# US 10,370,449 B2 · Methods for treating skin infection by administering an IL-4R antagonist

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- Number: US 10,370,449 B2
- Document ID: US10370449B2
- Status: Granted
- Kind: B2
- Application number: 14/632,988
- Filed: 2015-02-26
- Published: 2015-09-03
- Granted: 2019-08-06
- Earliest claimed: 2014-02-28
- Assignees: Regeneron Pharmaceuticals, Inc.; Sanofi Biotechnology
- Applicants: Regeneron Pharmaceuticals, Inc.; Sanofi Biotechnology
- Inventors: Neil Graham; Marius Ardeleanu; Allen Radin; Jennifer D. Hamilton; Ariel Teper
- Web page: https://patentgrep.com/patent/US10370449B2

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- 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 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- 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}
- A61K 2039/54: {characterised by the route of administration}
- C07K 2317/21: from primates, e.g. man
- 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: 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 present invention provides methods for treating, preventing or ameliorating skin infections, including bacterial and viral infections. In certain embodiments, the invention provides methods to reduce skin infection in a patient with atopic dermatitis (AD). Also provided are methods for improving skin barrier function, and methods for reducing the risk of inflammation due to microbial infection in a patient in need thereof. The methods of the present invention comprise administering to a patient in need thereof a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist such as an anti-IL-4R antibody.

## Claims

### Claim 1

A method for treating, preventing or ameliorating a skin infection comprising: a) selecting a patient with moderate-to-severe atopic dermatitis and having a microbial infection; and b) administering a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist to the patient in need thereof, wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rα; wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising SEQ ID NO: 1, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising SEQ ID NO: 2; and wherein the IL-4R antagonist is administered at a dose of 75-600 mg.

### Claim 2 (depends on 1)

The method of claim 1, wherein the skin infection is a bacterial infection.

### Claim 3 (depends on 1)

The method of claim 1, wherein the skin infection is a viral infection.

### Claim 4 (depends on 1)

The method of claim 1, wherein the skin infection is selected from the group consisting of impetigo, cellulitis, infected dermatitis, eczema herpeticum, folliculitis, infected blister, mycosis, tinea versicolor, Staphylococcus aureus infection, and Streptococcus infection.

### Claim 5 (depends on 4)

The method of claim 4, wherein the skin infection is Staphylococcus aureus infection.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is administered subcutaneously.

### Claim 7 (depends on 6)

The method of claim 6, wherein the IL-4R antagonist is administered at a dose of 300 mg.

### Claim 8 (depends on 1)

The method of claim 1, wherein HCDR1 comprises SEQ ID NO: 3, HCDR2 comprises SEQ ID NO: 4, HCDR3 comprises SEQ ID NO: 5, LCDR1 comprises SEQ ID NO: 6, LCDR2 comprises SEQ ID NO: 7, and LCDR3 comprises SEQ ID NO: 8.

### Claim 9 (depends on 8)

The method of claim 8, wherein the HCVR comprises SEQ ID NO: 1 and the LCVR comprises SEQ ID NO: 2.

### Claim 10 (depends on 1)

The method of claim 1, wherein the anti-IL-4Rα antibody is dupilumab or a bioequivalent thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein a second therapeutic agent is administered to the subject before, after, or concurrent with the pharmaceutical composition.

### Claim 12 (depends on 11)

The method of claim 11, wherein the second therapeutic agent is selected from the group consisting of an anti-bacterial agent, an anti-viral agent, an anti-fungal agent, another IL-4R antagonist, an IgE inhibitor, a corticosteroid, a non-steroid anti-inflammatory drug (NSAID), and IFNγ.

### Claim 13

A method of reducing microbial colonization of skin comprising: a) selecting a patient with moderate-to-severe atopic dermatitis and having microbial colonization in the skin; and b) sequentially administering a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist at an initial dose followed by one or more secondary doses to the patient in need thereof, wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rα; wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) of a HCVR comprising SEQ ID NO: 1, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a LCVR comprising SEQ ID NO: 2; and wherein the initial dose and the one or more secondary doses of the IL-4R antagonist are 75-600 mg.

### Claim 14 (depends on 13)

The method of claim 13, wherein the colonization is of a microbe selected from the group consisting of Staphylococcus aureus, Streptococcus spp., Pseudomonas aeruginosa, Bacteroides spp., molluscum contagiosum virus, Herpes simplex virus, coxsackievirus, vaccinia virus, Candida albicans, Microsporum spp., Trichophyton spp., Penicillium spp., Cladosporium spp., Alternaria spp., and Aspergillus spp.

### Claim 15 (depends on 14)

The method of claim 14, wherein the microbe is Staphylococcus aureus (S. aureus).

### Claim 16 (depends on 15)

The method of claim 15, wherein the S. aureus colonization is reduced by at least 20% from the baseline.

### Claim 17 (depends on 13)

The method of claim 13, wherein the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more secondary doses, and wherein each secondary dose comprises 300 mg and is administered weekly or biweekly.

### Claim 18 (depends on 13)

The method of claim 13, wherein HCDR1 comprises SEQ ID NO: 3, HCDR2 comprises SEQ ID NO: 4, HCDR3 comprises SEQ ID NO: 5, LCDR1 comprises SEQ ID NO: 6, LCDR2 comprises SEQ ID NO: 7, and LCDR3 comprises SEQ ID NO: 8.

### Claim 19 (depends on 13)

The method of claim 13, wherein the anti-IL-4Rα antibody is dupilumab or a bioequivalent thereof.

### Claim 20 (depends on 13)

The method of claim 13, wherein a second therapeutic agent is administered to the subject before, after, or concurrent with the pharmaceutical composition.

### Claim 21 (depends on 20)

The method of claim 20, wherein the second therapeutic agent is selected from the group consisting of an anti-bacterial agent, an anti-viral agent, an anti-fungal agent, another IL-4R antagonist, an IgE inhibitor, a corticosteroid, NSAID, and IFNγ.