# US 9,751,937 B2 · Antagonist antibodies against GDF-8 and uses therefor

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- Number: US 9,751,937 B2
- Document ID: US9751937B2
- Status: Granted
- Kind: B2
- Application number: 14/626,321
- Filed: 2015-02-19
- Published: 2015-11-26
- Granted: 2017-09-05
- Earliest claimed: 2012-06-15
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Michelle M. Mader; James R. Apgar; Kevin D. Parris
- Web page: https://patentgrep.com/patent/US9751937B2

## CPC

- C07K 16/22: against growth factors {; against 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 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- A61K 2039/505: {comprising antibodies}
- A61K 2039/622: {non-covalent binding}
- 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 2317/76: 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 disclosure provides improved neutralizing anti-GDF-8 antibodies capable of substantially higher levels of expression in host cells compared to previous anti-GDF-8 antibodies. Also provided are methods of using compositions comprising such antibodies to increase muscle mass or strength, and to treat or prevent muscular disorders, neuromuscular disorders, metabolic disorders, adipose tissue disorders or bone disorders.

## Claims

### Claim 1

A method of increasing the mass or strength of a muscle of a mammal, comprising administering to a mammal a therapeutically effective amount of an antibody or antigen binding fragment thereof that specifically binds GDF-8, said antibody or fragment comprising:
an antibody variable heavy (VH) region comprising first, second and third complementarity determining regions (CDR), wherein VH CDR1 comprises SEQ ID NO:10 or SEQ ID NO:20, VH CDR2 comprises SEQ ID NO:11 or SEQ ID NO:21, and VH CDR3 comprises SEQ ID NO:12; and
an antibody variable light (VL) region comprising first, second and third complementarity determining regions (CDR), wherein VL CDR1 comprises SEQ ID NO:13, VL CDR2 comprises SEQ ID NO:14, and VL CDR3 comprises SEQ ID NO:15;
wherein said VH region comprises leucine at the amino acid position corresponding to residue number 111 of SEQ ID NO:44 (Kabat position 108).

### Claim 2 (depends on 1)

The method of claim 1, wherein the fourth framework region (FR4) of said VH region comprises amino acids 106-116 of SEQ ID NO:44.

### Claim 3 (depends on 1)

The method of claim 1, wherein said VL region comprises glycine at the amino acid position corresponding to residue number 100 of SEQ ID NO:46 (Kabat position 100).

### Claim 4 (depends on 1)

The method of claim 1, wherein said VL region comprises glutamine at the amino acid position corresponding to residue number 100 of SEQ ID NO:46 (Kabat position 100).

### Claim 5 (depends on 4)

The method of claim 4, wherein the fourth framework region of said VL region comprises amino acids 98-107 of SEQ ID NO:46.

### Claim 6 (depends on 5)

The method of claim 5, wherein the fourth framework region of said VL region comprises amino acids 98-107 of SEQ ID NO:9.

### Claim 7 (depends on 1)

The method of claim 1, wherein the VH region comprises the amino acid sequence of SEQ ID NO:44.

### Claim 8 (depends on 7)

The method of claim 7, wherein the VL region comprises the amino acid sequence of SEQ ID NO:46.

### Claim 9 (depends on 7)

The method of claim 7, wherein the VL region comprises the amino acid sequence of SEQ ID NO:9.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody further comprises an antibody constant heavy (CH) region derived from an antibody subtype selected from the group consisting of IgA, IgG, IgD, IgE, or IgM.

### Claim 11 (depends on 1)

The method of claim 1, wherein the IgG subtype is IgG1.

### Claim 12 (depends on 1)

The method of claim 1, wherein said IgG subtype comprises at least one mutation that alters Fc domain function.

### Claim 13 (depends on 1)

The method of claim 1, wherein the muscle is skeletal muscle.

### Claim 14 (depends on 13)

The method of claim 13, wherein the skeletal muscle is active in breathing.

### Claim 15

A method of treating a muscular disorder in a mammal characterized by diminished muscle mass or strength, comprising administering to a mammal in need of treatment for a muscular disorder characterized by diminished muscle mass or strength a therapeutically effective amount of an antibody or antigen binding fragment thereof that specifically binds GDF-8, said antibody or fragment comprising:
an antibody variable heavy (VH) region comprising the first, second and third complementarity determining regions (CDR) from the VH region defined by the amino acid sequence of SEQ ID NO:44; and
an antibody variable light (VL) region comprising the first, second and third complementarity determining regions (CDR) from the VL region defined by the amino acid sequence of SEQ ID NO:46;
wherein said VH region comprises leucine at the amino acid position corresponding to residue number 111 of SEQ ID NO:44 (Kabat position 108).

### Claim 16 (depends on 15)

The method of claim 15, wherein the muscular disorder is selected from the group consisting of muscular dystrophy, muscle atrophy, sarcopenia, cachexia, muscle wasting syndrome, age-related loss of muscle mass or strength, and frailty.

### Claim 17 (depends on 15)

The method of claim 15, wherein the muscular disorder is muscular dystrophy.

### Claim 18 (depends on 17)

The method of claim 17, wherein the muscular dystrophy is Duchenne muscular dystrophy.

### Claim 19 (depends on 15)

The method of claim 15, wherein treatment is effective to increase the subject's performance in a 6 minute walk test.

### Claim 20 (depends on 15)

The method of claim 15, wherein said antibody is administered to a subject also being treated with a glucocorticoid.