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1. WO2020160156 - ANTICORPS ANTI-GAL3 ET LEURS UTILISATIONS

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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WHAT IS CLAIMED IS:

1. A method of inducing immune activation, comprising:

contacting a plurality of cells comprising a Gal3-expressing cell and a TIM-3- expressing cell with an antibody under conditions to disrupt an interaction between Gal3 and TIM-3, wherein the antibody specifically binds to Gal3, wherein the Gal3- expressing cell upon binding to the antibody expresses a cytokine which induces immune activation, and wherein the antibody is not IMT001.

2. The method of claim 1, wherein the cytokine is an interferon.

3. The method of claim 2, wherein the interferon is IFNy.

4. The method of claim 3, wherein the IFNy production is 150%, 160%, 170%, 180%, 190%, 200%, or more of IFNy production by an isotype antibody.

5. The method of claim 1, wherein the cytokine is an interleukin.

6. The method of claim 5, wherein the interleukin is IL-2.

7. The method of any one of the claims 1-6, wherein the immune activation comprises a proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, Natural Killer cells, or a combination thereof.

8. The method of any one of the claims 1-7, wherein the immune activation comprises an increase in Ml macrophage population within the plurality of cells.

9. The method of any one of the claims 1-8, wherein the immune activation comprises a decrease in M2 macrophage population within the plurality of cells.

10. A method of promoting T cell or Natural Killer (NK) cell proliferation, comprising:

contacting a plurality of cells comprising T cells, NK cells, and a Gal3- expressing cell with an antibody under conditions to effect proliferation of T cells and/or NK cells in the plurality of cells, wherein the antibody specifically binds to Gal3, and wherein the antibody is not IMT001.

11. The method of claim 10, wherein the plurality of cells further comprises a TIM-3 expressing cell.

12. The method of claim 11, wherein the antibody further disrupts an interaction of Gal3 and TIM-3.

13. A method of inducing immune activation, comprising:

contacting a plurality of cells comprising a Gal3-expressing cell and a TIM-3- expressing cell with an antibody under conditions to disrupt an 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%.

14. The method of claim 13, wherein the interaction occurs at one or more residues of Gal3 selected from region 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.

15. The method of claim 13, wherein the interaction occurs at one or more residues of Gal3 selected from region 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.

16. The method of any one of claims 13-15, wherein the interaction occurs at one or more residues of TIM-3 selected from region 91-111 or 82-111, wherein the residue positions correspond to positions 91-111 or 82-111 of SEQ ID NO: 2.

17. The method of any one of claims 13-15, wherein the interaction occurs at one or more residues of TIM-3 selected from region 91-111, 107-117, 96-102, 100-106, or 92-119, herein the residue positions correspond to positions 91-111, 107-117, 96-102, 100-106, or 92-119 of SEQ ID NO: 2.

18. The method of any one of the claims 13-17, wherein the TIM-3 is human TIM- 3.

19. The method of any one of the claims 1-18, wherein the Gal3 -expressing cell is a tumor cell.

20. The method of any one of the claims 1-19, wherein the plurality of cells is located within a tumor microenvironment (TME).

21. The method of any one of the claims 1-20, wherein the antibody induces a decrease of tumor cells within the TME.

22. The method of any one of the claims 1-21, wherein the plurality of cells further comprises tumor- infiltrating lymphocytes (TILs).

23. The method of any one of the claims 1-22, wherein the plurality of cells further comprises CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, or a combination thereof.

24. The method of any one of the claims 1, 10, 13, or 22, wherein the contacting further induces TIL proliferation.

25. The method of any one of the claims 1, 10, 13, or 23, wherein the contacting further induces proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, or a combination thereof.

26. The method of any one of the claims 1, 10, 13, or 22-25, wherein the contacting further comprises an increase in proliferation of Ml macrophages.

27. The method of any one of the claims 1, 10, 13, or 22-26, wherein the contacting further comprises a decrease in M2 macrophage population within the TME.

28. The method of any one of the claims 1-27, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 1-20 of SEQ ID NO: 1.

29. The method of any one of the claims 1-27, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 41-91 of SEQ ID NO: 1.

