Methods of treating a wasting syndrome, increasing growth hormone levels, and increasing GHSR activity with a LEAP2 antibody

Patent metadata

Field	Value
Publication number	US-11548942-B2
Application number	US-202016993974-A
Country	US
Kind code	B2
Filing date	Aug 14, 2020
Priority date	May 24, 2017
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The present disclosure provides binding agents that modulate the interaction between liver-expressed antimicrobial peptide 2 (LEAP2) and growth hormone secretagogue receptor (GHSR). Specifically, the present disclosure provides binding agents, such as LEAP2 peptides that bind GHSR and methods of their use to treat or ameliorate a neuroendocrine and/or metabolic disease or disorder such as obesity, diabetes, acromegaly, gigantism and/or Prader-Willi syndrome. The present disclosure also provides binding agents, such as antibodies, that bind LEAP2, and methods of their use to, e.g., treat or ameliorate a neuroendocrine and/or metabolic disease or disorder such as cachexia, anorexia, or other wasting syndromes, increase growth hormone levels, or increase GHSR activity.

First claim

The invention claimed is:

1. A method of treating a wasting syndrome in a human subject, the method comprising administering to the human subject a therapeutically effective amount of an antibody that specifically binds liver-expressed antimicrobial peptide 2 (LEAP2), wherein the antibody comprises: (1) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3 from the amino acid sequence of SEQ ID NO:7 and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3 from the amino acid sequence of SEQ ID NO: 8; or (2) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3 from the amino acid sequence of SEQ ID NO:9 and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3 from the amino acid sequence of SEQ ID NO: 10.

2. The method of claim 1 , wherein the antibody is an antibody fragment comprising at least one antigen-binding site.

3. The method of claim 1 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, a multispecific antibody, a Fab, Fab′, F(ab′) 2 , Fv, scFv, (scFv) 2 , a single chain antibody, or a dual variable region antibody.

4. The method of claim 1 , wherein the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.

5. The method of claim 1 , wherein the antibody:
(i) is an antagonist of LEAP2;
(ii) inhibits the binding of LEAP2 to GHSR; and/or
(iii) increases food intake.

6. The method of claim 1 , wherein: (1) the first VH has least 90% sequence identity to the amino acid sequence of SEQ ID NO:7 and the first VL has at least 90% identity to the amino acid sequence of SEQ ID NO:8, or (2) the second VH has at least 90% sequence identity to the amino acid sequence of SEQ ID NO:9 and the second VL has at least 90% identity to the amino acid sequence of SEQ ID NO:10.

7. The method of claim 1 , wherein: (1) the first VH comprises the amino acid sequence of SEQ ID NO:7 and the first VL comprises the amino acid sequence of SEQ ID NO:8, or (2) the second VH comprises the amino acid sequence of SEQ ID NO: 9 and the second VL comprises the amino acid sequence of SEQ ID NO:10.

