Nectin-4 antibodies and antibody-drug conjugates

HK40134744APending Publication Date: 2026-07-10ELI LILLY & CO
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Patent Information

Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
ELI LILLY & CO
Filing Date
2026-04-30
Publication Date
2026-07-10
Patent Text Reader

Abstract

The present disclosure provides nectin-4 antibody drug conjugates and pharmaceutical compositions thereof, and methods of using for the treatment of cancer.
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Description

Abstract of NECTIN-4 Antibody and Antibody-Drug Conjugate This disclosure provides Nectin-4 antibody-drug conjugates and pharmaceutical compositions thereof, as well as methods for treating cancer.

Claims

CLAIMSWe claim:

1. An antibody that binds human nectin-4, wherein the antibody comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises heavy chain complementarity7determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the LCVR comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein: a) the HCDR1 comprises SEQ ID NO: 4, the HCDR2 comprises SEQ ID NO: 5, the HCDR3 comprises SEQ ID NO: 6, the LCDR1 comprises SEQ ID NO:

7. the LCDR2 comprises SEQ ID NO: 8, and the LCDR3 comprises SEQ ID NO: 9; b) the HCDR1 comprises SEQ ID NO: 18, the HCDR2 comprises SEQ ID NO: 19, the HCDR3 comprises SEQ ID NO: 20, the LCDR1 comprises SEQ ID NO: 21, the LCDR2 comprises SEQ ID NO: 22, and the LCDR3 comprises SEQ ID NO: 23; c) the HCDR1 comprises SEQ ID NO: 28, the HCDR2 comprises SEQ ID NO: 29, the HCDR3 comprises SEQ ID NO: 30, the LCDR1 comprises SEQ ID NO: 31, the LCDR2 comprises SEQ ID NO: 32, and the LCDR3 comprises SEQ ID NO: 33; d) the HCDR1 comprises SEQ ID NO: 38, the HCDR2 comprises SEQ ID NO: 39, the HCDR3 comprises SEQ ID NO: 40, the LCDR1 comprises SEQ ID NO: 41, the LCDR2 comprises SEQ ID NO: 42, and the LCDR3 comprises SEQ ID NO: 43; e) the HCDR1 comprises SEQ ID NO: 48, the HCDR2 comprises SEQ ID NO: 49, the HCDR3 comprises SEQ ID NO: 50, the LCDR1 comprises SEQ ID NO: 41, the LCDR2 comprises SEQ ID NO: 42, and the LCDR3 comprises SEQ ID NO: 51;I) the HCDR1 comprises SEQ ID NO: 56, the HCDR2 comprises SEQ ID NO: 57, the HCDR3 comprises SEQ ID NO: 58, the LCDR1 comprises SEQ ID NO: 59, the LCDR2 comprises SEQ ID NO: 60, and the LCDR3 comprises SEQ ID NO: 61;g) the HCDR1 comprises SEQ ID NO: 66, the HCDR2 comprises SEQ ID NO:

67. the HCDR3 comprises SEQ ID NO: 68, the LCDR1 comprises SEQ ID NO: 69, the LCDR2 comprises SEQ ID NO: 70, and the LCDR3 comprises SEQ ID NO: 71 ; or h) the HCDR1 comprises SEQ ID NO: 76, the HCDR2 comprises SEQ ID NO: 77, the HCDR3 comprises SEQ ID NO: 78, the LCDR1 comprises SEQ ID NO: 69, the LCDR2 comprises SEQ ID NO: 70, and the LCDR3 comprises SEQ ID NO: 79.

2. The antibody of claim 1, wherein the HCDR1 comprises SEQ ID NO: 4, the HCDR2 comprises SEQ ID NO: 5, the HCDR3 comprises SEQ ID NO: 6, the LCDR1 comprises SEQ ID NO: 7, the LCDR2 comprises SEQ ID NO:

8. and the LCDR3 comprises SEQ ID NO: 9.

3. The antibody of claim 1, wherein the HCDR1 comprises SEQ ID NO: 18, the HCDR2 comprises SEQ ID NO: 19, the HCDR3 comprises SEQ ID NO: 20, the LCDR1 comprises SEQ ID NO: 21, the LCDR2 comprises SEQ ID NO: 22, and the LCDR3 comprises SEQ ID NO: 23.

