# US 10,307,480 B2 · Anti-pro/latent-myostatin antibodies and uses thereof

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- Number: US 10,307,480 B2
- Document ID: US10307480B2
- Status: Granted
- Kind: B2
- Application number: 15/524,651
- Filed: 2015-11-06
- Published: 2017-11-23
- Granted: 2019-06-04
- Earliest claimed: 2014-11-06
- Assignees: Scholar Rock, Inc.
- Applicants: Scholar Rock, Inc.
- Inventors: Michelle Straub; Dong Yun Lee; William K. McConaughy; Katherine Jane Turner; Nagesh K. Mahanthappa; Justin W. Jackson
- Web page: https://patentgrep.com/patent/US10307480B2

## CPC

- A61K 39/39533: {against materials from animals}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/06: Anabolic agents (androgens A61P5/26)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- G01N 33/74: involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors}
- A61K 2039/505: {comprising antibodies}
- C07K 14/475: Growth factors; Growth regulators
- C07K 16/22: against growth factors {; against growth regulators}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/622: Single chain antibody (scFv)
- 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 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- G01N 2800/10: Musculoskeletal or connective tissue disorders
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- 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)

## Abstract

Aspects of the present disclosure relate to antibodies that specifically bind proMyostatin and/or latent Myostatin and uses thereof.

## Claims

### Claim 1

An isolated antibody, or an antigen-binding fragment thereof, that specifically binds pro/latent Myostatin compared with mature Myostatin,
wherein the antibody, or antigen-binding fragment thereof, comprises six complementarity determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3,
wherein CDRH1 comprises a sequence that is at least 90% identical to a CDRH1 sequence as set forth as any one of SEQ ID NOs: 1, 2, 70, 71, and 77, or wherein CDRH1 comprises a sequence that is at least 90% identical to a CDRH1 sequence as set forth in any one of SEQ ID NOs: 65, 66, or 69,
wherein CDRH2 comprises a sequence that is at least 90% identical to a CDRH2 sequence as set forth as any one of SEQ ID NOs: 4, 5, 72, and 78, or wherein CDRH2 comprises a sequence that is at least 90% identical to a CDRH2 sequence as set forth in any one of SEQ ID NOs: 65, 66, 67 or 69,
wherein CDRH3 comprises a sequence that is at least 90% identical to a CDRH3 sequence as set forth as any one of SEQ ID NOs: 10, 73, 74, 75, 76, 79, and 80,
wherein CDRL1 comprises a sequence that is at least 90% identical to a CDRL1 sequence as set forth as any one of SEQ ID NOs: 12, 13, 87, 88, 89, and 98, or wherein CDRL1 comprises a sequence that is at least 90% identical to a CDRL1 sequence as set forth in any one of SEQ ID NOs: 84 or 85,
wherein CDRL2 comprises a sequence that is at least 90% identical to a CDRL2 sequence as set forth as any one of SEQ ID NOs: 18, 19, 90, 91, and 99, or wherein CDRL2 comprises a sequence that is at least 90% identical to a CDRL2 sequence as set forth in any one of SEQ ID NOs: 83, 84 or 86, and
wherein CDRL3 comprises a sequence that is at least 90% identical to a CDRL3 sequence as set forth as any one of SEQ ID NOs: 22, 93, 94, 95, 97, 100, and 101.

### Claim 2 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof of claim 1, which is a fully human antibody or a humanized antibody.

### Claim 3 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof of claim 1, comprising a heavy chain constant domain selected from the group consisting of: IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains.

### Claim 4 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof of claim 1, which is a monoclonal antibody or a multispecific antibody.

### Claim 5 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof of claim 1, which is a diabody, a chimeric antibody, a Fab fragment, a F(ab′)2 fragment, or an Fv fragment.

### Claim 6 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof of claim 1, comprising an Fc region.

### Claim 7 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, which has an equilibrium dissociation constant, Kd, of less than 10−6M.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 1, and an excipient.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 1.

### Claim 10 (depends on 9)

A method of treating a myopathy or a metabolic disorder in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 9, thereby treating the myopathy or metabolic disorder.

### Claim 11 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody comprises
a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 24 and SEQ ID NO: 25, or a heavy chain domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, and
a light chain variable domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 30 and SEQ ID NO: 31, or a light chain domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86.

### Claim 12 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody comprises
a heavy chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 24 and SEQ ID NO: 25, or a heavy chain domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, and
a light chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 30 and SEQ ID NO: 31, or a light chain domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86.

