# US 8,771,697 B2 · Methods of treatment using anti-IL-17A/IL-17F cross-reactive antibodies

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- Number: US 8,771,697 B2
- Document ID: US8771697B2
- Status: Granted
- Kind: B2
- Application number: 13/492,280
- Filed: 2012-06-08
- Published: 2012-10-25
- Granted: 2014-07-08
- Earliest claimed: 2008-05-05
- Assignees: NovImmune S.A.
- Applicants: Krzysztof Masternak; Olivier Leger
- Inventors: Krzysztof Masternak; Olivier Leger
- Web page: https://patentgrep.com/patent/US8771697B2

## CPC

- C07K 16/244: {Interleukins [IL]}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- 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 2317/56: variable (Fv) region, i.e. VH and/or VL
- 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)
- 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

This invention provides fully human monoclonal antibodies that recognize IL-17F, the IL-17F homodimer, IL-17A, the IL-17A homodimer, and/or the heterodimeric IL-17A/IL-17F protein complex. The invention further provides methods of using such monoclonal antibodies as a therapeutic, diagnostic, and prophylactic.

## Claims

### Claim 1

A method of treating a subject having an autoimmune disease, or inflammatory disorder, comprising administering to the subject an effective amount of an antibody, or an antigen-binding fragment thereof, that (1) binds IL-17A homodimer, IL-17F homodimer and IL-17A/IL-17F heterodimeric complex, and (2) exhibits (i) a binding affinity of at least 100 pM or less against human IL-17A homodimer, (ii) a binding affinity of at least 300 pM or less against human IL-17F homodimer, (iii) a binding affinity of at least 400 pM or less against human IL-17A/IL-17F heterodimeric complex, (iv) a neutralizing ability of at least 40 nM or less against the human IL-17A homodimer, (v) a neutralizing ability of at least 120 nM or less against the human IL-17F homodimer, and (vi) a neutralizing ability of at least 31 nM or less against the human IL-17A/IL-17F heterodimeric complex, wherein the binding affinity is measured by surface plasmon resonance, and the neutralizing ability is determined by measuring IL-6 secretion by the human IL-17 A homodimer, the human IL-17F homodimer or the human IL-17A/IL-17F heterodimeric complex-stimulated mouse or human embryonic fibroblasts.

### Claim 2 (depends on 1)

The method of claim 1, wherein said subject is a human.

### Claim 3

A method of treating a subject having rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, lupus erythomatosis, chronic obstructing pulmonary disease, idiopathic pulmonary fibrosis, or asthma, comprising administering to the subject an effective amount of an antibody, or an antigen-binding fragment thereof, that (1) binds IL-17A homodimer, IL-17F homodimer and IL-17A/IL-17F heterodimeric complex, and (2) exhibits (i) a binding affinity of at least 100 pM or less against human IL-17A homodimer, (ii) a binding affinity of at least 300 pM or less against human IL-17F homodimer, (iii) a binding affinity of at least 400 pM or less against human IL-17A/IL-17F heterodimeric complex, (iv) a neutralizing ability of at least 40 nM or less against the human IL-17A homodimer, (v) a neutralizing ability of at least 120 nM or less against the human IL-17F homodimer, and (vi) a neutralizing ability of at least 31 nM or less against the human IL-17A/IL-17F heterodimeric complex, wherein the binding affinity is measured by surface plasmon resonance, and the neutralizing ability is determined by measuring IL-6 secretion by the human IL-17 A homodimer, the human IL-17F homodimer or the human IL-17A/IL-17F heterodimeric complex-stimulated mouse or human embryonic fibroblasts.

### Claim 4 (depends on 3)

The method of claim 3, wherein said subject is a human.

### Claim 5 (depends on 1, 3)

The method of claim 3 or claim 1, wherein said antibody or antigen binding fragment binds IL-17A and IL-17F as a cross-reactive antibody.

### Claim 6 (depends on 1, 3)

The method of claim 3 or claim 1, wherein said antibody or antigen binding fragment binds the IL-17A homodimer, the IL-17F homodimer and the IL-17A/IL-17F heterodimeric complex and prevents one or more of IL-17F homodimer, IL-17A homodimer and IL-17A/IL-17F heterodimeric complex from binding with its receptor.

### Claim 7 (depends on 1, 3)

The method of claim 3 or claim 1, wherein said antibody or antigen binding fragment is a bispecific antibody.

### Claim 8 (depends on 1, 3)

The method of claim 3 or claim 1, wherein said antibody or antigen binding fragment is monoclonal.

### Claim 9 (depends on 1, 3)

The method of claim 3 or claim 1, wherein the antigen binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, and scFv fragments, and diabodies.

### Claim 10 (depends on 1, 3)

The method of claim 3 or claim 1, wherein the antibody or antigen binding fragment is an IgG4 isotype or an IgG1 isotype.

### Claim 11 (depends on 1, 3)

The method of claim 3 or claim 1, wherein the surface plasmon resonance is measured using a Biacore assay.

### Claim 12 (depends on 11)

The method of claim 11, wherein the Biacore assay is performed at 25° C.

### Claim 13

A method of treating a subject having an autoimmune disease, or inflammatory disorder, comprising administering to the subject an effective amount of an antibody, or an antigen-binding fragment thereof, wherein the antibody comprises a VH CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a VH CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 94, a VH CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 95, a VL CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 110, a VL CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 97 and a VL CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 111, and wherein said antibody binds IL-17F homodimer and IL-17A homodimer.

### Claim 14

A method of treating a subject having rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, lupus erythomatosis, chronic obstructing pulmonary disease, idiopathic pulmonary fibrosis, or asthma, comprising administering to the subject an effective amount of an antibody, or an antigen-binding fragment thereof, wherein the antibody comprises a VH CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a VH CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 94, a VH CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 95, a VL CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 110, a VL CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 97 and a VL CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 111, and wherein said antibody binds IL-17F homodimer and IL-17A homodimer.

### Claim 15 (depends on 13, 14)

The method of claim 14 or claim 13, wherein the antibody comprises a heavy chain variable region sequence comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:54 and a light chain variable region sequence comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:40, and wherein said antibody binds IL-17A homodimer, IL-17F homodimer and the IL-17A/IL-17F heterodimeric complex.

### Claim 16 (depends on 15)

The method of claim 15, wherein the antibody comprises a heavy chain variable region sequence comprising an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 54 and a light chain variable region sequence comprising an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 40.

### Claim 17 (depends on 15)

The method of claim 15, wherein the antibody comprises a heavy chain variable region sequence comprising an amino acid sequence of SEQ ID NO: 54 and a light chain variable region sequence comprising an amino acid sequence of SEQ ID NO: 40.