4. The antibody of claim 1, wherein the HCDR1 comprises SEQ ID NO: 28, the HCDR2 comprises SEQ ID NO: 29, the HCDR3 comprises SEQ ID NO: 30, the LCDR1 comprises SEQ ID NO: 31, the LCDR2 comprises SEQ ID NO: 32, and the LCDR3 comprises SEQ ID NO: 33.

5. The antibody of claim 1. wherein the HCDR1 comprises SEQ ID NO: 38, the HCDR2 comprises SEQ ID NO: 39, the HCDR3 comprises SEQ ID NO: 40, the LCDR1 comprises SEQ ID NO: 41, the LCDR2 comprises SEQ ID NO: 42, and the LCDR3 comprises SEQ ID NO: 43.

6. The antibody of claim 1, wherein the HCDR1 comprises SEQ ID NO: 48, the HCDR2 comprises SEQ ID NO: 49, the HCDR3 comprises SEQ ID NO: 50, the LCDR1comprises SEQ ID NO: 41, the LCDR2 comprises SEQ ID NO: 42, and the LCDR3 comprises SEQ ID NO: 51.

7. The antibody of claim 1 , wherein the HCDR1 comprises SEQ ID NO: 56, the HCDR2 comprises SEQ ID NO: 57, the HCDR3 comprises SEQ ID NO: 58, the LCDR1 comprises SEQ ID NO: 59, the LCDR2 comprises SEQ ID NO: 60, and the LCDR3 comprises SEQ ID NO: 61.

8. The antibody of claim 1, wherein the HCDR1 comprises SEQ ID NO: 66, the HCDR2 comprises SEQ ID NO: 67, the HCDR3 comprises SEQ ID NO: 68, the LCDR1 comprises SEQ ID NO: 69, the LCDR2 comprises SEQ ID NO:

70. and the LCDR3 comprises SEQ ID NO: 71.

9. The antibody of claim 1, wherein the HCDR1 comprises SEQ ID NO: 76, the HCDR2 comprises SEQ ID NO: 77, the HCDR3 comprises SEQ ID NO: 78, the LCDR1 comprises SEQ ID NO: 69, the LCDR2 comprises SEQ ID NO:

70. and the LCDR3 comprises SEQ ID NO: 79.

10. The antibody of claim 1, wherein: a) the HCVR comprises SEQ ID NO: 10 and the LCVR comprises SEQ ID NO: 11; b) the HCVR comprises SEQ ID NO: 14 and the LCVR comprises SEQ ID NO: 15; c) the HCVR comprises SEQ ID NO: 24 and the LCVR comprises SEQ ID NO: 25; d) the HCVR comprises SEQ ID NO: 34 and the LCVR comprises SEQ ID NO: 35; e) the HCVR comprises SEQ ID NO: 44 and the LCVR comprises SEQ ID NO: 45; f) the HCVR comprises SEQ ID NO: 52 and the LCVR comprises SEQ ID NO:g) the HCVR comprises SEQ ID NO: 62 and the LCVR comprises SEQ ID NO: 63; h) the HCVR comprises SEQ ID NO: 72 and the LCVR comprises SEQ ID NO: 73; or i) the HCVR comprises SEQ ID NO: 80 and the LCVR comprises SEQ ID NO: 81.

11. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 10 and a LCVR comprising SEQ ID NO: 11.

12. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 14 and a LCVR comprising SEQ ID NO: 15.

13. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 24 and a LCVR comprising SEQ ID NO: 25.

14. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 34 and a LCVR comprising SEQ ID NO: 35.

15. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 44 and a LCVR comprising SEQ ID NO: 45.

16. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 52 and a LCVR comprising SEQ ID NO: 53.

17. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 62 and a LCVR comprising SEQ ID NO: 63.

18. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 72 and a LCVR comprising SEQ ID NO: 73.

19. The antibody of claim 10, wherein the antibody comprises a HCVR comprising SEQ ID NO: 80 and a LCVR comprising SEQ ID NO: 81.

