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 20130133091A1
• Filed: 08/15/2011
• Published: 05/23/2013
• 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 Incorporated (Bristol-Myers Squibb Company), ONO Pharmaceutical Company Limited
• Inventors: Korman, Alan J., Srinivasan, Mohan, Wang, Changyu, Chen, Bing, Cardarelli, Josephine M., Sellby, Mark J., Huang, Haichun
• Granted Patent: US 8,779,105 B2
• Time in Patent Office: Days
• US Class Current: 800/18
• 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 nucleic acid encoding a heavy chain variable region of an anti-PD-1 monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3 domains, wherein the CDR3 domain comprises amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, and SEQ ID NO;

35, and conservative modifications thereof.

2. The isolated nucleic acid of claim 1, wherein the CDR2 domain comprises amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

22, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, and SEQ ID NO;

28, and conservative modifications thereof.

3. The isolated nucleic acid of claim 1, wherein the CDR1 domain comprises amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, and SEQ ID NO;

20, and SEQ ID NO;

21, and conservative modifications thereof.

7. An isolated nucleic acid encoding an anti-PD-1 monoclonal antibody, or antigen-binding portion thereof, comprising:

(a) the nucleic acid of claim 3;

(b) the nucleic acid of claim 6; and

(c) one or more nucleic acids encoding one or more constant domains, operatively linked together.

14. An expression vector comprising the nucleic acid of claim 1 and/or claim 4.

15. A host cell expressing a polypeptide or glycoprotein encoded by the nucleic acid of claim 1 and/or claim 4.

16. A transgenic mouse comprising the host cell of claim 15, wherein the mouse expresses a polypeptide encoded by the nucleic acid.

17. A hybridoma prepared from the transgenic mouse of claim 16, wherein the hybridoma produces a polypeptide encoded by the nucleic acid.

18. A process for producing an anti-PD-1 antibody, or antigen-binding portion thereof, comprising culturing a host cell transfected with the expression vector of claim 14.

4. An isolated nucleic acid encoding a light chain variable region of an anti-PD-1 monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3 domains, wherein the CDR3 comprises amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

50, SEQ ID NO;

51, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, and SEQ ID NO;

56, and conservative modifications thereof.

5. The isolated nucleic acid of claim 4, wherein the CDR2 domain comprises amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, and SEQ ID NO;

49, and conservative modifications thereof.

6. The isolated nucleic acid of claim 4, wherein the CDR1 domain comprises amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, and SEQ ID NO;

42, and conservative modifications thereof.

8. An isolated nucleic acid encoding a heavy chain variable region and a light chain variable region of an anti-PD-1 monoclonal antibody, or antigen-binding portion thereof, said variable regions 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.

9. An isolated nucleic acid encoding a heavy chain variable region comprising amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, and SEQ ID NO;

7.

10. An isolated nucleic acid encoding a light chain variable region comprising amino acids having a sequence selected from the group consisting of:

SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, and SEQ ID NO;

14.

11. An isolated nucleic acid encoding a heavy chain variable region, said nucleic acid comprising nucleotides having a sequence selected from the group consisting of:

SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

59, SEQ ID NO;

60, SEQ ID NO;

61, SEQ ID NO;

62, and SEQ ID NO;

63.

12. An isolated nucleic acid encoding a light chain variable region, said nucleic acid comprising nucleotides having a sequence selected from the group consisting of:

SEQ ID NO;

64, SEQ ID NO;

65, SEQ ID NO;

66, SEQ ID NO;

67, SEQ ID NO;

68, SEQ ID NO;

69, and SEQ ID NO;

70.

13. An isolated nucleic acid molecule encoding a monoclonal antibody, or an 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

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

or

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

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

wherein the antibody specifically binds to PD-1.