IP Library › Granted Patent US 12662541

Granted Patent B2

US 12662541 · App. 18/052,479 · Granted Jun 23, 2026

Antibody-drug conjugates against the receptor tyrosine kinase EphA5

Inventors: Renata Pasqualini (Newark, NJ); Wadih Arap (Newark, NJ); Fernanda I. Staquicini (Summit, NJ)

Assignees: Rutgers, The State University of New Jersey; MBrace Therapeutics, Inc.

C07K16/2866 A61K47/68031 A61K47/68037 A61K47/6811 A61K47/6889 C07K16/28 C07K2317/565

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Quick Facts

Patent No.: US 12662541
App. No.: 18/052,479
Granted: Jun 23, 2026
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates in certain aspects to antibodies, binding polypeptides, and immunoconjugates specific for human EPH receptor A5 (EphA5).

Claims (180)

1 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody comprising a heavy chain (HC) variable region and a light chain (LC) variable region, wherein the heavy chain variable region comprises three heavy chain complementarity-determining regions (HCDRs), wherein:

(i) HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16,

(ii) HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17, and

(iii) HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20; and wherein the light chain variable region comprises three light chain complementarity-determining regions (LCDRs), wherein

(iv) LCDR1 comprises the amino acid sequence set forth in SEQ ID NO 21,

(v) LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and

(vi) LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24,

(b) L is a linker; and

2 . The immunoconjugate of claim 1 , wherein the linker is a cleavable linker.

3 . The immunoconjugate of claim 2 , wherein the linker is a cathepsin-cleavable linker.

4 . The immunoconjugate of claim 3 , wherein the cathepsin-cleavable linker comprises a valine-citruline (Val-Cit).

5 . The immunoconjugate of claim 2 , wherein the linker is MC-VCP, having the structure:

6 . The immunoconjugate of claim 2 , wherein the linker comprises the structure:

7 . The immunoconjugate of claim 1 , wherein the linker is a pH cleavable linker.

8 . The immunoconjugate of claim 7 , wherein the linker is CL2A, having the structure:

9 . The immunoconjugate of claim 1 , wherein the cytotoxic drug is an auristatin.

10 . The immunoconjugate of claim 9 , wherein the auristatin is monomethyl auristatin E (MMAE) having the structure:

11 . The immunoconjugate of claim 1 , wherein the cytotoxic drug is SN38, having the structure:

12 . The immunoconjugate of claim 1 , wherein the L-D comprises the structure:

13 . The immunoconjugate of claim 1 , wherein the L-D comprises the structure:

14 . The immunoconjugate of claim 1 , wherein the L-D comprises the structure:

15 . The immunoconjugate of claim 1 , wherein the L-D comprises the structure:

16 . An immunoconjugate having the formula Ab-(L-D), wherein:

(i) HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16 ,

(ii) HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17, and

(iii) HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20; and wherein the light chain variable region comprises three light chain complementarity-determining regions (LCDRs),

wherein

(iv) LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 22,

(v) LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and

(vi) LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24,

(b) L is a linker; and

17 . The immunoconjugate of claim 16 , wherein the linker is a cleavable linker.

18 . The immunoconjugate of claim 17 , wherein the linker is a cathepsin-cleavable linker.

19 . The immunoconjugate of claim 18 , wherein the cathepsin-cleavable linker comprises a valine-citruline (Val-Cit).

20 . The immunoconjugate of claim 17 , wherein the linker is MC-VCP, having the structure:

21 . The immunoconjugate of claim 17 , wherein the linker comprises the structure:

22 . The immunoconjugate of claim 16 , wherein the linker is a pH cleavable linker.

23 . The immunoconjugate of claim 22 , wherein the linker is CL2A, having the structure:

24 . The immunoconjugate of claim 16 , wherein the cytotoxic drug is an auristatin.

25 . The immunoconjugate of claim 24 , wherein the auristatin is monomethyl auristatin E (MMAE) having the structure:

26 . The immunoconjugate of claim 16 , wherein the cytotoxic drug is SN38, having the structure:

27 . The immunoconjugate of claim 16 , wherein the L-D comprises the structure:

28 . The immunoconjugate of claim 16 , wherein the L-D comprises the structure:

29 . The immunoconjugate of claim 16 , wherein the L-D comprises the structure:

30 . The immunoconjugate of claim 16 , wherein the L-D comprises the structure:

31 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises three heavy chain complementarity-determining regions (HCDRs), wherein:

(i) HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16,

(ii) HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18, and

(iii) HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20; and wherein the light chain variable region comprises three light chain complementarity-determining regions (LCDRs),

wherein

(iv) LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21,

(v) LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and

(vi) LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24,

(b) L is a linker; and

32 . The immunoconjugate of claim 31 , wherein the linker is a cleavable linker.

33 . The immunoconjugate of claim 32 , wherein the linker is a cathepsin-cleavable linker.

34 . The immunoconjugate of claim 33 , wherein the cathepsin-cleavable linker comprises a valine-citruline (Val-Cit).

