more other cytokines, or any combination of therapeutically active compounds from that group.

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