Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics

• US 8,008,449 B2
• Filed: 05/02/2006
• Issued: 08/30/2011
• Est. Priority Date: 05/09/2005
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company), ONO Pharmaceutical Company Limited
• Inventors: Wang, Changyu, Chen, Bingliana, Cardarelli, Josephine M., Srinivasan, Mohan, Korman, Alan J., Selby, Mark J.
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US11/913,217
• Publication Number:
  US 20090217401A1
• Time in Patent Office: 1,946 Days
• Field of Search: None
• US Class Current: 530/388.15
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 51/10 Antibodies or immunoglobulins; Fragments thereof , the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• 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 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• 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 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• 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 isolated monoclonal antibodies, particularly human monoclonal antibodies, that specifically bind to PD-1 with high affinity. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for detecting PD-1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-1 antibodies. The present invention further provides methods for using a combination immunotherapy, such as the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat hyperproliferative disease, such as cancer. The invention also provides methods for altering adverse events related to treatment with such antibodies individually.

Claims

1. An isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof cross-competes for binding to PD-1 with a reference antibody or reference antigen-binding portion thereof comprising:

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

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

8;

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

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

9;

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

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

10;

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

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

11;

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

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

12;

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

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

13;

or

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

7 and a human light chain variable region comprising amino acids having the sequence set forth in SEO ID NO;

14.

7. A composition comprising the antibody, or antigen-binding portion thereof, of any one of claims 1, 2, 3, and 4-6, and a pharmaceutically acceptable carrier.

8. An immunoconjugate comprising the antibody, or antigen-binding portion thereof, of any one of claims 1, 2, 3, and 4-6, linked to a therapeutic agent.

9. A bispecific molecule comprising the antibody, or antigen-binding portion thereof, of any one of claims 1, 2, 3, and 4-6, linked to a second functional moiety having a different binding specificity than said antibody, or antigen-binding portion thereof.

12. The antibody or antigen-binding portion thereof of any one of claims 1, 2, and 3, wherein the antibody or antigen-binding portion thereof inhibits the suppression of CD4+CD25- T cells by regulatory T cells.

13. The antibody or antigen-binding portion thereof of any one of claims 1, 2, and 3, wherein the antibody or antigen-binding portion thereof enhances the antigen specific-memory response to a tumor or a pathogen.

14. The antibody or antigen-binding portion thereof of any one of claims 1, 2, and 3, wherein the antibody or antigen-binding portion thereof confers a persistent immunity to tumor relapse.

15. The antibody or antigen-binding portion thereof of any one of claims 1, 2, and 3, wherein the antibody or antigen-binding portion thereof is an IgG4 isotype.

16. The antibody or antigen-binding portion thereof of claim 15, wherein the antibody or antigen-binding portion thereof has neither ADCC activity nor CDC activity.

21. The antibody, or antigen-binding portion thereof of claim 1, wherein the reference antibody or reference antigen-binding portion thereof comprises:

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

3; and

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

10.

22. The antibody, or antigen-binding portion thereof of claim 1, wherein the reference antibody or reference antigen-binding portion thereof comprises:

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

4; and

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

11.

2. An isolated 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 CDR3domains, wherein the heavy chain variable region and light chain variable region CDR1, CDR2, and CDR3 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;

15;

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

22;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

29;

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

36;

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

43; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

50;

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

16;

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

23;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

30;

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

37;

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

44; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

51;

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

17;

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

24;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

31;

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

38;

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

45; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

52;

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

18;

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

25;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

32;

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

39;

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

46; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

53;

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

19;

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

26;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

33;

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

40;

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

47; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

54;

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

20;

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

27;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

34;

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

41;

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

48; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

55; and

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

21;

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

28;

a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

35;

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

42;

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

49; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

56,

wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

17. The antibody, or antigen-binding portion thereof of claim 2, which comprises:

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

17;

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

24;

(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

31;

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

38;

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

45; and

(f) a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

52.

18. The antibody, or antigen-binding portion thereof of claim 2, which comprises:

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

18;

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

25;

(c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

32;

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

39;

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

46; and

(f) a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

53.

3. An isolated monoclonal antibody, or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and light chain variable region are selected from the group consisting of:

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

1; and

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

8;

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

2; and

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

9;

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

3; and

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

10;

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

4; and

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

11;

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

5; and

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

12;

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

6; and

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

13; and

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

7; and

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

14,

wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

19. The antibody, or antigen-binding portion thereof of claim 3, which comprises:

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

3; and

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

10.

20. The antibody, or antigen-binding portion thereof of claim 3, which comprises:

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

4; and

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

11.

4. An isolated monoclonal antibody, or antigen-binding portion thereof, comprising:

a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 3-33 germline sequence; and

b) a light chain variable region that comprises amino acids having a sequence derived from a human V_K L6 germline sequence;

wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

5. An isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody is selected from the group consisting of:

a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V_H 4-39 germline sequence; and

b) a light chain variable region that comprises amino acids having a sequence derived from a human V_K L15 germline sequence;

wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

23. The immunoconjugate of claim 5, wherein the therapeutic agent is a cytotoxin or a radioactive isotope.

6. An isolated 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;

29; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

50 and conservative modifications thereof;

b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

30; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

51 and conservative modifications thereof;

c) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

31; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

52 and conservative modifications thereof;

d) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

32; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

53 and conservative modifications thereof;

e) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

33; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

54 and conservative modifications thereof;

f) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

34; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

55 and conservative modifications thereof; and

g) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

35; and

a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO;

56 and conservative modifications thereof;

wherein the antibody or antigen-binding portion thereof specifically binds to PD-1.

10. The antibody or antigen-binding portion thereof of claim 6, 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;

22 and conservative modifications thereof; and

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

43 and conservative modifications thereof;

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

23 and conservative modifications thereof; and

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

44 and conservative modifications thereof;

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

24 and conservative modifications thereof; and

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

45 and conservative modifications thereof;

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

25 and conservative modifications thereof; and

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

46 and conservative modifications thereof;

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

26 and conservative modifications thereof; and

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

47 and conservative modifications thereof;

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

27 and conservative modifications thereof; and

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

48 and conservative modifications thereof; and

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

28 and conservative modifications thereof; and

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

49 and conservative modifications thereof.

11. The antibody or antigen-binding portion thereof of claim 10, 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;

15 and conservative modifications thereof; and

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

36 and conservative modifications thereof;

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

16 and conservative modifications thereof; and

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

37 and conservative modifications thereof;

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

17 and conservative modifications thereof; and

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

38 and conservative modifications thereof;

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

18 and conservative modifications thereof; and

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

39 and conservative modifications thereof;

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

19 and conservative modifications thereof; and

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

40 and conservative modifications thereof;

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

20 and conservative modifications thereof; and

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

41 and conservative modifications thereof; and

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

21 and conservative modifications thereof; and

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

42 and conservative modifications thereof.