Anti-GAL3 antibodies and uses thereof

Abstract

Disclosed herein are antibodies that specifically bind to Gal3 and methods of using the same. In some embodiments, methods of inducing immune activation or promoting proliferation of T cells or natural killer cells using antibodies that specifically bind to Gal3 are also described herein. Also disclosed herein are methods and compositions for reducing fibrosis or its tendency in tissues using antibodies that specifically bind to Gal3. In some cases, anti-Gal3 antibodies also disrupt the interaction between Gal3 and TIM-3.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 798945, filed January 30, 2019, and U.S. Provisional Application Serial No. 62 / 798949, filed January 30, 2019, each of which is incorporated herein by reference in its entirety.

[0003] Reference to sequence list

[0004] This application is submitted together with the electronic sequence list. The sequence list is provided as a file entitled Seq List IMMUT003.TXT, which was created and last saved on January 29, 2020, and is 146,561 bytes in size. The information in the electronic format of the sequence list is incorporated herein by reference in its entirety. Technical Field

[0005] In some embodiments, this document discloses antibodies (or "anti-Gal3 antibodies") that specifically bind to Gal3 and disrupt the interaction between Gal3 and TIM-3, thereby promoting the proliferation of T cells or natural killer (NK) cells. This document also discloses methods and therapeutic approaches that utilize antibodies to elicit an immune response. This document further discloses methods for reducing fibrosis or its predisposition in tissues by contacting tissues with antibodies that specifically bind to Gal3. This document also describes methods for disrupting the Gal3-TIM-3 interaction using antibodies that specifically bind to Gal3, under conditions that reduce the expression of one or more fibrosis biomarkers in tissues. Background Technology

[0006] Galactolectin-3 (Gal3) is a lectin or carbohydrate-binding protein specific for β-galactosides. In human cells, Gal3 is expressed and can be found in the nucleus, cytoplasm, cell surface, and extracellular space. T-cell immunoglobulins and domain-containing mucin-3 (TIM-3) are proteins expressed on immune cells such as T cells, dendritic cells, NK cells, and monocytes. Summary of the Invention

[0007] In some embodiments, this document discloses antibodies (or "anti-Gal3 antibodies") that specifically bind to Gal3 and disrupt the interaction between Gal3 and TIM-3. In some embodiments, this document discloses antibodies that specifically bind to Gal3 and promote the proliferation of T cells or natural killer cells. In some embodiments, this document also discloses methods and treatments for inducing an immune response using antibodies.

[0008] The embodiments of the present invention provided herein are described by the following alternative numbering:

[0009] 1. A method for inducing immune activation, comprising:

[0010] Under conditions that disrupt the interaction between Gal3 and TIM-3, various cell types, including Gal3-expressing cells and TIM-3-expressing cells, are contacted with an antibody, wherein the antibody specifically binds to Gal3, wherein Gal3-expressing cells express cytokines that induce immune activation upon binding to the antibody, and wherein the antibody is not IMT001.

[0011] 2. The method according to alternative method 1, wherein the cytokine is interferon.

[0012] 3. The method according to alternative method 2, wherein the interferon is IFNγ.

[0013] 4. The method according to alternative method 3, wherein IFNγ is generated by 150%, 160%, 170%, 180%, 190%, 200% or more of IFNγ from the same type of antibody.

[0014] 5. The method according to alternative method 1, wherein the cytokine is an interleukin.

[0015] 6. The method according to alternative method 5, wherein the interleukin is IL-2.

[0016] 7. The method according to any one of alternative methods 1-6, wherein immune activation includes the proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, natural killer cells, or combinations thereof.

[0017] 8. The method according to any one of alternative methods 1-7, wherein immune activation includes an increase in multiple intracellular M1 macrophage populations.

[0018] 9. The method according to any one of alternative methods 1-8, wherein immune activation includes a reduction in multiple intracellular M2 macrophage populations.

[0019] 10. A method for promoting the proliferation of T cells or natural killer (NK) cells, comprising:

[0020] Under conditions that enable the proliferation of T cells and / or NK cells in a variety of cells, a variety of cells, including T cells, NK cells and Gal3-expressing cells, are contacted with an antibody, wherein the antibody specifically binds to Gal3, and wherein the antibody is not IMT001.

[0021] 11. The method according to alternative method 10, wherein the plurality of cells further includes TIM-3 expressing cells.

[0022] 12. The method according to alternative method 11, wherein the antibody further disrupts the interaction between Gal3 and TIM-3.

[0023] 13. A method for inducing immune activation, comprising:

[0024] Under conditions that disrupt the interaction between Gal3 and TIM-3, various cell types, including Gal3-expressing cells and TIM-3-expressing cells, were contacted with antibodies, wherein the antibodies specifically bound to Gal3, and wherein the Gal3-TIM-3 interaction was reduced to less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4%, or less than 1%.

[0025] 14. The method according to alternative method 13, wherein the interaction occurs at one or more residues of Gal3 selected from regions 145-168, 160-177 or 165-184, wherein the residue positions correspond to positions 145-168, 160-177 or 165-184 of SEQ ID NO:1.

[0026] 15. The method according to alternative method 13, wherein the interaction occurs at one or more residues of Gal3 selected from regions 149-156, 152-168, 163-169, 163-177 or 163-171, wherein the residue positions correspond to positions 149-156, 152-168, 163-169, 163-177 or 163-171 of SEQ ID NO:1.

[0027] 16. The method according to any one of alternative methods 13-15, wherein the interaction occurs at one or more residues of TIM-3 selected from regions 91-111 or 82-111, wherein the residue positions correspond to positions 91-111 or 82-111 of SEQ ID NO:2.

[0028] 17. The method according to any one of alternative methods 13-15, wherein the interaction occurs at one or more residues of TIM-3 selected from regions 91-111, 107-117, 96-102, 100-106 or 92-119, the residue positions herein corresponding to positions 91-111, 107-117, 96-102, 100-106 or 92-119 of SEQ ID NO:2.

[0029] 18. The method according to any one of alternatives 13-17, wherein TIM-3 is human TIM-3.

[0030] 19. The method according to any one of alternative methods 1-18, wherein the Gal3-expressing cells are tumor cells.

[0031] 20. The method according to any one of alternatives 1-19, wherein multiple cells are located within a tumor microenvironment (TME).

[0032] 21. The method according to any one of alternative methods 1-20, wherein the antibody induces a reduction in tumor cells within the TME.

[0033] 22. The method according to any one of alternative methods 1-21, wherein the plurality of cells further includes tumor-infiltrating lymphocytes (TILs).

[0034] 23. The method according to any one of alternative methods 1-22, wherein the plurality of cells further includes CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, or combinations thereof.

[0035] 24. The method according to any one of alternative methods 1, 10, 13 or 22, wherein contact further induces TIL proliferation.

[0036] 25. The method according to any one of alternative methods 1, 10, 13 or 23, wherein contact further induces the proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells or combinations thereof.

[0037] 26. The method according to any one of alternative methods 1, 10, 13 or 22-25, wherein the contact further includes an increase in M1 macrophage proliferation.

[0038] 27. The method according to any one of alternative methods 1, 10, 13 or 22-26, wherein the contact further includes a reduction of the M2 macrophage population within the TME.

[0039] 28. The method according to any one of alternative methods 1-27, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 1-20 of SEQ ID NO:1.

[0040] 29. The method according to any one of alternative methods 1-27, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 41-91 of SEQ ID NO:1.

[0041] 30. The method according to any one of alternative methods 1-27 or 29, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 41-71 of SEQ ID NO:1.

[0042] 31. The method according to any one of alternative methods 1-27 or 29, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 71-91 of SEQ ID NO:1.

[0043] 32. The method according to any one of alternative methods 1-31, wherein the antibody binds to at least one amino acid residue within peptide_1, peptide_4, peptide_5, peptide_6, peptide_7 or peptide_8.

[0044] 33. The method according to any one of alternative methods 1-32, wherein the antibody comprises less than 1 nM, 1.2 nM, 2 nM, 5 nM, 10 nM, 13.5 nM, 15 nM, 20 nM, 25 nM or 30 nM of K. D .

[0045] 34. The method according to any one of alternatives 1-33, wherein the antibody includes a humanized antibody.

[0046] 35. The method according to any one of alternative methods 1-34, wherein the antibody comprises a full-length antibody or a binding fragment thereof.

[0047] 36. The method according to any one of alternative methods 1-35, wherein the antibody comprises a bispecific antibody or a binding fragment thereof.

[0048] 37. The method according to any one of alternatives 1-36, wherein the antibody comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a biantibody, a microantibody, a nanobody, a single-domain antibody (sdAb), or a camelified antibody or a binding fragment thereof.

[0049] 38. The method according to any one of alternatives 1-37, wherein the antibody comprises an IgG framework.

[0050] 39. The method according to any one of alternatives 1-38, wherein the antibody comprises an IgG1, IgG2, or IgG4 framework.

[0051] 40. The method according to any one of alternative methods 1-39, wherein the antibody further comprises an Fc mutation.

[0052] 41. The method according to any one of alternative methods 1-33 or 35-40, wherein the antibody includes a chimeric antibody.

[0053] 42. The method according to any one of alternative methods 1, 10 or 13, further comprising administering the antibody to the subject prior to the contact step.

[0054] 43. The method according to alternative method 42, wherein the subject is diagnosed with cancer.

[0055] 44. The method according to alternative method 43, wherein the cancer is a solid tumor.

[0056] 45. The method according to alternative method 44, wherein the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, or lung cancer.

[0057] 46. ​​The method according to alternative method 43, wherein the cancer is a hematologic malignancy.

[0058] 47. The method according to any one of alternatives 43-46, wherein the cancer is a metastatic cancer.

[0059] 48. The method according to any one of alternatives 43-46, wherein the cancer is a recurrent or refractory cancer.

[0060] 49. The method according to any one of alternatives 42-48, wherein the antibody is formulated for systemic administration.

[0061] 50. The method according to any one of alternatives 42-49, wherein the antibody is formulated for parenteral administration.

[0062] 51. The method according to any one of alternative methods 42-50, wherein the antibody is administered in combination with another therapeutic agent.

[0063] 52. The method according to alternative method 51, wherein the antibody and another therapeutic agent are administered simultaneously.

[0064] 53. The method according to alternative method 51, wherein the antibody and the additional therapeutic agent are administered sequentially.

[0065] 54. The method according to alternative method 53, wherein the antibody is administered prior to the administration of another therapeutic agent.

[0066] 55. The method according to alternative method 53, wherein the antibody is administered after the administration of another therapeutic agent.

[0067] 56. The method according to any one of alternative methods 51-55, wherein the additional therapeutic agent includes an immune checkpoint modulator.

[0068] 57. The method according to any one of alternatives 51-55, wherein the additional therapeutic agent includes a chemotherapeutic agent, a targeted therapeutic agent, a hormone therapeutic agent, or a stem cell-based therapeutic agent.

[0069] 58. The method according to any of the preceding alternatives, wherein the subject is a human being.

[0070] 59. The method according to alternative method 58, wherein the antibody is administered before or after surgery.

[0071] 60. The method according to alternative method 58, wherein the antibody is applied in combination with radiation therapy, before radiation therapy, or after radiation therapy.

[0072] 61. The method according to any of the preceding alternatives, wherein the antibody has K D K higher than antibody IMT001 D .

[0073] 62. A method for reducing fibrosis or its tendency in tissues, comprising:

[0074] The tissue was exposed to an antibody that specifically binds to Gal3, under conditions that reduced the expression levels of fibrosis biomarkers in the tissue.

[0075] 63. The method according to alternative method 62, wherein the tissue further comprises TIM-3 expressing cells.

[0076] 64. The method according to alternative method 63, wherein the antibody further disrupts the interaction between Gal3 and TIM-3.

[0077] 65. The method according to alternative method 63, wherein the antibody does not disrupt the interaction between Gal3 and TIM-3.

[0078] 66. The method according to any one of alternative methods 62-65, wherein at least one fibrosis biomarker comprises α-smooth muscle actin (α-SMA).

[0079] 67. The method according to any one of alternative methods 62-65, wherein at least one fibrosis biomarker comprises fibronectin.

[0080] 68. The method according to any one of alternative methods 62-65, wherein at least one fibrosis biomarker comprises α-smooth muscle actin (α-SMA) and fibronectin.

[0081] 69. The method according to any one of alternatives 62-68, wherein the tissue is kidney tissue or liver tissue.

[0082] 70. The method according to any one of alternative methods 62-68, wherein the tissue is selected from the group consisting of: liver tissue, kidney tissue, skin tissue, lung tissue, heart tissue, brain tissue, intestinal tissue, bone marrow tissue, and soft tissue.

[0083] 71. The method according to any one of alternative methods 62-70, wherein the expression of at least one fibrosis biomarker in the antibody-treated tissue is less than the expression of at least one fibrosis biomarker in the control tissue treated with mIgG2b antibody.

[0084] 72. The method according to any one of alternative methods 62-71, wherein the antibody leads to a reduction in the accumulation of extracellular matrix proteins in the tissue.

[0085] 73. The method according to alternative method 72, wherein extracellular matrix proteins include collagen.

[0086] 74. The method according to alternative method 73, wherein the tissue comprises collagen-producing cells.

[0087] 75. The method according to alternative method 74, wherein the collagen-producing cells are fibroblasts.

[0088] 76. The method according to alternative method 75, wherein fibroblasts are activated by fibrogenic cytokines.

[0089] 77. The method according to alternative method 76, wherein the fibrogenic cytokine is TGF-β1.

[0090] 78. The method according to any one of alternative methods 62-77, wherein the tissue has elevated TGF-β1 expression.

[0091] 79. The method according to any one of alternatives 62-78, wherein the antibody includes a humanized antibody.

[0092] 80. The method according to any one of alternative methods 62-79, wherein the antibody comprises a full-length antibody or a binding fragment thereof.

[0093] 81. The method according to any one of alternative methods 62-79, wherein the antibody comprises a bispecific antibody or a binding fragment thereof.

[0094] 82. The method according to any one of alternative methods 62-79, wherein the antibody includes a chimeric antibody.

[0095] 83. The method according to any one of alternative methods 62-82, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 1-20 of SEQ ID NO:1.

[0096] 84. The method according to any one of alternative methods 62-82, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 41-91 of SEQ ID NO:1.

[0097] 85. The method according to any one of alternative methods 62-82 or 84, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 41-71 of SEQ ID NO:1.

[0098] 86. The method according to any one of alternative methods 62-82 or 84, wherein the antibody binds to at least one amino acid residue in the Gal3 region corresponding to residues 71-91 of SEQ ID NO:1.

[0099] 87. The method according to any one of alternative methods 62-86, wherein the antibody binds to at least one amino acid residue within peptide_1, peptide_4, peptide_5, peptide_6, peptide_7 or peptide_8.

[0100] 88. The method according to any one of alternative methods 62-87, wherein the antibody comprises a KD of less than 1 nM, 1.2 nM, 2 nM, 5 nM, 10 nM, 13.5 nM, 15 nM, 20 nM, 25 nM or 30 nM.

[0101] 89. The method according to any one of alternative methods 62-88, wherein the antibody comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a biantibody, a microantibody, a nanobody, a single-domain antibody (sdAb), or a camelified antibody or a binding fragment thereof.

[0102] 90. The method according to any one of alternatives 62-89, wherein the antibody comprises an IgG framework.

[0103] 91. The method according to any one of alternatives 62-90, wherein the antibody comprises an IgG1, IgG2, or IgG4 framework.

[0104] 92. The method according to any one of alternative methods 62-91, wherein the antibody further comprises an Fc mutation.

[0105] 93. The method according to any one of alternative methods 62-92, further comprising administering the antibody to the subject prior to the contact step.

[0106] 94. The method according to alternative method 93, wherein the subject is diagnosed with fibrotic disease.

[0107] 95. The method according to alternative 94, wherein the fibrotic disease is renal fibrosis.

[0108] 96. The method according to alternative method 94, wherein the fibrotic disease is liver fibrosis.

[0109] 97. The method according to any one of alternatives 93-96, wherein the antibody is formulated for systemic administration.

[0110] 98. The method according to any one of alternatives 93-96, wherein the antibody is formulated for parenteral administration.

[0111] 99. The method according to any one of alternative methods 93-98, wherein the subject is a mammal.

[0112] 100. The method according to any one of alternatives 64 and 66-99, wherein the Gal3-TIM-3 interaction is reduced to less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4%, or less than 1%.

[0113] 101. The method according to alternative method 100, wherein the interaction occurs at one or more residues of Gal3 selected from regions 145-168, 160-177 or 165-184, wherein the residue positions correspond to positions 145-168, 160-177 or 165-184 of SEQ ID NO:1.

[0114] 102. The method according to alternative method 100, wherein the interaction occurs at one or more residues of Gal3 selected from regions 149-156, 152-168, 163-169 or 163-171, wherein the residue positions correspond to positions 149-156, 152-168, 163-169 or 163-171 of SEQ ID NO:1.

[0115] 103. The method according to any one of alternative methods 100-102, wherein the interaction occurs at one or more residues of TIM-3 selected from regions 90-122 or 82-111, wherein the residue positions correspond to positions 90-122 or 82-111 of SEQ ID NO:2.

[0116] 104. The method according to any one of alternatives 100-102, wherein the interaction occurs at one or more residues of TIM-3 selected from regions 91-111, 107-117, 96-102, 100-106 or 92-119, the residue positions herein corresponding to positions 91-111, 107-117, 96-102, 100-106 or 92-119 of SEQ ID NO:2.

[0117] 105. Anti-Gal3 antibodies for the treatment of immune-related diseases in subjects, wherein the anti-Gal3 antibodies induce activation of the immune system.

[0118] 106. The anti-Gal3 antibody for treating immune-related diseases according to alternative method 105, wherein the anti-Gal3 antibody inhibits the interaction between Gal3 and TIM-3.

[0119] 107. An anti-Gal3 antibody for treating immune-related diseases according to alternative methods 105 or 106, wherein activation of the immune system includes the proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, NK cells, M1 macrophages, or combinations thereof.

[0120] 108. An anti-Gal3 antibody for treating immune-related diseases according to any one of alternative methods 105-107, wherein activation of the immune system includes a reduction of M2 macrophages.

[0121] 109. An anti-Gal3 antibody for treating an immune-related disease according to any one of alternative methods 105-108, wherein the immune-related disease is cancer.

[0122] 110. The anti-Gal3 antibody for treating immune-related diseases according to alternative method 109, wherein the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, or hematologic malignancy.

[0123] 111. The anti-Gal3 antibody for treating immune-related diseases as described in alternative methods 109 or 110, wherein the cancer is metastatic, recurrent, or refractory cancer.

[0124] 112. An anti-Gal3 antibody for treating immune-related diseases according to any of alternative methods 109-111, wherein the anti-Gal3 antibody is administered in combination with other therapeutic agents, such as immune checkpoint modulators, chemotherapeutic agents, targeted therapies, hormone therapies, stem cell-based therapies, surgical procedures, or radiation therapy.

[0125] 113. An anti-Gal3 antibody for treating an immune-related disease according to any one of alternative methods 105-108, wherein the immune-related disease is fibrosis and the anti-Gal3 antibody causes a decrease in the accumulation of extracellular matrix proteins in the tissue.

[0126] 114. The anti-Gal3 antibody for treating immune-related diseases according to alternative method 113, wherein the extracellular matrix protein includes collagen.

[0127] 115. The anti-Gal3 antibody for treating immune-related diseases according to alternative methods 113 or 114, wherein the expression level of at least one fibrosis biomarker is reduced in the subject, and wherein the at least one fibrosis biomarker includes α-SMA, fibronectin, or both.

[0128] 116. An anti-Gal3 antibody for treating immune-related diseases according to any one of alternative methods 113-115, wherein the tissue is selected from the group consisting of: liver tissue, kidney tissue, skin tissue, lung tissue, heart tissue, brain tissue, intestinal tissue, bone marrow tissue, and soft tissue.

[0129] 117. An anti-Gal3 antibody for treating immune-related diseases according to any one of alternative methods 113-116, wherein the fibrosis is renal fibrosis, hepatic fibrosis, pulmonary fibrosis, cardiac fibrosis, or vascular fibrosis. In some embodiments, this can be administered intravenously or subcutaneously.

[0130] 118. An anti-Gal3 antibody for treating immune-related diseases according to any one of alternative methods 105-117, wherein the anti-Gal3 antibody is formulated for systemic, parenteral, intravenous or subcutaneous administration.

[0131] 119. An anti-Gal3 antibody for treating immune-related diseases according to any one of alternative methods 105-118, wherein the subject is a human.

[0132] 120. The method according to any one of alternative methods 1-104, wherein the anti-Gal3 antibody is selected from one or more of the group consisting of: 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15 F10.2D6, 15G7.2A7, 19B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8 and mIMT001.

[0133] 121. The method according to any one of alternative methods 1-104, wherein the anti-Gal3 antibody is derived from 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, 15G7.2A7, 19B Antibodies against one, two, three, four, five, or six CDRs of one or more of the following: 5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8, and mIMT001.

[0134] 121. The method according to any one of alternative methods 1-104, wherein the anti-Gal3 antibody is IMT001-4, IMT006-1, IMT006-5 or IMT006-8.

[0135] 122. An anti-Gal3 antibody for treating immune-related diseases according to any one of alternative methods 105-119, wherein the anti-Gal3 antibody is selected from the group consisting of: 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10. 2C9, 15F10.2D6, 15G7.2A7, 19B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8 and mIMT001.

[0136] 123. An anti-Gal3 antibody for treating immune-related diseases according to any of alternative methods 105-119, wherein the anti-Gal3 antibody is IMT001-4, IMT006-1, IMT006-5 or IMT006-8.

[0137] 124. At least include Figures 35A-36B The antibody is an anti-GAL3 antibody against HCDR3 within any of the antibodies.

[0138] 125. The anti-GAL3 antibody according to alternative method 124, further comprising: Figures 35A-36B All three HCDRs within any one of the antibodies.

[0139] 126. The anti-GAL3 antibody according to alternative method 125, further comprising: Figures 35A-36B All three types of LCDR antibodies within any one of them.

[0140] 127. An anti-GAL3 antibody, comprising: Figure 36A Any of the inner heavy chain sequences, or sequences that are at least 80% identical to them.

[0141] 128. An anti-GAL3 antibody, comprising: Figure 36B Any of the inner light chain sequences, or sequences that are at least 80% identical to them.

[0142] 129. The anti-GAL3 antibody according to alternative method 128, further comprising: Figure 36A Any of the inner heavy chain sequences, or sequences that are at least 80% identical to them.

[0143] 130. An anti-GAL3 antibody comprising 6 CDRs, wherein the 6 CDRs, in their combined sequence, are similar to... Figure 35A and 35B The six CDRs in any group are at least 80% identical.

[0144] 131. An anti-GAL3 antibody comprising components derived from... Figure 38 At least one CDR.

[0145] 132. An anti-GAL3 antibody comprising components derived from... Figure 38 At least two CDRs.

[0146] 133. An anti-GAL3 antibody comprising components derived from... Figure 38 At least three CDRs

[0147] 134. An anti-GAL3 antibody comprising components derived from... Figure 38 At least four CDRs.

[0148] 135. An anti-GAL3 antibody comprising components derived from... Figure 38 At least five CDRs.

[0149] 136. An anti-GAL3 antibody comprising components derived from... Figure 38 At least five CDRs.

[0150] 137. An anti-GAL3 antibody comprising components derived from... Figure 38 There are six CDRs, and all six of them come from a single bin.

