Antibody specifically binding to GLP-1 R and fusion protein thereof with GLP-1

• US 10,059,773 B2
• Filed: 08/01/2014
• Issued: 08/28/2018
• Est. Priority Date: 08/13/2013
• Status: Active Grant

• Current Assignee: Gmax Biopharm LLC
• Original Assignee: Gmax Biopharm LLC
• Inventors: Zhang, Cheng, Jing, Shuqian, Zhang, Hua, Wang, Xiaofeng, Yao, Chenjiang
• Primary Examiner(s): Li, Ruixiang
• Application Number:
  US14/911,715
• Publication Number:
  US 20160362498A1
• Time in Patent Office: 1,488 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/31 fusions, other than Fc, for prolonged plasma life, e.g. albumin

Abstract

Disclosed in the present invention is an antibody specifically binding to GLP-1R and a fusion protein thereof with GLP-1. The fusion proteins can effectively bind to a human GLP-1R receptor and activate a receptor signaling pathway, thus are useful for treating diabetes, excessive weight, obesity and related disorders thereof.

Claims

1. An antibody specifically binding to GLP-1R, comprising:

(a) light chain CDR1 amino acid sequence;

SEQ ID NO;

37;

(b) light chain CDR2 amino acid sequence;

SEQ ID NO;

45;

(c) light chain CDR3 amino acid sequence;

SEQ ID NO;

53;

(d) heavy chain CDR1 amino acid sequence;

SEQ ID NO;

12;

(e) heavy chain CDR2 amino acid sequence;

SEQ ID NO;

19; and

(f) heavy chain CDR3 amino acid sequence;

SEQ ID NO;

27.

2. The antibody of claim 1, wherein the antibody comprises light chain variable region sequence:

SEQ ID NO;

105 and heavy chain variable region sequence;

SEQ ID NO;

79.

3. The antibody of claim 2, wherein the antibody further comprises an amino acid sequence selected from:

(a) light chain constant region amino acid sequence;

SEQ ID NO 106;

(b) light chain constant region amino acid sequence;

SEQ ID NO 107;

(c) heavy chain constant region amino acid sequence;

SEQ ID NO 108;

(d) heavy chain constant region amino acid sequence;

SEQ ID NO 109;

(e) light chain constant region amino acid sequence;

SEQ ID NO 106 and heavy chain constant region amino acid sequence;

SEQ ID NO 108;

(f) light chain constant region amino acid sequence;

SEQ ID NO 107 and heavy chain constant region amino acid sequence;

SEQ ID NO 108;

(g) light chain constant region amino acid sequence;

SEQ ID NO 106 and heavy chain constant region amino acid sequence;

SEQ ID NO 109; and

(h) light chain constant region amino acid sequence;

SEQ ID NO 107 and heavy chain constant region amino acid sequence;

SEQ ID NO 109.

4. A GLP-1 fusion protein comprising GLP-1 and the antibody of claim 1, wherein the GLP-1 comprises an amino acid sequence selected from SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, and SEQ ID NO;

127.

5. The GLP-1 fusion protein of claim 4, wherein the GLP-1 is fused with the light chain and/or heavy chain of the antibody in the form of N′

-R1-L-R2-C′

, N′

-R2-L-R1-C′

or N′

-R2-R1_r-C′

,

wherein;

L is a peptide linker, comprising a full-length, partial, or repeated amino acid sequence selected from SEQ ID NO;

110, SEQ ID NO;

111, and SEQ ID NO;

112;

R1 is an amino acid sequence of GLP-1;

R1_r is a reverse amino acid sequence of GLP-1;

R2 is an amino acid sequence of the light chain or heavy chain of the antibody;

C′

represents a carboxyl residual terminal of the GLP-1 fusion protein polypeptide; and

N′

represents an amino residual terminal of the GLP-1 fusion protein polypeptide.

6. A pharmaceutical composition comprising the GLP-1 fusion protein of claim 4 and a pharmaceutically acceptable carrier.

7. The GLP-1 fusion protein of claim 4, wherein the GLP-1 comprises amino acid sequence SEQ ID NO:

3, SEQ ID NO;

4, or SEQ ID NO;

5.

8. The GLP-1 fusion protein of claim 4, wherein the GLP-1 comprises amino acid sequence SEQ ID NO:

5.

9. The antibody of claim 1, wherein the antibody is a monoclonal antibody.

10. The antibody of claim 1, wherein the antibody is a humanized antibody.

11. A GLP-1 fusion protein comprising the antibody of claim 1 and GLP-1, wherein the GLP-1 comprises amino acid sequence SEQ ID NO:

3, SEQ ID NO;

4, or SEQ ID NO;

5.

12. The GLP-1 fusion protein of claim 11, wherein the GLP-1 comprises amino acid sequence SEQ ID NO:

5.

13. The GLP-1 fusion protein of claim 11, wherein the GLP-1 is fused with a light chain of the antibody via a peptide linker.

14. The GLP-1 fusion protein of claim 11, wherein the GLP-1 is fused with a light chain of the antibody in the form of N′

-R1-L-R2-C′

,

wherein;

L is a peptide linker comprising amino acid sequence SEQ ID NO;

110, SEQ ID NO;

111, or SEQ ID NO;

112;

R1 is the GLP-1;

R2 is a light chain of the antibody;

C′

represents a carboxyl residual terminal of the GLP-1 fusion protein polypeptide; and

N′

represents an amino residual terminal of the GLP-1 fusion protein polypeptide.

15. The GLP-1 fusion protein of claim 11, wherein the peptide linker comprises amino acid sequence SEQ ID NO:

110, SEQ ID NO;

111, or SEQ ID NO;

112.

16. A pharmaceutical composition comprising the GLP-1 fusion protein of claim 11 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.