An antigen-binding molecule, a pharmaceutical composition, and a method

Patent metadata

Field	Value
Publication number	US-2023002481-A1
Application number	US-202017610204-A
Country	US
Kind code	A1
Filing date	May 14, 2020
Priority date	May 15, 2019
Publication date	Jan 5, 2023
Grant date	—

Abstract

The present invention relates to antigen-binding molecules, pharmaceutical compositions, and methods. The present invention provides antigen-binding molecules that bind to C1s and comprise a heavy chain variable region, a light chain variable region and an Fc region.

First claim

1 . An antigen-binding molecule that binds to C1s and comprises a heavy chain variable region, a light chain variable region and an Fc region, wherein
(i) the heavy chain variable region and/or the light chain variable region comprise at least one amino acid that increases the ratio of KD value of the antigen-binding molecule to C1s at pH 4.0 to 6.5 to KD value of the antigen-binding molecule to C1s in pH 6.7 to about 10.0, KD (pH 4.0 to 6.5)/KD (pH 6.7 to about 10.0), compared to that of a first reference antibody comprising two heavy chain variable regions and two light chain variable regions, wherein the heavy chain variable region in the first reference antibody comprises an amino acid sequence of SEQ ID NO: 12 and the light chain variable region in the first reference antibody comprises an amino acid sequence of SEQ ID NO: 13; (ii) the Fc region comprises at least one amino acid that increases binding ability of the antigen-binding molecule to FcRn at pH 4.0 to 6.5 compared to that of the second reference antibody comprising paired Fc regions, wherein the Fc regions in a second reference antibody comprises an amino acid sequence of SEQ ID NO: 14; and (iii) the Fc region comprises at least one amino acid that increases binding ability of the antigen-binding molecule to Fcγ receptor in pH 6.7 to about 10.0 compared to that of the second reference antibody.

2 . The antigen-binding molecule of claim 1 , wherein the heavy chain variable region and the light chain variable region comprise at least one amino acid that increases stability of the antigen-binding molecule compared to that of the first reference antibody.

3 . The antigen-binding molecule of claim 1 , wherein the antigen-binding molecule comprises a constant region, wherein the Fc region of the antigen-binding molecule is in the constant region and the constant region comprises at least one amino acid that reduces immunogenicity of the antigen-binding molecule.

4 . The antigen-binding molecule of claim 1 , wherein the Fc region of the antigen-binding molecule comprises at least one amino acid that reduces binding activity to rheumatoid factor.

5 . The antigen-binding molecule of claim 1 , wherein a variable region in (i) comprises at least one of the following amino acids;
histidine at position 27 in the heavy chain variable region, proline at position 59 in the heavy chain variable region and histidine at position 96 in the light chain variable region (all numbers are according to Kabat numbering system).

6 . The antigen-binding molecule of claim 1 , wherein the Fc region in (ii) comprises at least one amino acid selected from a group consisting of leucine at position 428, alanine at position 434 and threonine at position 436 (all numbers are according to EU numbering system).

7 . The antigen-binding molecule of claim 1 , wherein the Fc region in (iii) comprises at least one of the following amino acids;
tyrosine at position 234, tryptophan at position 235, asparagine at position 236, aspartic acid at position 238, valine at position 250, isoleucine at position 264, aspartic acid at position 268, leucine at position 295, proline at position 307, threonine at position 326 and lysine at position 330 (all numbers are according to EU numbering system).

8 . The antigen-binding molecule of claim 1 , wherein the Fc region in (iii) comprises the amino acids of the following (a) or (b);
(a) tryptophan at position 235, asparagine at position 236, aspartic acid at position268, leucine at position 295, threonine at position 326 and lysine at position 330, or (b) tyrosine at position 234, aspartic acid at position 238, valine at position 250, isoleucine at position 264, proline at position 307 and lysine at position 330 (all numbers are according to EU numbering system).

9 . The antigen-binding molecule of claim 2 , wherein said at least one amino acid that increases stability of the antigen-binding molecule is either or both of alanine at position 96 in the heavy chain variable region and glutamic acid at position 53 in the light chain variable region (both numbers are according to Kabat numbering system).

10 . The antigen-binding molecule of claim 3 , wherein said at least one amino acid that can reduce the immunogenicity is arginine at position 214 according to EU numbering system.

11 . The antigen-binding molecule of claim 4 , wherein said at least one amino acid that reduces the binding activity to rheumatoid factor is either or both of arginine at position 438 and glutamic acid at position 440 (both numbers are according to EU numbering system).

12 . (canceled)

13 . The antigen-binding molecule of claim 1 , wherein the heavy chain variable region and the light chain variable region comprise human-derived frameworks.

14 . An antigen-binding molecule, which
(a) comprises either or both of a VH region having an amino acid sequence that comprises 95% identity to amino acid sequence of SEQ ID NO: 18 and a VL region having an amino acid sequence that comprises 95% identity to amino acid sequence of SEQ ID NO: 19; or (b) whose binding to C1s competes with an antibody that comprises a heavy chain variable region comprising HVR-H1 of SEQ ID NO: 20, HVR-H2 of SEQ ID NO: 21, HVR-H3 of SEQ ID NO: 22, and a light chain variable region comprising HVR-L1 of SEQ ID NO: 23, HVR-L2 of SEQ ID NO: 24, HVR-L3 of SEQ ID NO: 25.

15 . An antigen-binding molecule, which comprises either or both of a heavy chain variable region comprising HVR-H1 of SEQ ID NO: 20, HVR-H2 of SEQ ID NO: 21, HVR-H3 of SEQ ID NO: 22, and a light chain variable region comprising HVR-L1 of SEQ ID NO: 23, HVR-L2 of SEQ ID NO: 24, HVR-L3 of SEQ ID NO: 25.

16 . A nucleic acid encoding the antigen-binding molecule of claim 1 .

17 . A vector comprising the nucleic acid of claim 16 .

18 . A host cell comprising the nucleic acid of claim 16 .

19 . A method of making an antigen-binding molecule comprising, culturing the host cell of claim 18 , under conditions suitable for expression of the antibody.

20 . A nucleic acid encoding the antigen-binding molecule of claim 14 .

21 . A vector comprising the nucleic acid of claim 20 .

22 . A host cell comprising the nucleic acid of claim 20 .

23 . A method of making an antigen-binding molecule comprising, culturing the host cell of claim 22 , under conditions suitable for expression of the antibody.

24 . A nucleic acid encoding the antigen-binding molecule of claim 15 .

25 . A vector comprising the nucleic acid of claim 24 .

26 . A host cell comprising the nucleic acid of claim 24 .

27 . A method of making an antigen-binding molecule comprising, culturing the host cell of claim 26 , under conditions suitable for expression of the antibody.

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Koga Hikaru

Classifications

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K2317/72

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

• C07K2317/92

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

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title