[0151] 138. An anti-GAL3 antibody comprising components derived from... Figure 38 The six CDRs, or a set of six CDRs that are at least 80% identical to each other in their entire sequence. sequence list <110> Jinwa Pharmaceutical Co., Ltd. <120> Anti-GAL3 antibodies and their uses <130> IMMUT.003WO <150> 62 / 798945 <151> 2019-01-30 <150> 62 / 798949 <151> 2019-01-30 <160> 304 <170> PatentIn version 3.5 <210> 1 <211> 250 <212> PRT <213> Homo sapiens <400> 1 Met Ala Asp Asn Phe Ser Leu His Asp Ala Leu Ser Gly Ser Gly Asn 1 5 10 15 Pro Asn Pro Gln Gly Trp Pro Gly Ala Trp Gly Asn Gln Pro Ala Gly 20 25 30 Ala Gly Gly Tyr Pro Gly Ala Ser Tyr Pro Gly Ala Tyr Pro Gly Gln 35 40 45 Ala Pro Pro Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala Tyr Pro 50 55 60 Gly Ala Pro Gly Ala Tyr Pro Gly Ala Pro Ala Pro Gly Val Tyr Pro 65 70 75 80 Gly Pro Pro Ser Gly Pro Gly Ala Tyr Pro Ser Ser Gly Gln Pro Ser 85 90 95 Ala Thr Gly Ala Tyr Pro Ala Thr Gly Pro Tyr Gly Ala Pro Ala Gly 100 105 110 Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro Gly Gly Val Val Pro 115 120 125 Arg Met Leu Ile Thr Ile Leu Gly Thr Val Lys Pro Asn Ala Asn Arg 130 135 140 Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val Ala Phe His Phe Asn 145 150 155 160 Pro Arg Phe Asn Glu Asn Asn Arg Arg Val Ile Val Cys Asn Thr Lys 165 170 175 Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln Ser Val Phe Pro Phe 180 185 190 Glu Ser Gly Lys Pro Phe Lys Ile Gln Val Leu Val Glu Pro Asp His 195 200 205 Phe Lys Val Ala Val Asn Asp Ala His Leu Leu Gln Tyr Asn His Arg 210 215 220 Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly Ile Ser Gly Asp Ile 225 230 235 240 Asp Leu Thr Ser Ala Ser Tyr Thr Met Ile 245 250 <210> 2 <211> 301 <212> PRT <213> Homo sapiens <400> 2 Met Phe Ser His Leu Pro Phe Asp Cys Val Leu Leu Leu Leu Leu Leu 1 5 10 15 Leu Leu Thr Arg Ser Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln 20 25 30 Asn Ala Tyr Leu Pro Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu 35 40 45 Val Pro Val Cys Trp Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly 50 55 60 Asn Val Val Leu Arg Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser 65 70 75 80 Arg Tyr Trp Leu Asn Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr 85 90 95 Ile Glu Asn Val Thr Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile 100 105 110 Gln Ile Pro Gly Ile Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val 115 120 125 Ile Lys Pro Ala Lys Val Thr Pro Ala Pro Thr Arg Gln Arg Asp Phe 130 135 140 Thr Ala Ala Phe Pro Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala 145 150 155 160 Glu Thr Gln Thr Leu Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile 165 170 175 Ser Thr Leu Ala Asn Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu 180 185 190 Arg Asp Ser Gly Ala Thr Ile Arg Ile Gly Ile Tyr Ile Gly Ala Gly 195 200 205 Ile Cys Ala Gly Leu Ala Leu Ala Leu Ile Phe Gly Ala Leu Ile Phe 210 215 220 Lys Trp Tyr Ser His Ser Lys Glu Lys Ile Gln Asn Leu Ser Leu Ile 225 230 235 240 Ser Leu Ala Asn Leu Pro Pro Ser Gly Leu Ala Asn Ala Val Ala Glu 245 250 255 Gly Ile Arg Ser Glu Glu Asn Ile Tyr Thr Ile Glu Glu Asn Val Tyr 260 265 270 Glu Val Glu Glu Pro Asn Glu Tyr Tyr Cys Tyr Val Ser Ser Arg Gln 275 280 285 Gln Pro Ser Gln Pro Leu Gly Cys Arg Phe Ala Met Pro 290 295 300 <210> 3 <211> 20 <212> PRT <213> Homo sapiens [[ID=?]]<400> 3 Ala Asp Asn Phe Ser Leu His Asp Ala Leu Ser Gly Ser Gly Asn Pro 1 5 10 15 Asn Pro Gln Gly 20 <210> 4 <211> 20 <212> PRT <213> Homo sapiens <400> 4 Ser Gly Ser Gly Asn Pro Asn Pro Gln Gly Trp Pro Gly Ala Trp Gly 1 5 10 15 Asn Gln Pro Ala 20 <210> 5 <211> 20 <212> PRT <213> Homo sapiens <400> 5 Trp Pro Gly Ala Trp Gly Asn Gln Pro Ala Gly Ala Gly Gly Tyr Pro 1 5 10 15 Gly Ala Ser Tyr 20 <210> 6 <211> 20 <212> PRT <213> Homo sapiens <400> 6 Gly Ala Gly Gly Tyr Pro Gly Ala Ser Tyr Pro Gly Ala Tyr Pro Gly It should be noted that in the provided text, there is an unclear "?". I have translated it as "?", but it might need to be corrected according to the actual situation. 1 5 10 15 Gln Ala Pro Pro 20 <210> 7 <211> 20 <212> PRT <213> Homo sapiens <400> 7 Pro Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala Tyr Pro Gly Gln 1 5 10 15 Ala Pro Pro Gly 20 <210> 8 <211> 20 <212> PRT <213> Homo sapiens <400> 8 Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala Tyr Pro Gly Ala Pro 1 5 10 15 Gly Ala Tyr Pro 20 <210> 9 <211> 20 <212> PRT <213> Homo sapiens <400> 9 Ala Tyr Pro Gly Ala Pro Gly Ala Tyr Pro Gly Ala Pro Ala Pro Gly 1 5 10 15 Val Tyr Pro Gly 20 <210> 10 <211> 20 <212> PRT <213> Homo sapiens <400> 10 Gly Ala Pro Ala Pro Gly Val Tyr Pro Gly Pro Pro Ser Gly Pro Gly 1 5 10 15 Ala Tyr Pro Ser 20 <210> 11 <211> 20 <212> PRT <213> Homo sapiens <400> 11 Pro Pro Ser Gly Pro Gly Ala Tyr Pro Ser Ser Gly Gln Pro Ser Ala 1 5 10 15 Thr Gly Ala Tyr 20 <210> 12 <211> 20 <212> PRT <213> Homo sapiens <400> 12 Ser Gly Gln Pro Ser Ala Thr Gly Ala Tyr Pro Ala Thr Gly Pro Tyr 1 5 10 15 Gly Ala Pro Ala 20 <210> 13 <211> 20 <212> PRT <213> Homo sapiens <400> 13 Pro Ala Thr Gly Pro Tyr Gly Ala Pro Ala Gly Pro Leu Ile Val Pro 1 5 10 15 Tyr Asn Leu Pro 20 <210> 14 <211> 20 <212> PRT <213> Homo sapiens <400> 14 Gly Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro Gly Gly Val Val 1 5 10 15 Pro Arg Met Leu 20 <210> 15 <211> 20 <212> PRT <213> Homo sapiens <400> 15 Leu Pro Gly Gly Val Val Pro Arg Met Leu Ile Thr Ile Leu Gly Thr 1 5 10 15 Val Lys Pro Asn 20 <210> 16 <211> 20 <212> PRT <213> Homo sapiens <400> 16 Ile Thr Ile Leu Gly Thr Val Lys Pro Asn Ala Asn Arg Ile Ala Leu 1 5 10 15 Asp Phe Gln Arg 20 <210> 17 <211> 20 <212> PRT <213> Homo sapiens <400> 17 Ala Asn Arg Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val Ala Phe 1 5 10 15 His Phe Asn Pro 20 <210> 18 <211> 20 <212> PRT <213> Homo sapiens <400> 18 Gly Asn Asp Val Ala Phe His Phe Asn Pro Arg Phe Asn Glu Asn Asn 1 5 10 15 Arg Arg Val Ile 20 <210> 19 <211> 20 <212> PRT <213> Homo sapiens <400> 19 Arg Phe Asn Glu Asn Asn Arg Arg Val Ile Val Cys Asn Thr Lys Leu 1 5 10 15 Asp Asn Asn Trp 20 <210> 20 <211> 20 <212> PRT <213> Homo sapiens <400> 20 Val Cys Asn Thr Lys Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln 1 5 10 15 Ser Val Phe Pro 20 <210> 21 <211> 20 <212> PRT <213> Homo sapiens <400> 21 Gly Arg Glu Glu Arg Gln Ser Val Phe Pro Phe Glu Ser Gly Lys Pro 1 5 10 15 Phe Lys Ile Gln 20 <210> 22 <211> 20 <212> PRT <213> Homo sapiens <400> 22 Phe Glu Ser Gly Lys Pro Phe Lys Ile Gln Val Leu Val Glu Pro Asp 1 ,5, 10, 15 His Phe Lys Val 20 <210> 23 <211> 20 <212> PRT <213> Homo sapiens <400> 23 Val Leu Val Glu Pro Asp His Phe Lys Val Ala Val Asn Asp Ala His 1 5 10 15 Leu Leu Gln Tyr 20 <210> 24 <211> 20 <212> PRT <213> Homo sapiens <400> 24 Ala Val Asn Asp Ala His Leu Leu Gln Tyr Asn His Arg Val Lys Lys 1 5 10 15 Leu Asn Glu Ile 20 <210> 25 <211> 20 <212> PRT <213> Homo sapiens <400> 25 Asn His Arg Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly Ile Ser 1 5 10 15 Gly Asp Ile Asp 20 <210> 26 <211> 19 <212> PRT <213> Homo sapiens <400> 26 Ser Lys Leu Gly Ile Ser Gly Asp Ile Asp Leu Thr Ser Ala Ser Tyr 1 5 10 15 Thr Met Ile <210> 27 <211> 10 <212> PRT <213> Homo sapiens <400> 27 Pro Gly Ala Tyr Pro Gly Gln Ala Pro Pro 1 5 10 <210> 28 <211> 10 <212> PRT <213> Homo sapiens <400> 28 Gly Gln Ala Pro Pro Gly Ala Tyr Pro Gly 1 5 10 <210> 29 <211> 11 <212> PRT <213> Homo sapiens <400> 29 Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala 1 5 10 <210> 30 <211> 10 <212> PRT <213> Homo sapiens <400> 30 Ala Pro Pro Gly Ala Tyr Pro Gly Ala Pro 1 5 10 <210> 31 <211> 9 <212> PRT <213> Homo sapiens <400> 31 Tyr Pro Gly Ala Pro Gly Ala Tyr Pro 1 5 <210> 32 <211> 6 <212> PRT <213> Homo sapiens <400> 32 Ala Pro Pro Gly Ala Tyr 1 5 <210> 33 <211> 6 <212> PRT <213> Homo sapiens <400> 33 Gly Ala Tyr Pro Gly Gln 1 5 <210> 34 <211> 6 <212> PRT <213> Homo sapiens <400> 34 Pro Gly Gln Ala Pro Pro 1 5 <210> 35 <211> 958 <212> DNA <213> Homo sapiens <400> 35 gcccgcagca cctcctcgcc agcagccgtc cggagccagc caacgagcgg aaaatggcag 60 acaatttttc gctccatgat gcgttatctg ggtctggaaa cccaaaccct caaggatggc 120 ctggcgcatg ggggaaccag cctgctgggg cagggggcta cccaggggct tcctatcctg 180 gggcctaccc cgggcaggca cccccagggg cttatcctgg acaggcacct ccaggcgcct 240 accctggagc acctggagct tatcccggag cacctgcacc tggagtctac ccagggccac 300 ccagcggccc tggggcctac ccatcttctg gacagccaag tgccaccgga gcctaccctg 360 ccactggccc ctatggcgcc cctgctgggc cactgattgt gccttataac ctgcctttgc 420 ctgggggagt ggtgcctcgc atgctgataa caattctggg cacggtgaag cccaatgcaa 480 acagaattgc tttagatttc caaagaggga atgatgttgc cttccacttt aacccacgct 540 tcaatgagaa caacaggaga gtcattgttt gcaatacaaa gctggataat aactggggaa 600 gggaagaaag acagtcggtt ttcccatttg aaagtgggaa accattcaaa atacaagtac 660 tggttgaacc tgaccacttc aaggttgcag tgaatgatgc tcacttgttg cagtacaatc 720 atcgggttaa aaaactcaat gaaatcagca aactgggaat ttctggtgac atagacctca 780 ccagtgcttc atataccatg atataatctg aaaggggcag attaaaaaaa aaaaaagaat 840 ctaaacctta catgtgtaaa ggtttcatgt tcactgtgag tgaaaatttt tacattcatc 900 aatatccctc ttgtaagtca tctacttaat aaatattaca gtgaattacc tgtctcaa 958 <210> 36 <211> 2237 <212> DNA <213> Homo sapiens <400> 36 atttggagag ttaaaactgt gcctaacaga ggtgtcctct gacttttctt ctgcaagctc 60 catgttttca catcttccct ttgactgtgt cctgctgctg ctgctgctac tacttacaag gtcctcagaa gtggaataca gagcggaggt cggtcagaat gcctatctgc cctgcttcta caccccagcc gccccaggga acctcgtgcc cgtctgctgg ggcaaaggag cctgtcctgt 240 gtttgaatgt ggcaacgtgg tgctcaggac tgatgaaagg gatgtgaatt attggacatc cagatactgg ctaaatgggg atttccgcaa aggagatgtg tccctgacca tagagatgt gactctagca gacagtggga tctactgctg ccggatccaa atcccaggca taatgaatga tgaaaaattt aacctgaagt tggtcatcaa accagccaag gtcacccctg caccgactcg gcagagagac ttcactgcag cctttccag gatgcttacc accaggggac atggcccagc 540 agagacacag acactgggga gcctccctga fathers acacaatat ccacattggc 660. caatgagtta cgggactcta gattggccaa tgacttacgg gactctggag caaccatcag aataggcatc tacatcggag cagggatctg tgctgggctg gctctggctc ttatcttcgg 720 cgctttaatt ttcaaatggt attctcatag caaagagaag attachment tagcctcat ctctttggcc aacctccctc cctcaggatt ggcaaatgca gtagcagagg gaattcgctc 840 agaagaaaac atctatacca ttgaagagaa cgtatatgaa gtggaggagc ccaatgagta 900 ttattgctat gtcagcagca ggcagcaacc ctcacaacct ttgggttgtc gctttgcaat 960 gccatagatc caaccacctt atttttgagc ttggtgtttt gtctttttca gaaactatga 1020 gctgtgtcac ctgactggtt ttggaggttc tgtccactgc tatggagcag agttttccca 1080 ttttcagaag ataatgactc acatgggaat tgaactggga cctgcactga acttaaacag 1140 gcatgtcatt gcctctgtat ttaagccaac agagttaccc aacccagaga ctgttaatca 1200 tggatgttag agctcaaacg ggcttttata tacactagga attcttgacg tggggtctct 1260 ggagctccag gaaattcggg cacatcatat gtccatgaaa cttcagataa actagggaaa 1320 actgggtgct gaggtgaaag cataactttt ttggcacaga aagtctaaag gggccactga 1380 ttttcaaaga gatctgtgat ccctttttgt tttttgtttt tgagatggag tcttgctctg 1440 ttgcccaggc tggagtgcaa tggcacaatc tcggctcact gcaagctccg cctcctgggt 1500 tcaagcgatt ctcctgcctc agcctcctga gtggctggga ttacaggcat gcaccaccat 1560 gcccagctaa tttgttgtat ttttagtaga gacagggttt caccatgttg gccagtgtgg 1620 tctcaaactc ctgacctcat gatttgcctg cctcggcctc ccaaagcact gggattacag 1680 gcgtgagcca ccacatccag ccagtgatcc ttaaaagatt aagagatgac tggaccaggt 1740 ctaccttgat cttgaagatt cccttggaat gttgagattt aggcttattt gagcactgcc 1800 tgcccaactg tcagtgccag tgcatagccc ttcttttgtc tcccttatga agactgccct 1860 gcagggctga gatgtggcag gagctcccag ggaaaaacga agtgcatttg attggtgtgt 1920 attggccaag ttttgcttgt tgtgtgcttg aaagaaaata tctctgacca acttctgtat 1980 tcgtggacca aactgaagct atattttca cagaaaga agcagtgacg gggacacaa 2040 ttctgttgcc tggtggaaag aaggcaaagg ccttcagcaa tctatattac cagcgctgga 2100 tcctttgaca gagagtggtc cctaaactta aatttcaaga cggtataggc ttgatctgtc 2160 ttgcttattg ttgccccctg cgcctagcac aattctgaca caaattgga acttactaaa 2220 aatttttttt tactgtt 2237 <210> 37 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 2D10.2B2 <400> 37 Gly Tyr Thr Phe Thr Asp Tyr 1 5 <210> 38 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 3B11.2G2 <400> 38 Gly Tyr Lys Phe Lys Thr Tyr 1 5 <210> 39 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 4A11.2B5's VH CDR1 <400> 39 Gly Tyr Ser Phe Thr Asn Tyr 1 5 <210> 40 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 4G2.2G6 VH CDR1 <400> 40 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 41 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 6H6.2D6 <400> 41 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 42 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 7D8.2D8 VH CDR1 <400> 42 Gly Phe Thr Phe Ser Ser Tyr 1 5 <210> 43 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 12G5.D7 <400> 43 Gly Tyr Thr Phe Thr Asp Tyr 1 5 <210> 44 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 13A12.2E5 <400> 44 Gly Tyr Lys Phe Lys Thr Tyr 1 5 <210> 45 <211> 7 <212> PRT <213> Artificial sequence <220> <223> of 13G4.2F8 of VH CDR1 <400> 45 Gly Tyr Thr Phe Thr Ser Tyr 1 5 <210> 46 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 13H12.2F8 <400> 46 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 47 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 14H10.2C9 <400> 47 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 48 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 15F10.2D6 VH CDR1 <400> 48 Gly Phe Ala Phe Ser Ser Tyr 1 5 <210> 49 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 15G7.2A7's VH CDR1 <400> 49 Gly Tyr Thr Phe Thr Asp Tyr 1 5 <210> 50 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 19B5.2E6 <400> 50 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 51 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 19D9.2E5 <400> 51 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 52 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 20D11.2C6 VH CDR1 <400> 52 Gly Tyr Thr Phe Thr Asp Phe 1 5 <210> 53 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 20H5.A3's VH CDR1 <400> 53 Gly Tyr Ala Phe Thr Thr Tyr 1 5 <210> 54 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 23H9.2E4 <400> 54 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 55 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 24D12.2H9 VH CDR1 <400> 55 Gly Phe Ser Leu Thr Ser Tyr 1 5 <210> 56 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 846.1F5 <400> 56 Gly Tyr Thr Phe Thr Asn Tyr Gly 1 5 <210> 57 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 846.2H3 <400> 57 Gly Tyr Thr Phe Thr Asn Tyr Gly 1 5 <210> 58 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 846T.1H2's VH CDR1 <400> 58 Gly Tyr Thr Phe Thr Asn Tyr Gly 1 5 <210> 59 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of 9H2.2H10 <400> 59 Gly Tyr Thr Phe Thr Asn Tyr 1 5 <210> 60 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of IMT001-4 <400> 60 Gly Tyr Thr Phe Thr Asn Tyr 1 5 <210> 61 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of IMT006-1 <400> 61 Gly Tyr Ser Phe Thr Asn Tyr 1 5 <210> 62 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of IMT006-5 <400> 62 Gly Tyr Ser Phe Thr Asn Tyr 1 5 <210> 63 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 of IMT006-8 <400> 63 Gly Tyr Ser Phe Thr Asn Tyr 1 5 <210> 64 <211> 7 <212> PRT <213> Artificial sequence <220> <223> mIMT001's VH CDR1 <400> 64 Gly Tyr Thr Phe Thr Asn Tyr 1 5 <210> 65 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 2D10.2B2 <400> 65 Ile Tyr Pro Gly Ser Asn Asp Thr 1 5 <210> 66 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 3B11.2G2 <400> 66 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 67 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 4A11.2B5 <400> 67 Ile Tyr Pro Gly Ser Gly Asn Thr 1 5 <210> 68 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 4G2.2G6 VH CDR2 <400> 68 Ile Asn Thr His Ser Gly Val Pro 1 5 <210> 69 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 6H6.2D6 <400> 69 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 70 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 7D8.2D8 VH CDR2 <400> 70 Ile Ser Asp Gly Gly Ile Tyr Thr 1 5 <210> 71 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 12G5.D7 <400> 71 Ile Tyr Pro Gly Thr Gly Asn Thr 1 5 <210> 72 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 13A12.2E5 <400> 72 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 73 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 13G4.2F8 VH CDR2 <400> 73 Ile His Pro Asn Ser Gly Ser Thr 1 5 <210> 74 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 13H12.2F8 <400> 74 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 75 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 14H10.2C9 <400> 75 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 76 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 15F10.2D6 VH CDR2 <400> 76 Ile Ser Asp Gly Gly Val Tyr Thr 1 5 <210> 77 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 15G7.2A7's VH CDR2 <400> 77 Ile Asn Pro Asn Asn Gly Gly Thr 1 5 <210> 78 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 19B5.2E6 <400> 78 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 79 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 19D9.2E5 <400> 79 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 80 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 20D11.2C6 VH CDR2 <400> 80 Ile Asn Pro Lys Asn Gly Gly Ile 1 5 <210> 81 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 20H5.A3's VH CDR2 <400> 81 Val Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 82 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 23H9.2E4 <400> 82 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 83 <211> 7 <212> PRT <213> Artificial sequence <220> <223> 24D12.2H9 VH CDR2 <400> 83 Ile Trp Ser Gly Gly Ser Thr 1 5 <210> 84 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 846.1F5 <400> 84 Ile Asn Thr Tyr Thr Gly Glu Pro 1 5 <210> 85 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 846.2H3 <400> 85 Ile Asn Thr Tyr Thr Gly Glu Pro 1 5 <210> 86 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 846T.1H2 <400> 86 Ile Asn Thr Asn Thr Gly Glu Ser 1 5 <210> 87 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of 9H2.2H10 <400> 87 Ile Asp Pro Ser Asp Ser Glu Thr 1 5 <210> 88 <211> 6 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of IMT001-4 <400> 88 Asn Thr Asn Thr Gly Glu 1 5 <210> 89 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of IMT006-1 <400> 89 Ile Tyr Pro Gly Ser Gly Asn Thr 1 5 <210> 90 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of IMT006-5 <400> 90 Ile Tyr Pro Gly Ser Gly Asn Thr 1 5 <210> 91 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 of IMT006-8 <400> 91 Ile Tyr Pro Gly Ser Gly Asn Thr 1 5 <210> 92 <211> 6 <212> PRT <213> Artificial sequence <220> <223> mIMT001's VH CDR2 <400> 92 Asn Thr Asn Thr Gly Glu 1 5 <210> 93 <211> 13 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 2D10.2B2 <400> 93 Ala Asn Tyr Phe Gly Cys Ser Gly Trp Phe Phe Asp Val 1 5 10 <210> 94 <211> 12 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 3B11.2G2 <400> 94 Ala Arg Asp Gly Asn Tyr Gly Asp Pro Met Asp Tyr 1 5 10 <210> 95 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 4A11.2B5's VH CDR3 <400> 95 Ser Thr Ala Pro Gly Gly Phe Asp Val 1 5 <210> 96 <211> 12 <212> PRT <213> Artificial sequence <220> <223> 4G2.2G6 VH CDR3 <400> 96 Thr Arg Asp Gly Asn Asp Gly Asp Ala Met Asp Asn 1 5 10 <210> 97 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 6H6.2D6 <400> 97 Ala Arg Gly Pro Tyr Ala Met Asp Tyr 1 5 <210> 98 <211> 6 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 7D8.2D8 <400> 98 Val Arg Asp Gly Gly Tyr 1 5 <210> 99 <211> 15 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 12G5.D7 <400> 99 Ala Arg Phe Ala Tyr Tyr Tyr Gly Ser Gly Gly Tyr Phe Asp Tyr 1 5 10 15 <210> 100 <211> 12 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 13A12.2E5 <400> 100 Ala Arg Asp Gly Asn Tyr Gly Asp Pro Met Asp Tyr 1 5 10 <210> 101 <211> 12 <212> PRT <213> Artificial sequence <220> <223> 13G4.2F8 VH CDR3 <400> 101 Thr Arg Trp Gly Ile Tyr Tyr Tyr Ala Arg Asp Tyr 1 5 10 <210> 102 <211> 10 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 13H12.2F8 <400> 102 Ala Val Pro Tyr Glu Tyr Asp Gly Ala Tyr 1 5 10 <210> 103 <211> 10 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 14H10.2C9 <400> 103 Ser Thr Pro Tyr Glu Tyr Asp Gly Ala Tyr 1 5 10 <210> 104 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 15F10.2D6 VH CDR3 <400> 104 Val Arg Asp Gly Gly Tyr 1 5 <210> 105 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 15G7.2A7 VH CDR3 <400> 105 Thr Ser Gly Tyr Gly Phe Pro Tyr 1 5 <210> 106 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 19B5.2E6 <400> 106 Ala Arg Gly Pro Tyr Ala Met Asp Tyr 1 5 <210> 107 <211> 10 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 19D9.2E5 <400> 107 Ala Thr Pro Tyr Glu Tyr Asp Gly Ala Tyr 1 5 10 <210> 108 <211> 8 <212> PRT <213> Artificial sequence <220> <223> 20D11.2C6 VH CDR3 <400> 108 Thr Ser Gly Tyr Gly Phe Pro Tyr 1 5 <210> 109 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 20H5.A3's VH CDR3 <400> 109 Ala Arg Gly Pro Tyr Ala Met Asp Tyr 1 5 <210> 110 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 23H9.2E4 <400> 110 Ala Arg Gly Pro Tyr Ala Met Asp Tyr 1 5 <210> 111 <211> 14 <212> PRT <213> Artificial sequence <220> <223> 24D12.2H9 VH CDR3 <400> 111 Ala Lys Ser Pro Asp Gly Tyr Asp Val Ala Trp Phe Gly Tyr 1 5 10 <210> 112 <211> 15 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 846.1F5 <400> 112 Ala Arg Trp Gly Gly Tyr Asp Gly Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210> 113 <211> 15 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 846.2H3 <400> 113 Ala Arg Trp Gly Gly Tyr Asp Gly Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210> 114 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 846T.1H2's VH CDR3 <400> 114 Gln Pro Gly Gly Val Thr Gly Thr Leu Thr Thr 1 5 10 <210> 115 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of 9H2.2H10 <400> 115 Ala Arg His Gly Tyr Tyr Tyr Asp Tyr 1 5 <210> 116 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of IMT001-4 <400> 116 Ala Pro Tyr Asp Asn Phe Phe Ala Tyr 1 5 <210> 117 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of IMT006-1 <400> 117 Ser Thr Ala Pro Gly Gly Phe Asp Val 1 5 <210> 118 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of IMT006-5 <400> 118 Ser Thr Ala Pro Gly Gly Phe Asp Val 1 5 <210> 119 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 of IMT006-8 <400> 119 Ser Thr Ala Pro Gly Gly Phe Asp Val 1 5 <210> 120 <211> 9 <212> PRT <213> Artificial sequence <220> <223> mIMT001's VH CDR3 <400> 120 Ala Pro Tyr Asp Asn Phe Phe Ala Tyr 1 5 <210> 121 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 2D10.2B2's VL CDR1 <400> 121 Lys Ser Leu Leu His Ser Asp Gly Ile Thr Tyr 1 5 10 <210> 122 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 3B11.2G2's VL CDR1 <400> 122 Gln Ser Leu Leu Tyr Thr Asn Gly Lys Thr Tyr 1 5 10 <210> 123 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 4A11.2B5's VL CDR1 <400> 123 Lys Ser Leu Leu His Ser Asp Gly Ile Thr Tyr 1 5 10 <210> 124 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 4G2.2G6 VL CDR1 <400> 124 Gln Ser Leu Leu Tyr Thr Asp Gly Lys Thr Tyr 1 5 10 <210> 125 <211> 6 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 6H6.2D6 <400> 125 Gln Gly Ile Ser Asn Tyr 1 5 <210> 126 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 7D8.2D8 VL CDR1 <400> 126 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr 1 5 10 <210> 127 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 12G5.D7 VL CDR1 <400> 127 Gln Gly Ile Asn Ser Asn 1 5 <210> 128 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 13A12.2E5 VL CDR1 <400> 128 Gln Ser Leu Leu Tyr Thr Asn Gly Lys Thr Tyr 1 5 10 <210> 129 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 13G4.2F8 VL CDR1 <400> 129 Gln Asn Val Gly Thr Asn 1 5 <210> 130 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 13H12.2F8 <400> 130 Gln Ser Leu Phe His Ser Asp Gly Lys Thr Tyr 1 5 10 <210> 131 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 14H10.2C9 <400> 131 Gln Ser Leu Phe Asp Ser Asp Gly Lys Thr Tyr 1 5 10 <210> 132 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 15F10.2D6 VL CDR1 <400> 132 Gln Ser Ile Val His Asn Asn Gly Asn Thr Tyr 1 5 10 <210> 133 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 15G7.2A7 VL CDR1 <400> 133 Gln Asn Ile Asn Ile Trp 1 5 <210> 134 <211> 6 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 19B5.2E6 <400> 134 Gln Gly Ile Asn Asn Tyr 1 5 <210> 135 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 19D9.2E5 <400> 135 Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr 1 5 10 <210> 136 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 20D11.2C6 VL CDR1 <400> 136 Gln Asn Ile Tyr Ile Trp 1 5 <210> 137 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 20H5.A3's VL CDR1 <400> 137 Gln Asp Ile Ser Asn Tyr 1 5 <210> 138 <211> 6 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 23H9.2E4 <400> 138 Gln Gly Ile Asn Asn Tyr 1 5 <210> 139 <211> 6 <212> PRT <213> Artificial sequence <220> <223> 24D12.2H9 VL CDR1 <400> 139 Gln Asp Val Arg Thr Ala 1 5 <210> 140 <211> 12 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 846.1F5 <400> 140 Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr 1 5 10 <210> 141 <211> 12 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 846.2H3 <400> 141 Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr 1 5 10 <210> 142 <211> 11 <212> PRT <213> Artificial sequence <220> <223> 846T.1H2 VL CDR1 <220> <221> misc_feature <222> (3)..(3) <223> Xaa can be any naturally occurring amino acid. <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid. <400> 142 Gln Ser Xaa Lys Tyr Ser Xaa Gly Lys Thr Tyr 1 5 10 <210> 143 <211> 6 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of 9H2.2H10 <400> 143 Gln Asp Val Ser Thr Ala 1 5 <210> 144 <211> 16 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of IMT001-4 <400> 144 Arg Ser Ser Lys Ser Leu Leu Tyr Lys Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <210> 145 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of IMT006-1 <400> 145 Lys Ser Leu Leu His Ser Asp Gly Ile Thr Tyr 1 5 10 <210> 146 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of IMT006-5 <400> 146 Lys Ser Leu Leu His Ser Asp Gly Ile Thr Tyr 1 5 10 <210> 147 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 of IMT006-8 <400> 147 Lys Ser Leu Leu His Ser Asp Gly Ile Thr Tyr 1 5 10 <210> 148 <211> 16 <212> PRT <213> Artificial sequence <220> <223> mIMT001's VL CDR1 <400> 148 Arg Ser Ser Lys Ser Leu Leu Tyr Lys Asp Gly Lys Thr Tyr Leu Asn 1 5 10 15 <210> 149 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 2D10.2B2 <400> 149 Arg Met Ser 1 <210> 150 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 3B11.2G2's VL CDR2 <400> 150 Leu Val Ser 1 <210> 151 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 4A11.2B5's VL CDR2 <400> 151 Arg Met Ser 1 <210> 152 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 4G2.2G6 VL CDR2 <400> 152 Leu Val Ser 1 <210> 153 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 6H6.2D6 <400> 153 Tyr Thr Ser 1 <210> 154 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 7D8.2D8 VL CDR2 <400> 154 Lys Val Ser 1 <210> 155 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 12G5.D7 VL CDR2 <400> 155 His Ala Thr 1 <210> 156 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 13A12.2E5 VL CDR2 <400> 156 Leu Leu Ser 1 <210> 157 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 13G4.2F8 VL CDR2 <400> 157 Gly Ala Ser 1 <210> 158 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 13H12.2F8 <400> 158 Leu Val Ser 1 <210> 159 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 14H10.2C9 <400> 159 Leu Val Ser 1 <210> 160 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 15F10.2D6 VL CDR2 <400> 160 Lys Val Ser 1 <210> 161 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 15G7.2A7 VL CDR2 <400> 161 Lys Ala Ser 1 <210> 162 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 19B5.2E6 <400> 162 Tyr Ala Ser 1 <210> 163 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 19D9.2E5 <400> 163 Leu Val Ser 1 <210> 164 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 20D11.2C6 VL CDR2 <400> 164 Lys Ala Ser 1 <210> 165 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 20H5.A3's VL CDR2 <400> 165 Tyr Thr Ser 1 <210> 166 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 23H9.2E4 <400> 166 Tyr Ala Ser 1 <210> 167 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 24D12.2H9 VL CDR2 <400> 167 Trp Ala Ser 1 <210> 168 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 846.1F5 <400> 168 Trp Ala Ser 1 <210> 169 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 846.2H3 <400> 169 Trp Ala Ser 1 <210> 170 <211> 3 <212> PRT <213> Artificial sequence <220> <223> 846T.1H2 VL CDR2 <400> 170 Leu Val Cys 1 <210> 171 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of 9H2.2H10 <400> 171 Trp Ala Ser 1 <210> 172 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of IMT001-4 <400> 172 Leu Met Ser Thr His Ala Ser 1 5 <210> 173 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of IMT006-1 <400> 173 Arg Met Ser 1 <210> 174 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of IMT006-5 <400> 174 Arg Met Ser 1 <210> 175 <211> 3 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 of IMT006-8 <400> 175 Arg Met Ser 1 <210> 176 <211> 7 <212> PRT <213> Artificial sequence <220> <223> mIMT001's VL CDR2 <400> 176 Leu Met Ser Thr His Ala Ser 1 5 <210> 177 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 2D10.2B2 <400> 177 Ala Gln Met Ile Glu Phe Pro Leu Thr 1 5 <210> 178 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 3B11.2G2's VL CDR3 <400> 178 Leu Gln Ser Thr His Phe Pro Leu Thr 1 5 <210> 179 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 4A11.2B5's VL CDR3 <400> 179 Ala Gln Met Leu Glu Phe Pro Leu Thr 1 5 <210> 180 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 4G2.2G6 VL CDR3 <400> 180 Leu Gln Ser Thr His Phe Pro Leu Thr 1 5 <210> 181 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 6H6.2D6 <400> 181 Gln Gln Tyr Ser Glu Leu Pro Tyr Thr 1 5 <210> 182 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 7D8.2D8 VL CDR3 <400> 182 Phe Gln Gly Ser His Val Pro Leu Thr 1 5 <210> 183 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 12G5.D7 VL CDR3 <400> 183 Val Gln Tyr Ala Gln Phe Pro Pro Thr 1 5 <210> 184 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 13A12.2E5 VL CDR3 <400> 184 Leu Gln Ser Thr His Phe Pro Leu Thr 1 5 <210> 185 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 13G4.2F8 VL CDR3 <400> 185 Glu Gln Tyr Ser Asn Phe Pro Leu Thr 1 5 <210> 186 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 13H12.2F8 <400> 186 Trp Gln Gly Thr His Phe Pro Leu Thr 1 5 <210> 187 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 14H10.2C9 <400> 187 Trp Gln Gly Thr His Phe Pro Leu Thr 1 5 <210> 188 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 15F10.2D6 VL CDR3 <400> 188 Phe Gln Gly Ser His Val Pro Leu Thr 1 5 <210> 189 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 15G7.2A7 VL CDR3 <400> 189 Leu Gln Gly Gln Ser Tyr Pro Leu Thr 1 5 <210> 190 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 19B5.2E6 <400> 190 Gln Gln Tyr Ser Gln Val Pro Tyr Thr 1 5 <210> 191 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 19D9.2E5 <400> 191 Trp Gln Gly Thr His Phe Pro Leu Thr 1 5 <210> 192 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 20D11.2C6 VL CDR3 <400> 192 Leu Gln Gly Gln Ser Tyr Pro Leu Thr 1 5 <210> 193 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 20H5.A3's VL CDR3 <400> 193 Gln Gln Tyr Ser Lys Leu Pro Tyr Thr 1 5 <210> 194 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 23H9.2E4 VL CDR3 <400> 194 Gln Gln Tyr Ser Gln Val Pro Tyr Thr 1 5 <210> 195 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 24D12.2H9 VL CDR3 <400> 195 Gln Gln Tyr Ser Ser Tyr Pro Trp Thr 1 5 <210> 196 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 846.1F5 <400> 196 His Gln Tyr Leu Ser Ser Leu Thr 1 5 <210> 197 <211> 8 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 846.2H3 <400> 197 His Gln Tyr Leu Ser Ser Leu Thr 1 5 <210> 198 <211> 9 <212> PRT <213> Artificial sequence <220> <223> 846T.1H2 VL CDR3 <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid. <400> 198 Val Gln Gly Pro His Phe Xaa His Thr 1 5 <210> 199 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of 9H2.2H10 <400> 199 Gln Gln His Tyr Thr Thr Pro Leu Thr 1 5 <210> 200 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of IMT001-4 <400> 200 Gln Gln Leu Val Asp Tyr Pro Leu Thr 1 5 <210> 201 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of IMT006-1 <400> 201 Ala Gln Met Leu Glu Phe Pro Leu Thr 1 5 <210> 202 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of IMT006-5 <400> 202 Ala Gln Met Leu Glu Phe Pro Leu Thr 1 5 <210> 203 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 of IMT006-8 <400> 203 Ala Gln Met Leu Glu Phe Pro Leu Thr 1 5 <210> 204 <211> 9 <212> PRT <213> Artificial sequence <220> <223> mIMT001's VL CDR3 <400> 204 Gln Gln Leu Val Asp Tyr Pro Leu Thr 1 5 <210> 205 <211> 120 <212> PRT <213> Artificial sequence <220> <223> VH of 2D10.2B2 <400> 205 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Ser Asn Asp Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Gly Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Asn Tyr Phe Gly Cys Ser Gly Trp Phe Phe Asp Val Trp Gly Thr 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 206 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH of 3B11.2G2 <400> 206 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Lys Phe Lys Thr Tyr 20 25 30 Val Met Ser Trp Val Lys Gln Ala Pro Gly Lys Ala Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Glu Ile Ile Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Asp Gly Asn Tyr Gly Asp Pro Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 207 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of 4A11.2B5 <400> 207 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30 Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Thr Asn 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ser Thr Ala Pro Gly Gly Phe Asp Val Trp Gly Ser Gly Thr Thr Val 100 105 110 Thr Val Ser Ser 115 <210> 208 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH of 4G2.2G6 <400> 208 Gln Ile Gln Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Val Met Ser Trp Val Lys Gln Ala Pro Gly Lys Asp Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr His Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Asp Phe Ser Leu Glu Thr Ser Ala Asn Thr Ala Phe 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Thr Arg Asp Gly Asn Asp Gly Asp Ala Met Asp Asn Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 209 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of 6H6.2D6 <400> 209 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Ala Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Thr Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser Ser 115 <210> 210 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> VH of 7D8.2D8 <400> 210 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Ile Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Phe 65 70 75 80 Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Arg Asp Gly Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser 100 105 110 Ser <210> 211 <211> 122 <212> PRT <213> Artificial sequence <220> <223> VH of 12G5.D7 <400> 211 Gln Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Ala Arg Ile Tyr Pro Gly Thr Gly Asn Thr Asp Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ala Glu Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Phe Ala Tyr Tyr Tyr Gly Ser Gly Gly Tyr Phe Asp Tyr Trp 100 105 110 Gly His Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 212 <211> 119 <212> PRT <213> Artificial sequence <220> <223> VH of 13A12.2E5 <400> 212 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Lys Phe Lys Thr Tyr 20 25 30 Val Met Ser Trp Val Lys Gln Ala Pro Gly Lys Ala Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Glu Ile Ile Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Asp Gly Asn Tyr Gly Asp Pro Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 213 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH of 13G4.2F8 <400> 213 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Asn Ser Gly Ser Thr Asp Tyr Asn Glu Lys Phe 50 55 60 Lys Asn Lys Ala Thr Leu Asn Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Ile Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Trp Gly Ile Tyr Tyr Tyr Ala Arg Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 <210> 214 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH of 13H12.2F8 <400> 214 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Val Pro Tyr Glu Tyr Asp Gly Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <210> 215 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH of 14H10.2C9 <400> 215 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Gly Trp Val Lys Gln Ala Pro Gly Lys Asp Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ser Thr Pro Tyr Glu Tyr Asp Gly Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <210> 216 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> VH of 15F10.2D6 <400> 216 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Val Tyr Thr Tyr Tyr Thr Asp His Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asp Asn Leu Tyr 65 70 75 80 Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Arg Asp Gly Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser 100 105 110 Ser <210> 217 <211> 115 <212> PRT <213> Synthetic Sequence <220> <223> VH of 15G7.2A7 <400> 217 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45<00Gly Asp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Gly Tyr Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala 115 <210> 218 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of 19B5.2E6 <400> 218 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Ala Met Ser Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Leu<s 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser Ser 115 <210> 219 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH of 19D9.2E5 <400> 219 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Gly Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys 85 90 95 Ala Thr Pro Tyr Glu Tyr Asp Gly Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <210> 220 <211> 115 <212> PRT <213> Synthetic Sequence <220> <223> VH of 20D11.2C6 <400> 220 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe 20 25 30 Tyr Ile Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Lys Asn Gly Gly Ile Asn Tyr Asn Pro Lys Phe 50 55 60 Lys Ile Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ser Tyr 65 70 75 80 Met Asp Leu Arg Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Gly Tyr Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala 115 <210> 221 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of 20H5.A3 <400> 221 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Val Asn Thr Tyr Ser Gly Val Pro Thr Cys Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Arg Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser Ser 115 <210> 222 <211> 116 <212> PRT <213> Artificial sequence <220> <223> VH of 23H9.2E4 <400> 222 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ <220> <223> VH of 24D12.2H9 <400> 223 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Lys Ser Pro Asp Gly Tyr Asp Val Ala Trp Phe Gly Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 224 ?