# US 8,784,815 B2 · Human CTLA-4 antibodies and their uses

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- Number: US 8,784,815 B2
- Document ID: US8784815B2
- Status: Granted
- Kind: B2
- Application number: 13/666,672
- Filed: 2012-11-01
- Published: 2013-05-30
- Granted: 2014-07-22
- Earliest claimed: 1999-08-24
- Assignees: Medarex, Inc.
- Applicants: Alan J. Korman; Edward L. Halk; Nils Lonberg; Yashwant M. Deo; Tibor P. Keler
- Inventors: Alan J. Korman; Edward L. Halk; Nils Lonberg; Yashwant M. Deo; Tibor P. Keler
- Web page: https://patentgrep.com/patent/US8784815B2

## CPC

- C07K 16/2818: {against CD28 or CD152}
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- A01K 67/0276: Knock-out vertebrates
- A01K 67/0278: Knock-in vertebrates, e.g. humanised vertebrates
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/04: specific for metastasis
- C12N 15/8509: {for producing genetically modified animals, e.g. transgenic}
- A01K 2207/15: Humanized animals
- A01K 2217/00: Genetically modified animals
- A01K 2217/05: Animals comprising random inserted nucleic acids (transgenic)
- A01K 2217/072: maintaining or altering function, i.e. knock in
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2227/105: Murine
- A01K 2267/01: Animal expressing industrially exogenous proteins
- A01K 2267/025: Animal producing cells or organs for transplantation
- A01K 2267/03: Animal model, e.g. for test or diseases
- A01K 2267/0325: Animal model for autoimmune diseases
- A01K 2267/0381: Animal model for diseases of the hematopoietic system
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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 2319/00: Fusion polypeptide
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

## Claims

### Claim 1

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region and light chain variable region CDR3 domains are selected from the group consisting of:
(a) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35; and
(b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:38; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:36; and
binds to human CTLA-4 with a binding affinity of about 108 M−1 or greater.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises:
(a) a heavy chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:37 and 32, respectively; and a light chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:35 and 29, respectively;
(b) a heavy chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs: 37 and 33, respectively; and a light chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs: 35 and 30, respectively; or
(c) a heavy chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:38 and 34, respectively; and a light chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:36 and 31, respectively.

### Claim 3 (depends on 2)

The method of claim 2, wherein the antibody or antigen-binding portion thereof comprises:
(a) a heavy chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:37, 32 and 27, respectively; and a light chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:35, 29 and 24, respectively;
(b) a heavy chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:37, 33 and 27, respectively; and a light chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:35, 30 and 25, respectively; or
(c) a heavy chain variable region comprising CDR3, CDR2 and CDR1 comprising sequences set forth in SEQ ID NOs:38, 34 and 28, respectively; and a light chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:36, 31 and 26, respectively.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region derived from a human VH 3-30.3 gene; and (b) a light chain variable region derived from a human VK A-27 gene.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region derived from a human VH 3-33 gene; and (b) a light chain variable region derived from a human VK L-15 gene.

### Claim 6 (depends on 4)

The method of claim 4, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region CDR3 sequence set forth in SEQ ID NO: 37, and a light chain variable region CDR3 sequence set forth in SEQ ID NO: 35.

### Claim 7 (depends on 5)

The method of claim 5, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region CDR3 sequence set forth in SEQ ID NO: 38, and a light chain variable region CDR3 sequence set forth in SEQ ID NO: 36.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises at least one heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 17, 19 and 23.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises at least one light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 7, 9 and 13.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7.

### Claim 11 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9.

### Claim 12 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13.

### Claim 13 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 32 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 24, 29 and 35, respectively.

### Claim 14 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 33 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 25, 30 and 35, respectively.

### Claim 15 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 28, 34 and 38, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 26, 31 and 36, respectively.

### Claim 16

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof competes for binding to a human CTLA-4 polypeptide with a reference antibody comprising the amino acid sequence set forth in SEQ ID NO: 17, and the amino acid sequence set forth in SEQ ID NO: 7; and has a binding affinity of about 108M−1 or greater.

### Claim 17

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, comprising: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 32 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 24, 29 and 35, respectively.

### Claim 18

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, comprising: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 33 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 25, 30 and 35, respectively.

### Claim 19

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, comprising: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 28, 34 and 38, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 26, 31 and 36, respectively.

### Claim 20

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7.

### Claim 21

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9.

### Claim 22

A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13.

### Claim 23 (depends on 1, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1 and 16-22, wherein the antibody is a human antibody.

### Claim 24 (depends on 1, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1 and 16-22, wherein the antibody is a monoclonal antibody.

### Claim 25 (depends on 1, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1 and 16-22, wherein the antibody or antigen-binding portion thereof inhibits binding of human CTLA-4 to B7-1 or B7-2.

### Claim 26 (depends on 1, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1 and 16-22, wherein the antigen is a tumor antigen.

### Claim 27 (depends on 26)

The method of claim 26, wherein the tumor antigen is selected from the group consisting of a prostate tumor antigen, a melanoma tumor antigen, an epithelial tumor antigen, and a combination thereof.

### Claim 28 (depends on 1, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1 and 16-22, further comprising administering an antigen, or a fragment or an analog thereof, to the subject, wherein administration of the antigen in combination with the antibody, or antigen-binding portion thereof, increases the immune response to the antigen.

### Claim 29 (depends on 28)

The method of claim 28, wherein the antigen is a tumor antigen.