20. The antibody of any one of claims 1 -19, wherein the antibody has a human IgGl or IgG4 isotype.

21. The antibody of claim 20, wherein the antibody has a human IgGl iso type.

22. The antibody of claim 21, comprising alanine at residues 234 and 235 (according to EU Index numbering).

23. The antibody of claim 22, further comprising serine at position 265 (according to EU Index numbering).

24. The antibody of claim 1, wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein: a) the HC comprises amino acids 2-444 of SEQ ID NO: 2 and the LC comprises amino acids 2-215 of SEQ ID NO: 3; b) the HC comprises amino acids 2-444 of SEQ ID NO: 12 and the LC comprises ammo acids 2-215 of SEQ ID NO: 13; c) the HC comprises amino acids 2-443 of SEQ ID NO: 16 and the LC consists of SEQ ID NO: 17; d) the HC comprises amino acids 2-447 of SEQ ID NO: 26 and the LC consists of SEQ ID NO: 27; e) the HC comprises amino acids 2-446 of SEQ ID NO: 36 and the LC consists of SEQ ID NO: 37;1) the HC comprises amino acids 2-446 of SEQ ID NO: 46 and the LC consists of SEQ ID NO: 47; g) the HC comprises amino acids 2-446 of SEQ ID NO: 54 and the LC consists of SEQ ID NO: 55;h) the HC comprises amino acids 2-450 of SEQ ID NO: 64 and the LC comprises amino acids 2-216 of SEQ ID NO: 65; or i) the HC comprises amino acids 2-450 of SEQ ID NO: 74 and the LC comprises ammo acids 2-216 of SEQ ID NO: 75.

25. The antibody of claim 24, wherein: a) the HC consists of SEQ ID NO: 2 and the LC consists of SEQ ID NO: 3; b) the HC consists of SEQ ID NO: 12 and the LC consists of SEQ ID NO: 13; c) the HC consists of SEQ ID NO: 16 and the LC consists of SEQ ID NO: 17; d) the HC consists of SEQ ID NO: 26 and the LC consists of SEQ ID NO: 27; e) the HC consists of SEQ ID NO: 36 and the LC consists of SEQ ID NO: 37;I) the HC consists of SEQ ID NO: 46 and the LC consists of SEQ ID NO: 47; g) the HC consists of SEQ ID NO: 54 and the LC consists of SEQ ID NO: 55; h) the HC consists of SEQ ID NO: 64 and the LC consists of SEQ ID NO: 65; or i) the HC consists of SEQ ID NO: 74 and the LC consists of SEQ ID NO: 75.

26. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 2 and the LC consists of SEQ ID NO: 3.

27. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 12 and the LC consists of SEQ ID NO: 13.

28. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 16 and the LC consists of SEQ ID NO: 17.

29. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 26 and the LC consists of SEQ ID NO: 27.

30. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 36 and the LC consists of SEQ ID NO: 37.

31. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 46 and the LC consists of SEQ ID NO: 47.

32. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 54 and the LC consists of SEQ ID NO: 55.

33. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 64 and the LC consists of SEQ ID NO: 65.

34. The antibody of claim 24 or 25, wherein the HC consists of SEQ ID NO: 74 and the LC consists of SEQ ID NO: 75.

35. An antibody-drug conjugate (ADC) comprising the antibody of any one of claims 1- 34 conjugated to a cytotoxic agent.

36. The ADC of claim 35, wherein the cytotoxic agent is selected from the group consisting of a microtubule inhibitor, a topoisomerase I inhibitor, a DNA damaging agent, a DNA alkylating agent, and a DNA minor groove binder.

37. The ADC of claim 35 or 36, wherein the cytotoxic agent is a topoisomerase I inhibitor.

38. The ADC of claim 37, wherein the topoisomerase I inhibitor is a camptothecin analog.

39. The ADC of claim 38, wherein the camptothecin analog comprises the Formula: X-Y, wherein:Y is of the Formulaand X is *-CH2O-, *-(CH2)2O-, *-(CH2)3O-, *-(CH2)4O-, *-CH2NH-, *-(CH2)2NH-, *- (CH2)3NH-, *-(CH2)4NH-, *-CH2N(CH3)-, *-(CH2)2N(CH3)-, *-(CH2)3N(CH3)-, *- (CH2)4N(CH3)-,*-CH2N(R1)-, *-(CH2)2N(R’)-, *-(CH2)3N(R’)-, *-(CH2)4N(R1)-,*- CH2N(CH3)C(=O)CH2O-, *-CH2N(R1)C(=O)CH2O-, *-CH2NHC(=O)CH2O-, *- CH2NHC(=O)(CH2)2O-, *-CH2NHC(=O)(CH2)3O-, *-CH2NHC(=O)(CH2)4O-, *- CH2NHC(=O)(CH2)5O-, *-CH2NHC(=O)CH2-, *-CH2NHC(=O)(CH2)2-, *- CH2NHC(=O)(CH2)3-, *-CH2NHC(=O)(CH2)4-, *-CH2NHC(=O)(CH2)5-. *- CH2SCH2-. *-CH2S(CH2)2-, *-CH2S(CH2)3-, *-CH2S(CH2)4-, or *-CH2S(CH2)5-; wherein * is the site covalently attached to Y and R1is benzyl.