30. The method of any one of the claims 1-27 or 29, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 41-71 of SEQ

ID NO: 1.

31. The method of any one of the claims 1-27 or 29, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 71-91 of SEQ

ID NO: 1.

32. The method of any one of the claims 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.

33. The method of any one of the claims 1-32, wherein the antibody comprises a KD of less than InM, 1.2nM, 2nM, 5nM, 10nM, 13.5nM, 15nM, 20nM, 25nM, or 30nM.

34. The method of any one of the claims 1-33, wherein the antibody comprises a humanized antibody.

35. The method of any one of the claims 1-34, wherein the antibody comprises a full-length antibody or a binding fragment thereof.

36. The method of any one of the claims 1-35, wherein the antibody comprises a bispecific antibody or a binding fragment thereof.

37. The method of any one of the claims 1-36, wherein the antibody comprises a monovalent Fab', a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or binding fragment thereof.

38. The method of any one of the claims 1-37, wherein the antibody comprises an IgG framework.

39. The method of any one of the claims 1-38, wherein the antibody comprises an IgGl, IgG2, or IgG4 framework.

40. The method of any one of the claims 1-39, wherein the antibody further comprises a Fc mutation.

41. The method of any one of the claims 1-33 or 35-40, wherein the antibody comprises a chimeric antibody.

42. The method of any one of the claims 1, 10, or 13, further comprising administering to a subject the antibody prior to the contacting step.

43. The method of claim 42, wherein the subject is diagnosed with a cancer.

44. The method of claim 43, wherein the cancer is a solid tumor.

45. The method of claim 44, wherein the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, or lung cancer.

46. The method of claim 43, wherein the cancer is a hematologic malignancy.

47. The method of any one of the claims 43-46, wherein the cancer is a metastatic cancer.

48. The method of any one of the claims 43-46, wherein the cancer is a relapsed or refractory cancer.

49. The method of any one of the claims 42-48, wherein the antibody is formulated for systemic administration.

50. The method of any one of the claims 42-49, wherein the antibody is formulated for parenteral administration.

51. The method of any one of the claims 42-50, wherein the antibody is administered in combination with an additional therapeutic agent.

52. The method of claim 51, wherein the antibody and the additional therapeutic agent are administered simultaneously.

53. The method of claim 51, wherein the antibody and the additional therapeutic agent are administered sequentially.

54. The method of claim 53, wherein the antibody is administered prior to administering the additional therapeutic agent.

55. The method of claim 53, wherein the antibody is administered after administering the additional therapeutic agent.

56. The method of any one of the claims 51-55, wherein the additional therapeutic agent comprises an immune checkpoint modulator.

57. The method of any one of the claims 51-55, wherein the additional therapeutic agent comprises a chemotherapeutic agent, targeted therapeutic agent, hormonal therapeutic agent, or a stem cell-based therapeutic agent.

58. The method of any of the preceding claims, wherein the subject is a human.

59. The method of claim 58, wherein the antibody is administered either prior to or after surgery.

60. The method of claim 58, wherein the antibody is administered in conjunction with, before, or after radiation therapy.

61. The method of any of the preceding claims, wherein the antibody has a KD that is higher than the KD of antibody IMT001.

62. A method of reducing fibrosis or propensity thereof in a tissue, comprising: contacting the tissue with an antibody that specifically binds Gal3 antibody under conditions such that expression level of a fibrosis biomarker is reduced in the tissue.

63. The method of claim 62, wherein the tissue further comprises a TIM-3 expressing cell.

64. The method of claim 63, wherein the antibody further disrupts interaction of Gal3 and TIM-3.

65. The method of claim 63, wherein the antibody does not disrupt interaction of

Gal3 and TIM-3.

66. The method of any one of the claims 62-65, wherein the at least one fibrosis biomarker comprises a-smooth muscle actin (a-SMA).

67. The method of any one of the claims 62-65, wherein the at least one fibrosis biomarker comprises fibronectin.

68. The method of any one of the claims 62-65, wherein the at least one fibrosis biomarker comprises a-smooth muscle actin (a-SMA) and fibronectin.