### Claim 13 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody comprises heavy chain/light chain variable domain amino acid sequences selected from the group consisting of: SEQ ID NO: 24/SEQ ID NO: 30 and SEQ ID NO: 25/SEQ ID NO: 31, or heavy chain/light chain domain amino acid sequences selected from the group consisting of: SEQ ID NO: 64/SEQ ID NO: 81, SEQ ID NO: 65/SEQ ID NO: 82, SEQ ID NO: 66/SEQ ID NO: 83, SEQ ID NO: 67/SEQ ID NO: 84, SEQ ID NO: 68/SEQ ID NO: 85, and SEQ ID NO: 69/SEQ ID NO: 86.

### Claim 14 (depends on 1)

The isolated antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody, or antigen-binding fragment thereof, binds to the pro/latent Myostatin with a decreased affinity at an acidic pH as compared to a physiological pH.

### Claim 15

A method of assessing a biological sample obtained from a subject having a myopathy, the method comprising:
(a) preparing an immunological reaction mixture that comprises protein of a biological sample obtained from the subject and an antibody, or an antigen-binding fragment thereof that specifically binds latent Myostatin, wherein the antibody, or antigen-binding fragment thereof, comprises six complementarity determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3,
wherein CDRH1 comprises a sequence that is at least 90% identical to a CDRH1 sequence as set forth as any one of SEQ ID NOs: 1, 2, 70, 71, and 77, or wherein CDRH1 comprises a sequence that is at least 90% identical to a CDRH1 sequence as set forth in any one of SEQ ID NOs: 65, 66, or 69,
wherein CDRH2 comprises a sequence that is at least 90% identical to a CDRH2 sequence as set forth as any one of SEQ ID NOs: 4, 5, 72, and 78, or wherein CDRH2 comprises a sequence that is at least 90% identical to a CDRH2 sequence as set forth in any one of SEQ ID NOs: 65, 66, 67 or 69,
wherein CDRH3 comprises a sequence that is at least 90% identical to a CDRH3 sequence as set forth as any one of SEQ ID NOs: 10, 73, 74, 75, 76, 79, and 80,
wherein CDRL1 comprises a sequence that is at least 90% identical to a CDRL1 sequence as set forth as any one of SEQ ID NOs: 12, 13, 87, 88, 89, and 98, or wherein CDRL1 comprises a sequence that is at least 90% identical to a CDRL1 sequence as set forth in any one of SEQ ID NOs: 84 or 85,
wherein CDRL2 comprises a sequence that is at least 90% identical to a CDRL2 sequence as set forth as any one of SEQ ID NOs: 18, 19, 90, 91, and 99, or wherein CDRL2 comprises a sequence that is at least 90% identical to a CDRL2 sequence as set forth in any one of SEQ ID NOs: 83, 84 or 86, and
wherein CDRL3 comprises a sequence that is at least 90% identical to a CDRL3 sequence as set forth as any one of SEQ ID NOs: 22, 93, 94, 95, 97, 100, and 101;
(b) maintaining the immunological reaction mixture under conditions that permit binding complexes to form between the antibody and a latent Myostatin; and
(c) determining the extent of binding complex formation.

### Claim 16 (depends on 15)

The method of claim 15, wherein the antibody comprises
a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 24 and SEQ ID NO: 25, or a heavy chain domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, and
a light chain variable domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 30 and SEQ ID NO: 31, or a light chain domain comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86.

### Claim 17 (depends on 16)

The method of claim 16, wherein the antibody comprises
a heavy chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 24 and SEQ ID NO: 25, or a heavy chain domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, and
a light chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 30 and SEQ ID NO: 31, or a light chain domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of: SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86.

### Claim 18 (depends on 15)

The method of claim 15, wherein the antibody comprises heavy chain/light chain variable domain amino acid sequences selected from the group consisting of: SEQ ID NO: 24/SEQ ID NO: 30 and SEQ ID NO: 25/SEQ ID NO: 31, or heavy chain/light chain domain amino acid sequences selected from the group consisting of: SEQ ID NO: 64/SEQ ID NO: 81, SEQ ID NO: 65/SEQ ID NO: 82, SEQ ID NO: 66/SEQ ID NO: 83, SEQ ID NO: 67/SEQ ID NO: 84, SEQ ID NO: 68/SEQ ID NO: 85, and SEQ ID NO: 69/SEQ ID NO: 86.

### Claim 19 (depends on 15)

The method of claim 15, wherein the antibody, or antigen-binding fragment thereof, binds to the pro/latent Myostatin with a decreased affinity at an acidic pH as compared to a physiological pH.