40. The ADC of claim 38 or 39, wherein the camptothecin analog comprises any one of the following Formula:

41. The ADC of claim 40, wherein the camptothecin analog comprises the Formula:

42. The ADC of claim 40, wherein the camptothecin analog comprises the Formula:

43. The ADC of claim 40, wherein the camptothecin analog comprises the Formula:

44. The ADC of claim 40, wherein the camptothecin analog comprises the Formula:

45. The ADC of claim 40, wherein the camptothecin analog comprises the Formula:

46. The ADC of any one of claims 35-45, wherein the ADC further comprises a self- immolative spacer.

47. The ADC of claim 46, wherein the self-immolative spacer is -NH-CH2- or absent.

48. The ADC of any one of claims 35-47, wherein the ADC further comprises a linker which connects the antibody to the cytotoxic agent.

49. The ADC of claim 48, wherein the linker comprises a peptide unit.

50. The ADC of claim 49, wherein the peptide unit comprises Ala-Ala-Ala, Val-Cit, or Gly-Gly-Phe-Gly (SEQ ID NO: 102).

51. The ADC of claim 50, wherein the peptide unit comprises Ala- Ala- Ala.

52. The ADC of claim 50, wherein the peptide unit comprises Val-Cit.

53. The ADC of claim 50, wherein the peptide unit comprises Gly-Gly-Phe-Gly (SEQ ID NO: 102).

54. The ADC of any one of claims 48-53, wherein the linker further comprises a spacer unit A between the antibody and the peptide unit.

55. The ADC of claim 54, wherein spacer unit A is of the Formula:wherein z is from 1 to 5.

56. The ADC of claim 54, wherein spacer unit A is of the Formula:wherein z is from 1 to 5.

57. An antibody-drug conjugate (ADC), wherein the ADC is one of the Formula:wherein:Ab is the antibody of any one of claims 1-34, and n is from about 1 to 16.

58. The ADC of claim 57, wherein n is from about 2 to 12.

59. The ADC of claim 57, wherein n is from about 2 to 8.

60. The ADC of any one of claims 57-59, wherein the ADC is of the Formula:

61. The ADC of any one of claims 57-59, wherein the ADC is of the Formula:

62. The ADC of any one of claims 57-59, wherein the ADC is of the Formula:

63. The ADC of any one of claims 57-59, wherein the ADC is of the Formula:

64. The ADC of any one of claims 57-63, wherein n is about 2.

65. The ADC of any one of claims 57-63, wherein n is about 4.

66. The ADC of any one of claims 57-63, wherein n is about 6.

67. The ADC of any one of claims 57-63, wherein n is about 8.

68. The ADC of any one of claims 57-67, wherein connection to the antibody occurs through a thiol group on one or more cysteines of the antibody.

69. The ADC of claim 68, wherein the one or more cysteines are each a natural cysteine in the hinge region of the antibody.

70. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprises a HC comprising amino acids 2-444 of SEQ ID NO: 2 and a LC comprising amino acids 2- 215 of SEQ ID NO: 3, and wherein n is about 8.

71. The ADC of claim 70, wherein the Ab comprises a HC consisting of SEQ ID NO: 2 and a LC consisting of SEQ ID NO: 3.

72. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprises a HC comprising amino acids 2-444 of SEQ ID NO: 12 and a LC comprising amino acids 2-215 of SEQ ID NO: 13, and wherein n is about 8.

73. The ADC of claim 72, wherein the Ab comprises a HC consisting of SEQ ID NO: 12 and a LC consisting of SEQ ID NO: 13.

74. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprises a HC comprising amino acids 2-443 of SEQ ID NO: 16 and a LC consisting of SEQ ID NO: 17, and wherein n is about 8.

75. The ADC of claim 74, wherein the Ab comprises a HC consisting of SEQ ID NO: 16 and a LC consisting of SEQ ID NO: 17.

76. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprising amino acids 2-447 of SEQ ID NO: 26 and a LC consisting of SEQ ID NO: 27, and wherein n is about 8.

77. The ADC of claim 76, wherein the Ab comprises a HC consisting of SEQ ID NO: 26 and a LC consisting of SEQ ID NO: 27.

78. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprising amino acids 2-446 of SEQ ID NO: 36 and a LC consisting of SEQ ID NO: 37, and wherein n is about 8.