<211> 122 <212> PRT <213> Artificial sequence <220> <223> VH of 846.1F5 [[ID=5I]]<400> 224 It should be noted that there is a "?" marked in the translation of line which is due to the unclear meaning of the original " " in this context. If there is more context information, it can be more accurately translated.Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys 85 9�95 Ala Arg Trp Gly Gly Tyr Asp Gly Asp Tyr Tyr Ala Met Asp Tyr Trp 100 105 110 ; Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 225 <211> 122 <212> PRT <213> Artificial Sequence ;<220> <223> VH of 846.2H3 <400> 225 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Trp Gly Gly Tyr Asp Gly Asp Tyr Tyr Ala Met Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 226 <211> 118 <212> PRT <213> Synthetic Sequence <220> <223> VH of 846T.1H2 <400> 226 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Thr Gly Gly Gly Asn Trp Asp Phe Asp Tyr Trp Gly Gln Gly Thr [[ID=二十一]]100 105 110[[ID=二十二]] [[ID=二十三]]Thr Leu Thr Val Ser Ser[[ID=二十四]] [[ID=二十五]]115[[ID=二十六]] [[ID=二十七]]<210> 227[[ID=二十八]] [[ID=二十九]]<211> 115[[ID=三十]] [[ID=三十一]]<212> PRT[[ID=三十二]] [[ID=三十三]]<213> Artificial Sequence[[ID=三十四]] [[ID=三十五]]<220>[[ID=三十六]] [[ID=三十七]]<2所23> VH of 9H2.2H10[[ID=三十八]] [[ID=三十九]]<400> 227[[ID=四十]] [[ID=四十一]]Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Gly Pro Gly Ser[[ID=四十二]] [[ID=四十三]]1 5 10 15[[ID=四十四]] [[ID=四十五]]Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr[[ID=四十六]] [[ID=四十七]]20 25 30[[ID=四十八]] [[ID=四十九]]Trp Ile His Trp Val Lys Gln Arg Pro Leu Gln Gly Leu Glu Trp Ile It should be noted that in the above translation, there may be some inaccuracies in the translation of the specific content related to the patent sequence due to the complexity of the biological sequence. It is recommended to further verify and correct according to the actual situation in the context of patent translation. 35 40 45 Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95<小> Ala Arg His Gly Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <210> 228 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of IMT001-4 <400> 228 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Val Glu Glu Phe 50 55 60 Thr Gly Arg Phe Val Phe Ser Leu Glu Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Pro Tyr Asp Asn Phe Phe Ala Tyr Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser 115 <210> 229 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of IMT006-1 [[ID=二十九]]<400> 229 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 Tyr Ser Phe Thr Asn Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Ala Asp Thr 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 Ser Thr Ala Pro Gly Gly Phe Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser 115 <210> 230 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of IMT006-5 <400> 230 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 Tyr Ser Phe Thr Asn Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Thr Ala Pro Gly Gly Phe Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser 115 <210> 231 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH of IMT006-8 <400> 231 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 Tyr Ser Phe Thr Asn Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Thr Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Thr Ala Pro Gly Gly Phe Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser 115 <210> 232 <211> 116 <212> PRT <213> Artificial sequence <220> <223> VH of mIMT001 <400> 232 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Val Glu Glu Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Pro Tyr Asp Asn Phe Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala 115 <210> 233 <211> 112 <212> PRT <213> artificial sequence <220> <223> 2D10.2B2's VL <400> 233 Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly 1 5 10 15 Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Met 85 90 95 Ile Glu Phe Pro Leu Thr Phe Gly Ala Gly Thr Ile Leu Glu Leu Lys 100 105 110 <210> 234 <211> 112 <212> PRT <213> artificial sequence <220> <223> 3B11.2G2's VL <400> 234 Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Ala Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr 20 25 30 Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 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 Leu Gly Val Tyr Tyr Cys Leu Gln Ser 85 90 95 Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 235 <211> 112 <212> PRT <213> artificial sequence <220> <223> 4A11.2B5's VL <400> 235 Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly 1 5 10 15 Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Met 85 90 95 Leu Glu Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 236 <211> 112 <212> PRT <213> artificial sequence <220> <223> 4G2.2G6's VL <400> 236 Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr 20 25 30 Asp Gly Lys Thr Tyr Leu Ser Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp 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 Leu Gly Val Tyr Tyr Cys Leu Gln Ser 85 90 95 Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Val Lys 100 105 110 <210> 237 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL of 6H6.2D6 <400> 237 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Glu Leu Pro Tyr 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 238 <211> 112 <212> PRT <213> Artificial sequence <220> <223> VL of 7D8.2D8 <400> 238 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser 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 Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 239 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL of 12G5.D7 <400> 239 Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly<| 1 5 10 15 Asp Thr Val Ser Ile Thr Cys His Ala Ser Gln Gly Ile Asn Ser Asn 20 25 30 Met Gly Trp Leu Gln Gln Lys Pro Gly Lys Ser Phe Lys Gly Leu Ile 35 40 45 Tyr His Ala Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Pro 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 240 <211> 112 <212> PRT <213> Artificial sequence <220> <223> VL of 13A12.2E5 <400> 240 Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Ala Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr 20 25 30 Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Leu Ser Lys Leu Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Ala Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Ser 85 90 95 Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Met Lys 100 105 110 <210> 241 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL of 13G4.2F8 <400> 241 Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Glu Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn 20 25 30 Val Ala Trp Tyr Gln Gln Lys Ala Gly Gln Ser Leu Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Asn Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser 65 70 75 80 Glu Asp Met Thr Asn Tyr Phe Cys Glu Gln Tyr Ser Asn Phe Pro Leu 85 90 95 [[ID=​​​​​​​​​​​​​​​​​​​​​​​20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly 85 90 95 Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Met Lys 100 105 110 <210> 243 <211> 112 <212> PRT <213> Synthetic Sequence <220> <223> VL of 14H10.2C9 <400> 243 Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly [[ID=z38]]1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Phe Asp Ser 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly 85 90 95 Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Met Lys 100 105 110 <210> 244 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL of 15F10.2D6 <400> 244 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Asn 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser 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 Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 245 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL of 15G7.2A7 <400> 245 Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Thr Ile Ser Ile Thr Cys Arg Ala Ser Gln Asn Ile Asn Ile Trp 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Gln Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Gly Gln Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Val Met Lys 100 105 <210> 246 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL of 19B5.2E6 <400> 246 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gln Val Pro Tyr 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 247 <211> 112 <212> PRT <213> Artificial sequence <220> <223> VL of 19D9.2E5 <400> 247 Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Pro 35 40 45 Pro Lys Arg Leu Met Tyr Leu Val Ser Thr Leu Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly 85 90 95 Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Pro Glu Leu Lys 100 105 110 <210> 248 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL of 20D11.2C6 <400> 24 天冬氨酸-异亮氨酸-谷氨酰胺-甲硫氨酸-天冬酰胺-谷氨酰胺-丝氨酸-脯氨酸-丝氨酸-丝氨酸-亮氨酸-丝氨酸-丙氨酸-丝氨酸-亮氨酸-甘氨酸 1 5 10 15 天冬氨酸-苏氨酸-异亮氨酸-苏氨酸-异亮氨酸-苏氨酸-半胱氨酸-精氨酸-丙氨酸-丝氨酸-谷氨酰胺-天冬酰胺-异亮氨酸-酪氨酸-异亮氨酸-色氨酸 20 25 30 亮氨酸-丝氨酸-色氨酸-酪氨酸-谷氨酰胺-谷氨酰胺-赖氨酸-脯氨酸-甘氨酸-天冬酰胺-异亮氨酸-脯氨酸-赖氨酸-亮氨酸-亮氨酸-异亮氨酸 35 40 45 酪氨酸-赖氨酸-丙氨酸-丝氨酸-天冬酰胺-亮氨酸-组氨酸-苏氨酸-甘氨酸-缬氨酸-脯氨酸-丝氨酸-精氨酸-苯丙氨酸-丝氨酸-甘氨酸 50 55 60 丝氨酸-甘氨酸-丝氨酸-甘氨酸-苏氨酸-天冬氨酸-苯丙氨酸-苏氨酸-亮氨酸-苏氨酸-异亮氨酸-丝氨酸-苏氨酸-亮氨酸-谷氨酰胺-脯氨酸 65 70 75 80 谷氨酸-天冬氨酸-异亮氨酸-丙氨酸-苏氨酸-酪氨酸-苯丙氨酸-半胱氨酸-亮氨酸-谷氨酰胺-甘氨酸-谷氨酰胺-丝氨酸-酪氨酸-脯氨酸-亮氨酸 85 90 95 苏氨酸-苯丙氨酸-甘氨酸-丙氨酸-甘氨酸-苏氨酸-赖氨酸-亮氨酸-谷氨酸-甲硫氨酸-赖氨酸 100 105 <210> 249 <211> 107 <212> PRT <213> Synthetic sequence <220> <223> VL of 20H5.A3 <400> 249 天冬氨酸-异亮氨酸-谷氨酰胺-甲硫氨酸-苏氨酸-谷氨酰胺-苏氨酸-苏氨酸-丝氨酸-丝氨酸-亮氨酸-丝氨酸-丙氨酸-丝氨酸-亮氨酸-甘氨酸 1 5 10 15 天冬氨酸-精氨酸-缬氨酸-苏氨酸-异亮氨酸-天冬酰胺-半胱氨酸-丝氨酸-丙氨酸-丝氨酸-谷氨酰胺-天冬氨酸-异亮氨酸-丝氨酸-天冬酰胺-酪氨酸 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Ser Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Tyr Ser Lys Leu Pro Tyr 85 90 95 Thr Phe Gly Ser Gly Thr His Leu Glu Ile Lys 100 105 <210> 250 <211> 107 <212> PRT <213> Artificial Sequence <220><000332D><223> VL of 23H9.2E4 <400> 250 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 It should be noted that there seems to be a misspelling in the original text where "<000332D>" should probably be " ". I have made the correction in the translation for better understanding. If this is not what you intended, please let me know.Tyr Tyr Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gln Val Pro Tyr 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 251 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL of 24D12.2H9[[ID=‘27]] <400> 251 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Leu Ser Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 252 <211> 112 <212> PRT <213> artificial sequence <220> <223> 846.1F5's VL <400> 252 Asn Ile Met Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Pro Glu Asp Leu Ala Val Tyr Tyr Cys His Gln 85 90 95 Tyr Leu Ser Ser Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 253 <211> 112 <212> PRT <213> artificial sequence <220> <223> 846.2H3's VL <400> 253 Asn Ile Met Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Pro Glu Asp Leu Ala Val Tyr Tyr Cys His Gln 85 90 95 Tyr Leu Ser Ser Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 254 <211> 112 <212> PRT <213> Artificial sequence <220> <223> VL of 846T.1H2 <400> 254 Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95 Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 255 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL of 9H2.2H10 <400> 255 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 256 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL of IMT001-4 <400> 256 Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr His Ala 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 Tyr Cys Gln Gln Leu 85 90 95 Val Asp Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 257 <211> 112 <212> PRT <2(此处疑似有误,应为<213>)> Artificial sequence <220> <223> VL of IMT006-1 <400> 257 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 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 Tyr Cys Ala Gln Met 85 90 95 Leu Glu Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 258 <211> 112 <212> PRT <213> artificial sequence <220> <223> IMT006-5's VL <400> 258 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 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 Tyr Cys Ala Gln Met 85 90 95 Leu Glu Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 259 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL of IMT006-8 <400> 259 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 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 Tyr Cys Ala Gln Met 85 90 95 Leu Glu Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 260 <211> 112 <212> PRT <213> Synthetic Sequence <220> <223> VL of mIMT001 <400> 260 Asp Ile Val Ile Thr Gln Asp Glu Leu Ser Asn Pro Val Thr Ser Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Tyr Lys 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr His Ala Ser Gly Val Ser 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Glu Ile 65 70 75 80 Ser Arg Val Lys Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Leu 85 90 95 Val Asp Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 261 <211> 461 <212> PRT <213> Artificial Sequence <220> <223> hIgG4 (S228P) Constant Region of IMT001-4 <400> 261 Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly 1 5 10 15 Val Cys Ala Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys 20 25 30 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asn Tyr Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 50 55 60 Lys Trp Met Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Val 65 70 75 80 Glu Glu Phe Thr Gly Arg Phe Val Phe Ser Leu Glu Thr Ser Val Ser 85 90 95 Thr Ala Tyr Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val 100 105 110 Tyr Phe Cys Ala Pro Tyr Asp Asn Phe Phe Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 275 280 285 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 305 310 315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 325 330 335 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 355 360 365 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 420 425 430 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435 440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 450 455 460 <210> 262 <211> 241 <212> PRT <213> Artificial Sequence <220> <223> hκ Constant Region of IMT001-4 <400> 262 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Leu Ser 20 25 30 Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Lys Ser Leu Leu Tyr Lys Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Met Ser Thr 65 70 75 80 His Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 100 105 110 Tyr Tyr Cys Gln Gln Leu Val Asp Tyr Pro Leu Thr Phe Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 130 135 140 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 145 150 155 160 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 165 170 175 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 180 185 190 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 195 200 205 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 210 215 220 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 225 230 235 240 Cys <210> 263 <211> 466 <212> PRT <213> Artificial Sequence <220> <223> hIgG4 (S228P) of IMT006-4 is constant <400> 263 Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser 1 5 10 15 Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Val Gln Ser Gly 20 25 30 Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 35 40 45 Ser Gly Tyr Ser Phe Thr Asn Tyr Tyr Met His Trp Val Arg Gln Ala 50 55 60 Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Tyr Pro Gly Ser Gly 65 70 75 80 Asn Thr Asn Tyr Asn Glu Lys Phe Gln Gly Arg Val Thr Met Thr Ala 85 90 95 Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser 100 105 110 Asp Asp Thr Ala Val Tyr Tyr Cys Ser Thr Ala Pro Gly Gly Phe Asp 115 120 125 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 305 310 315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Leu Gly 465 <210> 264 <211> 239 <212> PRT <213> Artificial Sequence <220> <223> hκ constant of IMT006-4 <400> 264 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser 20 25 30 Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Lys Ser 35 40 45 Leu Leu His Ser Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys 五十 五十五 六十 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 100 105 110 Cys Ala Gln Met Leu Glu Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 130 135 140 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 145 150 155 160 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 165 170 175 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 180 18碎5 190 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 195 200 205 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 210 215 220 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 265 <211> 466 <212> PRT <213> Artificial Sequence <220> <223> hIgG4 (S228P) Constant Region of IMT006-5 <400> 265 Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser 1 5 10 15 Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Val Gln Ser Gly 20 25 30 Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 35 40 45 Ser Gly Tyr Ser Phe Thr Asn Tyr Tyr Met His Trp Val Arg Gln Ala 50 55 60 Pro Gly Gln Arg Leu Glu Trp Met Gly Trp Ile Tyr Pro Gly Ser Gly 65 70 75 80 Asn Thr Asn Tyr Asn Glu Lys Phe Gln Gly Arg Val Thr Ile Thr Ala 85 90 95 Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser 100 105 110 Glu Asp Thr Ala Val Tyr Tyr Cys Ser Thr Ala Pro Gly Gly Phe Asp 115 120 125 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 305 310 315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Leu Gly 465 <210> 266 <211> 239 <212> PRT <213> Artificial sequence <220> <223> hκ constant of IMT006-5 <400> 266 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser 20 25 30 Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Lys Ser 35 40 45 Leu Leu His Ser Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys 50 55 60 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 100 105 110 Cys Ala Gln Met Leu Glu Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 130 135 140 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 145 150 155 160 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 165 170 175 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 195 200 205 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 210 215 220 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 267 <211> 466 <212> PRT <213> Artificial Sequence <220> <223> hIgG4 (S228P) Constant Region of IMT006-8 <400> 267 Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser 1 5 10 15 Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Val Gln Ser Gly 20 25 30 Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 35 40 45 Ser Gly Tyr Ser Phe Thr Asn Tyr Tyr Ile His Trp Val Arg Gln Ala 50 55 60 Pro Gly Gln Arg Leu Glu Trp Met Gly Trp Ile Tyr Pro Gly Ser Gly 65 70 75 80 Asn Thr Asn Tyr Asn Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ala 85 90 95 Asp Thr Ser Ala Ser Thr Thr Tyr Met Glu Leu Ser Ser Leu Arg Ser 100 105 110 Glu Asp Thr Ala Val Tyr Tyr Cys Ser Thr Ala Pro Gly Gly Phe Asp 115 120 125 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 305 310 315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Leu Gly 465 <210> 268 <211> 239 <212> PRT <213> Artificial sequence <220> <223> hκ constant of IMT006-8 <400> 268 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro 20 25 30 Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser 35 40 45 Leu Leu His Ser Asp Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys 50 55 60 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 100 105 110 Cys Ala Gln Met Leu Glu Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 130 135 140 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 145 150 155 160 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 165 170 175 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 195 200 205 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 210 215 220 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 269 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = G or does not exist. <400> 269 Gly Tyr Thr Phe Thr Asn Tyr Xaa 1 5 <210> 270 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = I or does not exist. <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = S or does not exist. <400> 270 Xaa Asn Thr Asn Thr Gly Glu Xaa 1 5 <210> 271 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = Q or does not exist. <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = P or does not exist. <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = G or does not exist. <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = G or does not exist. <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = V or does not exist. <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = T or does not exist. <220> <221> MISC_FEATURE <222> (7)..(7) <223> X = G or A <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = T or P <220> <221> MISC_FEATURE <222> (9)..(9) <223> X = L or Y <220> <221> MISC_FEATURE <222> (10)..(10) <223> X = T or D <220> <221> MISC_FEATURE <222> (11)..(11) <223> X = T or N <220> <221> MISC_FEATURE <222> (12)..(12) <223> X = F or does not exist. <220> <221> MISC_FEATURE <222> (13)..(13) <223> X = F or does not exist. <220> <221> MISC_FEATURE <222> (14)..(14) <223> X = A or does not exist. <220> <221> MISC_FEATURE <222> (15)..(15) <223> X = Y or does not exist. <400> 271 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 <210> 272 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = R or does not exist. <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = S or does not exist. <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = S or does not exist. <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = K or Q <220> <221> MISC_FEATURE <222> (9)..(9) <223> X = S or K <220> <221> MISC_FEATURE <222> (10)..(10) <223> X = N or D <220> <221> MISC_FEATURE <222> (15)..(15) <223> X = L or does not exist. <220> <221> MISC_FEATURE <222> (16)..(16) <223> X = N or does not exist. <400> 272 Xaa Xaa Xaa Xaa Ser Leu Leu Tyr Xaa Xaa Gly Lys Thr Tyr Xaa Xaa 1 5 10 15 <210> 273 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = V or M <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = T or does not exist. <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = H or does not exist. <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = A or does not exist. <220> <221> MISC_FEATURE <222> (7)..(7) <223> X = S or does not exist. <400> 273 Leu Xaa Ser Xaa Xaa Xaa Xaa 1 5 <210> 274 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = V, Q, or does not exist. <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = G or L <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = T or V <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = H or D <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = F or Y <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = Q or L <400> 274 Xaa Gln Xaa Xaa Xaa Xaa Pro Xaa Thr 1 5 <210> 275 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 275 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 276 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 276 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 277 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = A or S <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = V or T <400> 277 Xaa Xaa Pro Tyr Glu Tyr Asp Gly Ala Tyr 1 5 10 <210> 278 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = L or F <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = D or H <400> 278 Gln Ser Leu Xaa Xaa Ser Asp Gly Lys Thr Tyr 1 5 10 <210> 279 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 279 Leu Val Ser 1 <210> 280 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 280 Trp Gln Gly Thr His Phe Pro Leu Thr 1 5 <210> 281 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = S or T <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = D or N <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = G or does not exist. <400> 281 Gly Tyr Xaa Phe Thr Xaa Tyr Xaa 1 5 <210> 282 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = I or does not exist. <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = N or does not exist. <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = I or T <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = P or T <220> <221> MISC_FEATURE <222> (7)..(7) <223> X = S or E <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = N, G, P or does not exist. <220> <221> MISC_FEATURE <222> (9)..(9) <223> X = N, D or does not exist. <220> <221> MISC_FEATURE <222> (10)..(10) <223> X = T or does not exist. <400> 282 Xaa Xaa Xaa Tyr Xaa Gly Xaa Xaa Xaa Xaa 1 5 10 <210> 283 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = A or does not exist. <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = R, N, or does not exist. <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = W, Y, or does not exist. <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = G, F, or does not exist. <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = G or S <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = Y, C, or T <220> <221> MISC_FEATURE <222> (7)..(7) <223> X = D, S, or A <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = G or P <220> <221> MISC_FEATURE <222> (9)..(9) <223> X = D, W, or G <220> <221> MISC_FEATURE <222> (10)..(10) <223> X = Y, F, or G <220> <221> MISC_FEATURE <222> (11)..(11) <223> X = Y or F <220> <221> MISC_FEATURE <222> (12)..(12) <223> X = A, D, or does not exist. <220> <221> MISC_FEATURE <222> (13)..(13) <223> X = M, V, or does not exist. <220> <221> MISC_FEATURE <222> (14)..(14) <223> X = D or does not exist. <220> <221> MISC_FEATURE <222> (15)..(15) <223> X = Y or does not exist. <400> 283 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 <210> 284 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = Q or does not exist. <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = K or S <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = S or V <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = L or Y <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = H or S <220> <221> MISC_FEATURE <222> (8)..(8) <223> X = D or N <220> <221> MISC_FEATURE <222> (9)..(9) <223> X = G or Q <220> <221> MISC_FEATURE <222> (10)..(10) <223> X = I or K <220> <221> MISC_FEATURE <222> (11)..(11) <223> X = T or N <400> 284 Xaa Xaa Xaa Leu Xaa Xaa Ser Xaa Xaa Xaa Xaa Tyr 1 5 10 <210> 285 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = W, R, or does not exist. <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = A, M, or does not exist. <400> 285 Xaa Xaa Ser 1 <210> 286 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = A, H, or does not exist. <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = M or Y <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = I or L <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = E or S <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = F or does not exist. <220> <221> MISC_FEATURE <222> (7)..(7) <223> X = P or S <400> 286 Xaa Gln Xaa Xaa Xaa Xaa Xaa Leu Thr 1 5 <210> 287 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (3)..(3) <223> X = A or T <400> 287 Gly Tyr Xaa Phe Thr Thr Tyr 1 5 <210> 288 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (1)..(1) <223> X = I or V <400> 288 Xaa Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 289 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 289 Ala Arg Gly Pro Tyr Ala Met Asp Tyr 1 5 <210> 290 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = G or D <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = S or N <400> 290 Gln Xaa Ile Xaa Asn Tyr 1 5 <210> 291 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = A or T <400> 291 Tyr Xaa Ser 1 <210> 292 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (5)..(5) <223> X = E, Q, or K <220> <221> MISC_FEATURE <222> (6)..(6) <223> X = L or V <400> 292 Gln Gln Tyr Ser Xaa Xaa Pro Tyr Thr 1 5 <210> 293 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (7)..(7) <223> X = F or Y <400> 293 Gly Tyr Thr Phe Thr Asp Xaa 1 5 <210> 294 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = N or K <400> 294 Ile Asn Pro Xaa Asn Gly Gly Ile 1 5 <210> 295 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 295 Thr Ser Gly Tyr Gly Phe Pro Tyr 1 5 <210> 296 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (4)..(4) <223> X = N or Y <400> 296 Gln Asn Ile Xaa Ile Trp 1 5 <210> 297 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 297 Lys Ala Ser 1 <210> 298 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 298 Leu Gln Gly Gln Ser Tyr Pro Leu Thr 1 5 <210> 299 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 299 Gly Tyr Lys Phe Lys Thr Tyr 1 5 <210> 300 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 300 Ile Asn Thr Tyr Ser Gly Val Pro 1 5 <210> 301 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 301 Ala Arg Asp Gly Asn Tyr Gly Asp Pro Met Asp Tyr 1 5 10 <210> 302 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 302 Gln Ser Leu Leu Tyr Thr Asn Gly Lys Thr Tyr 1 5 10 <210> 303 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Synthetic <220> <221> MISC_FEATURE <222> (2)..(2) <223> X = L or V <400> 303 Leu Xaa Ser 1 <210> 304 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic <400> 304 Leu Gln Ser Thr His Phe Pro Leu Thr 1 5 Attached Figure Description