35 . The immunoconjugate of claim 32 , wherein the linker is MC-VCP, having the structure:

36 . The immunoconjugate of claim 32 , wherein the linker comprises the structure:

37 . The immunoconjugate of claim 31 , wherein the linker is a pH cleavable linker.

38 . The immunoconjugate of claim 37 , wherein the linker is CL2A, having the structure:

39 . The immunoconjugate of claim 31 , wherein the cytotoxic drug is an auristatin.

40 . The immunoconjugate of claim 39 , wherein the auristatin is monomethyl auristatin E (MMAE) having the structure:

41 . The immunoconjugate of claim 31 , wherein the cytotoxic drug is SN38, having the structure:

42 . The immunoconjugate of claim 31 , wherein the L-D comprises the structure:

43 . The immunoconjugate of claim 31 , wherein the L-D comprises the structure:

44 . The immunoconjugate of claim 31 , wherein the L-D comprises the structure:

45 . The immunoconjugate of claim 31 , wherein the L-D comprises the structure:

46 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody comprising a heavy chain variable region and a light chain variable region, wherein

the heavy chain variable region comprises three heavy chain complementarity-determining regions (HCDRs), wherein:

(i) HCDR1 comprises the amino acid sequence set forth in SEQ IID NO: 16,

(ii) HCDR2 comprises the amino acid sequence set forth in SEQ IID NO: 18, and

(iii) HCDR3 comprises the amino acid sequence set forth in SEQ IID NO: 20; and wherein the light chain variable region comprises three light chain complementarity-determining regions (LCDRs),

wherein

(iv) LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 22,

(v) LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and

(vi) LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24,

(b) L is a linker; and

47 . The immunoconjugate of claim 46 , wherein the linker is a cleavable linker.

48 . The immunoconjugate of claim 47 , wherein the linker is a cathepsin-cleavable linker.

49 . The immunoconjugate of claim 48 , wherein the cathepsin-cleavable linker comprises a valine-citruline (Val-Cit).

50 . The immunoconjugate of claim 47 , wherein the linker is MC-VCP, having the structure:

51 . The immunoconjugate of claim 47 , wherein the linker comprises the structure:

52 . The immunoconjugate of claim 46 , wherein the linker is a pH cleavable linker.

53 . The immunoconjugate of claim 52 , wherein the linker is CL2A, having the structure:

54 . The immunoconjugate of claim 46 , wherein the cytotoxic drug is an auristatin.

55 . The immunoconjugate of claim 54 , wherein the auristatin is monomethyl auristatin E (MMAE) having the structure:

56 . The immunoconjugate of claim 46 , wherein the cytotoxic drug is SN38, having the structure:

57 . The immunoconjugate of claim 46 , wherein the L-D comprises the structure:

58 . The immunoconjugate of claim 46 , wherein the L-D comprises the structure:

59 . The immunoconjugate of claim 46 , wherein the L-D comprises the structure:

60 . The immunoconjugate of claim 46 , wherein the L-D comprises the structure:

61 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody which comprises a heavy chain variable region and a light chain variable region,

wherein the heavy chain variable region comprises three heavy chain complementarity-determining regions (HCDRs), wherein:

(i) HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16,

(ii) HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 19, and

(iii) HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20; and wherein the light chain variable region comprises three light chain complementarity-determining regions (LCDRs),

wherein

(iv) LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21,

(v) LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and

(vi) LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24,

(b) L is a linker; and

62 . The immunoconjugate of claim 61 , wherein the linker is a cleavable linker.

63 . The immunoconjugate of claim 62 , wherein the linker is a cathepsin-cleavable linker.

64 . The immunoconjugate of claim 63 , wherein the cathepsin-cleavable linker comprises a valine-citruline (Val-Cit).

65 . The immunoconjugate of claim 62 , wherein the linker is MC-VCP, having the structure:

66 . The immunoconjugate of claim 62 , wherein the linker comprises the structure:

67 . The immunoconjugate of claim 61 , wherein the linker is a pH cleavable linker.

68 . The immunoconjugate of claim 67 , wherein the linker is CL2A, having the structure:

69 . The immunoconjugate of claim 61 , wherein the cytotoxic drug is an auristatin.

70 . The immunoconjugate of claim 69 , wherein the auristatin is monomethyl auristatin E (MMAE) having the structure:

71 . The immunoconjugate of claim 61 , wherein the cytotoxic drug is SN38, having the structure:

72 . The immunoconjugate of claim 61 , wherein the L-D comprises the structure:

73 . The immunoconjugate of claim 61 , wherein the L-D comprises the structure:

74 . The immunoconjugate of claim 61 , wherein the L-D comprises the structure:

75 . The immunoconjugate of claim 61 , wherein the L-D comprises the structure:

76 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody comprising a heavy chain variable region and a light chain variable region, wherein

the heavy chain variable region comprises three heavy chain complementarity-determining regions (HCDRs), wherein:

(i) HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16,

(ii) HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 19, and

(iii) HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20; and wherein the light chain variable region comprises three light chain complementarity-determining regions (LCDRs),

wherein

(iv) LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 22,

(v) LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and

(vi) LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24,

(b) L is a linker; and

77 . The immunoconjugate of claim 76 , wherein the linker is a cleavable linker.

