Anti-epha4 antibody

Patent metadata

Field	Value
Publication number	US-2019077860-A1
Application number	US-201615753611-A
Country	US
Kind code	A1
Filing date	Sep 6, 2016
Priority date	Sep 8, 2015
Publication date	Mar 14, 2019
Grant date	—

Abstract

It is intended to provide an anti-EphA4 antibody or an EphA4-binding fragment thereof which is capable of binding to EphA4 and inhibiting the binding between EphA4 and its ligand, and a pharmaceutical composition comprising the anti-EphA4 antibody or the EphA4-binding fragment thereof as an active ingredient. A mouse anti-EphA4 antibody having binding affinity for EphA4 was obtained, and the sequences of complementarity-determining regions (CDRs) of the mouse anti-EphA4 antibody were identified. This allowed for preparation of a humanized antibody comprising the CDR sequences of the mouse anti-EphA4 antibody in heavy chain variable region and light chain variable region.

First claim

1 . An anti-EphA4 antibody or an EphA4-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region,
wherein the heavy chain variable region comprises (a) CDR-H1 comprising the amino acid sequence represented by or SEQ ID NO: 27; (b) CDR-H2 comprising the amino acid sequence represented by or SEQ ID NO: 29; and (c) CDR-H3 comprising the amino acid sequence represented by SEQ ID NO: 30; and wherein the light chain variable region comprises (d) CDR-L1 comprising the amino acid sequence represented by SEQ ID NO: 31; (e) CDR-L2 comprising the amino acid sequence represented by SEQ ID NO: 32; and (f) CDR-L3 comprising the amino acid sequence represented by SEQ ID NO: 33.

2 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 1 , wherein the antibody or the EphA4-binding fragment thereof is humanized.

3 . (canceled)

4 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 1 , wherein the antibody or the EphA4-binding fragment thereof comprises a heavy chain and a light chain, and a constant region of the heavy chain and a constant region of the light chain each comprise a human antibody-derived sequence.

5 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 4 , wherein the constant region of the heavy chain is derived from human IgG.

6 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 5 , wherein the human IgG is human IgG 1 or human IgG 2 .

7 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 4 , wherein the constant region of the light chain is derived from human Igκ.

8 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 1 , wherein the EphA4-binding fragment is selected from the group consisting of Fab, Fab′, F(ab′) 2 , and Fv.

9 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 8 , wherein the EphA4-binding fragment is F(ab′) 2 .

10 . A pharmaceutical composition comprising the anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 1 .

11 . The pharmaceutical composition according to claim 10 further comprising a pharmaceutically acceptable carrier.

12 . A method of treating amyotrophic lateral sclerosis (ALS) in a human subject in need thereof, comprising administering an effective amount of the pharmaceutical composition of claim 10 to the subject.

13 . An anti-EphA4 antibody or an EphA4-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 66, 68 or 70 and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 78, 80, 82 or 84.

14 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 66, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 78.

15 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 68, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 78.

16 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 70, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 78.

17 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 66, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 80.

18 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 68, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 80.

19 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 70, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 80.

20 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 66, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 82.

21 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 68, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 82.

22 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 70, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 82.

23 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the heavy chain variable region comprises the amino acid sequence represented by SEQ ID NO: 68, and the light chain variable region comprises the amino acid sequence represented by SEQ ID NO: 84.

24 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 13 , wherein the antibody or the EphA4-binding fragment thereof comprises a heavy chain and a light chain, and a constant region of the heavy chain and a constant region of the light chain each comprise a human antibody-derived sequence.

25 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 24 , wherein the constant region of the heavy chain is derived from human IgG.

26 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 25 , wherein the human IgG is human IgG consisting of human IgG 2 or a combination of human IgG 1 and human IgG 2 .

27 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 26 , wherein the human IgG is human IgG 2 .

28 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 27 , wherein the human IgG 2 has a C131S, C219S, V234A and/or G237A mutation under Eu numbering, and does not have a lysine residue at the carboxy terminal.

29 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 28 , wherein the human IgG 2 comprises the amino acid sequence represented by SEQ ID NO: 62.

30 . The anti-EphA4 antibody or the EphA4-binding fragment thereof according to claim 26 , wherein the human IgG is human IgG consisting of a combination of human IgG 1 and human IgG 2 .

31 . The anti-EphA4 antibody or the EphA4-binding fragment thereof accor

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Taguchi Ryota
• Imai Toshio
• Inoue Eiji
• Yamada Akio
• Nakatani Aki
• Hirayama Toshifumi
• Ono Yuichi
• Ito Shunsuke

Classifications

• C07K16/2866 Primary

  against receptors for cytokines, lymphokines, interferons · CPC title

• C12N15/62

  DNA sequences coding for fusion proteins · CPC title

• C07K16/28 Primary

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P21/02 Primary

  Muscle relaxants, e.g. for tetanus or cramps · CPC title