[0152] In addition to the features described above, additional features and variations will become apparent from the following drawings and description of exemplary embodiments. It should be understood that these drawings depict typical embodiments and are not intended to limit the scope.

[0153] Figure 1A-C elucidates the results of the co-immunoprecipitation assay, indicating that human Gal3 (hGal3) specifically pulls down human TIM-3 (hTIM-3). Figure 1A The expression of TIM-3 in 293T cells co-transfected with a plasmid encoding hTIM-3 (encoded by HA) and a plasmid encoding hGal3, hGal9, or hCEACAM1 is shown. Figure 1B The expression of hGal9, hGal3, or hCEACAM1 is shown. Figure 1C The results showed that hGal3, rather than CEACAM1, pulled down HA-labeled hTIM-3 in co-transfected 293T cells. The results also showed that human Gal9 (hGal9) pulled down hTIM-3, but this pull-down was accompanied by protein aggregation. Figure 1B This indicates that the binding between hGal9 and hTIM-3 can be nonspecific.

[0154] Figure 2 The results of a pull-down assay using a fusion protein comprising the hTIM-3 extracellular domain (hTIM-3Fc) fused to the Fc portion of hIgG are shown. The results demonstrate that the binding between Gal3 and TIM-3 is specific. As shown in the figure, hTIM-3Fc, rather than hFc or hPD1Fc, pulls down overexpressed, flag-labeled hGal3 protein from 293T cells.

[0155] Figure 3 The results of the cell adhesion assays indicate the specific interaction between hGal3 and hTIM-3. As shown in the figure, a significantly higher number of hGal3-expressing A20 cells (A20 Gal3 cells) adhered to the plate coated with hTIM-3Fc compared to plates coated with hVISTA Fc or hPD1 Fc. The results also indicated that a higher number of A20 PDL1 cells adhered to the plate coated with hPD1Fc compared to plates coated with human VISTA Fc (hVISTAFc) or hTIM-3Fc.

[0156] Figure 4A The image shows live A20 cells (peak on the left) and dead A20 cells (peak on the right) analyzed by flow cytometry.

[0157] Figure 4B -C shows live cells stained with anti-hFc APC antibody. Figure 4B ) and dead cells ( Figure 4CThe results of flow cytometry analysis were as follows. In Group 1, A20 Gal3 cells were not incubated with mTIM-3Fc protein as a control; in Group 2, A20 Gal3 cells were incubated with mTIM-3Fc protein; in Groups 3, 4, and 5, in addition to mTIM-3Fc protein, anti-mouse TIM-3 polyclonal antibody (R&D System, Minneapolis, MN) (Group 3), monoclonal antibody RMT3-23 (Bio Xcell, West Lebanon, NH) (Group 4), and monoclonal antibody 215015 (R&D Systems) (Group 5) were added to test whether these antibodies could block the binding of Gal3 and Tim3.

[0158] Figure 5A -C indicates the ELISA results, showing the specific binding of Gal3 to TIM-3. Figure 5A The study showed that plating plates coated with 10 μg / ml mGal3, mGal3 polyclonal antibody (mGal3pAb), and monoclonal antibody IMT001, instead of monoclonal antibody M3 / 38, blocked the interaction between Gal3 and Tim3. Figure 5B The results showed that lactose blocks Gal9, but not Gal3, from binding to TIM-3, indicating that the binding between Gal3 and Tim3 is sugar-independent. Figure 5C The antibody RMT3-23 was shown to block phosphatidylserine (PS), but not Gal3, from binding to TIM-3, indicating that the epitopes on TIM-3 that bind to Gal3 are different from those that bind to PS.

[0159] Figure 6A -B indicates that overexpressed Gal3 inhibits T cell activation. Figure 6A The mouse A20 cell clones #41, #31, and #15 were shown to overexpress Gal3. Figure 6B The study showed that when these cells were mixed with mouse DO11.10 T cells, they produced significantly less IL-2 compared to parental A20 cells.

[0160] Figure 7A -E indicates that the Gal3 antibody has antitumor activity in a lung metastasis model. Figure 7A High expression of Gal3 was observed on B16F10 tumor cells. Figure 7B Representative images of the entire lungs from the three treatment groups are shown. Figure 7C The number of metastatic colonies on the surface of the left lung lobe is shown (mean ± SEM). Figure 7D and Figure 7ELung weight and body weight (mean ± SEM) are shown in the different treatment groups. Animals treated with monoclonal anti-human Gal3 antibody showed a significant reduction in tumor number compared with animals treated with isotype control (p<0.01). Figure 7B Furthermore, the tumor burden, as indicated by lung weight, was significantly lower (p<0.05). Figure 7D However, animals treated with PD1 antibodies did not show a significant reduction in the number or burden of tumors in this lung metastasis model (p>0.05). Figure 7E Animals treated with either PD1 or Gal3 antibodies had similar body weights to the control group, indicating no side effects associated with the administration of either antibody.

[0161] Figure 8A -C indicates the antitumor activity of Gal3 antibody in 4T1 in situ tumor-induced lung metastases. Figure 8A Images show lung metastatic tumor colonies in mice that had been engrafted with 4T1 cells and then treated with either a control antibody (“isotype”) or IMT001. The antibody was administered intraperitoneally on days 0, 3, 7, 10, and 14 during a 30-day cycle. Images were taken on day 30 when the mice were euthanized. Figure 8B The weight measurements of these mice during the same period are shown. Figure 8C The number of tumor colonies metastasized on the surface of the left lung lobe of these mice was shown on day 30.

[0162] Figure 9 Tumor growth was shown in mice implanted with Renca tumor cells and mice treated with the Gal3 antibody. Mice treated with the Gal3 antibody (“IMT001”) showed a much smaller tumor size compared to mice implanted with Renca tumor cells and mice treated with an isotype control antibody (“iso”) (p<0.05), while the anti-mouse PD-1 antibody 29F had no effect (p>0.05).

[0163] Figure 10 Tumor growth was shown in mice implanted with MC38 colon cancer cells and mice treated with the anti-Gal3 antibody. Mice treated with the Gal3 antibody ("IMT001") showed significantly reduced tumor size compared to mice implanted with MC38 tumor cells and mice treated with an isotype control antibody ("iso") (p<0.05).

[0164] Figure 11A -D indicates the results of epitope mapping. Synthesized peptide arrays derived from the hGal3 protein sequence ( Figure 11A And dot blot analysis was performed using anti-Gal3 antibody IMT001. Figure 11BPeptides 5 and 6 showed strong signals indicating that the anti-Gal3 monoclonal antibody, IMT001, can bind to these peptides. To further map the binding epitopes of IMT001 on these peptides, several shorter peptides derived from these peptide sequences were synthesized. Figure 11C And their binding with IMT001 was measured by ELISA. Figure 11D The peptide with the sequence GQAPPGAYPG (SEQ ID NO:28) produced the highest signal.

[0165] Figure 12 The number of immune cells from mice implanted with B16F10 cells expressing various lymphocyte markers: CD3, CD4, CD8, CD19, or DX5 was summarized. These mice were treated with either an isotype control antibody or IMT001.

[0166] Figure 13A -B shows Gal3 expression on tumor-associated macrophages in human lung cancer as determined by immunohistochemistry (IHC). IMT001 was used to stain frozen sections of human lung cancer to detect Gal3 expression on tumor-associated macrophages. Figure 13A The results from stained squamous cell carcinoma were shown. Figure 13B This shows the results of staining from adenocarcinoma.

[0167] Figure 14A -C shows human M2 macrophages ( Figure 14C Instead of dendritic cells (DCs) Figure 14A ) or M1 macrophages ( Figure 14B The expression of Gal3 was detected on the )

[0168] Figure 15A -D indicates the immunomodulatory activity of the Gal3 antibody (“IMT001”) in the mouse macrophage / T cell response. Figure 15B Showing comparison with control ( Figure 15A In contrast, the expression of Gal3 in the mouse macrophage line RAW264.7 was detected by IHC. Figure 15C The expression of Gal3 in mouse macrophage lines was demonstrated by flow cytometry in cells stained with IMT001. The anti-Gal3 antibody IMT001, instead of the anti-mouse PD-1 antibody 29F, enhanced IL-2 production in RAW macrophage / DO11.10 T cell mixed responses. Figure 15D ).

[0169] Figure 16This study elucidates the ELISA assessment of GAL3-TIM3 interaction blockade via GAL3-binding antibodies. Results demonstrate that Gal3-targeting antibodies exhibit varying degrees of blockade against Gal3-TIM3 binding. The percentage of TIM3-GAL3 binding is shown in the absence of the antibody.

[0170] Figures 17A-17B The ELISA assessment of anti-GAL3 antibodies that bind to peptide fragments of GAL3 was explained. Figure 17A Antibodies mab1, mab3, mab4, and mab5; Figure 17B The antibodies mab2, mab3, mab6, and mab7 were used. The results demonstrated that Gal3-targeting antibodies exhibited different forms of blockade against Gal3-TIM3 binding.

[0171] Figure 18 The competitive binding assessment of anti-GAL3 antibodies to GAL3 by ELISA was elucidated. The results demonstrated that Gal3-targeting antibodies mab1 (801) and mab4 (804), but not mab5 (805), competitively bind to Gal3.

[0172] Figure 19A -C elucidates the binding and dissociation kinetics of anti-Gal3 antibodies and the biolayer interference measurement assessment of Gal3 (Gal3 binding antibody affinity). Figure 19A :mab1;kD=13.5nM.

[0173] Figure 19B :mab4;kD=1.2nM. Figure 19C :mab5;kD=32nM.

[0174] Figure 20 This study elucidated the evaluation of GAL3-enhanced CMV antigen recall in T-cell antigen-specific responses. The results demonstrated that Gal-3-targeting antibodies exhibited distinct T-cell activation through CMV-induced antigen recall.

[0175] Figure 21A -C elucidates the MALDI-MS identification of the GAL3 and TIM3 regions mediating the interaction between TIM3 and GAL3. Note that amino acid numbering is based on the protein as it matures after processing the signal peptide. See also Table 2. Figure 21A The potential sequences involved in the interface are explained. Figure 21B It elucidates the potential residues involved in the interaction. Figure 21C The sequence positions plotted on TIM-3 and Gal3 are illustrated. Note that the amino acid numbering is based on the mature protein after processing of the signal peptide.

[0176] Figure 22 Western blot analysis of fibrosis markers, α-smooth muscle actin (α-SMA), and fibronectin from renal tissue lysates of male unilateral urethral obstruction (UUO) mice or sham mice that were not treated with antibodies 14 days after ureteral ligation. GAPDH was used as a loading control.

[0177] Figure 23 Western blot analysis of fibrosis markers, α-SMA, and fibronectin, in liver tissue lysates from non-obese diabetic and inflammatory (N-IF) mice is shown. Animals were treated for 40 days with IMT001, anti-Gal3 antibody, and mIgG2b (control) antibody. GAPDH was used as a loading control.

[0178] Figure 24 The ability of the galactoglobulin-3 targeting antibody to block the binding of GAL3 and TIM3 was assessed by ELISA at a concentration of 3 μg / mL. The bars represent the mean plus or minus the standard deviation.

[0179] Figure 25 Comparison of the ability of GAL3 peptides to bind to GAL3-targeting antibodies that block GAL3-TIM3.

[0180] Figure 26 The galactolectin-3 binding antibody was identified by antibody competition. Values ​​indicate inhibition, as assessed using a biolayer interference analyzer.

[0181] Figure 27 The blocking effect of humanized anti-GAL3 antibody on GAL3-TIM3 was assessed by ELISA in a titration series. The plotted values ​​represent the mean plus / minus the standard deviation.

[0182] Figure 28A -D. Tumors transplanted with subcutaneous MBT2 and those treated with control, IMT001, anti-PD-L1 antibody or a combination thereof ( Figure 28A ), or use control, IMT001, anti-PD-1 antibody or a combination thereof ( Figure 28C Tumor volume in mice treated with anti-PD-L1 (anti-PD-L1) Figure 28B ) or anti-PD-1 ( Figure 28D The graph shows the tumor volume of each animal measured daily.

[0183] Figure 29A -D. Through gross histology ( Figure 29A ) and enumerated () Figure 29BThe formation of hepatocellular carcinoma was assessed in normal and STAM-CDAA mice treated with human IgG4 (huIgG4) or IMT001-4. Arrows highlight areas with tumors. Tumor formation was assessed in hematoxylin and eosin stained sections of liver samples. Figure 29C The arrows highlight areas with tumors. Serum α-fetoprotein (α-fetoprotein) levels in STAM-CDAA mice treated with huIgG4 or IMT001-4 were quantified. Figure 29D The circles indicate the average for each animal, and the lines indicate the average for each group.

[0184] Figure 30A -D. Hematoxylin and eosin stained sections of liver from MCD mouse models of NASH liver fibrosis treated with isotype control or miMT001. Figure 30A Histological findings based on image-quantified measurements of steatosis, hepatocellular ballooning degeneration, lobular inflammation, or NAFLD activity score (NAS). Figure 30B ). Liver samples stained with Picosirius red from mice treated as in (A) Figure 30C Based on image quantization Sirius red staining ( Figure 30D The bars represent the standard error of the mean plus or minus the mean for the seven animals.

[0185] Figure 31A -B. Sirius-stained liver samples from a STAM model of cholinergic deficiency with a CDAA-HFD (caused by isotype control or IMT001-4 treatment) of liver fibrosis. Figure 31A Based on image quantization of Sirius red staining ( Figure 31B The bars represent the standard error of the mean plus or minus the mean for each of the 5 domains from the 7 animals.

[0186] Figure 32A -C. Evaluate serum markers of renal fibrosis KIM-1 and NGAL in mice from a mouse model of unilateral ureteral obstruction (UUO) treated with isotype control, IMT001-4, IMT001-6, or metformin. Figure 32A ) and Sirius red stained kidney samples ( Figure 32B Image-based Sirius staining quantization Figure 32C The bars represent the standard error of the mean plus or minus the mean of three assessments for each of the seven animals in each group. The dots represent the average Sirius red staining of the individual animal, and the bars indicate the mean group value.

[0187] Figure 33A-B. IHC assessment of collagen 1a1 (Col1a1) deposition in kidney samples from UUO treated on day 1 after treatment with isotype control or mIMT001 ( Figure 33A The black arrows correspond to areas of collagen deposition. Quantitative analysis based on images (…). Figure 33B The bars represent the standard error of the mean plus or minus the mean for each of the 10 domains from each of the 7 animals in each group.

[0188] Figure 34A -B. Masson's trichrome staining assessment of pulmonary fibrosis in bleomycin-induced pulmonary fibrosis mouse models treated with isotype control or miMT001 ( Figure 34A Ashcroft score of tissue sections ( Figure 34B The bars represent the mean plus or minus the standard error of the mean for each of the 10 domains from each of the 8 animals in each group.

[0189] Figure 35A Some embodiments of the VH CDR region depict various implementations of anti-GAL3 antibodies. In some embodiments, any method or composition provided herein may include one or more of the CDRs provided herein, including one, two, or three of them.

[0190] Figure 35B Some embodiments of the VL CDR region depict various implementations of anti-GAL3 antibodies. In some embodiments, any method or composition provided herein may include one or more of the CDRs provided herein, including one, two, or three of them.

[0191] Figure 36A Some embodiments depicting the complete VH region of various implementations of anti-GAL3 antibodies are described herein. In some embodiments, any method or composition provided herein may include any of these VH regions.

[0192] Figure 36B Some embodiments depicting the complete VL region of various implementations of anti-GAL3 antibodies are described herein. In some embodiments, any method or composition provided herein may include any of these VL regions.

[0193] Figure 37 Various embodiments of GAL3 antibodies (including complete heavy chain or κ chain sequences) are depicted. In some embodiments, any one or more of the VH / VL and / or CDR provided in other figures can be combined with... Figure 37 Any one or more pairs of related sequences (e.g., the IgG4 portion or the κ sequence).

[0194] Figure 38A comparison of several embodiments depicting the VH CDR or VL CDR regions of various implementations of anti-Gal3 antibodies. In some embodiments, any methods or compositions provided herein may be used. Figure 38 The provided CDRs can be any 1, 2, 3, 4, 5, or 6.

[0195] Detailed description

[0196] Gal3 (Gal3, GAL3, or Gal-3) is expressed in a variety of cell types and is involved in a wide range of physiological and pathological processes, including cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, cell growth and differentiation, and tumor progression and metastasis. Gal3 is expressed on tumor cells and in the tumor microenvironment, such as tumor-associated macrophages, particularly M2 macrophages. Furthermore, it is involved in promoting fibroblast proliferation and transformation and mediating the activation of various profibrotic factors that contribute to collagen production. In addition, Gal3 is believed to play a crucial role in fibrosis in various tissues, including the liver, kidney, lung, and myocardium.

[0197] TIM-3 is a molecule expressed on immune cells, particularly T cells, and can suppress immune responses, such as T cell signaling, through its interaction with Gal3. Anti-Gal3 antibodies interfere with the interaction between Gal3 and TIM-3 and activate the immune response.

[0198] Tumors are often associated with immune infiltration as part of a reactive stroma enriched by macrophages. Tumor-associated macrophages (TAMs) play a crucial role in promoting tumor growth by facilitating angiogenesis and stroma degradation. When associated with tumors, macrophages exhibit functional polarization toward one of two phenotypically different macrophage subsets: M1 macrophages or M2 macrophages. M1 macrophages are known to produce pro-inflammatory cytokines and play an active role in cell destruction, while M2 macrophages primarily clear debris and promote angiogenesis and wound repair. Consequently, many tumors with abundant TAMs exhibit increased tumor growth rates, local proliferation, and distant metastasis. The M2 macrophage population phenotype is similar to that of the TAM population that promotes tumor growth and development. In some cases, in addition to expressing Gal3, M2 macrophages also express one or more cell surface markers selected from the group consisting of: CD206, IL-4r, IL-1ra, decoyIL-1r11, IL-10r, CD23, macrophage clearance receptors A and B, Ym-1, Ym-2, low-density receptor-associated protein 1 (LRP1), IL-6r, CXCR1 / 2, CD136, CD14, CD1a, CD1b, CD93, CD226, (FcyR), and PD-L1.

[0199] Tissue fibrosis is a progressive debilitating disease characterized by the massive accumulation of extracellular matrix (ECM) proteins such as collagen and fibronectin, leading to tissue scarring, organ damage, decreased organ function, and subsequent organ failure. Tissue fibrosis can occur in the kidneys, liver, lungs, heart, skin, pancreas, intestines, eyes, nervous system, joints, tendons, mediastinum, or retroperitoneum. Features of tissue fibrosis include epithelial and endothelial damage and dysfunction; abnormal proliferation of myofibroblasts (MFb), smooth muscle cells, and stellate cells; and ECM deposition. The presence of cytokines, chemokines, growth factors, and angiogenic factors further regulates the activation of ECM-producing cells during the pro-fibrotic process.

[0200] Galactolectin-3 (Gal3) is known to play important roles in cell proliferation, adhesion, differentiation, angiogenesis, and apoptosis. Furthermore, it is involved in promoting fibroblast proliferation and transformation and mediating the activation of various pro-fibrotic factors that contribute to collagen production. In addition, Gal3 is believed to play a crucial role in fibrosis in various tissues, including the liver, kidneys, lungs, and myocardium.

[0201] In some embodiments, this document discloses a method for reducing fibrosis or its tendency in tissues using anti-Gal3 antibodies. In some embodiments, reducing fibrosis or its tendency in tissues includes preventing fibrosis from occurring in normal tissues. In some embodiments, reducing fibrosis or its tendency in tissues includes slowing or halting the progression of fibrosis in fibrotic tissues. In some embodiments, reducing fibrosis or its tendency in tissues includes reducing the amount of fibrosis in fibrotic tissues. In some embodiments, reducing fibrosis or its tendency in tissues includes eliminating fibrosis in fibrotic tissues.

[0202] In some embodiments, this document also describes methods for monitoring the progression of tissue fibrosis by monitoring one or more fibrosis biomarkers. In other instances, this document discloses methods for treating tissue fibrosis with anti-Gal3 antibodies, wherein the anti-Gal3 antibody disrupts the interaction between Gal3 and TIM-3.

[0203] In the following detailed description, reference is made to the accompanying drawings, which form a part thereof. In the drawings, like symbols generally identify like components unless the context otherwise requires. The illustrative embodiments described in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter set forth herein. It will be readily understood that aspects of this disclosure, as generally described herein and illustrated in the drawings, can be arranged, substituted, combined, separated, and designed in a variety of different configurations, all of which are expressly contemplated herein.

[0204] Unless otherwise defined, the technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For the purposes of this disclosure, the following terms are defined as follows.

[0205] The articles “a” and “a kind” used in this article refer to one or more of the grammatical objects of the article (e.g., at least one). By example, “a kind of element” means one or more elements.

[0206] "About" means referring to a change in quality, level, value, quantity, frequency, percentage, size, size, amount, weight, or length as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%.

[0207] Throughout this specification, unless the context otherwise requires, the words “comprising,” “including,” and “containing” will be understood to imply inclusion of the stated steps or elements or groups of steps or elements, but do not exclude any other steps or elements or groups of steps or elements. “Comprising of” means to include and be limited to anything that follows the phrase “comprising of.” Therefore, the phrase “comprising of” indicates that the listed elements are necessary or mandatory, and that other elements may be absent. “Substantially comprising” means to include any elements listed accompanying the phrase, and is limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure of the listed elements. Therefore, the phrase “substantially comprising” indicates that the listed elements are necessary or mandatory, but other elements are optional and may be present or absent depending on whether they substantially affect the activity or action of the listed elements.

[0208] In some embodiments, an anti-Gal3 antibody or a binding fragment thereof, or a composition comprising an anti-Gal3 antibody or a binding fragment thereof, is provided. In some embodiments, a method is provided to block or disrupt the interaction between Gal3 and TGF-β receptors in vitro or in vivo using an anti-Gal3 antibody or a binding fragment thereof, or a composition comprising an anti-Gal3 antibody or a binding fragment thereof. In some embodiments, the method of blocking or disrupting the interaction between Gal3 and TIM-3 using an anti-Gal3 antibody or a binding fragment thereof, or a composition comprising an anti-Gal3 antibody or a binding fragment thereof, is used to treat, cure, or prevent a disease or disorder in a subject. In some embodiments, the disease or disorder is cancer, breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, or a hematologic malignancy. In some embodiments, the cancer is metastatic cancer, recurrent cancer, or refractory cancer. In some embodiments, the antibody is administered in combination with another therapeutic agent, such as an immune checkpoint inhibitor, a chemotherapeutic agent, a targeted therapy agent, a hormone therapy agent, or a stem cell-based therapeutic agent. In some implementations, the disease or disorder is fibrosis in tissues such as liver tissue, kidney tissue, skin tissue, lung tissue, heart tissue, brain tissue, intestinal tissue, bone marrow tissue, or soft tissue.

[0209] As used herein, the terms “individual,” “subject,” and “patient” mean any mammal or bird. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human, including but not limited to farm animals (e.g., cattle, pigs, horses, chickens, etc.), livestock, pets, primates, dogs, cats, mice, and rats. These terms do not require or limit the use of supervision (e.g., continuous or intermittent) characterized by a healthcare worker (e.g., a physician, registered nurse, registered nurse, physician assistant, healthcare professional, or hospice worker).

[0210] As used herein, the terms “polypeptide,” “peptide,” and “protein,” used interchangeably herein, refer to polymers of amino acids of any length. Polymers may be linear, cyclic, or branched; they may include modified amino acids and may be interrupted by non-amino acid components. The term also covers polymers of modified amino acids, for example, those modified by sulfation, glycosylation, lipidation, acetylation, phosphorylation, iodination, methylation, oxidation, proteolytic processing, phosphorylation, isopreneation, racemization, selenization, transfer-RNA-mediated addition of amino acids to form proteins, such as arginination, ubiquitination, or any other manipulation, such as conjugation with a labeled component.

[0211] As used herein, the term “amino acid” refers to natural and / or non-natural or synthetic amino acids, including both glycine and its D or L optical isomers, as well as amino acid analogs and peptide mimics.

[0212] "Derived from" a specified protein refers to the source of the polypeptide or amino acid sequence. Preferably, the polypeptide has an amino acid sequence or a portion thereof that is substantially identical to the amino acid sequence of the polypeptide encoded in the sequence, wherein the portion consists of at least 10-20 amino acids, or at least 20-30 amino acids, or at least 30-50 amino acids, or is immunologically identifiable with the polypeptide encoded in the sequence. The term also includes polypeptides expressed from a specified nucleic acid sequence.

[0213] As used herein, the term "antibody" is intended to encompass any polypeptide chain-containing molecular structure having a specific shape suitable for recognizing epitopes, wherein one or more non-covalently binding interactions stabilize the complex between the molecular structure and the epitope. The antibodies utilized in this invention may be polyclonal antibodies, although monoclonal antibodies are preferred because they can be replicated through cell culture or recombinant methods and can be modified to reduce their antigenicity.