78 . The immunoconjugate of claim 77 , wherein the linker is a cathepsin-cleavable linker.

79 . The immunoconjugate of claim 78 , wherein the cathepsin-cleavable linker comprises a valine-citruline (Val-Cit).

80 . The immunoconjugate of claim 77 , wherein the linker is MC-VCP, having the structure:

81 . The immunoconjugate of claim 77 , wherein the linker comprises the structure:

82 . The immunoconjugate of claim 76 , wherein the linker is a pH cleavable linker.

83 . The immunoconjugate of claim 82 , wherein the linker is CL2A, having the structure:

84 . The immunoconjugate of claim 76 , wherein the cytotoxic drug is an auristatin.

85 . The immunoconjugate of claim 84 , wherein the auristatin is monomethyl auristatin E (MMAE) having the structure:

86 . The immunoconjugate of claim 76 , wherein the cytotoxic drug is SN38, having the structure:

87 . The immunoconjugate of claim 76 , wherein the L-D comprises the structure:

88 . The immunoconjugate of claim 76 , wherein the L-D comprises the structure:

89 . The immunoconjugate of claim 76 , wherein the L-D comprises the structure:

90 . The immunoconjugate of claim 76 , wherein the L-D comprises the structure:

91 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody comprising the heavy chain set forth in SEQ ID NO: 38 and the light chain set forth in SEQ ID NO: 40; and

(b) the L-D comprises the structure:

92 . An immunoconjugate having the formula Ab-(L-D), wherein:

(a) Ab is an antibody comprising the heavy chain set forth in SEQ ID NO: 39 and the light chain set forth in SEQ ID NO: 40; and

(b) the L-D comprises the structure:

93 . A pharmaceutical composition comprising the immunoconjugate of claim 91 .

94 . A pharmaceutical composition comprising the immunoconjugate of claim 92 .

95 . The immunoconjugate of claim 1 , wherein the antibody heavy chain constant region comprises at least 95% identity to SEQ ID NO: 14.

96 . The immunoconjugate of claim 1 , wherein the antibody heavy chain constant region comprises at least 99% identity to SEQ ID NO: 14.

97 . The immunoconjugate of claim 1 , wherein the antibody light chain constant region comprises at least 95% identity to SEQ ID NO: 15.

98 . The immunoconjugate of claim 1 , wherein the antibody light chain constant region comprises at least 95% identity to SEQ ID NO: 15.

99 . The immunoconjugate of claim 1 , wherein the antibody heavy chain comprising the HCDR 1, HCDR2, and HCDR3 further comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 38.

100 . The immunoconjugate of claim 1 , wherein the antibody heavy chain comprises an amino acid sequence at least 99% identity to SEQ ID NO: 38.

101 . The immunoconjugate of claim 99 wherein the antibody light chain comprising the LCDR 1, LCDR2, and LCDR3 has an amino acid sequence having at least 95% identity to SEQ ID NO: 40.

102 . The immunoconjugate of claim 99 , wherein the antibody light chain comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 40.

103 . The immunoconjugate of claim 1 , wherein the heavy chain variable region comprising the HCDR1, HCDR2, and HCDR3 has an amino acid sequence having at least 99% identity to SEQ ID NO: 5.

104 . The immunoconjugate of claim 103 , wherein the light chain variable region comprising the HCDR1, HCDR2, and HCDR3 has an amino acid sequence having at least 99% identity to SEQ ID NO: 11.

105 . The immunoconjugate of claim 31 , wherein the antibody heavy chain constant region comprises at least 95% identity to SEQ ID NO: 14.

106 . The immunoconjugate of claim 31 , wherein the antibody heavy chain constant region comprises at least 99% identity to SEQ ID NO: 14.

107 . The immunoconjugate of claim 31 , wherein the antibody light chain constant region comprises at least 95% identity to SEQ ID NO: 15.

108 . The immunoconjugate of claim 31 , wherein the antibody light chain constant region comprises at least 99% identity to SEQ ID NO: 15.

109 . The immunoconjugate of claim 31 , wherein the antibody heavy chain comprising the HCDR 1, HCDR2, and HCDR3 further comprises at least 95% identity to SEQ ID NO: 39.

110 . The immunoconjugate of claim 31 , wherein the antibody heavy chain comprises at least 99% identity to SEQ ID NO: 39.

111 . The immunoconjugate of claim 109 , wherein the antibody light chain comprising the LCDR 1, LCDR2, and LCDR3 further comprises at least 95% identity to SEQ ID NO: 40.

112 . The immunoconjugate of claim 109 , wherein the antibody light chain comprises at least 99% identity to SEQ ID NO: 40.

113 . The immunoconjugate of claim 31 , wherein the antibody heavy chain variable region comprises an amino acid sequence at least 99% identity to SEQ ID NO: 6.

114 . The immunoconjugate of claim 113 , wherein the antibody light chain variable region comprises an amino acid sequence at least 99% identity to SEQ ID NO: 11.