# US 10,766,958 B2 · Methods of treating vitiligo using PD-1 binding antibodies

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- Number: US 10,766,958 B2
- Document ID: US10766958B2
- Status: Granted
- Kind: B2
- Application number: 15/707,906
- Filed: 2017-09-18
- Published: 2018-04-05
- Granted: 2020-09-08
- Earliest claimed: 2016-09-19
- Assignees: Celgene Corporation
- Applicants: Celgene Corporation
- Inventors: Garth E. Ringheim
- Web page: https://patentgrep.com/patent/US10766958B2

## CPC

- C07K 16/2818: {against CD28 or CD152}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61P 17/00: Drugs for dermatological disorders
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- 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

Provided herein are methods for managing, treating, or preventing vitiligo using proteins that specifically bind to Programmed Death-1 (PD-1) and modulate the expression and/or activity of PD-1.

## Claims

### Claim 1

A method of managing or treating vitiligo in a subject, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds to PD-1, wherein the antibody or antigen-binding fragment comprises:
a light chain variable region (VL) comprising:
a VL complementarity determining region 1 (CDR1) comprising SEQ ID NO:1,
a VL CDR2 comprising SEQ ID NO:2, and
a VL CDR3 comprising SEQ ID NO:3; and
a heavy chain variable region (VH) comprising:
a VH CDR1 comprising SEQ ID NO:4,
a VH CDR2 comprising SEQ ID NO:5, and
a VH CDR3 comprising SEQ ID NO:6.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a VL comprising an amino acid sequence of SEQ ID NO:8.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a VL comprising an amino acid sequence of SEQ ID NO:10.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a VH comprising an amino acid sequence of SEQ ID NO:11.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a VH comprising an amino acid sequence of SEQ ID NO:12.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a VH comprising an amino acid sequence of SEQ ID NO:13.

### Claim 7 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises
a VL comprising an amino acid sequence of SEQ ID NO:8; and
a VH comprising an amino acid sequence of SEQ ID NO:11.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises
a VL comprising an amino acid sequence of SEQ ID NO:8; and
a VH comprising an amino acid sequence of SEQ ID NO:12.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises
a VL comprising an amino acid sequence of SEQ ID NO:8; and
a VH comprising an amino acid sequence of SEQ ID NO:13.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises
a VL comprising an amino acid sequence of SEQ ID NO:10; and
a VH comprising an amino acid sequence of SEQ ID NO:11.

### Claim 11 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises
a VL comprising an amino acid sequence of SEQ ID NO:10; and
a VH comprising an amino acid sequence of SEQ ID NO:12.

### Claim 12 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises
a VL comprising an amino acid sequence of SEQ ID NO:10; and
a VH comprising an amino acid sequence of SEQ ID NO:13.

### Claim 13 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a human IgG1 Fc region, or a mutant thereof.

### Claim 14 (depends on 9)

The method of claim 9, wherein the antibody or antigen-binding fragment comprises a human IgG1 Fc region, or a mutant thereof.

### Claim 15 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a human IgG1-K322A Fc region.

### Claim 16 (depends on 9)

The method of claim 9, wherein the antibody or antigen-binding fragment comprises a human IgG1-K322A Fc region.

### Claim 17

The method of 1, wherein the antibody or antigen-binding fragment comprises a human IgG4 Fc region, or a mutant thereof.

### Claim 18

The method of 9, wherein the antibody or antigen-binding fragment comprises a human IgG4 Fc region, or a mutant thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a human IgG4P Fc region.

### Claim 20 (depends on 9)

The method of claim 9, wherein the antibody or antigen-binding fragment comprises a human IgG4P Fc region.

### Claim 21 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a human IgG4PE Fc region.

### Claim 22 (depends on 9)

The method of claim 9, wherein the antibody or antigen-binding fragment comprises a human IgG4PE Fc region.

### Claim 23 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 24 (depends on 7)

The method of claim 7, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 25 (depends on 8)

The method of claim 8, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 26 (depends on 9)

The method of claim 9, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 27 (depends on 10)

The method of claim 10, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 28 (depends on 11)

The method of claim 11, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 29 (depends on 12)

The method of claim 12, wherein the antibody or antigen-binding fragment comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.

### Claim 30 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 31 (depends on 7)

The method of claim 7, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 32 (depends on 8)

The method of claim 8, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 33 (depends on 9)

The method of claim 9, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 34 (depends on 10)

The method of claim 10, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 35 (depends on 11)

The method of claim 11, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 36 (depends on 12)

The method of claim 12, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 37 (depends on 23)

The method of claim 23, wherein the antibody or antigen-binding fragment further comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 38 (depends on 24)

The method of claim 24, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 39 (depends on 25)

The method of claim 25, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 40 (depends on 26)

The method of claim 26, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 41 (depends on 27)

The method of claim 27, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 42 (depends on 28)

The method of claim 28, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 43 (depends on 29)

The method of claim 29, wherein the antibody or antigen-binding fragment comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41.

### Claim 44 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a light chain comprising an amino acid sequence of SEQ ID NO:31.

### Claim 45 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:32.

### Claim 46 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises:
a light chain comprising an amino acid sequence of SEQ ID NO:31; and
a heavy chain comprising an amino acid sequence of SEQ ID NO:32.

### Claim 47 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:33.

### Claim 48 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises:
a light chain comprising an amino acid sequence of SEQ ID NO:31; and
a heavy chain comprising an amino acid sequence of SEQ ID NO:33.

### Claim 49 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:34.

### Claim 50 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises:
a light chain comprising an amino acid sequence of SEQ ID NO:31; and
a heavy chain comprising an amino acid sequence of SEQ ID NO:34.

### Claim 51 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:35.

### Claim 52 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment comprises:
a light chain comprising an amino acid sequence of SEQ ID NO:31; and
a heavy chain comprising an amino acid sequence of SEQ ID NO:35.

### Claim 53 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment specifically binds to human PD-1 and/or monkey PD-1, but not rodent PD-1.

### Claim 54 (depends on 53)

The method of claim 53, wherein the KD for binding to purified human PD-1 is from about 100 pM to about 10 nM, and the KD for binding to human PD-1 expressed on cell surface and monkey PD-1 expressed on cell surface is from about 100 pM to about 10 nM.

### Claim 55 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment has attenuated ADCC activity and/or attenuated CDC activity.

### Claim 56 (depends on 1)

The method of claim 1, wherein the antibody is a monoclonal antibody.

### Claim 57 (depends on 1)

The method of claim 1, wherein the antibody is a humanized antibody.

### Claim 58 (depends on 1)

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

### Claim 59 (depends on 1)

The method of claim 1, wherein the antibody is a chimeric antibody.

### Claim 60 (depends on 57)

The method of claim 57, wherein the humanized antibody is a deimmunized antibody.

### Claim 61 (depends on 57)

The method of claim 57, wherein the humanized antibody is a composite human antibody.

### Claim 62 (depends on 1)

The method of claim 1 wherein the antibody or antigen-binding fragment is a Fab, a Fab′, a F(ab′)2, a Fv, a scFv, a dsFv, a diabody, a triabody, a tetrabody, or a multispecific antibody formed from antibody fragments.

### Claim 63 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment is conjugated to an agent.

### Claim 64 (depends on 63)

The method of claim 63, wherein the agent is selected from the group consisting of a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound, and a chemiluminescent compound.

### Claim 65 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment further comprises a pharmaceutically acceptable carrier.

### Claim 66 (depends on 1)

The method of claim 1, wherein the immune cells in the subject express PD-1.