[0214] In addition to whole immunoglobulins (or their recombinant counterparts), immunoglobulin fragments or “binding fragments” including epitope binding sites (e.g., Fab’, F(ab’)2, single-chain variable fragments (scFv), biantibodies, microantibodies, nanobodies, single-domain antibodies (sdAb), or other fragments) can be used as antibody portions in this invention. Such antibody fragments can be generated from whole immunoglobulins by cleavage with ricin, pepsin, papain, or other proteases. Minimal immunoglobulins can be designed using recombinant immunoglobulin technology. For example, the “Fv” immunoglobulin used in this invention can be generated by linking a variable light chain region to a variable heavy chain region via a peptide linker (e.g., polyglycine or another sequence that does not form an α-helix or β-sheet motif). Nanobodies or single-domain antibodies can also be derived from alternative organisms such as dromedary camels, camels, llamas, alpacas, or sharks. In some embodiments, the antibody can be a conjugate, such as a PEGylated antibody, a drug, a radioisotope, or a toxin conjugate. Monoclonal antibodies targeting specific epitopes or combinations of epitopes will allow for the targeting and / or consumption of cell populations expressing biomarkers. Various techniques can be used to screen cell populations expressing biomarkers using monoclonal antibodies, including magnetic separation using antibody-coated magnetic beads, antibody “panning” using antibodies attached to a solid matrix (i.e., a plate), and flow cytometry (e.g., U.S. Patent No. 5,985,660, which is expressly incorporated herein by reference in its entirety).

[0215] As used herein, the term “humanization” for non-human (e.g., rodent or primate) antibodies refers to a hybrid immunoglobulin, immunoglobulin chain or fragment thereof containing a minimal sequence derived from a non-human immunoglobulin.

[0216] The “variable region” of an antibody refers to the variable region of the antibody light chain alone or in combination, or the variable region of the antibody heavy chain. As is known in the art, the variable regions of the heavy and light chains each consist of four frame regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions, and contribute to the formation of the antigen-binding site of the antibody. If a variant of the subject variable region is desired, particularly having substitutions in amino acid residues outside the CDR regions (i.e., in the frame regions), appropriate amino acid substitutions can be identified by comparing the subject variable region with the variable regions of other antibodies containing CDR1 and CDR2 sequences in the same canonical class as the subject variable region, preferably conserved amino acid substitutions (Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987).

[0217] In some embodiments, the precise characterization of the CDR and the identification of residues, including the antibody binding site, are accomplished by resolving the structure of the antibody and / or the antibody-ligand complex. In some embodiments, this can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In some embodiments, various analytical methods can be employed to identify or approximate the CDR region. Examples of such methods include, but are not limited to, Kabat definition, Chothia definition, IMGT method (Lefranc et al., 2003) Dev Comp Immunol. 27:55-77), computational programs such as Paratome (Kunik et al., 2012, Nucl Acids Res. W521-4), AbM definition, and conformational definition.

[0218] Kabat definitions are the standard for numbering residues in antibodies and are commonly used to identify CDR regions. See, for example, Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8. Chothia definitions are similar to Kabat definitions, but Chothia definitions take into account the location of certain structural loop regions. See, for example, Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83. AbM definitions use an integrated set of computer programs generated by the Oxford Molecular Group, which models antibody structures. See, for example, Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; “AbM.TM., A Computer Program for Modeling Variable Regions of Antibodies”, Oxford, UK; Oxford Molecular, Ltd. AbM definitions use a combination of knowledge databases and ab initio methods to model the tertiary structure of antibodies derived from primary sequences, such as those described by Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” PROTEINS, Structural, Function and Genetics Suppl., 3:194-198. Contact definitions are based on the analysis of available complex crystal structures. See, for example, MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to here as the “conformational definition” of CDRs, the positions of CDRs can be identified as residues that contribute enthalpy to antigen binding. See, for example, Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Other CDR boundary definitions may not strictly follow one of the methods above, but will still overlap with at least a portion of the Kabat CDR, although they may be shortened or lengthened based on predictions or experimental findings that a particular residue or group of residues does not significantly affect antigen binding. As used herein, a CDR can refer to a CDR defined by any method known in the art, including combinations of methods. The methods used herein can utilize CDRs defined according to any of these methods.In some embodiments containing more than one CDR, the CDR may be defined according to any one of the following conformational definitions: Kabat, Chothia, extended, IMGT, Paratome, AbM, and / or, or any combination thereof. In some embodiments, the residues in the variable region are numbered using the IMGT numbering system. In the sequences provided herein, the CDRs are plotted according to IMGT (https: / / world wide web.Ebi.ac.uk / ipd / imgt / hla / align.html).

[0219] As is known in the art, the “constant region” of an antibody refers to the constant region of the antibody light chain, alone or in combination, or the constant region of the antibody heavy chain.

[0220] As used herein, the term "competitive" with respect to antibodies means that a first antibody or its antigen-binding moiety binds to an epitope in a manner sufficiently similar to that of a second antibody or its antigen-binding moiety, such that the binding of the first antibody to its homologous epitope is detectably reduced in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. Alternatives to this, where the binding of the second antibody to its epitope is also detectably reduced in the presence of the first antibody, may be, but are not necessarily, in this case. That is, the first antibody may inhibit the binding of the second antibody to its epitope, while the second antibody does not inhibit the binding of the first antibody to its corresponding epitope. However, when each antibody detectably inhibits the binding of another antibody to its homologous epitope or ligand, whether to the same, greater, or lesser extent, antibodies are referred to as "cross-competing" with each other for binding to their respective epitopes. This invention covers competitive and cross-competitive antibodies. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope or a portion thereof), those skilled in the art will recognize, based on the teachings provided herein, that antibodies encompassing such competitive and cross-competitive antibodies can be used in the methods disclosed herein.

[0221] Antibodies that “preferentially bind” or “specifically bind” (as used interchangeably herein) to epitopes are well understood terms in the art, and methods for determining such specificity or preferential binding are well known in the art. A molecule is said to “specifically bind” or “preferentially bind” if it reacts or associates with a particular cell or substance more frequently and / or more rapidly, and / or with a longer duration and / or greater affinity, compared to its association with alternative cells or substances. An antibody is said to “specifically bind” or “preferentially bind” to a target if, compared to its association with other substances, it binds with greater affinity and / or avidity, and / or more readily, and / or with a longer duration. For example, an antibody that specifically or preferentially binds to a CFD epitope is an antibody that binds to that epitope with greater affinity and / or avidity, and / or more readily, and / or with a longer duration, compared to its association with other CFD or non-CFD epitopes. Reading this definition also helps to understand that, for example, an antibody (or part or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Therefore, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, mentioning binding implies preferential binding.

[0222] As used herein, “substantially pure” means a substance that is at least 50% pure (i.e., free of contaminants), more preferably at least 90% pure, more preferably at least 95% pure, even more preferably at least 98% pure, and most preferably at least 99% pure.

[0223] "Host cell" includes individual cells or cell cultures that can be, or have been, a recipient of a vector for incorporating a polynucleotide intercalation. Host cells include progeny of a single host cell, and progeny may not necessarily be identical to the original parent cell due to natural, accidental, or intentional mutations (in morphological or genomic DNA complementarity). Host cells include cells transfected in vivo with the polynucleotides of this invention.

[0224] As is known in the art, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. The "Fc region" can be a native sequence Fc region or a variant Fc region. Although the boundaries of the immunoglobulin heavy chain Fc region may vary, the human IgG heavy chain Fc region is generally defined as extending from an amino acid residue at position Cys226 or Pro230 to its C-terminus. The residues in the Fc region are numbered using EU index numbers, as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The Fc region of an immunoglobulin typically contains two constant domains, CH2 and CH3. As is known in the art, the Fc region can exist in dimer or monomeric form.

[0225] As used herein, “vector” means a construct capable of delivering and preferably expressing one or more genes or sequences of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmids, granules or phage vectors, DNA or RNA expression vectors associated with cationic condensers, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as production cells.

[0226] As used in this article, "expression regulatory sequence" means the nucleic acid sequence that guides nucleic acid transcription. The expression regulatory sequence can be a promoter, such as a constitutive or inducible promoter, or an enhancer. The expression regulatory sequence is operatively linked to the nucleic acid sequence to be transcribed.

[0227] As used herein, “pharmaceuticalally acceptable carrier” or “pharmaceuticalally acceptable excipient” includes any material that, when combined with an active ingredient, allows that ingredient to remain biologically active and does not react with the subject’s immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline, water, emulsions such as oil / water emulsions, various types of wetting agents, detergents such as polysorbate 20 to prevent aggregation, and sugars such as sucrose as cryoprotectants. Preferred diluents for aerosol or parenteral administration are phosphate-buffered saline (PBS) or normal (0.9%) saline. Compositions including such carriers are formulated using well-known, conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990 and Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0228] As used in this article, the term "k" 结合 "This refers to the rate constant of antibody (or bioconjugate) binding to antigen. Specifically, the rate constant (k) is measured using full-length antibodies and / or Fab antibody fragments (i.e., monovalent) and CFD." 结合 and k 解离 ) and equilibrium dissociation constant.

[0229] As used in this article, the term "k" 解离 "Refers to the rate constant of antibody (or bioconjugate) dissociation from antibody / antigen complex."

[0230] As used in this article, the term "K" D "Refers to the equilibrium dissociation constant of antibody-antigen (or bioconjugate-antigen) interaction."

[0231] As used herein, the term “treatment” (and as is well understood in the art) means a method for obtaining a beneficial or desired outcome, including clinical outcomes, in a subject’s condition. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, reduction of the severity of the disease, stabilization (i.e., non-exacerbation) of the disease state, prevention of the transmission or spread of the disease, delay or slowing of disease progression, improvement or relief of the disease state, reduction of disease relapse, and remission, whether partial or complete, detectable or undetectable. “Treatment” as used herein also includes preventative treatment. Treatment methods include administering a therapeutically effective amount of an active agent to a subject. Administration steps may consist of a single administration or may include a series of administrations. The composition is administered to the subject in an amount and duration sufficient to treat the patient. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the patient’s age and genetic characteristics, the concentration of the active agent, the activity of the composition used in the treatment, or combinations thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. Changes in dosage can be caused by standard diagnostic assays known in the art and become apparent. In some embodiments, prolonged administration may be required.

[0232] The term "administration" includes oral administration, local contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or administration via implanted sustained-release devices, such as microosmotic pumps, to the subject. Administration can be via any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. "Co-administration" means administering the first compound described herein concurrently with, or immediately before, the administration of the second compound described herein.

[0233] As used herein, the term "therapeutic target" refers to a gene or gene product that, upon modulation of its activity, can provide regulation of a disease phenotype (e.g., fibrosis or cancer) (e.g., by regulating expression, biological activity, etc.). As used throughout, "regulation" means an increase or decrease in the phenomenon referred to (e.g., regulation of biological activity means an increase or decrease in biological activity).

[0234] The terms “cancer,” “tumor,” “carcinoma,” and “carcinoma,” used interchangeably herein, refer to cells exhibiting relatively autonomous growth such that they display an abnormal growth phenotype characterized by significantly uncontrolled cell proliferation. Generally, cells of interest for detection or treatment in this application include precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. Detection of cancer cells is of particular interest. The term “normal” as used in the context of “normal cells” means cells that have not undergone a transformation phenotype or exhibit the morphology of non-transformed cells displaying the tissue type being examined. “Cancerous phenotype” generally refers to any of a variety of biological phenomena characteristic of cancer cells, which can vary depending on the type of cancer. Cancerous phenotypes are typically identified by abnormalities in, for example, cell growth or proliferation (e.g., uncontrolled growth or proliferation), cell cycle regulation, cell motility, cell-cell interactions, or metastasis.

[0235] The term "tumor microenvironment" refers to the cellular environment in which the tumor exists, including tumor cells and surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signal transduction molecules, and the extracellular matrix.

[0236] The term "immune cells" refers to hematopoietic cells that participate in the specific recognition of antigens. Immune cells include antigen-presenting cells (APCs), such as dendritic cells or macrophages, B cells, T cells, natural killer cells, and bone marrow cells, such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes.

[0237] The term "immune response" refers to a T-cell-mediated, NK-cell-mediated, macrophage-mediated, and / or B-cell-mediated immune response. Exemplary immune responses include B-cell responses (e.g., antibody production), NK-cell responses, or T-cell responses (e.g., cytokine production and cytotoxicity) and activation of cytokine-responsive cells, such as macrophages. The term "activating an immune response" refers to enhancing a T-cell-mediated and / or B-cell-mediated immune response using methods known to those skilled in the art. In some embodiments, the enhancement level is at least 20-50%, alternatively at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 120%, at least 150%, or at least 200%.

[0238] As used herein, the term "transforming growth factor β receptor" (TGF-β receptor) refers to a family of serine / threonine kinase receptors expressed on the cell surface that are specific to the protein transforming growth factor β (TGF-β). The interaction between TGF-β and its receptor triggers signaling pathways responsible for many functions, including but not limited to cell growth, differentiation (e.g., stem cells, immune cells), apoptosis, homeostasis, chemotaxis, inflammation, and immune cell activation.

[0239] As used herein, the term "fibrosis" refers to a medical condition in which tissues or organs harden or scar due to the unregulated production of extracellular matrix proteins such as collagen. Fibrosis is associated with chronic inflammation, in which immune cells, such as macrophages, signal fibroblasts to express extracellular matrix proteins in response. This signaling is achieved through pathways such as the TGF-β pathway, although other pro-fibrotic pathways also exist. Fibrosis includes, but is not limited to, liver fibrosis, bridging fibrosis, cirrhosis, kidney fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, cardiovascular fibrosis, arterial fibrosis, venous thrombosis, cardiac fibrosis, pulmonary artery fibrosis, joint fibrosis, Crohn's disease, Dupuitren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peronis disease, renal systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or systemic sclerosis.

[0240] The terms “%w / w” or “%wt / wt” mean the percentage expressed as the weight of an ingredient or reagent as a percentage of the total weight of the composition multiplied by 100.

[0241] In some embodiments, this document discloses methods for inducing immune activation, including contacting an anti-Gal3 antibody with a variety of cells, including Gal3-expressing cells and TIM-3-expressing cells. In some embodiments, this document discloses methods for reducing fibrosis, including contacting a tissue comprising Gal3-expressing cells and at least one fibrosis biomarker with an anti-Gal3 antibody for a sufficient time to reduce the expression of at least one fibrosis biomarker in the tissue. In some embodiments, the anti-Gal3 antibody results in a reduction in the accumulation of one or more extracellular matrix proteins in the tissue, including but not limited to collagen.

[0242] In some cases, upon binding to anti-Gal3 antibodies, Gal3-expressing cells express cytokines that induce immune activation. In some cases, the cytokines are interferons. In some cases, the interferon is IFNγ. In some cases, IFNγ production is 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 300%, 400%, 500%, 600%, or more of the IFNγ produced by the allotype antibody. In some cases, IFNγ production is 150% of the IFNγ produced by the allotype antibody. In some cases, IFNγ production is 160% of the IFNγ produced by the allotype antibody. In some cases, IFNγ production is 170% of the IFNγ produced by the allotype antibody. In some cases, IFNγ production is 180% of the IFNγ produced by the allotype antibody. In some cases, IFNγ production is 190% of that produced by the alloantibody. In some cases, IFNγ production is 200% of that produced by the alloantibody. In some cases, IFNγ production is greater than 200% of that produced by the alloantibody. In some cases, IFNγ production is greater than 300% of that produced by the alloantibody. In some cases, IFNγ production is greater than 400% of that produced by the alloantibody. In some cases, IFNγ production is greater than 500% of that produced by the alloantibody. In some cases, the cytokine is interleukin. In some cases, the interleukin is IL-2.

[0243] In some cases, immune activation includes the proliferation of CD3+ T lymphocytes, CD4+ helper T cells, CD8+ cytotoxic T cells, natural killer (NK) cells, or a combination thereof. In some cases, immune activation includes the proliferation of CD3+ T lymphocytes. In some cases, immune activation includes the proliferation of CD4+ helper T cells. In some cases, immune activation includes the proliferation of CD8+ cytotoxic T cells. In some cases, immune activation includes the proliferation of NK cells. In some cases, immune activation includes the proliferation of both T cells and NK cells.

[0244] In some cases, immune activation involves an increase in the intracellular M1 macrophage population across multiple cell types. In other cases, immune activation involves a decrease in the intracellular M2 macrophage population across multiple cell types. In still others, immune activation involves both an increase in the intracellular M1 macrophage population and a decrease in the intracellular M2 macrophage population across multiple cell types.

[0245] In some cases, anti-Gal3 antibodies bind to Gal3 and disrupt the interaction between Gal3 and TIM-3. In some cases, disruption of the Gal3-TIM-3 interaction includes partial inhibition of this interaction. In some cases, disruption of the Gal3-TIM-3 interaction includes complete inhibition of this interaction. In some cases, the Gal3-TIM-3 interaction is reduced to less than 99%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 59%, less than 55%, less than 50%, less than 45%, less than 40%, less than 34%, less than 30%, less than 25%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In some cases, the Gal3-TIM-3 interaction is reduced to less than 70%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 60%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 59%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 50%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 40%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 34%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 30%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 20%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 14%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 10%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 7%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 5%. In some cases, the Gal3-TIM-3 interaction was reduced to less than 4%. In some cases, Gal3-TIM-3 interactions were reduced to less than 1%.

[0246] In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 selected from regions 145-168, 160-177, or 165-184, wherein the residue positions correspond to positions 145-168, 160-177, or 165-184 of SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 from regions 160-177, wherein the residue positions correspond to positions 160-177 of SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 from regions 165-184, wherein the residue positions correspond to positions 165-184 of SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 selected from regions 149-156, 152-168, 163-169, or 163-171, wherein the residue positions correspond to positions 149-156, 152-168, 163-169, or 163-171 in SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 from regions 149-156, wherein the residue positions correspond to positions 149-156 in SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 from regions 152-168, wherein the residue positions correspond to positions 152-168 in SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 from regions 163-169, where the residue positions correspond to positions 163-169 of SEQ ID NO:1. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of Gal3 from regions 163-171, where the residue positions correspond to positions 163-171 of SEQ ID NO:1.

[0247] In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 selected from regions 91-111 or 82-111, where the residue positions correspond to positions 91-111 or 82-111 of SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 91-111, where the residue positions correspond to positions 91-111 of SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 82-111, where the residue positions correspond to positions 82-111 of SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 selected from regions 91-111, 107-117, 96-102, 100-106, or 92-119, where the residue positions correspond to positions 91-111, 107-117, 96-102, 100-106, or 92-119 in SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 91-111, where the residue positions correspond to positions 91-111 in SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 107-117, where the residue positions correspond to positions 107-117 in SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 96-102, where the residue positions correspond to positions 96-102 of SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 100-106, where the residue positions correspond to positions 100-106 of SEQ ID NO:2. In some cases, the interaction between Gal3 and TIM-3 occurs at one or more residues of TIM-3 from regions 92-119, where the residue positions correspond to positions 92-119 of SEQ ID NO:2. In some cases, TIM-3 is human TIM-3.

[0248] In some embodiments, methods for promoting the proliferation of T cells or natural killer (NK) cells are disclosed herein, including exposing a plurality of cells, including T cells, NK cells, and Gal3-expressing cells, to an anti-Gal3 antibody for a sufficient period of time to promote the proliferation of T cells or NK cells in the plurality of cells. In some embodiments, methods for promoting the proliferation of T cells and natural killer (NK) cells are disclosed herein, including exposing a plurality of cells, including T cells, NK cells, and Gal3-expressing cells, to an anti-Gal3 antibody for a sufficient period of time to promote the proliferation of T cells and NK cells in the plurality of cells. In some embodiments, the plurality of cells further includes TIM-3-expressing cells. In some embodiments, the anti-Gal3 antibody binds to Gal3 and disrupts the interaction between Gal3 and TIM-3. In some embodiments, the anti-Gal3 antibody binds to Gal3 and disrupts the interaction between Gal3 and TIM-3 by more than 25%, more than 50%, more than 100%, or more than 200%.

[0249] In some embodiments, the multiple cells further include tumor-infiltrating lymphocytes (TILs). In some cases, the multiple cells further include CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, or combinations thereof. In some cases, the multiple cells further include CD3+ T lymphocytes. In some cases, the multiple cells further include CD4+ T helper cells. In some cases, the multiple cells further include CD8+ cytotoxic T cells. In some cases, the multiple cells further include both CD3+ T lymphocytes and CD4+ T helper cells. In some cases, the multiple cells further include both CD3+ T lymphocytes and CD8+ cytotoxic T cells. In some cases, the multiple cells further include both CD4+ T helper cells and CD8+ cytotoxic T cells. In some cases, the multiple cells further include both CD3+ T lymphocytes, CD4+ T helper cells, and CD8+ cytotoxic T cells.

[0250] In some embodiments, contact further induces TIL proliferation. In some cases, contact further induces the proliferation of CD3+ T lymphocytes, CD4+ helper T cells, CD8+ cytotoxic T cells, or combinations thereof. In some cases, contact further induces the proliferation of CD3+ T lymphocytes. In some cases, contact further induces the proliferation of CD4+ helper T cells. In some cases, contact further induces the proliferation of CD8+ cytotoxic T cells. In some cases, contact further induces the proliferation of both CD3+ T lymphocytes and CD4+ helper T cells. In some cases, contact further induces the proliferation of both CD3+ T lymphocytes and CD8+ cytotoxic T cells. In some cases, contact further induces the proliferation of both CD4+ helper T cells and CD8+ cytotoxic T cells. In some cases, contact further induces the proliferation of CD3+ T lymphocytes, CD4+ helper T cells, and CD8+ cytotoxic T cells.

[0251] In some embodiments, the contact further includes an increase in M1 macrophage proliferation. In some embodiments, the contact further includes a decrease in the M2 macrophage population within the TME. In some embodiments, the contact further includes an increase in M1 macrophage proliferation and a decrease in the M2 macrophage population within the TME.

[0252] In some embodiments, the anti-Gal3 antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 1-20 of SEQ ID NO:1. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 41-91 of SEQ ID NO:1. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 41-71 of SEQ ID NO:1. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 71-91 of SEQ ID NO:1. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within peptide 1, peptide 4, peptide 5, peptide 6, peptide 7, or peptide 8. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within peptide 1. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within peptide 4. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue within peptide 5. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue in peptide 6. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue in peptide 7. In some cases, the anti-Gal3 antibody binds to at least one amino acid residue in peptide 8.

[0253] In some embodiments, the anti-Gal3 antibody includes binding affinity (K0) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM. D) In some embodiments, the anti-Gal3 antibody comprises less than 1 nM of K. D In some embodiments, the anti-Gal3 antibody comprises less than 1.2 nM of K. D In some embodiments, the anti-Gal3 antibody comprises less than 2 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 5 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 10 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 13.5 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 15 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 20 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 25 nM of K+. D In some embodiments, the anti-Gal3 antibody comprises less than 30 nM of K+. D .

[0254] In some embodiments, anti-Gal3 antibodies comprise humanized antibodies. In other embodiments, anti-Gal3 antibodies comprise chimeric antibodies. In some cases, anti-Gal3 antibodies comprise full-length antibodies or their binding fragments. In some cases, anti-Gal3 antibodies comprise bispecific antibodies or their binding fragments. In some cases, anti-Gal3 antibodies comprise monovalent Fab', bivalent Fab2, single-chain variable fragments (scFv), biantibodies, microantibodies, nanobodies, single-domain antibodies (sdAbs), or camelified antibodies or their binding fragments.

[0255] In some embodiments, the anti-Gal3 antibody is a bispecific antibody or a binding fragment thereof. Exemplary forms of bispecific antibodies include, but are not limited to, knobs-into-holes (KiH), asymmetric reengineering technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibodies (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), ELISA readers, bispecific binding agents based on T-cell receptors (BEAT), bispecific T-cell binding agents (BiTE), biclonal antibodies, Fab-scFv-Fc, dual-action Fab (DAF), FinomAb, scFv-Fc-(Fab)-fusion, docking and locking (DNL), Adaptir (formerly SCORPION), tandem biantibodies (TandAb), dual-affinity retargeting (DART), nanobodies, tripois, tandem scFv (taFv), trihead, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH. In some cases, anti-Gal3 antibodies are bispecific antibodies or their binding fragments, including those described in Brinkmann and Kontermann, “The making of bispecific antibodies,” MABS 9(2):182-212 (2017). Figure 2 The bispecific antibody form explained in the text.

[0256] In some embodiments, the anti-Gal3 antibody includes a frame region selected from IgM, IgG (e.g., IgG1, IgG2, IgG3, or IgG4), IgA, or IgE. In some cases, the anti-Gal3 antibody includes an IgM frame. In some cases, the anti-Gal3 antibody includes an IgG (e.g., IgG1, IgG2, IgG3, or IgG4) frame. In some cases, the anti-Gal3 antibody includes an IgG1 frame. In some cases, the anti-Gal3 antibody includes an IgG2 frame. In some cases, the anti-Gal3 antibody includes an IgG4 frame. In some embodiments, the anti-Gal3 antibody may further include an Fc mutation. In some embodiments, Figure 37 Any one or more of the Fc or κ regions in this text can be related to the present article, including Figures 35A-36B Any CDR, VH / VL sequence pairing.

[0257] In some embodiments, anti-Gal3 antibodies include one or more mutations in the framework region, such as the CH1 domain, CH2 domain, CH3 domain, hinge region, or combinations thereof. In some cases, one or more mutations regulate Fc receptor interactions, for example, to increase Fc effector functions such as ADCC and / or complement-dependent cytotoxicity (CDC). In some cases, one or more mutations stabilize the antibody and / or increase its half-life. In other cases, one or more mutations regulate glycosylation.

[0258] In some embodiments, the Fc region includes one or more mutations that regulate Fc receptor interactions, for example, to enhance effector functions such as ADCC and / or CDC. In this embodiment, exemplary residues that regulate effector function when mutated include S228, S239, K326, A330, I332, or E333, wherein the residue positions correspond to IgG1 and the residue numbering is based on Kabat numbering (EU index of Sequences of Proteins of Immunological Interest, Kabat et al., 1991). In some embodiments, one or more mutations include S228P, S239D, K326W, A330L, I332E, E333A, E333S, or combinations thereof. In some cases, one or more mutations include S228P, S239D, I332E, or combinations thereof. In some cases, one or more mutations include S228P, S239D, A330L, I332E, or combinations thereof. In some cases, one or more mutations include K326W, E333S, or combinations thereof. In some cases, the mutation includes E333A. In some embodiments, the Fc region is the IgG4 Fc region. In some embodiments, the S228P mutation is located in the hinge region of IgG4. In some embodiments, the S228P mutation enhances the stability of IgG4 by preventing Fab arm exchange.

[0259] In some embodiments, the anti-Gal3 antibody includes a humanization score quantified as the overall sequence similarity of the humanized antibody compared to IMGT-cured humanoid antibodies. In some embodiments, the anti-Gal3 antibody includes a humanization score quantified as the overall sequence similarity of the humanized antibody compared to IMGT-cured humanoid antibodies. In some embodiments, the anti-Gal3 antibody includes a humanization score of 70 or higher, 80 or higher, 81 or higher, 82 or higher, 83 or higher, 84 or higher, 85 or higher, 86 or higher, 87 or higher, 88 or higher, 89 or higher, 90 or higher, or 95 or higher. In some embodiments, the anti-Gal3 antibody includes a humanization score of 80 or higher. In some embodiments, the anti-Gal3 antibody includes a humanization score of 83 or higher. In some embodiments, the anti-Gal3 antibody includes a humanization score of 85 or higher. In some embodiments, the anti-Gal3 antibody includes a humanization score of 87 or higher. In some embodiments, the anti-Gal3 antibody includes a humanization score of 90 or higher. In some cases, anti-Gal3 antibodies include humanization scores of 70 or higher for the heavy chain, 80 or higher, 81 or higher, 82 or higher, 83 or higher, 84 or higher, 85 or higher, 86 or higher, 87 or higher, 88 or higher, 89 or higher, 90 or higher, or 95 or higher, and optionally 80 or higher, 85 or higher, or 87 or higher. In some cases, anti-Gal3 antibodies include humanization scores of 70 or higher for the light chain, 80 or higher, 81 or higher, 82 or higher, 83 or higher, 84 or higher, 85 or higher, 86 or higher, 87 or higher, 88 or higher, 89 or higher, 90 or higher, or 95 or higher, and optionally 80 or higher, 83 or higher, or 85 or higher.

