# US 2019/0169281 A1 · Angptl8-binding agents and methods of use thereof

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- Number: US 2019/0169281 A1
- Document ID: US20190169281A1
- Status: Published application
- Kind: A1
- Application number: 16/184,548
- Filed: 2018-11-08
- Published: 2019-06-06
- Earliest claimed: 2017-11-10
- Assignees: NGM Biopharmaceuticals, Inc.
- Applicants: NGM Biopharmaceuticals, Inc.
- Inventors: Chun Chu; Xunshan Ding; Zhonghao Liu; Yan Wang; Yiyuan Yin; Wenwu Zhai
- Web page: https://patentgrep.com/patent/US20190169281A1

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61K 31/20: having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61K 49/0058: {Antibodies}
- A61K 51/1021: {against cytokines, e.g. growth factors, VEGF, TNF, lymphokines or interferons}
- A61P 3/06: Antihyperlipidemics
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07K 14/475: Growth factors; Growth regulators
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure provides binding agents, such as antibodies, that specifically bind Angiopoietin-like protein 8 (ANGPTL8), including human ANGPTL8, and methods of their use.

## Claims

### Claim at position 1

1-80. (canceled)

### Claim 81

An antibody or antigen-binding fragment thereof that specifically binds human ANGPTL8, which comprises:
(a) a heavy chain CDR1 comprising GYTFTDYTIH (SEQ ID NO:11), a heavy chain CDR2 comprising WFYPGSDNIKYNAKFKD (SEQ ID NO:16), and a heavy chain CDR3 comprising HEAFSYYDVAWFAY (SEQ ID NO:21); and
a light chain CDR1 comprising RSSQSLVHSNGNTYLH (SEQ ID NO:25), a light chain CDR2 comprising TVSNRFS (SEQ ID NO:29), and a light chain CDR3 comprising SQTTHFPYT (SEQ ID NO:32);
(b) a heavy chain CDR1 comprising GYTFTDYTIH (SEQ ID NO:11), a heavy chain CDR2 comprising WFYPGSDNIKFNAKFRD (SEQ ID NO:37), and a heavy chain CDR3 comprising HEAFYVYDVAWFAN (SEQ ID NO:38); and
a light chain CDR1 comprising RSSQSLVHSNGNTYLH (SEQ ID NO:25), a light chain CDR2 comprising TVSNRFS (SEQ ID NO:29), and a light chain CDR3 comprising SQSTHFPYT (SEQ ID NO:41); or
(c) a heavy chain CDR1 comprising GYTFTDYTIH (SEQ ID NO:11); a heavy chain CDR2 comprising WFYPGSDNIKYNEKFKD (SEQ ID NO:46), and a heavy chain CDR3 comprising HEAYYVYDVAWFAY (SEQ ID NO:48); and
a light chain CDR1 comprising SSSQSLVHSNGNTFLH (SEQ ID NO:52), a light chain CDR2 comprising TVSNRFS (SEQ ID NO:29) and a light chain CDR3 comprising SQSTHFPYT (SEQ ID NO:41).

### Claim 82 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which comprises:
(a) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:35, and a light chain variable region having at least 90% sequence identity to SEQ ID NO:36;
(b) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:62, and a light chain variable region having at least 90% sequence identity to SEQ ID NO:63;
(c) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:44, and a light chain variable region having at least 90% sequence identity to SEQ ID NO:45; or
(d) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:56, and a light chain variable region having at least 90% sequence identity to SEQ ID NO:57.

### Claim 83 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which comprises a heavy chain variable region comprising SEQ ID NO:35 and a light chain variable region comprising SEQ ID NO:36.

### Claim 84 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which comprises a heavy chain variable region comprising SEQ ID NO:44 and a light chain variable region comprising SEQ ID NO:45.

### Claim 85 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which comprises a heavy chain variable region comprising SEQ ID NO:56 and a light chain variable region comprising SEQ ID NO:57.

### Claim 86 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which comprises a heavy chain variable region comprising SEQ ID NO:62 and a light chain variable region comprising SEQ ID NO:63.

### Claim 87

An antibody that specifically binds ANGPTL8, which comprises a heavy chain of SEQ ID NO:64 and a light chain of SEQ ID NO:65.

### Claim 88 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which is a monoclonal antibody.

### Claim 89 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which is a humanized, human, or chimeric antibody.

### Claim 90 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which is a Fab, Fab′, F(ab′)2, Fv, scFv, (scFv)2, single chain antibody, dual variable region antibody, single variable region antibody, linear antibody, a V region, a bispecific antibody, or a multispecific antibody.

### Claim 91 (depends on 81)

The antibody or antigen-binding fragment thereof of claim 81, which:
(i) is an antagonist of ANGPTL8;
(ii) inhibits ANGPTL8 activity;
(iii) lowers triglyceride levels;
(iv) lowers LDL-cholesterol levels; and/or
(v) increases HDL-cholesterol levels.

### Claim 92 (depends on 81)

A pharmaceutical composition that comprises the antibody or antigen-binding fragment thereof of claim 81, and a pharmaceutically acceptable carrier.

### Claim 93 (depends on 81)

A polynucleotide molecule that encodes the antibody of claim 81.

### Claim 94 (depends on 93)

A vector comprising the polynucleotide of claim 93.

### Claim 95 (depends on 93)

A cell comprising the polynucleotide of claim 93.

### Claim 96 (depends on 81)

A host cell producing the antibody of claim 81.

### Claim 97

An antibody or antigen-binding fragment thereof that specifically binds ANGPTL8, which comprises heavy chain CDR1, CDR2, and CDR3, and light chain CDR1, CDR2, and CDR3 from:
(a) the antibody designated 1E5 that comprises a heavy chain variable region comprising SEQ ID NO:35 and a light chain variable region comprising SEQ ID NO:36;
(b) the antibody designated 1E9 that comprises a heavy chain variable region comprising SEQ ID NO:44 and a light chain variable region comprising SEQ ID NO:45; or
(c) the antibody designated 1A8 that comprises a heavy chain variable region comprising SEQ ID NO:56 and a light chain variable region comprising SEQ ID NO:57.

### Claim 98 (depends on 81)

A method of lowering triglyceride levels in a subject with elevated triglyceride levels, the method comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 81.

### Claim 99 (depends on 98)

The method of claim 98, wherein the subject is administered one or more additional therapeutic agents.

### Claim 100 (depends on 99)

The method of claim 99, wherein the additional therapeutic agent is selected from the group consisting of: a fibrate, a statin, omega-3 fatty acids, and niacin.

### Claim 101 (depends on 81)

A method of increasing HDL-cholesterol levels in a subject, the method comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 81.

### Claim 102 (depends on 81)

A method of treating a disease or disorder associated with elevated triglyceride levels in a subject, the method comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 81.

### Claim 103 (depends on 102)

The method of claim 102, wherein the disease or disorder is metabolic syndrome, obesity, diabetes, cardiovascular disease, hyperlipidemia, hypertriglyceridemia, pancreatitis, renal disease, or hypothyroidism.