High-affinity anti-vegf antibody

Patent metadata

Field	Value
Publication number	US-2021228700-A1
Application number	US-202117229271-A
Country	US
Kind code	A1
Filing date	Apr 13, 2021
Priority date	Jan 6, 2016
Publication date	Jul 29, 2021
Grant date	—

Abstract

An object of the present invention is to provide an antibody having significantly high affinity for VEGF compared to the prior art. The present invention provides a monoclonal antibody against VEGF, which binds to a vascular endothelial growth factor (VEGF) with a dissociation constant of 1×10−11 mol/L or less.

First claim

1 . A monoclonal antibody against VEGF, or an antigen-binding fragment thereof, that binds to a vascular endothelial growth factor (VEGF), comprising:
CDR-H1 that comprises the amino acid sequence of SEQ ID NO: 14, CDR-H2 that comprises the amino acid sequence of SEQ ID NO: 16, and CDR-H3 that comprises the amino acid sequence of SEQ ID NO: 18; and CDR-L1 that comprises the amino acid sequence of SEQ ID NO: 20, CDR-L2 that comprises the amino acid sequence of Trp-Ala-Ser, and CDR-L3 that comprises the amino acid sequence of SEQ ID NO: 22.

2 . The monoclonal antibody, or the antigen-binding fragment thereof, according to claim 1 , wherein the monoclonal antibody inhibits binding of a vascular endothelial growth factor (VEGF) to at least one receptor selected from the group consisting of vascular endothelial growth factor receptor-1 (VEGFR1) and vascular endothelial growth factor receptor-2 (VEGFR2).

3 . The monoclonal antibody, or the antigen-binding fragment thereof, according to claim 1 , wherein the monoclonal antibody is a chimeric antibody, a humanized antibody, or a caninized antibody.

4 . The antibody, or the antigen-binding fragment thereof, according to claim 1 , further comprising a heavy chain constant region comprising an amino acid sequence derived from a human IgG1 heavy chain constant region and a light chain constant region comprising an amino acid sequence derived from a human IgG1 light chain constant region.

5 . The antibody, or the antigen-binding fragment thereof, according to claim 4 , wherein the amino acid sequence derived from a human IgG1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 42, and the amino acid sequence derived from a human IgG1 light chain constant region comprises the amino acid sequence of SEQ ID NO: 44.

6 . The antibody, or the antigen-binding fragment thereof, according to claim 5 , comprising:
a heavy chain that comprises the amino acid sequence of SEQ ID NO: 34, and the amino acid sequence of SEQ ID NO: 42; and a light chain that comprises the amino acid sequence of SEQ ID NO: 36, and the amino acid sequence of SEQ ID NO: 44.

7 . The antibody, or the antigen-binding fragment thereof, according to claim 1 , further comprising a heavy chain constant region comprising an amino acid sequence derived from a canine IgGB heavy chain constant region and a light chain constant region comprising an amino acid sequence derived from a canine Ig light chain (κ chain) constant region or a canine Ig light chain (λ chain) constant region.

8 . The antibody, or the antigen-binding fragment thereof, according to claim 7 , wherein an amino acid sequence derived from a canine IgGB heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 46, an amino acid sequence derived from a canine Ig light chain (κ chain) constant region comprises the amino acid sequence of SEQ ID NO: 48, and an amino acid sequence derived from a canine Ig light chain (X chain) constant region comprises the amino acid sequence of SEQ ID NO: 50.

9 . The antibody, or the antigen-binding fragment thereof, according to claim 8 , comprising:
a heavy chain that comprises the amino acid sequence of SEQ ID NO: 34 and the amino acid sequence of SEQ ID NO: 46; and a light chain that comprises the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 48 or 50.

10 . The antigen-binding fragment according to claim 1 , wherein the antigen-binding fragment is a single-chain antibody or a double-chain antibody.

11 . A hybridoma that produces the monoclonal antibody according to claim 1 .

12 . A pharmaceutical composition comprising the monoclonal antibody, or the antigen-binging fragment thereof, according to claim 1 ; and a pharmaceutically acceptable carrier.

13 . A kit comprising the monoclonal antibody, or the antigen-binding fragment thereof, according to claim 1 ; and a buffer, an enzyme solution, a secondary antibody, a solution for dilution, and/or instructions.

14 . A method for treating a VEGF-mediated cancer or a VEGF-mediated eye disease in a subject in need thereof, comprising a step of administering a therapeutically effective amount of the antibody, or the antigen-binding fragment thereof, according to claim 1 to the subject.

15 . The method according to claim 14 , wherein the therapeutically effective amount inhibits angiogenesis or vascular hyperpermeability.

16 . The method according to claim 15 , wherein the angiogenesis is pathological angiogenesis.

17 . The method according to claim 14 , wherein the cancer is a solid cancer.

18 . The method according to claim 14 , wherein the cancer is selected from the group consisting of colorectal cancer, rectal cancer, breast cancer, non-small-cell lung cancer, non-Hodgkin's lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreas cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid tumor, head and neck cancer, melanoma, ovarian cancer, and mesothelioma.

19 . The method according to claim 14 , wherein the VEGF-mediated eye disease is at least one selected from age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular glaucoma, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization associated with pathological myopia, pterygium, rubeosis, pannus, Stevens-Johnson syndrome, and an immunological rejection in a transplanted tissue of the eye.

20 . The monoclonal antibody, or an antigen-binding fragment thereof, of claim 1 , comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 34 and a light chain comprising the amino acid sequence of SEQ ID NO: 36.

21 . The monoclonal antibody, or an antigen-binding fragment thereof, of claim 20 , wherein the antibody, or antigen-binding fragment thereof, binds to the vascular endothelial growth factor (VEGF) with a dissociation constant of 1×10 −11 mol/L or less.

Assignees

• Order Made Medical Res Inc
• Santen Pharmaceutical Co Ltd

Inventors

• Murakami Yasufumi
• Mukoubata Shigeki
• Akiyama Hirotada
• Konomi Koji

Classifications

• C07K2317/76

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

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/92

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

• A61K2039/505

  comprising antibodies · CPC title

• A61P35/00

  Antineoplastic agents · CPC title