[0260] In some embodiments, the anti-Gal3 antibody includes complementarity-determining regions (CDRs) as provided herein. In some embodiments, the CDR is a portion of the antibody heavy chain (VH). In some embodiments, the CDR is a portion of the light chain (VL). In some embodiments, the VH includes VH CDR1, VH CDR2, and / or VH CDR3. In some embodiments, VH CDR1 includes one of the sequences in SEQ ID NO: 37-64. In some embodiments, VH CDR2 includes one of the sequences in SEQ ID NO: 65-92. In some embodiments, VH CDR3 includes one of the sequences in SEQ ID NO: 93-120. In some embodiments, the VL includes VL CDR1, VL CDR2, and / or VL CDR3. In some embodiments, VL CDR1 includes one of the sequences in SEQ ID NO: 121-148. In some embodiments, VL CDR2 includes one of the sequences in SEQ ID NO: 149-176. In some embodiments, VL CDR3 includes one of the sequences of SEQ ID NO:177-204. In some embodiments, VH includes one of the sequences of SEQ ID NO:205-232. In some embodiments, VL includes one of the sequences of SEQ ID NO:233-260. In some embodiments, the anti-Gal3 antibody includes an hIgG4 constant region. In some embodiments, the hIgG4 constant region includes an hIgG4 constant region sequence from SEQ ID NO:261, 263, 265, or 267. In some embodiments, the anti-Gal3 antibody includes an hκ constant region. In some embodiments, the hκ constant region includes an hκ constant region sequence from SEQ ID NO:262, 264, 266, or 268.

[0261] In some implementations, anti-Gal3 includes Figure 35AThe sequences depicted in -B, 36A-B, or 37. In some embodiments, the anti-Gal3 antibody is selected from the group consisting of: 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, 15G7.2A7. 19B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8 and mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, 15G7.2A7, 19 B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8, or mIMT001 or any combination thereof. In some embodiments, the anti-Gal3 antibody is mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is not mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is 4A11.2B5. In some embodiments, the anti-Gal3 antibody is mIMT001 and / or 4A11.2B5. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 HCDRs from mIMT001 and / or 4A11.2B5. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 LCDRs from mIMT001 and / or 4A11.2B5. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 HCDRs from mIMT001 and / or 4A11.2B5 and 1, 2, or 3 LCDRs from mIMT001 and / or 4A11.2B5, optionally having 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.In some embodiments, the anti-Gal3 antibody comprises one, two, or three HCDRs from mIMT001 and / or 4A11.2B5 and one, two, or three LCDRs from mIMT001 and / or 4A11.2B5, and further comprises mIMT001 and / or 4A11.2B5 VH and VL sequences (e.g.). Figure 36A and 36B (The sequence shown in the image) or is at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to the VH and VL sequences.

[0262] In some embodiments, the anti-Gal3 antibody is any one of IMT001-4, IMT006-1, IMT006-5, or IMT006-8. In some embodiments, the anti-Gal3 antibody is any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 HCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 LCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 HCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8, and 1, 2, or 3 LCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8. In some embodiments, the anti-Gal3 antibody comprises 1, 2, or 3 HCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8, and 1, 2, or 3 LCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8, optionally having 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions therein. In some embodiments, the anti-Gal3 antibody comprises one, two, or three HCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8 and one, two, or three LCDRs from any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8, and further comprises any one of the VH and VL sequences of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8 (e.g., ...). Figure 36A and36B (The sequence shown in the image) or is at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to the VH and VL sequences.

[0263] In some implementations, the anti-GAL3 antibody competitively binds to one or more of the following: 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, and 15G7.2. A7, 19B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8 and mIMT001 (IMT001).

[0264] In some implementations, the anti-Gal3 antibody includes at least Figures 35A-36B Any of the antibodies containing HCDR3. In some embodiments, the anti-GAL3 antibody further includes... Figures 35A-36B The antibody contains all three HCDRs. In some embodiments, the anti-GAL3 antibody further includes... Figures 35A-36B All three LCDRs within any one of the antibodies.

[0265] In some implementations, the anti-Gal3 antibody includes Figure 36A Any of the inner heavy chain sequences, or sequences that are at least 80% identical to them, such as 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identical to them.

[0266] In some implementations, the anti-Gal3 antibody includes Figure 36B Any of the inner light chain sequences, or sequences that are at least 80% identical to, such as 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identical. In some embodiments, the anti-GAL3 antibody further comprises... Figure 36A Any of the inner heavy chain sequences, or sequences that are at least 80% identical to them, such as 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identical to them.

[0267] In some embodiments, the anti-Gal3 antibody comprises six CDRs, wherein in their combined sequence, the six CDRs are associated with... Figure 35A and 35B Any six CDR groups must be at least 80% identical, such as 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical.

[0268] In some embodiments, the anti-Gal3 antibody includes at least one component derived from... Figure 38 The CDR (with 1, 2, or 3 conserved amino acid substitutions). Anti-GAL3 antibodies consist of at least two amino acids derived from... Figure 38 The CDR (with 1, 2, or 3 conserved amino acid substitutions). Anti-GAL3 antibodies consist of at least three amino acid derivatives. Figure 38 The CDR (with 1, 2, or 3 conserved amino acid substitutions) (with 1, 2, or 3 conserved amino acid substitutions). Anti-GAL3 antibodies include at least four amino acid substitutions derived from... Figure 38 The CDR (with 1, 2, or 3 conserved amino acid substitutions). Anti-GAL3 antibodies consist of at least five amino acids derived from... Figure 38 The CDR (with 1, 2, or 3 conserved amino acid substitutions). Anti-GAL3 antibodies consist of six amino acids derived from... Figure 38 The CDR (with 1, 2, or 3 conserved amino acid substitutions). In some embodiments, the anti-Gal3 antibody comprises six amino acids derived from... Figure 38 The CDR, and wherein the six are from a single bin. In some embodiments, the anti-Gal3 antibody comprises six from... Figure 38 The CDRs, or a set of 6 CDRs that are at least 80% identical to them in their entire sequence.

[0269] In some embodiments, a method for inducing immune activation includes, substantially comprises, or consists of the following: contacting a variety of cells, including Gal3-expressing cells and TIM-3-expressing cells, with an antibody under conditions that disrupt the interaction between Gal3 and TIM-3, wherein the antibody specifically binds to Gal3, and wherein the Gal3-expressing cells express cytokines that induce immune activation upon binding to the antibody. In some embodiments, the cytokines are interferons or interleukins. In some embodiments, the cytokines are IFNγ or IL-2. In some embodiments, immune activation includes the proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, natural killer cells, or combinations thereof. In some embodiments, a method for promoting T cell or NK cell proliferation includes, substantially comprises, or consists of the following: contacting a variety of cells, including T cells, NK cells, and Gal3-expressing cells, with an antibody under conditions that achieve T cell and / or NK cell proliferation in a variety of cells, wherein the antibody specifically binds to Gal3. In some embodiments, a method for inducing immune activation includes, substantially comprises, or consists of the following: contacting a variety of cells, including Gal3-expressing cells and TIM-3-expressing cells, with an antibody under conditions that disrupt the interaction between Gal3 and TIM-3, wherein the antibody specifically binds to Gal3, and wherein the Gal3-TIM-3 interaction is reduced to less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4%, or less than 1%. In some embodiments, a method for reducing fibrosis or its tendency in tissues includes, substantially comprises, or consists of the following: contacting tissue with an antibody that specifically binds to an anti-Gal3 antibody under conditions that reduce the expression level of fibrosis biomarkers in the tissue. In some embodiments, an anti-Gal3 antibody is used to treat an immune-related disease in a subject, wherein the anti-Gal3 antibody induces activation of the immune system.In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is selected from the group consisting of: 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, 15G 7.2A7, 19B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8 and mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, 15G7.2A7, 19 B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, 9H2.2H10, IMT001-4, IMT006-1, IMT006-5, IMT006-8, or mIMT001 or any combination thereof. In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is mIMT001 (IMT001). In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is not mIMT001 (IMT001). In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is 4A11.2B5, IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8. In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is mIMT001, 4A11.2B5, IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8. In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is one or more of IMT001-4, IMT006-1, IMT006-5, or IMT006-8.

[0270] In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is not mIMT001 (IMT001). In some embodiments or any of the foregoing embodiments, the anti-Gal3 antibody is IMT001-4, IMT006-1, IMT006-5 and / or IMT006-8.

[0271] Regarding the properties of the various antibodies, note that IMT001-4, IMT006-1, and IMT006-5 are humanized antibodies. mIMT001 is a mouse antibody derived from IMT001. 4A11.2B5 is the original mouse antibody derived from IMT006-1 and IMT006-5. mIMT001, 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, 15G7.2A7, 19B5.2E6, 19D9.2E5, 20D11.2C6, 20H5.A3, 23H9.2E4, 24D12.2H9, 846.1F5, 846.2H3, 846T.1H2, and 9H2.2H10 are all mouse antibodies. IMT001-4, IMT006-1, IMT006-5 and IMT006-8 are all humanized antibodies.

[0272] Treatment

[0273] In some embodiments, this document discloses a method for inducing immune activation, comprising, substantially comprising, or consisting of: contacting an antibody with a variety of cells, including Gal3-expressing cells and TIM-3-expressing cells, substantially comprising Gal3-expressing cells and TIM-3-expressing cells, or comprising Gal3-expressing cells and TIM-3-expressing cells, under conditions that disrupt the interaction between Gal3 and TIM-3. In some embodiments, the antibody is an anti-Gal3 antibody.

[0274] In some embodiments, this document discloses a method for reducing fibrosis, which includes exposing a tissue comprising Gal3-expressing cells and at least one fibrosis biomarker to an anti-Gal3 antibody for a sufficient time to reduce the expression of at least one fibrosis biomarker in the tissue. In some cases, the anti-Gal3 antibody leads to a reduction in the accumulation of one or more extracellular matrix proteins in the tissue, including but not limited to collagen.

[0275] In some embodiments, the anti-Gal3 antibody is not IMT001. In some embodiments, the antibody is IMT001. In some embodiments, the anti-Gal3 antibody is 4A11.2B5. In some embodiments, the anti-Gal3 antibody is IMT001-4, IMT006-1, IMT006-5, or IMT006-8.

[0276] In some embodiments, the anti-Gal3 antibody inhibits or disrupts the interaction between Gal3 and TIM-3. In some embodiments, the Gal3-TIM-3 interaction is reduced to 99%, 95%, 90%, 80%, 78%, 70%, 66%, 60%, 56%, 52%, 50%, 40%, 30%, 29%, 27%, 20%, 19%, 17%, 10%, 5%, 4%, 3%, 2%, 1%, 0%, approximately 99%, approximately 95%, approximately 90%, approximately 80%, approximately 78%, approximately 70%, approximately 66%, approximately 60%, approximately 56%, approximately 52%, approximately 50%, approximately 40%, approximately 30%, and approximately 29%. %, approximately 27%, approximately 20%, approximately 19%, approximately 17%, approximately 10%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, approximately 1%, approximately 0%, less than 99%, less than 95%, less than 90%, less than 80%, less than 78%, less than 70%, less than 66%, less than 60%, less than 56%, less than 52%, less than 50%, less than 40%, less than 30%, less than 29%, less than 27%, less than 20%, less than 19%, less than 17%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%.

[0277] In some implementations, the anti-Gal3 antibody does not inhibit or disrupt the interaction between Gal3 and TIM-3.

[0278] In some embodiments, the interaction occurs at one or more residues of Gal3 selected from regions 145-168, 160-177, or 165-184, wherein the residue positions correspond to positions 145-168, 160-177, or 165-184 in SEQ ID NO:1. In some embodiments, the interaction occurs at one or more residues of Gal3 selected from regions 149-156, 152-168, 163-169, or 163-171, wherein the residue positions correspond to positions 149-156, 152-168, 163-169, or 163-171 in SEQ ID NO:1. In some embodiments, the interaction occurs at one or more residues of TIM-3 selected from regions 90-122 or 82-111, wherein the residue positions correspond to positions 90-122 or 82-111 in SEQ ID NO:2. In some implementations, the interaction occurs at one or more residues of TIM-3 selected from regions 91-111, 107-117, 96-102, 100-106, or 92-119, the residue positions herein corresponding to positions 91-111, 107-117, 96-102, 100-106, or 92-119 of SEQ ID NO:2.

[0279] In some embodiments, Gal3-expressing cells express cytokines that induce immune activation after binding to the antibody. As used herein, the term "cytokine" refers to a small protein, polypeptide, or peptide involved in cell signaling. Cytokines include, but are not limited to, chemokines, interferons, interleukins, lymphokines, tumor necrosis factor, CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, and C... CL26, CCL27, CCL28, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CX CL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, XCL1, XCL2, INFα, INFβ, INFγ, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL- 19. IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, GM-CSF, TNFα, TNFβ, TNFγ, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15, TNFSF18, or TNFSF19, or any combination thereof.

[0280] In some embodiments, the cytokine is interferon. In some embodiments, the interferon is IFNγ. In some embodiments, antibody-induced IFNγ production is 100%, 150%, 160%, 170%, 180%, 190%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more of IFNγ produced from an allotype antibody. In some embodiments, the cytokine is interleukin. In some embodiments, the interleukin is IL-2.

[0281] In some embodiments, immune activation or activation of the immune system includes, substantially consists of, or comprises the following: proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, TFH cells, Th3 cells, Th17 cells, natural killer T (NKT) cells, or natural killer (NK) cells, or combinations thereof. In some embodiments, immune activation or activation of the immune system includes, substantially consists of, or comprises the following: promotion of T cell or NK cell proliferation. In some embodiments, immune activation or activation of the immune system includes, substantially consists of, or comprises the following: an increase in various intracellular populations of M1 macrophages, neutrophils, mast cells, eosinophils, basophils, or dendritic cells. In some embodiments, immune activation or activation of the immune system includes, substantially consists of, or comprises the following: a decrease in various intracellular populations of M2 macrophages.

[0282] In some implementations, TIM-3 is human TIM-3.

[0283] In some embodiments, the multiple cell types include, are substantially composed of, or consist of tumor cells. In some embodiments, the multiple cell types are located within the tumor microenvironment (TME) and include, are substantially composed of, or consist of tumor cells and immune cells. In some embodiments, the TME includes tumor cells, immune cells, cancer-associated fibroblasts, myeloid-derived suppressor cells, neutrophils, tumor-infiltrating lymphocytes (TILs), or any combination thereof. In some embodiments, the multiple cell types include, are substantially composed of, or consist of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, TFH cells, Th3 cells, Th17 cells, natural killer T (NKT) cells, natural killer (NK) cells, M1 macrophages, neutrophils, mast cells, eosinophils, basophils, or dendritic cells. In some embodiments, anti-TIM-3 antibodies induce a reduction in tumor cells within the TME.

[0284] In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 1-20 of SEQ ID NO:1. In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 41-91 of SEQ ID NO:1. In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 41-71 of SEQ ID NO:1. In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 71-91 of SEQ ID NO:1.

[0285] In some embodiments, the antibody binds to at least one amino acid residue within peptide_1, peptide_2, peptide_3, peptide_4, peptide_5, peptide_6, peptide_7, peptide_8, peptide_9, peptide_10, peptide_11, peptide_12, peptide_13, peptide_14, peptide_15, peptide_16, peptide_17, peptide_18, peptide_19, peptide_20, peptide_21, peptide_22, peptide_23, or peptide_24, or any combination thereof.

[0286] In some embodiments, the antibodies include 1 fM, 10 fM, 100 fM, 1 pM, 10 pM, 100 pM, 1 nM, 1.2 nM, 2 nM, 5 nM, 10 nM, 13.5 nM, 15 nM, 20 nM, 25 nM, 30 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 1 μM, 10 μM, 100 μM, about 1 fM, about 10 fM, about 100 fM, about 1 pM, about 10 pM, about 100 pM, about 1 nM, about 1.2 nM, about 2 nM, about 5 nM, about 10 nM, about 13.5 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, etc. nM, approximately 100nM, approximately 200nM, approximately 300nM, approximately 400nM, approximately 500nM, approximately 1μM, approximately 10μM, approximately 100μM, less than 1fM, less than 10fM, less than 100fM, less than 1pM, less than 10pM, less than 100pM, less than 1nM, less than 1.2nM, less than 2nM, less than 5nM, less than 10nM, less than 13.5nM, less than 15nM, less than 20nM, less than 25nM, less than 30nM, less than 100nM, less than 200nM, less than 300nM, less than 400nM, less than 500nM, less than 1μM, less than 10μM, or K less than 100μM D .

[0287] In some embodiments, the antibody includes a humanized antibody. In some embodiments, the antibody includes a full-length antibody or a binding fragment thereof. In some embodiments, the antibody includes a bispecific antibody or a binding fragment thereof. In some embodiments, the antibody includes a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a biantibody, a microantibody, a nanobody, a single-domain antibody (sdAb), or a camelified antibody or a binding fragment thereof. In some embodiments, the antibody includes an IgG framework. In some embodiments, the antibody includes an IgG1, IgG2, or IgG4 framework. In some embodiments, the antibody further includes an Fc mutation. In some embodiments, the antibody includes a chimeric antibody.

[0288] In some embodiments, the anti-Gal3 antibody is selected from the group consisting of: 2D10.2B2, 3B11.2G2, 4A11.2B5, 4G2.2G6, 6H6.2D6, 7D8.2D8, 12G5.D7, 13A12.2E5, 13G4.2F8, 13H12.2F8, 14H10.2C9, 15F10.2D6, and 15G7.2A7. The anti-Gal3 antibody is mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is not mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is not mIMT001 (IMT001). In some embodiments, the anti-Gal3 antibody is 4A11.2B5. In some embodiments, the anti-Gal3 antibody is mIMT001 and / or 4A11.2B5. In some embodiments, the antibody competitively binds to Gal3 with one or more of these antibodies (including any one of IMT001-4, IMT006-1, IMT006-5, and / or IMT006-8). In some embodiments, the antibody is one or more of the following: IMT001-4, IMT006-1, IMT006-5, or IMT006-8. In some embodiments, the antibody used in the method comprises one or more CDRs from one or more of the following: IMT001-4, IMT006-1, IMT006-5, or IMT006-8. In some embodiments, the antibody used in the method comprises one or more VH, VL, or VH and VL from one or more of the following: IMT001-4, IMT006-1, IMT006-5, or IMT006-8.

[0289] In some embodiments, the method further includes administering an anti-Gal3 antibody to the subject prior to the contact step.

[0290] In some implementations, the subject is diagnosed with cancer.

[0291] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, prostate cancer, melanoma, bladder cancer, uterine cancer, pancreatic cancer, thyroid cancer, brain cancer, bone cancer, sarcoma, or stomach cancer. In some embodiments, lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or small cell lung cancer (SCLC).

[0292] In some implementations, cancer is a hematologic malignancy, including but not limited to leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, acute monocytic leukemia, or any combination thereof.

[0293] In some implementations, the cancer is metastatic cancer. In other implementations, the cancer is recurrent or refractory cancer. Staging of cancer or tumor is used to determine the progression of cancer or tumor within a patient. The accepted standard for classifying solid tumors is the TNM classification, which differentiates tumors based on tumor size (T), extent of spread to lymph nodes (N), and metastasis (M). These classifications are further divided into stages, where stage 0 growth is non-malignant, locally contains stage I and II tumors, stage III tumors have spread to nearby lymph nodes, and stage IV tumors have metastasized. While the TNM standard is the widely used classification method, alternative or modified standards that can represent the behavior of a specific cancer type can also be used. Accordingly, while these standards can be used to determine progression, the prognosis of early or late-stage cancer or tumor is independent of a specific classification.

[0294] In some embodiments, this document discloses a method for reducing fibrosis or its predisposition in a subject's tissue by contacting the tissue with an antibody. In some embodiments, the antibody specifically binds to Gal3 or an anti-Gal3 antibody. In some embodiments, contact induces the expression level of at least one fibrosis biomarker to be reduced in the tissue. In some embodiments, the tissue includes at least one TIM-3-expressing cell. In some embodiments, the anti-Gal3 antibody disrupts the interaction between Gal3 and TIM-3. In some embodiments, the anti-Gal3 antibody does not disrupt the interaction between Gal3 and TIM-3.

[0295] In some embodiments, reducing fibrosis or its tendency in tissue includes preventing fibrosis from occurring in normal tissue. In some embodiments, reducing fibrosis or its tendency in tissue includes slowing or halting the progression of fibrosis in fibrotic tissue. In some embodiments, reducing fibrosis or its tendency in tissue includes reducing the amount of fibrosis in fibrotic tissue. In some embodiments, reducing fibrosis or its tendency in tissue includes eliminating fibrosis in fibrotic tissue.

[0296] In some embodiments, this document also describes methods for monitoring the progression of tissue fibrosis by monitoring one or more fibrosis biomarkers. In some embodiments, this document discloses methods for treating tissue fibrosis with anti-Gal3 antibodies, wherein the anti-Gal3 antibody disrupts the interaction between Gal3 and TIM-3.

[0297] In some embodiments, at least one fibrosis biomarker comprises, is substantially composed of, or is composed of: α-smooth muscle actin (α-SMA), fibronectin, collagen, collagen I, collagen III, collagen IV, elastin, laminin, hyaluronic acid, or proteoglycan, or any combination thereof. In some embodiments, at least one fibrosis biomarker comprises, is substantially composed of, or is composed of: α-smooth muscle actin (α-SMA). In some embodiments, at least one fibrosis biomarker comprises, is substantially composed of, or is composed of: fibroblasts. In some embodiments, at least one fibrosis biomarker comprises, is substantially composed of, or is composed of: α-smooth muscle actin (α-SMA) and fibronectin.

[0298] In some embodiments, the tissue is selected from the group consisting of: liver tissue, kidney tissue, skin tissue, lung tissue, heart tissue, brain tissue, colorectal tissue, intestinal tissue, bone marrow tissue, breast tissue, prostate tissue, bladder tissue, uterine tissue, pancreatic tissue, thyroid tissue, muscle tissue, stomach tissue, and soft tissue. In some embodiments, the tissue is kidney tissue or liver tissue.

[0299] In some embodiments, the expression of at least one fibrosis biomarker in tissues treated with anti-Gal3 antibody is lower than the expression of at least one fibrosis biomarker in control tissues treated with mIgG2b antibody.

[0300] In some embodiments, anti-Gal3 antibodies lead to a reduction in the accumulation of extracellular matrix (ECM) proteins in tissues. In some embodiments, the extracellular matrix includes, is substantially composed of, or is composed of: aggregates, nestins, cadherins, clathrin, collagen, defensins, elastin, entactin, fibrin, fibronectin, keratin, laminin, microtubule-actin crosslinking factor 1, SPARC-like proteins, nesprin (nesprin-1, nesprin-2, nesprin-3), fibrosheath interacting proteins, myosins, conjugated actin, platelet affinity proteins, integrins, ankle proteins, export proteins, transport proteins, tendinogen, angular cheilitis proteins, sorting protein-associated receptors, tensin, or titin, or any combination thereof. In some embodiments, extracellular matrix proteins include, are substantially composed of, or are composed of: collagen. In some embodiments, the tissue includes, is substantially composed of, or is composed of: collagen-producing cells. In some embodiments, the collagen-producing cells are fibroblasts. In some embodiments, the fibroblasts are activated by fibrogenic cytokines. In some embodiments, the fibrogenic cytokines are TGF-β, TGF-β1, IL-1β, TNF-α, or GM-CSF. In some embodiments, the tissue has elevated expression of fibrogenic cytokines.

[0301] In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 1-20 of SEQ ID NO:1. In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 41-91 of SEQ ID NO:1. In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 41-71 of SEQ ID NO:1. In some embodiments, the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 71-91 of SEQ ID NO:1.

[0302] In some embodiments, the subject is diagnosed with fibrotic disease or fibrosis. In some embodiments, the subject is diagnosed with fibrotic disease. In some embodiments, the fibrotic disease is renal fibrosis. In some embodiments, the fibrotic disease is liver fibrosis. In some embodiments, the antibody is formulated for systemic administration. In some embodiments, the antibody is formulated for parenteral administration. In some embodiments, the subject is a mammal.

[0303] In some embodiments, the fibrotic disease or fibrosis is liver fibrosis, bridging fibrosis, cirrhosis, kidney (renal) fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, cardiovascular fibrosis, arterial fibrosis, venous thrombosis, joint fibrosis, Crohn's disease, Dupuitren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peronis disease, renal systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or systemic sclerosis. In some embodiments, the fibrotic disease is kidney (renal) fibrosis. In some embodiments, the fibrotic disease is liver fibrosis.

[0304] In some implementations, the method involves an antibody that binds to Gal3 but disrupts the interaction between Gal3 and TIM-3. This could be a direct obstruction of the interaction region between Gal3 and TIM-3, or an indirect alteration, such as binding that causes a conformational change in Gal3, rendering it no longer bind to TIM-3 or active with TIM-3. It can also be generated by binding to a first portion of Gal3, where other portions of the antibody impede or alter the interaction between Gal3 and TIM-3.

[0305] In some embodiments, the use of anti-Gal3 antibodies in the manufacture of pharmaceuticals or compositions is disclosed. In some embodiments, the pharmaceuticals or compositions are used to treat immune-related diseases. In some embodiments, the pharmaceuticals or compositions are used to treat cancer. In some embodiments, the pharmaceuticals or compositions are used to treat fibrotic diseases or fibrosis.

[0306] In some embodiments, the anti-Gal3 antibody is used to treat the subject's disease. In some embodiments, the anti-Gal3 antibody inhibits the interaction between Gal3 and TIM-3. In some embodiments, the anti-Gal3 antibody does not inhibit the interaction between Gal3 and TIM-3.

[0307] In some embodiments, anti-Gal3 antibodies are used to treat diseases that are immune-related, and in which anti-Gal3 antibodies induce activation of the subject's immune system. In some embodiments, the immune-related disease is an autoimmune disease. In some embodiments, the immune-related disease is an immunodeficiency. In some embodiments, an immunodeficiency is immunosenescence, humoral immunity deficiency, B cell deficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency. In some embodiments, activation of the immune system includes the proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, TFH cells, Th3 cells, Th17 cells, natural killer T (NKT) cells, NK cells, or M1 macrophages, or combinations thereof. In some embodiments, activation of the immune system includes a reduction in M2 macrophages.

[0308] In some implementations, anti-Gal3 antibodies are used to treat diseases, where the disease is cancer and anti-TIM-3 antibodies are used to treat cancer.

[0309] In some embodiments, anti-Gal3 antibodies are used to treat diseases, wherein the disease is a fibrotic disease or fibrosis. In some embodiments, anti-Gal3 antibodies are used to treat diseases that cause a reduction in the accumulation of extracellular matrix proteins in tissues.

[0310] In some implementations, anti-Gal3 antibodies used to treat diseases are administered in combination with other therapeutic agents, such as immune checkpoint modulators, chemotherapeutic agents, targeted therapies, hormone therapies, stem cell-based therapies, surgical procedures, or radiation therapy.

[0311] In some embodiments, the antibody is formulated for systemic administration. In some embodiments, the antibody is formulated for parenteral, subcutaneous, intramuscular, intradermal, or intravenous administration, or any combination thereof.

[0312] In some embodiments, the anti-Gal3 antibody is administered to the subject in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes an immunotherapeutic agent. In some embodiments, the additional therapeutic agent includes an immune checkpoint modulator. In some embodiments, the additional therapeutic agent includes a chemotherapeutic agent, a targeted therapeutic agent, a hormone therapeutic agent, or a stem cell-based therapeutic agent.

[0313] In some embodiments, the additional therapeutic agent includes an immunotherapeutic agent. In some embodiments, the immunotherapy is adoptive cell therapy. Exemplary adoptive cell therapies include AFP TCR, MAGE-A10 TCR, or NY-ESO-TCR from Adaptimmune; ACTR087 / rituximab from Unum Therapeutics; anti-BCMA CAR-T cell therapy, anti-CD19 "armored" CAR-T cell therapy, JCAR014, JCAR018, JCAR020, JCAR023, JCAR024, or JTCR016 from Juno Therapeutics; JCAR017 from Celgene / Juno Therapeutics; anti-CD19 CAR-T cell therapy from Intrexon; anti-CD19 CAR-T cell therapy, axicabtagene ciloleucel, KITE-718, KITE-439, or NY-ESO-1T-cell receptor therapy from Kite Pharma; anti-CEA CAR-T therapy from Sorrento Therapeutics; and TNK... Anti-PSMA CAR-T cell therapy from Therapeutics / SorrentoTherapeutics; ATA520 from Atara Biotherapeutics; AU101 and AU105 from Aurora BioPharma; baltaleucel-T (CMD-003) from Cell Medica; bb2121 from bluebird bio; BPX-501, BPX-601, or BPX-701 from Bellicum Pharmaceuticals; BSK01 from Kiromic; IMCgp100 from Immunocore; JTX-2011 from Jounce Therapeutics; LN-144 or LN-145 from Lion Biotechnologies; MB-101 or MB-102 from Mustang Bio; NKR-2 from Celyad; PNK-007 from Celgene; tisagenlecleucel-T from Novartis Pharmaceuticals; or from Tessa Therapeutics' TT12.

