Monoclonal antibodies to programmed death 1 (PD-1)

• US 8,779,105 B2
• Filed: 08/15/2011
• Issued: 07/15/2014
• Est. Priority Date: 05/09/2005
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company), ONO Pharmaceutical Company Limited
• Original Assignee: Medarex LLC (Bristol-Myers Squibb Company)
• Inventors: Korman, Alan J., Srinivasan, Mohan, Wang, Changyu, Selby, Mark J., Chen, Bing, Cardarelli, Josephine M., Huang, Haichun
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US13/210,137
• Publication Number:
  US 20130133091A1
• Time in Patent Office: 1,065 Days
• US Class Current: 530/388.1
• 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. A monoclonal antibody or an antigen-binding portion thereof, which cross-competes for binding to PD-1 with a reference antibody or antigen-binding portion thereof that comprises:

(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;

or

(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.

2. The monoclonal antibody or antigen-binding portion thereof of claim 1, wherein the reference antibody or antigen-binding portion thereof 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.

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

(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;

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

12;

(d) 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;

or

(e) 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.

22. The monoclonal antibody or antigen-binding portion thereof of any one of claims 1, 5 and 10, which is a chimeric antibody.

23. The monoclonal antibody or antigen-binding portion thereof of any one of claims 1, 5 and 10, which is a humanized antibody.

24. The monoclonal antibody or antigen-binding portion thereof of any one of claims 1, 5 and 10, which is a human antibody.

25. The monoclonal antigen-binding portion thereof of any one of claims 1, 5 and 10, which is a Fab, Fab′

, F(ab′

)₂, dAb, Fd, Fv, or a single chain Fv fragment or an isolated CDR.

27. A composition comprising the monoclonal antibody or antigen-binding portion thereof of any one of claims 1, 5 and 10, and a pharmaceutically acceptable carrier.

28. An immunoconjugate comprising the monoclonal antibody or antigen-binding portion thereof of any one of claims 1, 5 and 10, linked to a therapeutic agent.

29. The immunoconjugate of claim 28, wherein the therapeutic agent is a cytotoxin or a radioactive isotope.

30. A bispecific molecule comprising the monoclonal antibody or antigen-binding portion thereof of any one of claims 1, 5 and 10, linked to a second functional moiety having a different binding specificity than said antibody, or antigen-binding portion thereof.

5. A monoclonal antibody or an antigen-binding portion thereof, which cross-competes for binding to PD-1 with a reference 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 selected from the group consisting of:

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

15;

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

22;

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

29;

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

36;

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

43; and

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

50;

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

16;

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

23;

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

30;

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

37;

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

44; and

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

51;

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

17;

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

24;

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

31;

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

38;

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

45; and

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

52;

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

18;

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

25;

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

32;

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

39;

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

46; and

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

53;

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

19;

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

26;

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

33;

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

40;

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

47; and

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

54;

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

20;

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

27;

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

34;

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

41;

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

48; and

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

55; and

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

21;

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

28;

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

35;

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

42;

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

49; and

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

56, and wherein the monoclonal antibody or antigen-binding portion thereof exhibits at least one of the following properties;

(i) binds to human PD-1 with a K_D of 1×

10<sup>−

7</sup> M or less, wherein the K_D is measured by surface plasmon resonance (Biacore) analysis;

(ii) binds to human PD-1 with an on rate (k_on) of about 0.76×

10⁵ l/Ms or more, wherein the on rate (k_on) is measured by surface plasmon resonance (Biacore) analysis; and

(iii) binds to human PD-1 with an off rate (k_off) of about 4.5×

10<sup>−

−

4</sup> l/s or less, wherein the off rate (k_off) is measured by surface plasmon resonance (Biacore) analysis.

6. The monoclonal antibody or antigen-binding portion thereof of claim 5, which exhibits two, three, four, five or all of the following properties:

(i) binds to human PD-1 with a K_D of 1×

10<sup>−

7</sup> M or less, wherein the K_D is measured by surface plasmon resonance (Biacore) analysis;

(ii) binds to human PD-1 with an on rate (k_on) of about 0.76×

10⁵ l/Ms or more, wherein the on rate (k_on) is measured by surface plasmon resonance (Biacore) analysis; and

(iii) binds to human PD-1 with an off rate (k_off) of about 4.5×

10<sup>−

4</sup> l/s or less, wherein the off rate (k_off) is measured by surface plasmon resonance (Biacore) analysis;

(iv) stimulates antigen-specific memory responses to a tumor or a pathogen;

(v) stimulates antibody responses in vivo; and

(vi) stimulates an immune response in a subject.

7. The monoclonal antibody or antigen-binding portion thereof of claim 5, wherein the reference antibody or antigen-binding portion thereof comprises:

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

17;

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

24;

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

31;

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

38;

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

45; and

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

52.

8. The monoclonal antibody or antigen-binding portion thereof of claim 5, wherein the reference antibody or antigen-binding portion thereof comprises:

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

18;

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

25;

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

32;

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

39;

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

46; and

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

53.

9. The monoclonal antibody or antigen-binding portion thereof of claim 5, wherein the reference antibody or antigen-binding portion thereof comprises:

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

15;

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

22;

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

29;

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

36;

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

43; and

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

50;

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

16;

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

23;

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

30;

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

37;

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

44; and

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

51;

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

19;

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

26;

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

33;

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

40;

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

47; and

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

54;

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

20;

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

27;

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

34;

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

41;

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

48; and

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

55;

or

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

21;

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

28;

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

35;

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

42;

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

49; and

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

56.

26. The monoclonal antibody or antigen-binding portion thereof of claim 5, wherein the CDR sequences are delineated using the Kabat system of CDR determination.

10. A monoclonal antibody or an antigen-binding portion thereof, which binds to the same epitope on PD-1 as does a reference antibody or antigen-binding portion thereof comprising:

(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;

or

(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.

11. The monoclonal antibody or antigen-binding portion thereof of claim 10, wherein the reference antibody or antigen-binding portion thereof 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.

12. The monoclonal antibody or antigen-binding portion thereof of claim 10, wherein the reference antibody or reference antigen-binding portion thereof 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.

13. The monoclonal antibody or antigen-binding portion thereof of claim 10, wherein the reference antibody or antigen-binding portion thereof comprises:

(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;

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

12;

(d) 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;

or

(e) 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.

14. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, which inhibits the suppression of CD4⁺ CD25⁻

T cells by regulatory T cells.

15. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, which increases activation of T cells.

16. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, which confers a persistent immunity to tumor relapse.

17. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, further comprising a heavy chain constant region which is of a human IgG1, IgG2, IgG3, or IgG4 isotype.

18. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, which is of an IgG1 isotype.

19. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, which is of an IgG4 isotype.

20. The monoclonal antibody or antigen-binding portion thereof of claim 19, which mediates neither ADCC activity nor CDC activity.

21. The monoclonal antibody or antigen-binding portion thereof of any one of claims 3, 8, and 12, further comprising a light chain constant region which is a human kappa or lambda constant region.