69. The method of any one of the claims 62-68, wherein the tissue is a kidney tissue or liver tissue.

70. The method of any one of the claims 62-68, wherein the tissue is selected from a group consisting of a liver tissue, a kidney tissue, a skin tissue, a lung tissue, a heart tissue, a brain tissue, an intestine tissue, a bone marrow tissue, and a soft tissue.

71. The method of any one of the claims 62-70, wherein expression of the at least one fibrosis biomarker in the tissue treated with the antibody is less than expression of the at least one fibrosis biomarker in a control tissue treated with a mIgG2b antibody.

72. The method of any one of the claims 62-71, wherein the antibody results in reduced accumulation of extracellular matrix proteins in the tissue.

73. The method of claim 72, wherein the extracellular matrix proteins comprises collagen.

74. The method of claim 73, wherein the tissue comprises a collagen-producing cell.

75. The method of claim 74, wherein the collagen-producing cell is a fibroblast cell.

76. The method of claim 75, wherein the fibroblast cell is activated by a fibrogenic cytokine.

77. The method of claim 76, wherein the fibrogenic cytokine is TGF-b1.

78. The method of any one of claims 62-77, wherein the tissue has an elevated TGF-b1 expression.

79. The method of any one of the claims 62-78, wherein the antibody comprises a humanized antibody.

80. The method of any one of the claims 62-79, wherein the antibody comprises a full-length antibody or a binding fragment thereof.

81. The method of any one of the claims 62-79, wherein the antibody comprises a bispecific antibody or a binding fragment thereof.

82. The method of any one of the claims 62-79, wherein the antibody comprises a chimeric antibody.

83. The method of any one of the claims 62-82, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 1-20 of SEQ

ID NO: 1.

84. The method of any one of the claims 62-82, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 41-91 of SEQ

ID NO: 1.

85. The method of any one of the claims 62-82 or 84, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 41-71 of

SEQ ID NO: 1.

86. The method of any one of the claims 62-82 or 84, wherein the antibody binds to at least one amino acid residue within a Gal3 region that corresponds to residues 71-91 of

SEQ ID NO: 1.

87. The method of any one of the claims 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.

88. The method of any one of the claims 62-87, wherein the antibody comprises a KD of less than InM, 1.2nM, 2nM, 5nM, lOnM, 13.5nM, 15nM, 20nM, 25nM, or 30nM.

89. The method of any one of the claims 62-88, wherein the antibody comprises a monovalent Fab', a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or binding fragment thereof.

90. The method of any one of the claims 62-89, wherein the antibody comprises an IgG framework.

91. The method of any one of the claims 62-90, wherein the antibody comprises an IgGl, IgG2, or IgG4 framework.

92. The method of any one of the claims 62-91, wherein the antibody further comprises a Fc mutation.

93. The method of any one of claims 62-92, further comprising administering to a subject the antibody prior to the contacting step.

94. The method of claim 93, wherein the subject is diagnosed with a fibrotic disease.

95. The method of claim 94, wherein the fibrotic disease is renal fibrosis.

96. The method of claim 94, wherein the fibrotic disease is liver fibrosis.

97. The method of any one of the claims 93-96, wherein the antibody is formulated for systemic administration.

98. The method of any one of the claims 93-96, wherein the antibody is formulated for parenteral administration.

99. The method of any one of the claims 93-98, wherein the subject is a mammal.

100. The method of any one of claims 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%.

101. The method of claim 100, wherein the interaction occurs at one or more residues of Gal3 selected from region 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.

102. The method of claim 100, wherein the interaction occurs at one or more residues of Gal3 selected from region 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.

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

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

105. An anti-Gal3 antibody for use in the treatment of an immune related disease in a subject, wherein the anti-Gal3 antibody induces activation of the immune system.

106. The anti-Gal3 antibody for use in the treatment of an immune related disease of claim 105, wherein the anti-Gal3 antibody inhibits the interaction between Gal3 and TIM-3.

107. The anti-Gal3 antibody for use in the treatment of an immune related disease of claim 105 or 106, wherein the activation of the immune system comprises proliferation of CD3+ T lymphocytes, CD4+ T helper cells, CD8+ cytotoxic T cells, NK cells, Ml macrophages, or a combination thereof.

108. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 105-107, wherein the activation of the immune system comprises a reduction in M2 macrophages.

109. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 105-108, wherein the immune related disease is cancer.

110. The anti-Gal3 antibody for use in the treatment of an immune related disease of claim 109, wherein the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, or a hematological malignancy.

111. The anti-Gal3 antibody for use in the treatment of an immune related disease of claim 109 or 110, wherein the cancer is a metastatic cancer, a relapsed cancer, or a refractory cancer.

112. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 109-111, wherein the anti-Gal3 antibody is administered in combination with an additional therapeutic agent, such as an immune checkpoint modulator, chemotherapeutic agent, targeted therapeutic agent, hormonal therapeutic agent, stem cell-based therapeutic agent, surgery, or radiation therapy.

113. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 105-108, wherein the immune related disease is fibrosis, and the anti-Gal3 antibody results in reduced accumulation of extracellular matrix proteins in a tissue.

114. The anti-Gal3 antibody for use in the treatment of an immune related disease of claim 113, wherein the extracellular matrix proteins comprises collagen.

115. The anti-Gal3 antibody for use in the treatment of an immune related disease of claim 113 or 114, wherein the expression level of at least one fibrosis biomarker in a subject is reduced, and wherein the at least one fibrosis biomarker comprises a-SMA, fibronectin, or both.

116. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 113-115, wherein the tissue is selected from a group consisting of a liver tissue, a kidney tissue, a skin tissue, a lung tissue, a heart tissue, a brain tissue, an intestine tissue, a bone marrow tissue, and a soft tissue.

117. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 113-116, wherein the fibrosis is renal fibrosis, liver fibrosis, lung fibrosis, cardiac fibrosis, or vascular fibrosis.

118. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 105-117, wherein the anti-Gal3 antibody is formulated for systemic administration, parenteral administration, intravenous administration, or subcutaneous administration.

119. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 105-118, wherein the subject is a human.

120. The method of any one of claims 1-104, 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.

121. The method of any one of claims 1-104, wherein the anti-Gal3 antibody is one or more of IMT001-4, IMT006-1, IMT006-5, or IMT006-8.

122. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 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.

123. The anti-Gal3 antibody for use in the treatment of an immune related disease according to any one of claims 105-119, wherein the anti-Gal3 antibody is IMT001-4, IMT006-1, IMT006-5, or IMT006-8.

124. An anti-GAL3 antibody comprising at least the HCDR3 within any one of the antibodies of FIGs. 35A-36B.

125. The anti-GAL3 antibody of claim 124, further comprising all 3 HCDRs within any one of the antibodies of FIGs. 35A-36B.

126. The anti-GAL3 antibody of claim 125, further comprising all 3 LCDRs within any one of the antibodies of FIGs. 35A-36B.

127. An anti-GAL3 antibody that comprises any one of the heavy chain sequences within FIG. 36A, or a sequence that is at least 80% identical thereto.

128. An anti-GAL3 antibody that comprises any one of the light chain sequences within FIG. 36B or a sequence that is at least 80% identical thereto.

129. The anti-GAL3 antibody of Claim 128 that further comprises any one of the heavy chain sequences within FIG. 36A, or a sequence that is at least 80% identical thereto.

130. An anti-GAL3 antibody that comprises 6 CDRs, wherein the 6 CDRs are, across their combined sequences, at least 80% identical to any set of 6 CDRs within FIGs. 35A and 35B.

131. An anti-GAL3 antibody that comprises at least one of the CDRs from FIG. 38.

132. An anti-GAL3 antibody that comprises at least two of the CDRs from FIG. 38.

133. An anti-GAL3 antibody that comprises at least three of the CDRs from FIG. 38.

134. An anti-GAL3 antibody that comprises at least four of the CDRs from FIG. 38.

135. An anti-GAL3 antibody that comprises at least five of the CDRs from FIG. 38.

136. An anti-GAL3 antibody that comprises six of the CDRs from FIG. 38.

137. An anti-GAL3 antibody that comprises six of the CDRs from FIG. 38, and wherein all six are from a single bin.

138. An anti-GAL3 antibody that comprises six of the CDRs from FIG.38, or a set of 6 CDRs which, across their entire sequence, is at least 80% identical thereto.