[0314] In some implementations, immunotherapy is a dendritic cell-based therapy.

[0315] In some implementations, immunotherapy includes cytokine-based therapies, including, for example, interleukins (ILs) such as IL-2, IL-15, or IL-21; interferon (IFN)-α; or granulocyte-macrophage colony-stimulating factor (GM-CSF).

[0316] In some implementations, the immunotherapy includes an immune checkpoint modulator. Exemplary immune checkpoint modulators include PD-1 modulators such as nivolumab (Opdivo) from Bristol-Myers Squibb, pembrolizumab (Keytruda) from Merck, AAGEN2034 from Agenus, BGB-A317 from BeiGene, Bl-754091 from Boehringer-Ingelheim Pharmaceuticals, CBT-501 (genolimzumab) from CBT Pharmaceuticals, INCSHR1210 from Incyte, JNJ-63723283 from Janssen Research & Development, MEDI0680 from MedImmune, MGA 012 from MacroGenics, and others from Novartis. Pharmaceuticals' PDR001, Pfizer's PF-06801591, Regeneron Pharmaceuticals / Sanofi's REGN2810 (SAR439684), or TESARO's TSR-042; CTLA-4 modulators such as ipilimumab (Yervoy) or Agenus' AGEN 1884; PD-L1 modulators such as astraZeneca's durvalumab (Imfinzi), Genentech's atezolizumab (MPDL3280A), EMD Serono / Pfizer's avelumab, CytomX Therapeutics' CX-072, Novartis Pharmaceuticals' FAZ053, 3D Medicine / Alphamab's KN035, Eli Lilly's LY3300054, or EMD Serono's M7824 (anti-PD-L1 / TGFβ capture); LAG3 modulators such as BMS-986016 from Bristol-Myers Squibb, IMP701 from Novartis Pharmaceuticals, LAG525 from Novartis Pharmaceuticals, or REGN3767 from Regeneron Pharmaceuticals;OX40 modulators include BMS-986178 from Bristol-Myers Squibb, GSK3174998 from GlaxoSmithKline, INCAGN1949 from Agenus / Incyte, MEDI0562 from MedImmune, PF-04518600 from Pfizer, or RG7888 from Genentech; GITR modulators include GWN323 from Novartis Pharmaceuticals, INCAGN1876 from Agenus / Incyte, MEDI1873 from MedImmune, MK-4166 from Merck, or TRX518 from Leap Therapeutics; KIR modulators include lirelurumab from Bristol-Myers Squibb; or TIM modulators include MBG453 from Novartis Pharmaceuticals or TSR-022 from Tesaro.

[0317] In some embodiments, additional therapeutic agents include chemotherapeutic agents. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents such as cyclophosphamide, dichloromethyldiethylamine, chlorambucil, levosaltolysin, dacarbazine, or nitrosourea; anthracyclines such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or pentorubicin; cytoskeleton disruptors such as paclitaxel, docetaxel, ketoxantrone, or tesole; epolemycin; histone deacetylase inhibitors such as vorinostatin or romidixin; topoisomerase I inhibitors such as irinotecan or topotecan; and topoisomerase II inhibitors such as etoposide, teniposide, or tafluthrin. Pomodoroside; kinase inhibitors such as bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vemodil; nucleotide analogs and pro-analytes such as azacitidine, imidazothiopurine, capecitabine, cytarabine, deoxyfluorouridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine; platinum-based reagents such as carboplatin, cisplatin, or oxaliplatin; retinoids such as retinoic acid, retinoic acid, or bexarotine; or vinblastine alkaloids and derivatives such as vincristine, vinblastine, vinorelbine, or vinorelbine.

[0318] In some embodiments, additional therapeutic agents include hormone-based therapeutic agents. Exemplary hormone-based therapeutic agents include, but are not limited to, aromatase inhibitors such as letrozole, anastrozole, exemestane, or ammoniaglutide; gonadotropin-releasing hormone (GnRH) analogs such as leuprorelin or goserelin; selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, toremifene, or fulvestrant; antiandrogens such as flutamide or bicalutamide; progestins such as medroxyprogesterone acetate or medroxyprogesterone acetate; androgens such as flumethyltestosterone; estrogens such as diethylstilbestrol (DES), estradiol preparations, or polyestradiol phosphate; or somatostatin analogs such as octreotide.

[0319] In some implementations, the additional therapeutic agent is a first-line therapeutic agent.

[0320] In some embodiments, the anti-Gal3 antibody and an additional therapeutic agent are administered simultaneously. In some embodiments, the anti-Gal3 antibody and the additional therapeutic agent are administered sequentially. In some embodiments, the anti-Gal3 antibody is administered to the subject before the administration of the additional therapeutic agent. In some embodiments, the anti-Gal3 antibody is administered to the subject after the administration of the additional therapeutic agent.

[0321] In some implementations, the additional therapeutic agent and the anti-Gal3 antibody are formulated as separate doses.

[0322] In some embodiments, the subject has already undergone surgery. In some cases, the anti-Gal3 antibody and optionally an additional therapeutic agent are administered to the subject prior to surgery. In some embodiments, the anti-Gal3 antibody and optionally an additional therapeutic agent are administered to the subject after surgery.

[0323] In some implementations, the subject has already undergone radiation exposure. In some implementations, the anti-Gal3 antibody and optionally an additional therapeutic agent are administered to the subject during or after radiation therapy. In some cases, the anti-Gal3 antibody and optionally an additional therapeutic agent are administered to the subject before radiation exposure.

[0324] In some implementations, the subject is a mammal. In some implementations, the subject is a human.

[0325] In some embodiments, this document discloses methods for reducing fibrosis or its tendency in tissues by contacting tissues with antibodies that specifically bind to Gal3. In some embodiments, this document also describes methods for disrupting Gal3-TIM-3 interactions by antibodies that specifically bind to Gal3 under conditions that reduce the expression of one or more fibrosis biomarkers in tissues.

[0326] In some embodiments, methods for reducing fibrosis or its tendency in tissues are disclosed herein, comprising: contacting the tissue with an antibody that specifically binds to a Gal3 antibody, under conditions that reduce the expression levels of fibrosis biomarkers in the tissue. In some embodiments, the tissue further comprises TIM-3 expressing cells. In some embodiments, the antibody further disrupts the interaction between Gal3 and TIM-3. In some embodiments, the antibody does not disrupt the interaction between Gal3 and TIM-3. In some embodiments, at least one fibrosis biomarker includes α-smooth muscle actin (α-SMA). In some embodiments, at least one fibrosis biomarker includes fibronectin. In some embodiments, at least one fibrosis biomarker includes α-smooth muscle actin (α-SMA) and fibronectin. In some embodiments, the tissue is kidney tissue or liver tissue. In some embodiments, the tissue is selected from the group consisting of: liver tissue, kidney tissue, skin tissue, lung tissue, heart tissue, brain tissue, intestinal tissue, bone marrow tissue, and soft tissue. In some embodiments, the expression of at least one fibrosis biomarker in tissue treated with the antibody is lower than the expression of at least one fibrosis biomarker in control tissue treated with mIgG2b antibody. In some embodiments, the antibody leads to a decrease in the accumulation of extracellular matrix proteins in the tissue. In some embodiments, the extracellular matrix proteins include collagen. In some embodiments, the tissue includes collagen-producing cells. In some embodiments, the collagen-producing cells are fibroblasts. In some embodiments, the fibroblasts are activated by fibrogenic cytokines. In some embodiments, the fibrogenic cytokine is TGF-β1. In some embodiments, the tissue has elevated TGF-β1 expression.

[0327] Antibody production

[0328] In some embodiments, anti-Gal3 antibodies are generated by injecting production animals with an antigen composition using a standard protocol. See, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. When using the whole protein or a large portion of the protein, antibodies can be generated by immunizing production animals with the protein and a suitable adjuvant (e.g., Freund's, Freund's complete, oil-in-water emulsion, etc.). When using smaller peptides, it is advantageous to conjugate the peptide with a larger molecule to prepare an immunostimulatory conjugate. Commonly available conjugated proteins for this purpose include bovine serum albumin (BSA) and keyhole hemocyanin (KLH). To generate antibodies against a specific epitope, peptides derived from the complete sequence can be used. Alternatively, to generate antibodies against a relatively short peptide portion of a protein target, excellent immune responses can be induced by linking the peptide to a carrier protein, such as ovalbumin, BSA, or KLH.

[0329] Polyclonal or monoclonal anti-Gal3 antibodies can be produced from animals that have been genetically modified to produce human immunoglobulins. Transgenic animals can be produced by initially producing "knockout" animals that do not produce natural antibodies in the animal, and then stably transforming the animal with a human antibody locus (e.g., by using an artificial human chromosome). In this case, only human antibodies are then produced from the animal. The techniques used to produce such animals and from which antibodies are derived are described in U.S. Patent Nos. 6,162,963 and 6,150,584, which are incorporated herein by reference in their entirety. Such antibodies may be referred to as human xenoantibodies.

[0330] Alternatively, anti-Gal3 antibodies can be generated from a phage library containing the human variable region. See U.S. Patent No. 6,174,708, which is incorporated herein by reference in its entirety.

[0331] In some aspects of some of the embodiments disclosed herein, the anti-Gal3 antibody is produced by a hybridoma.

[0332] For monoclonal anti-Gal3 antibodies, hybridomas can be formed by isolating stimulated immune cells, such as those from the spleen of an inoculated animal. These cells can then be fused to immortalized cells, such as myeloma cells or transformed cells, which can replicate indefinitely in cell cultures, thereby producing immortalized immunoglobulin-secreting cell lines. The immortalized cell lines used can be selected to lack enzymes necessary for utilizing certain nutrients. Many such cell lines (such as myeloma) are known to those skilled in the art and include, for example, thymidine kinase (TK) or hypoxanthine-guanine phosphotransferase (HGPRT). These deficiencies allow for the selection of fusion cells based on their growth capacity on, for example, hypoxanthine-aminopterin thymidine medium (HAT).

[0333] In addition, anti-Gal3 antibodies can be produced through genetic engineering.

[0334] The anti-Gal3 antibodies disclosed herein may have a reduced tendency to induce undesirable immune responses in humans, such as anaphylactic shock, and may also exhibit a reduced tendency to elicit immune responses that would prevent repeated doses of antibody therapeutics or imaging agents (e.g., human-anti-mouse antibody "HAMA" response). Such anti-Gal3 antibodies include, but are not limited to, humanized, chimeric, or xenogeneic human anti-Gal3 antibodies.

[0335] Chimeric anti-Gal3 antibodies can be prepared, for example, by combining mouse variable light and heavy chain regions (VK and VH) obtained from mouse (or other animal-derived) hybridoma clones with human constant light and heavy chain regions to produce antibodies that primarily have human domains in a recombinant manner. The generation of such chimeric antibodies is well known in the art and can be achieved by standard methods (e.g., as described, for example, in U.S. Patent No. 5,624,659, which is incorporated herein by reference in its entirety).

[0336] The term "humanization," applicable to non-human (e.g., rodent or primate) antibodies, refers to a hybrid immunoglobulin, immunoglobulin chain, or fragment thereof containing a minimal sequence derived from a non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (receptor antibodies) in which residues from the complementarity-determining region (CDR) of the receptor are replaced by residues from the CDR of a non-human species (donor antibody) possessing the desired specificity, affinity, and capability, such as a mouse, rat, rabbit, or primate. In some embodiments, Fv frame region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may include residues not found in the receptor antibody or in the input CDR or frame sequence. These modifications further improve and optimize antibody performance and minimize immunogenicity when introduced into the human body. In some examples, humanized antibodies will include at least one, and typically two, variable regions, where all or substantially all of the CDR regions correspond to those of the non-human immunoglobulin and all or substantially all of the FR regions are those of the human immunoglobulin sequence. Humanized antibodies may also include at least a portion of the immunoglobulin constant region (Fc), typically those of human immunoglobulins.

[0337] Humanized antibodies can be engineered to contain human-like immunoglobulin domains and incorporate only the complementarity-determining regions of animal-derived antibodies. This can be accomplished by carefully examining the sequences of hypervariable loops in the variable regions of monoclonal antigen-binding units or monoclonal antibodies and matching them to the structures of human antigen-binding units or human antibody chains. See, for example, U.S. Patent No. 6,187,287, which is incorporated herein by reference in its entirety.

[0338] Methods for humanizing nonhuman antibodies are well known in the art. A “humanized” antibody is an antibody in which at least a portion of its sequence has been altered from its original form to make it more like a human immunoglobulin. In some versions, the heavy (H) chain and light (L) chain constant (C) regions are replaced with human sequences. This can be a fusion polypeptide including a variable (V) region and a heterologous immunoglobulin C region. In some versions, the complementarity-determining region (CDR) includes a nonhuman antibody sequence, while the V frame region has also been converted to a human sequence. See, for example, EP 0329400. In some versions, the V region is humanized by designing a common sequence between the human and mouse V regions and converting residues outside the CDR that differ between the common sequences.

[0339] In principle, the frame sequence from humanized antibodies can be used as a template for CDR transplantation; however, it has been shown that directly replacing the CDR into such a frame leads to a significant loss of binding affinity to the antigen. Glaser et al. (1992) J. Immunol. 149:2606; Tempest et al. (1992) Biotechnology 9:266 and Shalaby et al. (1992) J. Exp. Med. 17:217. The higher the homology between the human antibody (HuAb) and the original mouse antibody (muAb), the less likely the human frame will introduce affinity-reducing distortions into the mouse CDR. Based on sequence homology searches against antibody sequence databases, HuAb IC4 provides good frame homology to muM4TS.22, although other highly homologous HuAbs will also be applicable, especially the κL chain from human subgroup I or the H chain from human subgroup III. Kabat et al. (1987). Various computer programs, such as ENCAD (Levitt et al. (1983) J. Mol. Biol. 168:595), can be used to predict the ideal sequence for the V region. This invention therefore covers HuAbs with different variable (V) regions. Determining suitable V region sequences and optimizing these sequences is within the skill of those skilled in the art. Methods for obtaining antibodies with reduced immunogenicity are also described in U.S. Patent Nos. 5,270,202 and EP 699,755.

[0340] Humanized antibodies can be prepared through a process of analyzing parental sequences and various conceptual humanized products using three-dimensional models of parental and humanized sequences. Three-dimensional immunoglobulin models are familiar to those skilled in the art. Available computer programs are available to interpret and display the possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. Examining these displays allows analysis of the possible roles of residues in the function of the candidate immunoglobulin sequence, i.e., analyzing how residues affect the candidate immunoglobulin's ability to bind its antigen. Thus, FR residues can be selected and combined from shared and input sequences to achieve desired antibody characteristics, such as increased affinity for target antigens.

[0341] The process for humanizing a subject antigen-binding unit can be as follows: The most suitable germline receptor heavy and light chain variable regions are selected based on the homology, canonical structure, and physical properties of the human antibody lineage intended for transplantation. Computer modeling of the mVH / VL versus the transplanted hVH / VL is performed, and a prototype humanized antibody sequence is generated. If the modeling indicates a frameback mutation is required, a second variant with the indicated FW alteration is generated. A DNA fragment encoding the selected germline frame and mouse CDR is synthesized. The synthesized DNA fragment is subcloned into an IgG expression vector, and the sequence is confirmed by DNA sequencing. The humanized antibody is expressed in cells, such as 293F, and the protein is tested, for example, in MDM phagocytosis assays and antigen-binding assays. The antigen-binding affinity of the humanized antigen-binding unit is compared to that of the parent antigen-binding unit, for example, by performing FACS on cells expressing the target antigen. If the affinity is more than 2-fold lower than that of the parent antigen-binding unit, a second round of humanized variants can be generated and tested as described above.

[0342] As mentioned above, anti-Gal3 antibodies can be "monovalent" or "multivalent". The former has one binding site per antigen-binding unit, while the latter contains multiple binding sites capable of binding more than one of the same or different types of antigens. Depending on the number of binding sites, antigen-binding units can be bivalent (with two antigen-binding sites), trivalent (with three antigen-binding sites), tetravalent (with four antigen-binding sites), etc.

[0343] Multivalent anti-Gal3 antibodies can be further classified based on their binding specificity. A “monospecific” anti-Gal3 antibody is a molecule capable of binding to one or more antigens of the same class. A “multispecific” anti-Gal3 antibody is a molecule that has binding specificity to at least two different antigens. While such a molecule typically binds only two different antigens (i.e., a bispecific anti-Gal3 antibody), antibodies with additional specificity, such as trispecific antibodies, are also covered by this expression when used herein. This disclosure further provides multispecific anti-Gal3 antibodies. Multispecific anti-Gal3 antibodies are multivalent molecules capable of binding to at least two different antigens, for example, bispecific and trispecific molecules exhibiting binding specificity to two and three different antigens, respectively.

[0344] Monoclonal antibodies can be obtained by injecting mice with a composition including an antigen, such as Gal3 or its epitopes, removing the spleen to obtain B-lymphocytes, fusing the B-lymphocytes with myeloma cells to generate a hybridoma, cloning the hybridoma, selecting positive clones that produce antibodies against the antigen, culturing the clones that produce antibodies against the antigen, and isolating the antibodies from the hybridoma culture.

[0345] The resulting monoclonal antibodies can be isolated and purified from hybridoma cultures using a variety of well-established techniques. These techniques include affinity chromatography with protein-A agarose, size exclusion chromatography, and ion exchange chromatography. See, for example, Coligan, pp. 2.7.1–2.7.12 and 2.9.1–2.9.3. See also Baines et al., “Purification of Immunoglobulin G (IgG)”, in METHODS IN MOLECULAR BIOLOGY, Vol. 10, pp. 79–104 (The Humana Press, Inc. 1992). After the initial generation of antibodies against the target protein, the antibodies can be sequenced and subsequently prepared using recombinant techniques. Humanization and chimerism of mouse antibodies and antibody fragments are well known to those skilled in the art. See, for example, Leung et al., Hybridoma 13:469 (1994); US20140099254A1, each of which is explicitly incorporated into this paper in its entirety by reference.

[0346] Human antibodies can be produced using transgenic mice that have been genetically engineered to produce specific human antibodies in response to antigenic challenges using target proteins. See Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994). Human antibodies against target proteins can also be constructed via genetic or chromosomal transfection methods, phage display technology, or in vitro activated B cell construction. See, for example, McCafferty et al., 1990, Nature 348:552-553; U.S. Patents 5,567,610 and 5,229,275, each of which is expressly incorporated herein by reference in its entirety.

[0347] In some implementations, the Gal3-TIM-3 interaction can be reduced to less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4%, or less than 1%.

[0348] Polynucleotides and carriers

[0349] In some embodiments, this disclosure provides isolated nucleic acids encoding any of the anti-Gal3 antibodies disclosed herein. In some embodiments, this disclosure provides vectors comprising nucleic acid sequences encoding any of the anti-Gal3 antibodies disclosed herein. In some embodiments, the invention provides isolated nucleic acids encoding the light chain CDR and heavy chain CDR of the anti-Gal3 antibodies disclosed herein.

[0350] Anti-Gal3 antibodies for the subject can be prepared using recombinant DNA technology, synthetic chemistry techniques, or a combination thereof. For example, using standard molecular techniques known in the art, sequences encoding the desired components of the anti-Gal3 antibody, including light chain CDRs and heavy chain CDRs, are typically assembled and cloned into an expression vector. These sequences can be assembled from other vectors encoding the desired protein sequence, from fragments generated by PCR using their respective template nucleic acids, or through the assembly of synthetic oligonucleotides encoding the desired sequence. The expression system can be created by transfecting suitable cells with an expression vector containing the anti-Gal3 antibody of interest.

[0351] Using conventional techniques, including but not limited to hybridization, PCR, and DNA sequencing, nucleotide sequences corresponding to various regions of the light or heavy chains of existing antibodies can be readily obtained and sequenced. Hybridoma cells that produce monoclonal antibodies serve as a preferred source of antibody nucleotide sequences. Large quantities of hybridoma cells that produce a range of monoclonal antibodies can be obtained from public or private repositories. The largest depository is the U.S. Type Culture Collection (atcc.org), which offers a diverse collection of well-defined hybridoma cell lines. Alternatively, antibody nucleotides can be obtained from immunized or non-immunized rodents or humans and formed from organs such as the spleen and peripheral blood lymphocytes. Specific techniques applicable to the extraction and synthesis of antibody nucleotides are described in Orlandi et al. (1989) Proc. Natl. Acad. Sci. USA 86:3833-3837; Larrick et al. (1989) Biochem. Biophys. Res. Commun. 160:1250-1255; Sastry et al. (1989) Proc. Natl. Acad. Sci., USA 86:5728-5732 and US Patent No. 5,969,108.

[0352] The polynucleotide encoding anti-Gal3 antibodies can also be modified, for example, by replacing homologous non-human sequences with coding sequences for the constant regions of the human heavy and light chains. In this way, chimeric antibodies that retain the binding specificity of the original anti-Gal3 antibody are prepared.

[0353] Host cells for antibody production

[0354] In some embodiments, this disclosure provides host cells expressing any of the anti-Gal3 antibodies disclosed herein. Subject host cells typically comprise nucleic acids encoding any of the anti-Gal3 antibodies disclosed herein. In some embodiments, the host cell is a Chinese hamster ovary (CHO) cell. In some embodiments, the host cell is an NSO cell.

[0355] This invention provides host cells transfected with the polynucleotides, vectors, or vector libraries described above. The vector can be introduced into suitable prokaryotic or eukaryotic cells by any of a number of suitable methods, including electroporation, microbolite bombardment; lipid transfection, infection (wherein the vector is coupled to a pathogen), transfection with calcium chloride, rubidium chloride, calcium phosphate, DEAE-glucan, or other substances. The choice of method for introducing the vector will generally depend on the characteristics of the host cells.

[0356] For most animal cells, any of the methods mentioned above are suitable for vector delivery. Preferred animal cells are vertebrate cells, preferably mammalian cells, which are capable of expressing exogenously introduced gene products in large quantities, for example, at milligram levels. Non-limiting examples of preferred cells are NIH3T3 cells, COS, HeLa, and CHO cells.

[0357] Once introduced into a suitable host cell, the expression of anti-Gal3 antibodies can be determined using any nucleic acid or protein assay known in the art. For example, the presence of light chain CDRs or heavy chain CDRs or transcribed mRNAs of anti-Gal3 antibodies can be detected and / or quantified using probes complementary to any region of the polynucleotide encoding the anti-Gal3 antibody, by conventional hybridization assays (e.g., Northern blot analysis), amplification procedures (e.g., RT-PCR), SAGE (US Patent No. 5,695,937), and array-based techniques (see, for example, US Patent Nos. 5,405,783, 5,412,087, and 5,445,934).

[0358] The expression of the vector can also be determined by examining the expressed anti-Gal3 antibody. Various techniques for protein analysis are available in the art. These include, but are not limited to, radioimmunoassay, ELISA (enzyme-linked immunosorbent assay), sandwich immunoassay, immunoradioassay, in situ immunoassay (using, for example, colloidal gold, enzyme, or radioisotope labeling), Western blot analysis, immunoprecipitation assay, immunofluorescence assay, and SDS-PAGE.

[0359] Payload

[0360] In some embodiments, the anti-Gal3 antibody further includes a payload. In some cases, the payload includes a small molecule, a protein or a functional fragment thereof, a peptide, or a nucleic acid polymer.

[0361] In some cases, the number of payloads conjugated to anti-Gal3 antibodies (e.g., drug-to-antibody ratio or DAR) is approximately 1:1, one payload to one anti-Gal3 antibody. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 2:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 3:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 4:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 6:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 8:1. In some cases, the ratio of payload to anti-Gal3 antibody is approximately 12:1.

[0362] In some embodiments, the payload is a small molecule. In some embodiments, the small molecule is a cytotoxic payload. Exemplary cytotoxic payloads include, but are not limited to, microtubule disruptors, DNA modifiers, or Akt inhibitors.

[0363] In some embodiments, the load includes a microtubule disruptor. Exemplary microtubule disruptors include, but are not limited to, 2-methoxyestradiol, auristatin, chalcone, colchicine, cobustatin, cryptophycin, dictyostatin, dolastain, soft coral alcohol, epothilone, laulimalide, maytansine, noscapaxin, paclitaxel, peloruside, phomopsin, podophyllotoxin, rhizobium, spongiformin, taxane, tubulysin, vinblastine alkaloids, vinorelbine, or their derivatives or analogs.

[0364] In some embodiments, maytansine is a maytanyl alkaloid. In some embodiments, maytansine alkaloid is DM1, DM4, or anserin. In some embodiments, maytansine alkaloid is DM1. In some embodiments, maytansine alkaloid is DM4. In some embodiments, maytansine alkaloid is anserin. In some embodiments, maytansine alkaloid is a maytansine alkaloid derivative or analogue, such as those described in U.S. Patent Nos. 5,208,020, 5,416,064, 7,276,497, and 6,716,821, or U.S. Publications Nos. 2013029900 and 20130323268.

[0365] In some embodiments, the load is salitoxin, or a derivative or analogue thereof. In some embodiments, the salitoxin is salitoxin 10 or salitoxin 15, or a derivative or analogue thereof. In some embodiments, an analogue of salitoxin 10 is auripstatin, soblidotin, symplostatin 1, or symplostatin 3. In some embodiments, an analogue of salitoxin 15 is cimadolin or tacidolin.

[0366] In some embodiments, the saurus toxin 10 analogue is auristatin or an auristatin derivative. In some embodiments, auristatin or an auristatin derivative is auristatin E (AE), auristatin F (AF), auristatin E 5-benzoylvalerate (AEVB), methylauristatin E (MMAE), methylauristatin F (MMAF), or methylauristatin D (MMAD), auristatin PE, or auristatin PYE. In some embodiments, the auristatin derivative is methylauristatin E (MMAE). In some embodiments, the auristatin derivative is methylauristatin F (MMAF). In some embodiments, auristatin is an auristatin derivative or analogue, such as those described in U.S. Patent Nos. 6,884,869, 7,659,241, 7,498,298, 7,964,566, 7,750,116, 8,288,352, 8,703,714, and 8,871,720.

[0367] In some embodiments, the payload includes a DNA modifier. In some embodiments, the DNA modifier includes a DNA cleaving agent, a DNA intercalating agent, a DNA transcription inhibitor, or a DNA cross-linking agent. In some embodiments, the DNA cleaving agent includes bleomycin A2, galicariin, or derivatives or analogs thereof. In some embodiments, the DNA intercalating agent includes doxorubicin, epirubicin, PNU-159682, domicatin, pyrrolobenzodiazepines, oligomycin C, daunorubicin, pentorubicin, topotecan, or derivatives or analogs thereof. In some embodiments, the DNA transcription inhibitor includes dermatomycin. In some embodiments, the DNA cross-linking agent includes mitomycin C.

[0368] In some embodiments, the DNA modifier includes acridine, anthracycline, camptothecin, doxorubicin, domicatin, enediyne, etoposide, indobenzodiazepine, fuscin, teniposide, or derivatives or analogs thereof.

[0369] In some embodiments, anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, cytomegalocin, scintillans, nemorubicin, pinantrone, sabarubicin, or pentorubicin.

[0370] In some embodiments, analogues of camptothecin are topotecan, irinotecan, cilaranotecan, cocinotecan, ixatecan, letopotecan, gemmatonotecan, belotetane, rubitecan, or SN-38.

[0371] In some embodiments, domicatin is domicatin A, domicatin B1, domicatin B2, domicatin C1, domicatin C2, domicatin D, domicatin SA, or CC-1065. In some embodiments, endoyne is calcipomycin, esparmycin, or danendycin A.

[0372] In some embodiments, pyrrolobenzodiazepines are anthramycin, gibberellin, chezamycin, DC-81, mazethramycin, neoothramycins A, neoothramycin B, porothramycin, prothracarcin, sibanomicin (DC-102), siberycin, or chamomycin. In some embodiments, pyrrolobenzodiazepines are chamomycin derivatives, such as those described in U.S. Patent Nos. 8,404,678 and 8,163,736. In some embodiments, pyrrolobenzodiazepine is, for example, described in U.S. Patent Nos. 8426402, 8802667, 8809320, 6562806, 6608192, 7704924, 7067511, US7612062, 7244724, 7528126, 7049311, 8633185, 8501934, and 8697688 and U.S. Publication No. US20140294868.

[0373] In some embodiments, pyrrolobenzodiazepine is a pyrrolobenzodiazepine dimer. In some embodiments, the PBD dimer is a symmetrical dimer. Examples of symmetrical PBD dimers include, but are not limited to, SJG-136 (SG-2000), ZC-423 (SG2285), SJG-720, SJG-738, ZC-207 (SG2202), and DSB-120. In some embodiments, the PBD dimer is an asymmetrical dimer. Examples of asymmetrical PBD dimers include, but are not limited to, derivatives of SJG-136, such as those described in U.S. Patent Nos. 8,697,688 and 9,242,013 and U.S. Publication No. 20,140,286,970.

