# US 8,540,990 B2 · Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same

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- Number: US 8,540,990 B2
- Document ID: US8540990B2
- Status: Granted
- Kind: B2
- Application number: 11/911,305
- Filed: 2006-04-11
- Published: 2011-02-10
- Granted: 2013-09-24
- Earliest claimed: 2005-04-11
- Assignees: Rinat Neuroscience Corp.
- Applicants: Arnon Rosenthal; David Louis Shelton; Patricia Ann Walicke
- Inventors: Arnon Rosenthal; David Louis Shelton; Patricia Ann Walicke
- Web page: https://patentgrep.com/patent/US8540990B2

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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 invention concerns anti-NGF antibodies (such as anti-NGF antagonist antibodies), and polynucleotides encoding the same. The invention further concerns use of such antibodies and/or polynucleotides in the treatment and/or prevention of pain, including post-surgical pain, rheumatoid arthritis pain, and osteoarthritis pain.

## Claims

### Claim 1

A method for reducing stiffness in an individual having osteoarthritis comprising administering an effective amount of a monoclonal anti-NGF antagonist antibody to the individual, wherein the anti-NGF antagonist antibody blocks the interaction of human NGF with p75 and trkA,
wherein the anti-NGF antagonist antibody: (a) binds NGF with a KD of less than about 2 nM; (b) inhibits human NGF-dependent survival of mouse E13.5 trigeminal neurons with an IC50 of about 100 pM or less, wherein the IC50 is measured in the presence of about 15 pM human NGF; and (c) inhibits human NGF-dependent survival of mouse E 13.5 trigeminal neurons with an IC50 of about 10 pM or less, wherein the IC50 is measured in the presence of about 1.5 pM of NGF.

### Claim 2 (depends on 1)

The method of claim 1, wherein the individual is a human.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is administered at a dosing frequency in a range from once every week to once every twelve weeks.

### Claim 4 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is administered once every month, once every two months, once every three months, once every four months, once every five months, or once every six months.

### Claim 5 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is administered once every three months.

### Claim 6 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is administered at a dose in a range from about 3 μg/kg to about 1 mg/kg.

### Claim 7 (depends on 6)

The method of claim 6, wherein the anti-NGF antagonist antibody is administered at a dose of about 100 μg/kg.

### Claim 8 (depends on 6)

The method of claim 6, wherein the anti-NGF antagonist antibody is administered at a dose of about 300 μg/kg.

### Claim 9 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is administered intravenously.

### Claim 10 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is administered subcutaneously.

### Claim 11 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody is a humanized antibody.

### Claim 12 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody binds human NGF.

### Claim 13 (depends on 12)

The method of claim 12, wherein the anti-NGF antagonist antibody further binds rodent NGF.

### Claim 14 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody comprises a heavy chain variable region comprising: (a) a CDR1 region shown in SEQ ID NO: 3; (b) a CDR2 region shown in SEQ ID NO:4; and (c) a CDR3 region shown in SEQ ID NO:5, and a light chain variable region comprising: (a) a CDR1 region shown in SEQ ID NO:6; (b) a CDR2 region shown in SEQ ID NO:7; and (c) a CDR3 region shown in SEQ ID NO:8.

### Claim 15 (depends on 14)

The method of claim 14, wherein the anti-NGF antagonist antibody is an antibody comprising the amino acid sequences shown in SEQ ID NOS: 1 and 2.

### Claim 16 (depends on 15)

The method of claim 15, wherein the anti-NGF antagonist antibody is an antibody comprising the amino acid sequences shown in SEQ ID NOS: 16 and 17.

### Claim 17 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody competes for binding to human NGF with an antibody comprising the amino acid sequences shown in SEQ ID NOS: 1 and 2.

### Claim 18 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody binds essentially the same epitope as an antibody comprising the amino acid sequences shown in SEQ ID NOS: 1 and 2.

### Claim 19 (depends on 1)

The method of claim 1, wherein the anti-NGF antagonist antibody binds to an epitope comprising: residues K32, K34 and E35 within variable region 1 of human NGF (hNGF); residues F79 and T81 within variable region 4 of hNGF; residues H84 and K88 within variable region 4 of hNGF; and/or residue R103 between variable region 5 of hNGF and the C-terminus.

### Claim 20

A method for reducing stiffness in an individual having osteoarthritis comprising administering an effective amount of a monoclonal anti-NGF antagonist antibody to the individual, wherein the anti-NGF antagonist antibody blocks the interaction of human NGF with p75 and trkA,
wherein the anti-NGF antagonist antibody binds to an epitope comprising: residues K32, K34 and E35 within variable region 1 of human NGF (hNGF); residues F79 and T81 within variable region 4 of hNGF; residues H84 and K88 within variable region 4 of hNGF; and/or residue R103 between variable region 5 of hNGF and the C-terminus.

### Claim 21 (depends on 20)

The method of claim 20, wherein the individual is a human.

### Claim 22 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is administered at a dosing frequency in a range from once every week to once every twelve weeks.

### Claim 23 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is administered once every month, once every two months, once every three months, once every four months, once every five months, or once every six months.

### Claim 24 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is administered once every three months.

### Claim 25 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is administered at a dose in a range from about 3 μg/kg to about 1 mg/kg.

### Claim 26 (depends on 25)

The method of claim 25, wherein the anti-NGF antagonist antibody is administered at a dose of about 100 μg/kg.

### Claim 27 (depends on 25)

The method of claim 25, wherein the anti-NGF antagonist antibody is administered at a dose of about 300 μg/kg.

### Claim 28 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is administered intravenously.

### Claim 29 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is administered subcutaneously.

### Claim 30 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody is a humanized antibody.

### Claim 31 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody binds human NGF.

### Claim 32 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody further binds rodent NGF.

### Claim 33 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody: (a) binds NGF with a KD of less than about 2 nM; (b) inhibits human NGF-dependent survival of mouse E13.5 trigeminal neurons with an IC50 of about 100 pM or less, wherein the IC50 is measured in the presence of about 15 pM human NGF; and (c) inhibits human NGF-dependent survival of mouse E 13.5 trigeminal neurons with an IC50 of about 10 pM or less, wherein the IC50 is measured in the presence of about 1.5 pM of NGF.

### Claim 34 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody comprises a heavy chain variable region comprising: (a) a CDR1 region shown in SEQ ID NO: 3; (b) a CDR2 region shown in SEQ ID NO:4; and (c) a CDR3 region shown in SEQ ID NO:5, and a light chain variable region comprising: (a) a CDR1 region shown in SEQ ID NO:6; (b) a CDR2 region shown in SEQ ID NO:7; and (c) a CDR3 region shown in SEQ ID NO:8.

### Claim 35 (depends on 34)

The method of claim 34, wherein the anti-NGF antagonist antibody is an antibody comprising the amino acid sequences shown in SEQ ID NOS: 1 and 2.

### Claim 36 (depends on 35)

The method of claim 35, wherein the anti-NGF antagonist antibody is an antibody comprising the amino acid sequences shown in SEQ ID NOS: 16 and 17.

### Claim 37 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody competes for binding to human NGF with an antibody comprising the amino acid sequences shown in SEQ ID NOS: 1 and 2.

### Claim 38 (depends on 20)

The method of claim 20, wherein the anti-NGF antagonist antibody binds essentially the same epitope as an antibody comprising the amino acid sequences shown in SEQ ID NOS: 1 and 2.