IP Library › Granted Patent US 10,894,824
Granted Patent B2
US 10,894,824 · App. 16/579,078 · Granted Jan 19, 2021

Multispecific antibodies that target HPTP-β (VE-PTP) and VEGF

Inventor: Kevin Peters (Cincinnati, OH)
Assignee: Aerpio Pharmaceuticals, Inc.
C07K16/22C07K16/40A61K9/0019A61K9/0048C07K2317/31C07K2317/35C07K2317/51C07K2317/92
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Quick Facts
Patent No.
US 10,894,824
App. No.
16/579,078
Granted
Jan 19, 2021
Kind
B2
Abstract

The disclosure provides compositions comprising multi-specific compounds, including a compound that targets a phosphatase and a receptor tyrosine kinase agonist. Also provided are methods for the treatment of conditions associated with angiogenesis, comprising administering a multi-specific compound that targets a phosphatase and a receptor tyrosine kinase agonist.

Claims (88)

1. An antibody comprising:

(a) a first domain that activates Tie2, wherein the first domain comprises:

(i) a heavy chain variable region that comprises an amino acid sequence that is any one of SEQ ID NOs: 76-80, an amino acid sequence that is any one of SEQ ID NOs: 81-87, and an amino acid sequence that is any one of SEQ ID NOs: 88-90; and

(ii) a light chain variable region that comprises an amino acid sequence that is any one of SEQ ID NOs: 91-93, an amino acid sequence that is any one of SEQ ID NOs: 94-96, and an amino acid sequence that is any one of SEQ ID NOs: 97-98; and

(b) a second domain that specifically binds a receptor tyrosine kinase agonist.

2. The antibody of claim 1 , wherein the antibody is a multi-specific antibody.

3. The antibody of claim 1 , wherein the antibody inhibits HPTP-β.

4. The antibody of claim 1 , wherein the antibody inhibits VE-PTP.

5. The antibody of claim 1 , wherein the antibody inhibits the receptor tyrosine kinase agonist.

6. The antibody of claim 1 , wherein the antibody inhibits VEGF receptor signaling.

7. The antibody of claim 1 , wherein the antibody inhibits a VEGF.

8. The antibody of claim 1 , wherein the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, or SEQ ID NO: 244.

9. The antibody of claim 1 , wherein the second domain comprises an amino acid sequence that is any one of SEQ ID NOs: 99-113, an amino acid sequence that is any one of SEQ ID NOs: 114-123, an amino acid sequence that is any one of SEQ ID NOs: 124-131, an amino acid sequence that is any one of SEQ ID NOs: 132-137, an amino acid sequence that is any one of SEQ ID NOs: 138-143, and an amino acid sequence that is any one of SEQ ID NOs: 144-146.

10. The antibody of claim 1 , wherein the second domain comprises:

(a) an amino acid sequence that is any one of SEQ ID NOs: 99-103;

(b) an amino acid sequence that is any one of SEQ ID NOs: 114-118;

(c) an amino acid sequence that is any one of SEQ ID NOs: 124-125;

(d) an amino acid sequence that is any one of SEQ ID NOs: 132-134;

(e) an amino acid sequence that is any one of SEQ ID NOs: 138-140; and

(f) an amino acid sequence that is SEQ ID NO: 144.

11. The antibody of claim 1 , wherein the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 147 or SEQ ID NO: 148.

12. The antibody of claim 1 , wherein the second domain comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 233-242.

13. The antibody of claim 1 , wherein the second domain comprises:

(i) an amino acid sequence that is any one of SEQ ID NOs: 104-113;

(ii) an amino acid sequence that is any one of SEQ ID NOs: 119-123;

(iii) an amino acid sequence that is any one of SEQ ID NOs: 126-131;

(iv) an amino acid sequence that is any one of SEQ ID NOs: 135-137;

(v) an amino acid sequence that is any one of SEQ ID NOs: 141-143; and

(vi) an amino acid sequence that is any one of SEQ ID NOs: 145-146.

14. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, or SEQ ID NO: 257; and

(b) a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, or SEQ ID NO: 253.

15. The antibody of claim 1 , wherein the antibody is a tetravalent bispecific antibody, wherein:

(a) the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, or SEQ ID NO: 244;

(b) the antibody comprises a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, or SEQ ID NO: 249;

(c) the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, or SEQ ID NO: 253; and

(d) the antibody comprises a linker, wherein the linker attaches the second domain to the heavy chain amino acid sequence, wherein the linker comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 31-75.

16. The antibody of claim 1 , wherein the antibody is a hexavalent bispecific antibody, wherein:

(a) the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, or SEQ ID NO: 244;

(b) the antibody comprises a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, or SEQ ID NO: 249;

(c) the antibody comprises a first linker, wherein the first linker attaches the second domain to the heavy chain amino acid sequence, wherein the first linker comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 31-75;

(d) the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, or SEQ ID NO: 253;

(e) the antibody comprises a third domain that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, or SEQ ID NO: 244; and

(f) the antibody comprises a second linker, wherein the second linker attaches the third domain to the light chain amino acid sequence, wherein the second linker comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 31-75.

17. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 262 or any one of SEQ ID NOs: 246-249; and

(b) a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 261, or SEQ ID NO: 260.

18. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, or SEQ ID NO: 257; and

(b) a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 261, or SEQ ID NO: 260.

19. The antibody of claim 1 , wherein the antibody is a tetravalent bispecific antibody, wherein:

(a) the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22;

(b) the antibody comprises a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 247;

(c) the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250; and

(d) the antibody comprises a linker, wherein the linker attaches the second domain to the heavy chain amino acid sequence, wherein the linker comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 31.

20. The antibody of claim 1 , wherein the antibody is a hexavalent bispecific antibody, wherein:

(a) the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22;

(b) the antibody comprises a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 247;

(c) the antibody comprises a first linker, wherein the first linker attaches the second domain to the heavy chain amino acid sequence, wherein the first linker comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 31;

(d) the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250;

(e) the antibody comprises a third domain that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22; and

(f) the antibody comprises a second linker, wherein the second linker attaches the third domain to the light chain amino acid sequence, wherein the second linker comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 31.

21. The antibody of claim 1 , wherein the antibody is a tetravalent bispecific antibody, wherein:

(a) the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, or SEQ ID NO: 244;

(b) the antibody comprises a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, or SEQ ID NO: 249;

(c) the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, or SEQ ID NO: 253; and

(d) the antibody comprises a linker, wherein the linker attaches the second domain to the light chain amino acid sequence, wherein the linker comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 31-75.

22. The antibody of claim 1 , wherein the antibody is a tetravalent bispecific antibody, wherein:

(a) the second domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 22;

(b) the antibody comprises a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 247;

(c) the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain, and is at least 80% identical to SEQ ID NO: 250; and

(d) the antibody comprises a linker, wherein the linker attaches the second domain to the light chain amino acid sequence, wherein the linker comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 31.

23. The antibody of claim 1 , wherein the first domain activates Tie2 by modulating a phosphatase that activates Tie2.

24. The antibody of claim 1 , wherein the heavy chain variable region of the first domain comprises an amino acid sequence that is SEQ ID NO: 2 and the light chain variable region of the first domain comprises an amino acid sequence that is SEQ ID NO: 5.

25. The antibody of claim 1 , wherein the antibody comprises a light chain amino acid sequence that contains the light chain variable region of the first domain and is SEQ ID NO: 250; and a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain and is SEQ ID NO: 247 or SEQ ID NO: 262.

26. The antibody of claim 1 , wherein the heavy chain variable region of the first domain comprises the amino acid sequence that is SEQ ID NO: 76, the amino acid sequence that is SEQ ID NO: 81, and the amino acid sequence that is SEQ ID NO: 88; and the light chain variable region of the first domain comprises the amino acid sequence that is SEQ ID NO: 91, the amino acid sequence that is SEQ ID NO: 94, and the amino acid sequence that is SEQ ID NO: 97.

27. The antibody of claim 1 , wherein the heavy chain variable region of the first domain comprises the amino acid sequence that is SEQ ID NO: 76, the amino acid sequence that is SEQ ID NO: 81, and the amino acid sequence that is SEQ ID NO: 88.

28. The antibody of claim 1 , wherein the light chain variable region of the first domain comprises the amino acid sequence that is SEQ ID NO: 91, the amino acid sequence that is SEQ ID NO: 94, and the amino acid sequence that is SEQ ID NO: 97.

29. The antibody of claim 1 , wherein the heavy chain variable region of the first domain comprises the amino acid sequence that is SEQ ID NO: 76, the amino acid sequence that is SEQ ID NO: 81, and the amino acid sequence that is SEQ ID NO: 88; the light chain variable region of the first domain comprises the amino acid sequence that is SEQ ID NO: 91, the amino acid sequence that is SEQ ID NO: 94, and the amino acid sequence that is SEQ ID NO: 97; and the second domain comprises at least one amino acid sequence that is SEQ ID NO: 147 or SEQ ID NO: 148.

30. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, or SEQ ID NO: 257; and

(b) a light chain amino acid sequence that contains the light chain variable region of the first domain, and is SEQ ID NO: 250.

31. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is SEQ ID NO: 247 or SEQ ID NO: 262; and

(b) a light chain amino acid sequence that contains the light chain variable region of the first domain, and is SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, or SEQ ID NO: 261.

32. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain amino acid sequence that contains the heavy chain variable region of the first domain, and is SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, or SEQ ID NO: 257; and

(b) a light chain amino acid sequence that contains the light chain variable region of the first domain, and is SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, or SEQ ID NO: 261.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 9, 2021
From: AERPIO PHARMACEUTICALS, INC.
To: EYEPOINT PHARMACEUTICALS, INC.
Reel/Frame 057448/0033 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 3, 2020
From: PETERS, KEVIN
To: AERPIO PHARMACEUTICALS, INC.
Reel/Frame 051989/0569 →