Method of treating ectopic ossification or diffuse intrinsic pontine glioma in a subject by administering an anti-ALK2 antibody

Patent metadata

Field	Value
Publication number	US-11859006-B2
Application number	US-201916977572-A
Country	US
Kind code	B2
Filing date	Mar 4, 2019
Priority date	Mar 5, 2018
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

This application relates to a pharmaceutical composition for use in a method for treating and/or preventing a patient having ectopic ossification and/or brain tumor, wherein the patient has an active mutation in ALK2 protein which is responsible for ectopic ossification or brain tumor; an amino acid residue at position 330 of ALK2 is proline; and an active ingredient of this composition is an anti-ALK2 antibody or an antigen-binding fragment thereof comprising a property of binding to ALK2, a property of cross-linking ALK2, and a property of inhibiting BMP signal transduction.

First claim

The invention claimed is:

1. A method for binding a mutated ALK2 in a subject, comprising:
administering to a subject that has an active mutation in ALK2 an anti-ALK2 antibody or an antigen-binding fragment thereof or a pharmaceutical composition comprising an anti-ALK2 antibody or an antigen-binding fragment thereof;
wherein the active mutation in ALK2 comprises at least one mutation selected from L196P, delP197_F198insL, R202I, R206H, Q207E, R258S, R258G, G325A, G328E, G328R, G328W, G356D, and R375P, relative to SEQ ID NO: 1, but does not have a mutation of an amino acid residue at position 330 of SEQ ID NO: 1,
wherein the subject has ectopic ossification or diffuse intrinsic pontine glioma (DIPG).

2. The method according to claim 1 , wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3, which comprise the amino acid sequences of:
SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively,
SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, respectively,
SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, or
SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26, respectively; and
a light chain variable region comprising a CDRL1, a CDRL2, and a CDRL3, which comprise the amino acid sequences of:
SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively,
SEQ ID NO: 8, SEQ ID NO: 17, and SEQ ID NO: 10, respectively,
SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively,
SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, respectively, or
SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 29, respectively.

3. The method according to claim 1 , wherein the anti-ALK2 antibody or the antigen-binding fragment thereof specifically binds to a polypeptide consisting of amino acid residues from position 21 to position 123 in the amino acid sequence of SEQ ID NO: 1.

4. The method according to claim 1 , wherein the active mutation in ALK2 is not a G328V mutation.

5. The method according to claim 1 , wherein the active mutation in ALK2 comprises at least one mutation selected from R206H, R258G, G328E, G328W, and G356D.

6. The method according to claim 1 , wherein the subject has ectopic ossification.

7. The method according to claim 1 , wherein the subject has fibrodysplasia ossificans progressiva (FOP) or diffuse intrinsic pontine glioma (DIPG).

8. The method according to claim 7 , wherein the subject has fibrodysplasia ossificans progressiva (FOP).

9. The method of claim 1 , wherein the subject has diffuse intrinsic pontine glioma (DIPG).

10. The method of claim 1 , wherein the anti-ALK2 antibody or the antigen-binding fragment thereof binds to:
(i) an epitope comprising each residue of glutamic acid at position 38, glycine at position 39, isoleucine at position 59, asparagine at position 60, aspartic acid at position 61, glycine at position 62, phenylalanine at position 63, histidine at position 64, valine at position 65, tyrosine at position 66, asparagine at position 102, threonine at position 104, glutamine at position 106, and leucine at position 107 in the amino acid sequence of SEQ ID NO: 1; or
(ii) an epitope comprising each residue of glutamic acid at position 38, glycine at position 39, leucine at position 40, isoleucine at position 59, asparagine at position 60, aspartic acid at position 61, glycine at position 62, phenylalanine at position 63, histidine at position 64, valine at position 65, tyrosine at position 66, and threonine at position 104 in the amino acid sequence of SEQ ID NO: 1.