79. The ADC of claim 78, wherein the Ab comprises a HC consisting of SEQ ID NO: 36 and a LC consisting of SEQ ID NO: 37.

80. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprising amino acids 2-446 of SEQ ID NO: 46 and a LC consisting of SEQ ID NO: 47, and wherein n is about 8.

81. The ADC of claim 80, wherein the Ab comprises a HC consisting of SEQ ID NO: 46 and a LC consisting of SEQ ID NO: 47.

82. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprising amino acids 2-446 of SEQ ID NO: 54 and a LC consisting of SEQ ID NO:

55. and wherein n is about 8.

83. The ADC of claim 82, wherein the Ab comprises a HC consisting of SEQ ID NO: 54 and a LC consisting of SEQ ID NO: 55.

84. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprising amino acids 2-450 of SEQ ID NO: 64 and a LC comprising amino acids 2-216 of SEQ ID NO: 65, and wherein n is about 8.

85. The ADC of claim 84, wherein the Ab comprises a HC consisting of SEQ ID NO: 64 and a LC consisting of SEQ ID NO: 65.

86. The ADC of any one of claims 57-63 or 68-69, wherein the Ab comprising amino acids 2-450 of SEQ ID NO: 74 and a LC comprising amino acids 2-216 of SEQ ID NO: 75, and wherein n is about 8.

87. The ADC of claim 86, wherein the Ab comprises a HC consisting of SEQ ID NO: 74 and a LC consisting of SEQ ID NO: 75.

88. A pharmaceutical composition comprising the antibody of any one of claims 1-34 and one or more pharmaceutically acceptable carriers, diluents, or excipients.

89. A pharmaceutical composition comprising the ADC of any one of claims 35-87 and one or more pharmaceutically acceptable carriers, diluents, or excipients.

90. A method of treating cancer, comprising administering to a patient in need thereof, an effective amount of the ADC of any one of claims 35-87.

91. The method of claim 90, wherein the cancer is urothelial carcinoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, head and neck cancer, ovarian cancer, or prostate cancer.

92. The method of claim 90 or 91, wherein the cancer is urothelial carcinoma.

93. The method any one of claims 90-92, wherein the patient being treated has relapsed after being administered enfortumab vedotin, or has become refractory to enfortumab vedotin.

94. The method any one of claims 90-92, wherein the patient is ineligible for treatment with enfortumab vedotin.

95. The method of any one of claims 90-94, further comprising administrating simultaneously, separately, or sequentially a PD-1 inhibitor or PD-L1 inhibitor.

96. The ADC of any one of claims 35-87, for use in therapy.

97. The ADC of any one of claims 35-87, for use in the treatment of cancer.

98. The ADC for use of claim 97, wherein the cancer is urothelial carcinoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, head and neck cancer, ovarian cancer, or prostate cancer.

99. The ADC for use of claim 98, wherein the cancer is urothelial carcinoma.

100. The ADC for use of any one of claims 97-99, wherein the cancer has relapsed after treatment with enfortumab vedotin, or the cancer has become refractory to enfortumab vedotin.

101. The ADC for use of any one of claims 97-99, wherein prior use of enfortumab vedotin was contraindicated.

102. The ADC for use of any one of claims 97-101, wherein the ADC is administered in simultaneous, separate, or sequential combination with a PD-1 inhibitor or PD-L1 inhibitor.

103. A pharmaceutical composition for use in treating cancer, comprising an effective amount of the ADC of any one of Claims 35-87.

104. The composition for use of claim 103, wherein the cancer is urothelial carcinoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, head and neck cancer, ovarian cancer, or prostate cancer.

105. The composition of claims 103 or 104, which is administered in simultaneous, separate, or sequential combination with a PD-1 inhibitor or PD-L1 inhibitor.

106. The use of an ADC of any one of claims 35-87 for the manufacture of a medicament for the treatment of cancer.

107. The use of claim 106, wherein the cancer is urothelial carcinoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, head and neck cancer, ovarian cancer, or prostate cancer.

108. The use of claim 106 or 107, wherein said medicament further comprises a PD-1 inhibitor or PD-L1 inhibitor.

109. A method of producing an ADC, the method comprising contacting the antibody of any one of claims 1-34 with a compound of the formula:

110. The method of claim 109, further comprising, reducing the antibody with a reducing agent to produce a reduced nectin-4 antibody prior to the contacting.

111. The method of claim 110, wherein the reducing agent is DTT or TCEP.