Vegf antagonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2026055171-A1
Application number	US-202519234063-A
Country	US
Kind code	A1
Filing date	Jun 10, 2025
Priority date	Jun 11, 2024
Publication date	Feb 26, 2026
Grant date	—

Abstract

The present disclosure relates to VEGF antagonists. VEGF antagonists disclosed herein comprise a VEGF binding domain and a multimerization domain. Certain VEGF antagonists disclosed herein comprise five or more dimers, each dimer comprising two polypeptides, each polypeptide comprising a VEGF binding domain and a multimerization domain comprising an IgG Fc domain and, optionally, an IgM tailpiece. The disclosure further provides pharmaceutical compositions comprising the VEGF antagonists and methods of use of the VEGF antagonists in therapy, e.g., for treating angiogenic eye disorders. Also disclosed are nucleic acids encoding the VEGF antagonists, recombinant cells that express the VEGF antagonists, and methods of producing the VEGF antagonists.

First claim

1 . A VEGF antagonist comprising five or more dimers, each dimer comprising two polypeptide chains, each polypeptide chain comprising, in N- to C-terminal orientation:
(a) a VEGF binding domain comprising:
(i) an Ig-like domain 2 of VEGFR1 comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 13; and
(ii) an Ig-like domain 3 of VEGFR2 comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 15 or SEQ ID NO:50; and
(b) a multimerization domain comprising, in N- to C-terminal orientation:
(i) an IgG Fc domain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:1; and
(ii) an IgM tailpiece having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2.

2 . The VEGF antagonist of claim 1 , wherein the IgM tailpiece comprises the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:4.

3 . (canceled)

4 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain has at least 98% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 5-12 and 52-58.

5 . (canceled)

6 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain comprises the amino acid cysteine at position 309, as defined by EU numbering.

7 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain comprises the amino acid isoleucine at position 253 or the amino acid cysteine at position 253, as defined by EU numbering.

8 . (canceled)

9 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain comprises the amino acids aspartic acid at position 359 and leucine at position 361, as defined by EU numbering.

10 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain comprises the amino acids serine at position 442, leucine at position 443, and proline at position 445, as defined by EU numbering.

11 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain comprises one or more mutations that decrease affinity for FcRn as compared to an IgG Fc domain having the amino acid sequence of SEQ ID NO:1.

12 . (canceled)

13 . The VEGF antagonist of claim 1 , wherein the IgG Fc domain comprises one or more mutations that decrease affinity for a FcγR as compared to an IgG Fc domain having the amino acid sequence of SEQ ID NO: 1.

14 .- 17 . (canceled)

18 . A VEGF antagonist comprising five or more dimers, each dimer comprising two polypeptides, each polypeptide comprising, in N- to C-terminal orientation:
(a) a VEGF binding domain comprising:
(i) an Ig-like domain 2 of VEGFR1 comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:13; and
(ii) an Ig-like domain 3 of VEGFR2 comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 15 or SEQ ID NO:50; and
(b) a multimerization domain having at least 95% identity to the amino acid sequence of SEQ ID NO: 5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, or SEQ ID NO: 11.

19 . The VEGF antagonist of claim 18 , wherein the multimerization domain has at least 99% identity to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, or SEQ ID NO:11.

20 . The VEGF antagonist of claim 18 , wherein the multimerization domain comprises the amino acid sequence of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, or SEQ ID NO: 11.

21 .- 38 . (canceled)

39 . The VEGF antagonist of claim 1 , wherein the Ig-like domain 2 of VEGFR1 has at least 98% sequence identity to SEQ ID NO:13 or SEQ ID NO: 14.

40 .- 42 . (canceled)

43 . The VEGF antagonist of claim 1 , wherein the Ig-like domain 3 of VEGFR2 has at least 98% sequence identity to SEQ ID NO:15 or SEQ ID NO:50.

44 . (canceled)

45 . The VEGF antagonist of claim 1 , wherein the VEGF binding domain comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 16.

46 . (canceled)

47 . (canceled)

48 . A VEGF antagonist comprising five or more dimers, each dimer comprising two polypeptides, each comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20.

49 . The VEGF antagonist of claim 48 , wherein each polypeptide comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20.

50 . The VEGF antagonist of claim 48 , wherein each polypeptide comprises the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20.

51 .- 59 . (canceled)

60 . The VEGF antagonist of claim 1 , wherein the VEGF antagonist comprises six dimers.

61 . A VEGF antagonist comprising:
(a) a VEGF binding domain; and (b) a multimerization domain comprising:
(i) a chimeric IgG Fc domain comprising an amino acid sequence that has at least 90% identity to SEQ ID NO: 1, provided that the chimeric IgG Fc domain has the sequence P-V-A-absent at amino acids 233 to 236 and the amino acid substitution P329A as compared to SEQ ID NO:1, as defined by EU numbering; and
(ii) an IgM tailpiece having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:2.

62 . The VEGF antagonist of claim 61 , wherein the VEGF binding domain is a Fab or component thereof or an scFv.

63 . (canceled)

64 . The VEGF antagonist of claim 61 , wherein the VEGF binding domain comprises a VEGF receptor or portion thereof.

65 . The VEGF antagonist of claim 64 , wherein the VEGF binding domain comprises, in N- to C-terminal orientation, an Ig-like domain 2 of VEGFR1 and an Ig-like domain 3 of VEGFR2.

66 . (canceled)

67 . (canceled)

68 . The VEGF antagonist of claim 61 , wherein the VEGF antagonist comprises a dimer comprising two polypeptides, each polypeptide comprising the VEGF binding domain, the chimeric IgG Fc domain, and the IgM tailpiece.

69 . The VEGF antagonist of claim 68 , wherein the VEGF antagonist comprises five or more dimers.

70 . A composition comprising a population of VEGF antagonists according to claim 1 .

71 . (canceled)

72 . (canceled)

73 . The composition of claim 70 , wherein at least 80% of the population of VEGF antagonists are molecules comprising five or more dimers.

74 .- 76 . (canceled)

77 . The composition of claim 70 , which is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients.

78 . A nucleic acid or plurality of nucleic acids encoding the polypeptides of the VEGF antagonist of claim 1 .

79 . A host cell engineered to express the nucleic acid(s) of claim 78 .

80 . A method of producing a VEGF antagonist comprising culturing the host cell of claim 79 under conditions sufficient to express the polypeptides.

81 . (canceled)

82 . A method of inhibiting VEGF receptor activity in a cell comprising contacting the cell with the VEGF antagonist of claim 1 .

83 . (canceled)

84 . A method for treating an angio

Assignees

• Regeneron Pharma

Inventors

• Solomon Paige
• Wang Nianshuang
• Shen Yang
• Olson William
• Lin Chia-Yang
• Davis Samuel

Classifications

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/71

  Decreased effector function due to an Fc-modification · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title