11. The method of claim 1 , wherein the anti-ALK2 antibody or the antigen-binding fragment thereof is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, a diabody, a multispecific antibody, or F(ab′)2.

12. The method of claim 2 , wherein the anti-ALK2 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising:
a1) an amino acid sequence consisting of amino acid residues from position 20 to position 142 of the amino acid sequence of SEQ ID NO: 31,
a2) an amino acid sequence consisting of amino acid residues from position 20 to position 142 of the amino acid sequence of SEQ ID NO: 33,
a3) an amino acid sequence consisting of amino acid residues from position 20 to position 140 of the amino acid sequence of SEQ ID NO: 34,
a4) an amino acid sequence consisting of amino acid residues from position 20 to position 140 of the amino acid sequence of SEQ ID NO: 36,
a5) an amino acid sequence consisting of amino acid residues from position 20 to position 140 of the amino acid sequence of SEQ ID NO: 38,
a6) an amino acid sequence consisting of amino acid residues from position 20 to position 140 of the amino acid sequence of SEQ ID NO: 39,
a7) an amino acid sequence having at least 95% identity to any one amino acid sequence selected from the amino acid sequences a1) to a6),
a8) an amino acid sequence having at least 99% identity to any one amino acid sequence selected from the amino acid sequences a1) to a6), or
a9) an amino acid sequence comprising a substitution(s), a deletion(s), or an addition(s) of one or several amino acid residues in any one amino acid sequence selected from the amino acid sequences a1) to a6); and
the anti-ALK2 antibody or the antigen-binding fragment thereof comprises a light chain variable region comprising:
b1) an amino acid sequence consisting of amino acid residues from position 21 to position 133 of the amino acid sequence of SEQ ID NO: 32,
b2) an amino acid sequence consisting of amino acid residues from position 21 to position 129 of the amino acid sequence of SEQ ID NO: 35,
b3) an amino acid sequence consisting of amino acid residues from position 21 to position 129 of the amino acid sequence of SEQ ID NO: 37,
b4) an amino acid sequence having at least 95% identity to any one amino acid sequence selected from the amino acid sequences b1) to b3),
b5) an amino acid sequence having at least 99% identity to any one amino acid sequence selected from the amino acid sequences b1) to b3), or
b6) an amino acid sequence comprising a substitution(s), a deletion(s), or an addition(s) of one or several amino acid residues in any one amino acid sequence selected from the amino acid sequences b1) to b3).

13. The method of claim 1 , wherein the anti-ALK2 antibody is:
an antibody consisting of a heavy chain comprising a heavy chain variable region consisting of amino acid residues from position 20 to position 142 of the amino acid sequence of SEQ ID NO: 31 and a light chain comprising a light chain variable region consisting of amino acid residues from position 21 to position 133 of the amino acid sequence of SEQ ID NO: 32;
an antibody consisting of a heavy chain comprising a heavy chain variable region consisting of amino acid residues from position 20 to position 142 of the amino acid sequence of SEQ ID NO: 33 and a light chain comprising a light chain variable region consisting of amino acid residues from position 21 to position 133 of the amino acid sequence of SEQ ID NO: 32;
an antibody consisting of a heavy chain comprising a heavy chain variable region consisting of amino acid residues from position 20 to position 140 of the amino acid sequence of SEQ ID NO: 34 and a light chain comprising a light chain variable region consisting of amino acid residues from position 21 to position 129 of the amino acid sequence of SEQ ID NO: 35;
an antibody consisting of a heavy chain comprising a heavy chain variable region consisting of amino acid residues from position 20 to position 140 of the amino acid sequence of SEQ ID NO: 36 and a light chain

Assignees

• Univ Saitama Medical
• Daiichi Sankyo Co Ltd

Inventors

• Katagiri Takenobu
• TSUKAMOTO Sho
• Kumagai Keigo
• TSUJI Shinnosuke

Classifications

• C07K16/2896 Primary

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title

• C12Q1/6883

  for diseases caused by alterations of genetic material · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title