[0374] In some embodiments, the payload includes an Akt inhibitor. In some cases, the Akt inhibitor includes ipatasertib (GDC-0068) or a derivative thereof.

[0375] In some embodiments, the payload includes polymerase inhibitors, including but not limited to polymerase II inhibitors such as α-amanitin and poly(ADP-ribose) polymerase (PARP) inhibitors. Exemplary PARP inhibitors include, but are not limited to, iniparib (BSI 201), tapazolidinib (BMN-673), olaparib (AZD-2281), olaparib, rucapapazolidinib (AG014699, PF-01367338), veliparib (ABT-888), CEP 9722, MK 4827, BGB-290, or 3-aminobenzamide.

[0376] In some implementations, the payload includes a detectable portion. Exemplary detectable portions include fluorescent dyes; enzymes; substrates; chemiluminescent portions; specific binding portions such as streptoacidin, avidin, or biotin; or radioisotopes.

[0377] In some embodiments, the payload includes immunomodulators. Useful immunomodulators include antihormones that block the effects of hormones on tumors and immunosuppressants that inhibit cytokine production, downregulate self-antigen expression, or mask MHC antigens. Representative antihormones include antiestrogens, such as tamoxifen, raloxifene, aromatase inhibitors of 4(5)-imidazole, 4-hydroxytamoxifen, trivoxifen, raloxifene, LY 117018, onapnstone, and toremifene; and antiandrogens such as flutamide, nilumet, bicalutamide, leuprorelin, and goserelin; and antiadrenergic agents. Elucidating immunosuppressants include, but are not limited to, 2-amino-6-aryl-5-substituted pyrimidines, azathioprine, cyclophosphamide, bromocriptine, danazol, dapsone, glutaraldehyde, anti-idiotypic antibodies against MHC antigens and MHC fragments, cyclosporine A, steroids such as glucocorticoids, streptokinase, or rapamycin.

[0378] In some embodiments, the payload includes an immunomodulator. Exemplary immunomodulators include, but are not limited to, gancyclovier, etanercept, tacrolimus, sirolimus, vorticol, cyclosporine, rapamycin, cyclophosphamide, imidazoline, mycophenolate mofetil, methotrexate, glucocorticoids and their analogues, xanthine, stem cell growth factors, lymphotoxins, hematopoietic factors, tumor necrosis factor (TNF) (e.g., TNFα), interleukins (e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, and IL-21), colony-stimulating factors (e.g., granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)), interferons (e.g., interferon-α, interferon-β, interferon-γ), stem cell growth factors referred to as "S1 factors," erythropoietin, and thrombopoietin, or combinations thereof.

[0379] In some embodiments, the payload includes immunotoxins. Immunotoxins include, but are not limited to, ricin, radionuclides, pokeweed antiviral proteins, Pseudomonas exotoxin A, diphtheria toxin, ricin A chain, fungal toxins such as restriction proteins, and phospholipases. Generally, see “Chimeric Toxins,” Olsnes and Pihl, Pharmac. Ther. 15:355-381 (1981) and “Monoclonal Antibodies for Cancer Detection and Therapy,” eds. Baldwin and Byers, pp. 159-179, 224-266, Academic Press (1985).

[0380] In some embodiments, the payload includes a nucleic acid polymer. In some embodiments, the nucleic acid polymer includes short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA), and antisense oligonucleotides. In some embodiments, the nucleic acid polymer includes mRNA encoding, for example, a cytotoxic protein or peptide, or an apoptosis-inducing protein or peptide. Exemplary cytotoxic proteins or peptides include bacterial cytotoxins such as α-pore-forming toxins (e.g., cytolysin A from *E. coli*), β-pore-forming toxins (e.g., α-hemolysin, PVL-leukocytoxin, aerolysin, Clostridium ε-toxin, *Clostridium perfringens* enterotoxin), and binary toxins (anthrax toxin, edema toxin, Clostridium botulinum C2 toxin, *Clostridium spirochete* toxin, *Clostridium perfringens* enterotoxin), and ditoxins (anthrax toxin, edema toxin, Clostridium botulinum C2 toxin, *Clostridium spirochete* toxin, *Clostridium perfringens* enterotoxin). This includes toxins such as iota toxins, Clostridium difficile lethal toxins (A and B), prions, parasporins, cholesterol-dependent cytolysins (e.g., pneumococcal hemolysin), pore-forming toxins (e.g., bacitracin A), cyanobacterial toxins (e.g., microcystin, arthrophyllin), hemotoxins, neurotoxins (e.g., botulinum neurotoxin), cytotoxins, cholera toxin, diphtheria toxin, Pseudomonas exotoxin A, tetanus toxin, or immunotoxins (idarubicin, ricin A, CRM9, pokeweed antiviral protein, DT). Exemplary apoptosis-inducing proteins or peptides include apoptosis protease activator-1 (Apaf-1), cytochrome c, caspase initiation proteins (CASP2, CASP8, CASP9, CASP10), apoptosis inducing factor (AIF), p53, p73, p63, Bcl-2, Bax, granzyme B, poly-ADP-ribose polymerase (PARP), and p21-activated kinase 2 (PAK2). In some embodiments, the nucleic acid polymer includes a nucleic acid decoy. In some embodiments, the nucleic acid decoy is a protein-binding nucleic acid mimic, such as an RNA-based protein-binding mimic. Exemplary nucleic acid decoys include trans-activation region (TAR) decoys and Rev response element (RRE) decoys.

[0381] In some cases, the payload is an aptamer. An aptamer is a small oligonucleotide or peptide molecule that binds to a specific target molecule. Exemplary nucleic acid aptamers include DNA aptamers, RNA aptamers, or XNA aptamers, which are RNA and / or DNA aptamers comprising one or more non-natural nucleotides. Exemplary nucleic acid aptamers include ARC19499 (Archemix Corp.), REG1 (Regado Biosciences), and ARC1905 (Ophthotech).

[0382] Nucleic acids according to some embodiments described herein optionally include naturally occurring nucleic acids, or one or more nucleotide analogs, or have a structure different from naturally occurring nucleic acids. For example, 2'-modification includes a halo, alkoxy, and allyloxy group. In some embodiments, the 2'-OH group is substituted with a group selected from H, OR, R, halo, SH, SR, NH2, NHR, NR2, or CN, wherein R is a C1-C6 alkyl, alkenyl, or alkynyl, and the halo is F, Cl, Br, or I. Examples of linkages to the modification include thiophosphate and 5'-N-phosphorous amide linkages.

[0383] According to some embodiments described herein, nucleic acids are utilized with various nucleotide analogs, modified backbones, or non-naturally occurring nucleoside linkages. In some cases, nucleic acids include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine) or modified nucleosides. Examples of modified nucleotides include base-modified nucleosides (e.g., cytarabine, inosine, isoguanosine, muscarin, pseudouridine, 2,6-diaminopurine, 2-aminopurine, 2-thiothymidine, 3-deazo-5-azacytidine, 2'-deoxyuridine, 3-nitropyrrole, 4-methylindole, 4-thiouridine, 4-thiothymidine, 2-aminoadenosine, 2-thiothymidine, 2-thiouridine, 5-bromocytidine, 5-iodouridine, inosine, 6-azauridine, 6-chloropurine, 7-deazo-azaadenosine, 7-deazoguanosine, 8-azaadenosine, 8-azidoadenosine, benzimidazole, M1-methyladenosine, pyrrolopyrimidine, 2- Amino-6-chloropurine, 3-methyladenosine, 5-propynylcytidine, 5-propynyluridine, 5-bromouridine, 5-fluorouridine, 5-methylcytidine, 7-deazoadenosine, 7-deazoguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine), chemically or biologically modified bases (e.g., methylated bases), modified sugars (e.g., 2'-fluororibose, 2'-aminoribose, 2'-azidoribose, 2'-O-methylribose, L-enantiomeric nucleoside arabinose, and hexose), modified phosphate groups (e.g., thiophosphate esters and 5'-N-phosphoramide linkages), and combinations thereof. Natural and modified nucleotide monomers for nucleic acid chemical synthesis are readily available. In some cases, nucleic acids containing such modifications exhibit improved properties compared to nucleic acids composed solely of naturally occurring nucleotides. In some embodiments, the nucleic acid modifications described herein are used to reduce and / or prevent digestion by nucleases (e.g., exonucleases, endonucleases, etc.). For example, the structure of the nucleic acid can be stabilized by including a nucleotide analog at the 3' end of one or both strands to reduce digestion.

[0384] Different nucleotide modifications and / or backbone structures may be present at different locations in nucleic acids. Such modifications include morpholine, peptide nucleic acid (PNA), methylphosphonic acid nucleotide, thiolphosphonic acid nucleotide, 2'-fluoroN3P5'-phosphinamide, 1',5'-dehydrated hexadiol nucleic acid (HNA), or combinations thereof.

[0385] Conjugation Chemistry

[0386] In some implementations, the payload is naturally conjugated to the anti-Gal3 antibody described herein. In some implementations, the conjugation is as described in: Dawson et al., “Synthesis of proteins by native chemical ligation,” Science 1994, 266, 776-779; Dawson et al., “Modulation of Reactivity in Native Chemical Ligation through the Use of Thiol Additives,” J. Am. Chem. Soc. 1997, 119, 4325–4329; Hackeng et al., “Protein synthesis by native chemical ligation: Expanded scope by using straightforward methodology,” Proc. Natl. Acad. Sci. USA 1999, 96, 10068–10073; or Wu et al., “Building complex glycopeptides: Development of acysteine-free native chemical ligation protocol,” Angew. Chem. Int. Ed. 2006, 45, 4116–4125. In some implementations, the coupling is as described in U.S. Patent No. 8,936,910.

[0387] In some embodiments, the payload is conjugated to the anti-Gal3 antibody described herein using a site-specific method of "traceless" conjugation technology (Philochem). In some embodiments, the "traceless" conjugation technology utilizes the N-terminal 1,2-aminothiol group on the binding site, which is then conjugated to a polynucleotide molecule containing an aldehyde group. (See Casi et al., "Site-specific traceless coupling of potent cytotoxic drugs to recombinant antibodies for pharmacodelivery," JACS134(13):5887-5892(2012)).

[0388] In some embodiments, the payload is conjugated to the anti-Gal3 antibody described herein by means of a site-directed approach utilizing unnatural amino acids incorporated into the binding moiety. In some embodiments, the unnatural amino acid includes p-acetylphenylalanine (pAcPhe). In some embodiments, the keto group of pAcPhe is selectively coupled to an alkoxy-amine-derived conjugate moiety to form an oxime bond. (See Axup et al., “Synthesis of site-specific antibody-drug conjugates using unnatural amino acids,” PNAS 109(40):16101-16106(2012)).

[0389] In some embodiments, the payload is conjugated to the anti-Gal3 antibody described herein using a site-directed approach utilizing an enzyme-catalyzed process. In some embodiments, the site-directed approach utilizes SMARTag. TM Technology (Redwood). In some implementations, SMARTag TMThe technique involves the oxidation of cysteine ​​to formylgly (FGly) residues via formylglyase (FGE) in the presence of an aldehyde tag, followed by conjugation of FGly to an alkylhydrain-functionalized polynucleotide molecule via hydrazine-Pictet-Spengler (HIPS). (See Wu et al., “Site-specific chemical modification of recombinant proteins produced in mammalian cells by using the genetically encoded aldehyde tag,” PNAS 106(9):3000-3005(2009); Agarwal et al., “APictet-Spengler ligation for protein chemical modification,” PNAS 110(1):46-51(2013)).

[0390] In some embodiments, the enzyme-catalyzed process includes microbial transglutaminase (mTG). In some cases, the loading is conjugated to the anti-Gal3 antibody using a process catalyzed by microbial transglutaminase. In some embodiments, mTG catalyzes the formation of a covalent bond between the amide side chain of glutamine within the recognition sequence and the primary amine of the functionalized polynucleotide molecule. In some embodiments, mTG is produced from Streptomyces mobarensis. (See Strop et al., “Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates,” Chemistry and Biology 20(2)161-167(2013)).

[0391] In some embodiments, the payload is conjugated to the anti-Gal3 antibody by a method described in PCT Publication No. WO2014 / 140317, which utilizes a sequence-specific transpeptidase.

[0392] In some embodiments, the payload is conjugated to the anti-Gal3 antibody described herein by methods as described in U.S. Patent Publications 2015 / 0105539 and 2015 / 0105540.

[0393] Connector

[0394] In some embodiments, the linkers described above comprise natural or synthetic polymers consisting of long chains of branched or unbranched monomers and / or two-dimensional or three-dimensional cross-linked networks of monomers. In some embodiments, the linkers comprise polysaccharides, lignin, rubber, or polyalkylene oxides (e.g., polyethylene glycol).

[0395] In some embodiments, the linker includes, but is not limited to, α-, ω-dihydroxy polyethylene glycol, biodegradable lactone-based polymers such as polyacrylic acid, polylactic acid (PLA), poly(glycolic acid) (PGA), polypropylene, polystyrene, polyolefins, polyamides, polycyanoacrylates, polyimides, polyethylenterephthalate (PET, PETG), polyethylene terephthalate (PETE), polytetramethylene glycol (PTG), or polyurethanes, and mixtures thereof. As used herein, mixture refers to the use of different polymers in the same compound and to block copolymers. In some cases, the block copolymer is a polymer in which at least one portion of the polymer is composed of monomers of another polymer. In some embodiments, the linker comprises a polyepoxide. In some embodiments, the linker comprises PEG. In some embodiments, the linker comprises polyvinylimide (PEI) or hydroxyethyl starch (HES).

[0396] In some cases, the polyepoxide (e.g., PEG) is a polydisperse or monodisperse compound. In some embodiments, the polydisperse material comprises a dispersion of materials with different molecular weights, characterized by an average weight (weight average) size and degree of dispersion. In some embodiments, the monodisperse PEG comprises molecules of a single size. In some embodiments, the linker is a polydisperse or monodisperse polyepoxide (e.g., PEG) and the indicated molecular weight represents the average molecular weight of the polyepoxide, for example, PEG molecules.

[0397] In some embodiments, the linker comprises a polyepoxide (e.g., PEG) and the molecular weight of the polyepoxide (e.g., PEG) is about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, or 2... 600, 2700, 2800, 2900, 3000, 3250, 3350, 3500, 3750, 4000, 4250, 4500, 4600, 4750, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 10,000, 12,000, 20,000, 35,000, 40,000, 50,000, 60,000, or 100,000 Da.

[0398] In some embodiments, the polyepoxide (e.g., PEG) is a discrete PEG, wherein the discrete PEG is a polymerized PEG comprising more than one repeating ethylene oxide unit. In some embodiments, the discrete PEG (dPEG) comprises 2 to 60, 2 to 50, or 2 to 48 repeating ethylene oxide units. In some embodiments, dPEG comprises about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50, or more repeating ethylene oxide units. In some embodiments, dPEG comprises about 2 or more repeating ethylene oxide units. In some cases, dPEG is synthesized stepwise from pure (e.g., about 95%, 98%, 99%, or 99.5%) starting material to a single molecular weight compound. In some cases, dPEG has a specific molecular weight rather than an average molecular weight. In some cases, the dPEG described in this article is from Quanta Biodesign, LMD.

[0399] In some embodiments, the linker is a discrete PEG, optionally comprising 2 to 60, 2 to 50, or 2 to 48 repeating ethylene oxide units. In some cases, the linker comprises a dPEG comprising about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50, or more repeating ethylene oxide units. In some cases, the linker is a dPEG from Quanta Biodesign, LMD.

[0400] In some embodiments, the linker is a polypeptide linker. In some embodiments, the polypeptide linker comprises at least 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or more amino acid residues. In some embodiments, the polypeptide linker comprises at least 2, 3, 4, 5, 6, 7, 8 or more amino acid residues. In some embodiments, the polypeptide linker comprises at most 2, 3, 4,...

Claims

1. Use of an anti-Gal3 antibody in the preparation of a medicament for activating an immune response in a subject, wherein the anti-Gal3 antibody disrupts the interaction between Gal3 and TIM-3, wherein the antibody binds to a peptide on Gal3 that is SEQ ID NO: 8, and wherein the antibody does not include VH consisting of SEQ ID NO: 228, and VL consisting of SEQ ID NO:

256.

2. The use according to claim 1, wherein the use comprises contacting a plurality of cells including Gal3-expressing cells and TIM-3-expressing cells with the antibody under conditions that disrupt the interaction between Gal3 and TIM-3.

3. The use according to claim 1, wherein Upon binding to antibodies, Gal3-expressing cells express cytokines that induce immune activation.

4. The use according to claim 3, wherein the cytokine is interferon. The use according to claim 4 , wherein the interferon is IFNγ.

6. The use according to claim 5, wherein IFNγ production is 150%, 160%, 170%, 180%, 190%, 200% or more of the IFNγ production by the isotype antibody.

7. The use according to claim 3, wherein the cytokine is an interleukin.

8. The use according to claim 7, wherein the interleukin is IL-2.

9. The use according to any one of claims 1 to 8, wherein the immune activation comprises proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, natural killer cells or a combination thereof.

10. The use according to claim 9, wherein the immune activation comprises an increase in the M1 macrophage population in the plurality of cells.

11. The use according to claim 9, wherein the immune activation comprises a reduction in the M2 macrophage population in multiple cells.

12. Use of an anti-Gal3 antibody in the preparation of a medicament for promoting proliferation of T cells or natural killer (NK) cells, wherein the anti-Gal3 antibody disrupts the interaction between Gal3 and TIM-3, wherein the antibody binds to a peptide on Gal3 of SEQ ID NO: 8, and wherein the antibody does not include VH consisting of SEQ ID NO: 228, and VL consisting of SEQ ID NO:

256.

13. The use according to claim 12, wherein the use comprises contacting a plurality of cells including T cells, NK cells and Gal3-expressing cells with the antibody under conditions that affect proliferation of T cells and / or NK cells in the plurality of cells.

14. The use according to claim 13, wherein the plurality of cells further comprises TIM-3 expressing cells.

15. The use according to any one of claims 1-8 or 13, wherein the Gal3-TIM-3 interaction is reduced to less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4% or less than 1%.

16. The use according to claim 15, wherein TIM-3 is human TIM-3.

17. The use according to any one of claims 2 or 13, wherein the Gal3 expressing cells are tumor cells.

18. The use according to claim 17, wherein the plurality of cells are located within a tumor microenvironment (TME).

19. The use according to claim 18, wherein the antibody induces a reduction in tumor cells within the TME.

20. The use according to any one of claims 2 or 13, wherein the plurality of cells further comprises tumor infiltrating lymphocytes (TIL).

21. The use according to any one of claims 2 or 13, wherein the plurality of cells further comprises CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells or a combination thereof.

22. The use according to any one of claims 2 or 13, wherein the contact further induces TIL proliferation.

23. The use according to any one of claims 2 or 13, wherein the contacting further induces proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, or a combination thereof.

24. The use according to any one of claims 2 or 13, wherein the contacting further comprises an increase in M1 macrophage proliferation.

25. The use according to any one of claims 2 or 13, wherein the contacting further comprises a reduction in the M2 macrophage population within the TME.

26. The use according to any one of claims 1 or 12, wherein the antibody binds to a region within Gal3 corresponding to residues 51-70 of SEQ ID NO:

1.

27. The use of claim 26, wherein the antibody comprises a K of less than 1 nM, 1.2 nM, 2 nM, 5 nM, 10 nM, 13.5 nM, 15 nM, 20 nM, 25 nM or 30 nM. D .

28. The use according to claim 27, wherein the antibody comprises a humanized antibody.

29. The use according to claim 28, wherein the antibody comprises a full-length antibody or a binding fragment thereof.

30. The use according to claim 29, wherein the antibody comprises a bispecific antibody or a binding fragment thereof.

31. The use according to claim 30, wherein the antibody comprises a monovalent Fab', a bivalent Fab2, a single chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single domain antibody (sdAb) or a camelized antibody or a binding fragment thereof.

32. The use according to claim 31, wherein the antibody comprises an IgG framework.

33. The use according to claim 32, wherein the antibody comprises an IgG1, IgG2 or IgG4 framework.

34. The use according to claim 33, wherein the antibody further comprises an Fc mutation.

35. The use of claim 27, wherein the antibody comprises a chimeric antibody.

36. The use of claim 1 or 12, further comprising administering an antibody to the subject prior to the contacting step.

37. The use according to claim 36, wherein the subject is diagnosed with cancer.

38. The use according to claim 37, wherein the cancer is a solid tumor.

39. The use according to claim 38, wherein the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer or lung cancer.

40. The use according to claim 37, wherein the cancer is a hematological malignancy.

41. The use according to any one of claims 37-40, wherein the cancer is a metastatic cancer.

42. The use according to any one of claims 37-40, wherein the cancer is a relapsed or refractory cancer.

43. The use according to claim 36, wherein the antibody is formulated for systemic administration.

44. The use of claim 36, wherein the antibody is formulated for parenteral administration.

45. The use according to any one of claims 43-44, wherein the antibody is administered in combination with an additional therapeutic agent.

46. ​​The use of claim 45, wherein the antibody and the additional therapeutic agent are administered simultaneously.

47. The use of claim 45, wherein the antibody and the additional therapeutic agent are administered sequentially.

48. The use of claim 47, wherein the antibody is administered prior to administration of the additional therapeutic agent.

49. The use of claim 47, wherein the antibody is administered after administration of the additional therapeutic agent.

50. The use of claim 45, wherein the additional therapeutic agent comprises an immune checkpoint modulator.

51. The use of claim 45, wherein the additional therapeutic agent comprises a chemotherapeutic agent, a targeted therapeutic agent, a hormonal therapeutic agent, or a stem cell-based therapeutic agent.

52. The use according to claim 36, wherein the subject is a human.

53. The use of claim 52, wherein the antibody is administered before or after surgery.

54. The use of claim 52, wherein the antibody is administered in combination with, before, or after radiation therapy.

55. according to any one of claims 1 or 12 described purposes, wherein the K of antibody D Higher than the K of antibodies including D A VH consisting of the sequence SEQ ID NO: 228, and VL consisting of sequence SEQ ID NO:

256.

56. Use of an anti-Gal3 antibody in the preparation of a medicament for reducing fibrosis or its propensity in a tissue, wherein the anti-Gal3 antibody disrupts the interaction between Gal3 and TIM-3, wherein the antibody binds to a peptide on Gal3 of SEQ ID NO: 8, and wherein the antibody does not include VH consisting of SEQ ID NO: 228, and VL consisting of SEQ ID NO:

256.

57. The use according to claim 56, wherein the tissue further comprises TIM-3 expressing cells.

58. The use according to claim 57, wherein the antibody further disrupts the interaction of Gal3 and TIM-3.

59. The method of claim 57, wherein the antibody does not disrupt the interaction of Gal3 and TIM-3.

60. The use according to any one of claims 56-59, wherein at least one fibrosis biomarker comprises alpha-smooth muscle actin (α-SMA).

61. The use according to any one of claims 56-59, wherein at least one fibrosis biomarker comprises fibronectin.

62. The use according to any one of claims 56-59, wherein at least one fibrosis biomarker comprises alpha-smooth muscle actin (α-SMA) and fibronectin.

63. The use according to claim 56, wherein the tissue is kidney tissue or liver tissue.

64. The use according to claim 56, wherein the tissue is selected from the group consisting of liver tissue, kidney tissue, skin tissue, lung tissue, heart tissue, brain tissue, intestinal tissue, bone marrow tissue and soft tissue.

65. The use according to any one of claims 63-64, wherein the expression of at least one fibrosis biomarker in the tissue treated with the antibody is less than the expression of at least one fibrosis biomarker in the control tissue treated with the mIgG2b antibody.

66. The use of claim 56, wherein the antibody results in a reduction in the accumulation of extracellular matrix proteins in a tissue.

67. The use according to claim 66, wherein the extracellular matrix protein comprises collagen.

68. The use according to claim 67, wherein the tissue comprises collagen producing cells.

69. Use according to claim 68, wherein the collagen producing cells are fibroblasts.

70. The use according to claim 69, wherein the fibroblasts are activated by fibrogenic cytokines.

71. The use according to claim 70, wherein the fibrogenic cytokine is TGF-β1.

72. The use according to any one of claims 63-64, wherein the tissue has elevated TGF-β1 expression.

73. The use of claim 56, wherein the antibody comprises a humanized antibody.

74. The use according to claim 56, wherein the antibody comprises a full-length antibody or a binding fragment thereof.

75. The use according to any one of claims 73-74, wherein the antibody comprises a bispecific antibody or a binding fragment thereof.

76. The use of claim 56, wherein the antibody comprises a chimeric antibody.

77. The use according to claim 56, wherein the antibody binds to at least one amino acid residue within the Gal3 region corresponding to residues 51-70 of SEQ ID NO:

1.

78. The use of claim 77, wherein the antibody comprises a K of less than 1 nM, 1.2 nM, 2 nM, 5 nM, 10 nM, 13.5 nM, 15 nM, 20 nM, 25 nM or 30 nM. D .

79. The use according to claim 78, wherein the antibody comprises a monovalent Fab', a bivalent Fab2, a single chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single domain antibody (sdAb) or a camelized antibody or a binding fragment thereof.

80. The use according to claim 79, wherein the antibody comprises an IgG framework.

81. The use according to claim 80, wherein the antibody comprises an IgG1, IgG2 or IgG4 framework.

82. The use according to any one of claims 79-81, wherein the antibody further comprises an Fc mutation.

83. The use according to any one of claims 56, further comprising administering an antibody to the subject prior to the contacting step.

84. The use of claim 83, wherein the subject is diagnosed with a fibrotic disease.

85. The use according to claim 84, wherein the fibrotic disease is renal fibrosis.

86. The use according to claim 84, wherein the fibrotic disease is liver fibrosis.

87. The use of claim 83, wherein the antibody is formulated for systemic administration.

88. The use of claim 83, wherein the antibody is formulated for parenteral administration.

89. The use according to any one of claims 87-88, wherein the subject is a mammal.

90. The use of claim 58, wherein the Gal3-TIM-3 interaction is reduced to less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4% or less than 1%.

91. The use according to any one of claims 1, 12 or 56, wherein the anti-Gal3 antibody comprises (1) a heavy chain variable region comprising VH-CDR1, VH-CDR2 and VH-CDR3, and (2) a light chain variable region comprising VL-CDR1, VL-CDR2 and VL-CDR3; wherein VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:37, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:65, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:93, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:121, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:149, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:177; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:38, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:66, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:94, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:122, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:150, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:178; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:39, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:67, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:95, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:123, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:151, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:179; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:44, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:72, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:100, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:128, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:156, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:184; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:46, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:74, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:102, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:130, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:158, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:186; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:47, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:75, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:103, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:131, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:159, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:187; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:56, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:84, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:112, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:140, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:168, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:196; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:57, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:58, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:113, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:140, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:168, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:196; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:58, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:86, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:114, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:142, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:170, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:198; VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:61, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:89, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:117, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:145, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:173, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:201; VH-CDR1 comprises the amino acid sequence consisting of SEQ ID NO:62, VH-CDR2 comprises the amino acid sequence consisting of SEQ ID NO:90, VH-CDR3 comprises the amino acid sequence consisting of SEQ ID NO:118, VL-CDR1 comprises the amino acid sequence consisting of SEQ ID NO:146, VL-CDR2 comprises the amino acid sequence consisting of SEQ ID NO:174, and VL-CDR3 comprises the amino acid sequence consisting of SEQ ID NO:202; or VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:63, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:91, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:119, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:147, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:175, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:

203.

92. The use according to any one of claims 1, 12 or 56, wherein the anti-Gal3 antibody comprises (1) a heavy chain variable region comprising VH-CDR1, VH-CDR2 and VH-CDR3, and (2) a light chain variable region comprising VL-CDR1, VL-CDR2 and VL-CDR3; wherein VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:61, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:89, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:117, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:145, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:173, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:201; VH-CDR1 comprises the amino acid sequence consisting of SEQ ID NO:62, VH-CDR2 comprises the amino acid sequence consisting of SEQ ID NO:90, VH-CDR3 comprises the amino acid sequence consisting of SEQ ID NO:118, VL-CDR1 comprises the amino acid sequence consisting of SEQ ID NO:146, VL-CDR2 comprises the amino acid sequence consisting of SEQ ID NO:174, and VL-CDR3 comprises the amino acid sequence consisting of SEQ ID NO:202; or VH-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:63, VH-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:91, VH-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:119, VL-CDR1 comprises an amino acid sequence consisting of SEQ ID NO:147, VL-CDR2 comprises an amino acid sequence consisting of SEQ ID NO:175, and VL-CDR3 comprises an amino acid sequence consisting of SEQ ID NO:203.

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