HUMAN CTLA-4 ANTIBODIES AND THEIR USES

• US 20140234331A1
• Filed: 04/28/2014
• Published: 08/21/2014
• Est. Priority Date: 08/24/1999
• Status: Abandoned Application

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex LLC (Bristol-Myers Squibb Company)
• Inventors: Korman, Alan J., Halk, Edward L., Lonberg, Nils, Deo, Yashwant M., Keler, Tibor P.
• Application Number:
  US14/263,207
• Publication Number:
  US 20140234331A1
• Time in Patent Office: Days
• US Class Current: 424/144.1
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/072 maintaining or altering function, i.e. knock in
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/01 Animal expressing industrially exogenous proteins
• CPC Class Codes: A01K 2267/025 Animal producing cells or organs for transplantation
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 2267/0325 Animal model for autoimmune diseases
• CPC Class Codes: A01K 2267/0381 Animal model for diseases of the hematopoietic system
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C12N 15/8509 : for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: 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

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

1. A monoclonal antibody or antigen-binding portion thereof, comprising 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

wherein the antibody or antigen-binding portion thereof binds to human CTLA-4 with a binding affinity of about 10⁸ M<sup>−

1</sup> or greater.

2. The antibody or antigen-binding portion thereof of claim 1, wherein the heavy chain variable region and light chain variable region CDR2 domains are selected from the group consisting of:

(a) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID No;

32; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

29;

(b) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

30; and

(c) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34; and

a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31.

3. The antibody or antigen-binding portion thereof of claim 2, wherein the heavy chain variable region and light chain variable region CDR1 domains are selected from the group consisting of:

(a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

24;

(b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

25; and

(c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

28; and

a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

26.

22. A method for increasing an immune response to an antigen in a subject, which method comprising administering to the subject the antibody or antigen-binding portion thereof of claim 1.

23. A method for treating cancer in a subject, which method comprising administering to the subject the antibody or antigen-binding portion thereof of claim 1.

4. A monoclonal antibody or an antigen-binding portion thereof that specifically binds to human CTLA-4 and comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:

17, 19 and 23.

5. The monoclonal antibody or antigen-binding portion thereof of claim 4, wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

17.

6. The monoclonal antibody or antigen-binding portion thereof of claim 4, wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

19.

7. The monoclonal antibody or antigen-binding portion thereof of claim 4, wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

23.

20. An isolated nucleic acid encoding the heavy chain variable region of claim 4.

8. A monoclonal antibody or an antigen-binding portion thereof that specifically binds to human CTLA-4 and comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:

7, 9 and 13.

9. The monoclonal antibody or antigen-binding portion thereof of claim 8, wherein the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

7.

10. The monoclonal antibody or antigen-binding portion thereof of claim 8, wherein the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

9.

11. The monoclonal antibody or antigen-binding portion thereof of claim 8, wherein the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:

13.

21. An isolated nucleic acid encoding the light chain variable region of claim 8.

12. A monoclonal antibody or antigen-binding portion thereof that specifically binds to human CTLA-4 and comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3;

and a light chain variable region comprising CDR1, CDR2, and CDR3, wherein the heavy chain CDR1, CDR2, and CDR3 are selected from the group consisting of;

(a) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

37;

(b) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

37; and

a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

28, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

38.

13. The antibody or antigen-binding portion thereof of claim 12, comprising a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:

27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

32, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

37.

14. The antibody or antigen-binding portion thereof of claim 12, comprising a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:

27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

33, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

37.

15. The antibody or antigen-binding portion thereof of claim 12, comprising a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:

28, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

34, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

38.

16. A monoclonal antibody or antigen-binding portion thereof that specifically binds to PD-1 and comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3, and a light chain variable region that comprises CDR1, CDR2, and CDR3, wherein the light chain CDR1, CDR2, and CDR3 are selected from the group consisting of:

(a) a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

24, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

29, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

35;

(b) a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

25, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

30, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

35; and

(c) a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO;

26, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

36.

17. The monoclonal antibody or antigen-binding portion thereof of claim 16, comprising a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:

24, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

29, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

35.

18. The monoclonal antibody or antigen-binding portion thereof of claim 16, comprising a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:

25, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

30, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

35.

19. The monoclonal antibody or antigen-binding portion thereof of claim 16, comprising a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:

26, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO;

31, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

36.