8. The method of claim 7 , wherein the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.

9. The method of claim 1 , wherein the antibody is humanized.

10. The method of claim 1 , wherein the wasting syndrome is anorexia.

11. The method of claim 1 , wherein the wasting syndrome is cachexia.

12. The method of claim 1 , wherein:
(a) the first VH CDR1 comprises the amino acid sequence of SEQ ID NO:20, the first VH CDR2 comprises the amino acid sequence of SEQ ID NO:21, the first VH CDR3 comprises the amino acid sequence of SEQ ID NO:22, the first VL CDR1 comprises the amino acid sequence of SEQ ID NO:23, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO:24, and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO:25;
(b) the first VH CDR1 comprises the amino acid sequence of SEQ ID NO:32, the first VH CDR2 comprises the amino acid sequence of SEQ ID NO:36, the first VH CDR3 comprises the amino acid sequence of SEQ ID NO:40, the first VL CDR1 comprises the amino acid sequence of SEQ ID NO:43, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO:46, and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO:25;
(c) the first VH CDR1 comprises the amino acid sequence of SEQ ID NO:33, the first VH CDR2 comprises the amino acid sequence of SEQ ID NO:21, the first VH CDR3 comprises the amino acid sequence of SEQ ID NO:22, the first VL CDR1 comprises the amino acid sequence of SEQ ID NO:23, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO:24, and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO:25;
(d) the first VH CDR1 comprises the amino acid sequence of SEQ ID NO:34, the first VH CDR2 comprises the amino acid sequence of SEQ ID NO:37, the first VH CDR3 comprises the amino acid sequence of SEQ ID NO:41, the first VL CDR1 comprises the amino acid sequence of SEQ ID NO:44, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO:46, and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO:48;
(e) the first VH CDR1 comprises the amino acid sequence of SEQ ID NO:35, the first VH CDR2 comprises the amino acid sequence of SEQ ID NO:38, the first VH CDR3 comprises the amino acid sequence of SEQ ID NO:42, the first VL CDR1 comprises the amino acid sequence of SEQ ID NO:45, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO:47, and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO:49; or
(f) the first VH CDR1 comprises the amino acid sequence of SEQ ID NO:20, the first VH CDR2 comprises the amino acid sequence of SEQ ID NO:39, the first VH CDR3 comprises the amino acid sequence of SEQ ID NO:22, the first VL CDR1 comprises the amino acid sequence of SEQ ID NO:23, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO:24, and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO:25;
(g) the second VH CDR1 comprises the amino acid sequence of SEQ ID NO:26, the second VH CDR2 comprises the amino acid sequence of SEQ ID NO:27, the second VH CDR3 comprises the amino acid sequence of SEQ ID NO:28, the second VL CDR1 comprises the amino acid sequence of SEQ ID NO:29, the second VL CDR2 comprises the amino acid sequence of SEQ ID NO:30, and the second VL CDR3 comprises the amino acid sequence of SEQ ID NO:31;
(h) the second VH CDR1 comprises the amino acid sequence of SEQ ID NO:50, the second VH CDR2 comprises the amino acid sequence of SEQ ID NO:54, the second VH CDR3 comprises the amino acid sequence of SEQ ID NO:58, the second VL CDR1 comprises the amino acid sequence of SEQ ID NO:61, the second VL CDR2 comprises the amino acid sequence of SEQ ID NO:64, and the second VL CDR3 comprises the amino acid sequence of SEQ ID NO:31;
(i) the second VH CDR1 comprises the amino acid sequence of SEQ ID NO:51, the second VH CDR2 comprises the amino acid sequence of SEQ ID NO:27, the second VH CDR3 comprises the amino acid sequence of SEQ ID NO:28, the second VL CDR1 comprises the amino acid sequence of SEQ ID NO:29, the second VL CDR2 comprises the amino acid sequence of SEQ ID NO:30, and the second VL CDR3 comprises the amino acid sequence of SEQ ID NO:31;
(j) the second VH CDR1 comprises the amino acid sequence of SEQ ID NO:52, the second VH CDR2 comprises the amino acid sequence of SEQ ID NO:55, the second VH CDR3 comprises the amino acid sequence of SEQ ID NO:59, the second VL CDR1 comprises the amino acid sequence of SEQ ID NO:62, the second VL CDR2 comprises the amino acid sequence of SEQ ID NO:64, and the second VL CDR3 comprises the amino acid sequence of SEQ ID NO:66;
(k) the second VH CDR1 comprises the amino acid sequence of SEQ ID NO:53, the second VH CDR2 comprises the amino acid sequence of SEQ ID NO:56, the second VH CDR3 comprises the amino acid sequence of SEQ ID NO:60, the second VL CDR1 comprises the amino acid sequence of SEQ ID NO:63, the second VL CDR2 comprises the amino acid sequence of SEQ ID NO:65, and the second VL CDR3 comprises the amino acid sequence of SEQ ID NO:67; or
(l) the second VH CDR1 comprises the amino acid sequence of SEQ ID NO:26, the second VH CDR2 comprises the amino acid sequence of SEQ ID NO:57, the second VH CDR3 comprises the amino acid sequence of SEQ ID NO:28, the second VL CDR1 comprises the amino acid sequence of SEQ ID NO:29, the second VL CDR2 comprises the amino acid sequence of SEQ ID NO:30, and the second VL CDR3 comprises the amino acid sequence of SEQ ID NO:

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Kaplan Daniel David
• Ge Xuecai
• Tian Hui

Classifications

• A61P3/04 Primary

  Anorexiants; Antiobesity agents · CPC title

• C07K16/18

  against material from animals or humans · CPC title

• A61K38/04

  Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof ({enzyme inhibitors A61K38/005;} gastrins {A61K38/2207}, somatostatins A61K38/31, melanotropins A61K38/34 {; protease inhibitors A61K38/55}) · CPC title

• C07K16/26 Primary

  against hormones {; against hormone releasing or inhibiting factors} · CPC title

• A61K2039/505

  comprising antibodies · CPC title