# US 12,180,289 B2 · Binding proteins and methods of use thereof

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- Number: US 12,180,289 B2
- Document ID: US12180289B2
- Status: Granted
- Kind: B2
- Application number: 17/194,144
- Filed: 2021-03-05
- Published: 2022-03-10
- Granted: 2024-12-31
- Earliest claimed: 2016-03-31
- Assignees: NGM Biopharmaceuticals, Inc.
- Applicants: NGM Biopharmaceuticals, Inc.
- Inventors: Wenyan Shen; Jie Tang; Yan Wang; Hugo Matern
- Web page: https://patentgrep.com/patent/US12180289B2

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C07K 14/475: Growth factors; Growth regulators
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- 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 2039/505: {comprising antibodies}
- C07K 2299/00: Coordinates from 3D structures of peptides, e.g. proteins or enzymes
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/30: characterized by aspects of specificity or valency
- 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 2317/55: Fab or Fab'
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present disclosure provides binding proteins, such as antibodies, that bind to a GDNF Family Receptor Alpha Like (GFRAL) protein, including human GFRAL protein, and methods of their use.

## Claims

### Claim 1

A method for treating cachexia, involuntary weight loss, sarcopenia, or muscle wasting in a human subject suffering from cancer associated with elevated levels of GDF15, the method comprising administering to the human subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds to a GDNF Family Receptor Alpha-Like (GFRAL) protein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), and
wherein the VH comprises a VH complementarity determining region (CDR) 1, a VH CDR2, and a VH CDR3 from the amino acid sequence of SEQ ID NO:3, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 from the amino acid sequence of SEQ ID NO:4.

### Claim 2

A method for treating a GDF15-mediated cancer in a human subject, the method comprising administering to the human subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds to a GDNF Family Receptor Alpha-Like (GFRAL) protein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL),
wherein the VH comprises a VH complementarity determining region (CDR) 1, a VH CDR2, and a VH CDR3 from the amino acid sequence of SEQ ID NO:3, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 from the amino acid sequence of SEQ ID NO:4,
wherein the human subject has an elevated serum level of GDF 15; and
wherein the GDF15-mediated cancer is prostate cancer.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
(a) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 137, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426;
(b) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:48, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:137, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426;
(c) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:139, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:227, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:303, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:377, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 427;
(d) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 138, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:226, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:302, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:377, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426;
(e) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:50, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:140, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:228, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:304, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:378, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 428; or
(f) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:141, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426.

### Claim 4 (depends on 1)

The method of claim 1, wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO:48, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 137, the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:426.

### Claim 5 (depends on 1)

The method of claim 1, wherein the VH comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1982 and the VL comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO:1997.

### Claim 6 (depends on 1)

The method of claim 1, wherein the VH comprises an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1982 and the VL comprises an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1997.

### Claim 7 (depends on 1)

The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:1982 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1997.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody is an IgG1 antibody.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody comprises a kappa light chain.

### Claim 11 (depends on 9)

The method of claim 9, wherein the antibody comprises a kappa light chain.

### Claim 12 (depends on 2)

The method of claim 2, wherein:
(a) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:137, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426;
(b) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:48, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 137, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426;
(c) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:49, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 139, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:227, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:303, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:377, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 427;
(d) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:47, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 138, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:226, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:302, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:377, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426;
(e) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:50, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 140, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:228, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:304, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:378, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 428; or
(f) the VH CDR1 comprises the amino acid sequence of SEQ ID NO:46, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 141, the VH CDR3 comprises the amino acid sequence of SEQ ID NO:225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 426.

### Claim 13 (depends on 2)

The method of claim 2, wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO:48, the VH CDR2 comprises the amino acid sequence of SEQ ID NO:137, the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 225, the VL CDR1 comprises the amino acid sequence of SEQ ID NO:301, the VL CDR2 comprises the amino acid sequence of SEQ ID NO:376, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO:426.

### Claim 14 (depends on 2)

The method of claim 2, wherein the VH comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1982 and the VL comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1997.

### Claim 15 (depends on 2)

The method of claim 2, wherein the VH comprises an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1982 and the VL comprises an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1997.

### Claim 16 (depends on 2)

The method of claim 2, wherein the VH comprises the amino acid sequence of SEQ ID NO:1982 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:1997.

### Claim 17 (depends on 2)

The method of claim 2, wherein the antibody is a humanized antibody.

### Claim 18 (depends on 2)

The method of claim 2, wherein the antibody is an IgG1 antibody.

### Claim 19 (depends on 2)

The method of claim 2, wherein the antibody comprises a kappa light chain.

### Claim 20 (depends on 18)

The method of claim 18, wherein the antibody comprises a kappa light chain.