PD-1 SPECIFIC ANTIBODIES AND USES THEREOF

• US 20110171220A1
• Filed: 09/14/2009
• Published: 07/14/2011
• Est. Priority Date: 09/12/2008
• Status: Active Grant

• Current Assignee: Oxford University Innovation Limited (University of Oxford)
• Original Assignee: Isis Innovation Limited
• Inventors: Davis, Simon
• Granted Patent: US 9,181,342 B2
• Time in Patent Office: Days
• US Class Current: 424/135.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

One aspect of the present disclosure provides antibodies that can act as agonists of PD-1, thereby modulating immune responses regulated by PD-1. Another aspect of the disclosure provides compositions comprising PD-1 specific antibodies and their use in methods of down regulating the immune response. These methods can be practiced on any subject, including humans or animals. Anti-PD-1 antibodies disclosed herein may be used, in another aspect of the invention, to detect PD-1 or its fragments in a biological sample. The amount of PD-1 detected may be correlated with the expression level of PD-1, and associated with the activation status of immune cells (e.g., activated T cells, B cells, and/or monocytes) in the subject.

Claims

1-40. -40. (canceled)

41. An isolated antibody selected from the group consisting of:

a) a monoclonal antibody produced by the hybridoma clone 19;

b) a monoclonal antibody that binds to the same epitope as the monoclonal antibody produced by the hybridoma clone 19, wherein said antibody has;

i) a dissociation constant that is the same or differs from that of the antibody produced by the hybridoma clone 19;

or ii) a dissociation constant of between 0.04 sec<sup>−

1</sup> and 2.00 sec<sup>−

1</sup>;

c) a bispecific, humanized, single-chain, chimeric, synthetic or recombinant antibody that binds to the same epitope as the antibody produced by the hybridoma clone 19, wherein said antibody has;

i) a dissociation constant that is the same or differs from that of the antibody produced by the hybridoma clone 19;

or ii) a dissociation constant of between 0.04 sec<sup>−

1</sup> and 2.00 sec<sup>−

1</sup>;

d) an antigen binding fragment that binds to the same epitope as the monoclonal antibody produced by clone 19, wherein said antigen binding fragment has;

i) a dissociation constant that is the same or differs from that of the antibody produced by the hybridoma clone 19;

or ii) dissociation constant of between 0.04 sec<sup>−

1</sup> and 2.00 sec<sup>−

1</sup>;

e) an isolated antibody or antigen binding fragment competing with an antibody comprising SEQ ID NO;

12 and SEQ ID NO;

14 for binding to PD-1;

f) an isolated antibody or antigen binding fragment that competes with an antibody comprising SEQ ID NO;

12 and SEQ ID NO;

14 for binding to PD-1 and binds to the same PD-1 epitope as an antibody comprising SEQ ID NO;

12 and SEQ ID NO;

14;

g) an isolated antibody or antigen binding fragment competing with an antibody comprising SEQ ID NO;

12 and SEQ ID NO;

14 for binding to PD-1, said antibody comprising;

i) SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31 and SEQ ID NO;

32;

or ii) SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, amino acids 6-10 of SEQ ID NO;

30, SEQ ID NO;

31 and SEQ ID NO;

32; and

h) an isolated antibody or antigen binding fragment comprising SEQ ID NO;

12 and SEQ ID NO;

14.

42. A pharmaceutical composition comprising an antibody according to claim 41.

43. A composition of matter selected from:

a) one or more isolated nucleic acids encoding an antibody according to claim 41;

b) one or more nucleic acids encoding an antibody, said nucleic acids comprising SEQ ID NO;

11 and SEQ ID NO;

13;

c) a vector comprising one or more nucleic acids according to a) or b);

or

d) a host cell comprising a vector according to c) or a nucleic acid according to a) or b).

48. A method of isolating PD-1 or PD-1-expressing cells comprising contacting an antibody according to claim 41 with PD-1 or a PD-1 expressing cell, said antibody having the binding specificity of clone 19.

49. A method of inducing tolerance to a specific antigen comprising administering a specific antigen to a subject in combination with an anti-PD-1 specific antibody according to claim 41, said anti-PD-1 specific antibody having the binding specificity of the antibody produced by clone 19.

50. The method according to claim 49, wherein an additional specific monoclonal antibody that binds to an epitope that is distinct and non-overlapping to the epitope bound by an antibody produced by clone 19.

51. The method according to claim 50, wherein said additional PD-1 specific monoclonal antibody binds to the same epitope as the antibody produced by clone 10.

52. The method according to claim 50, wherein said additional PD-1 specific monoclonal antibody binds to the same epitope as the antibody produced by clone 2.

53. A method for reducing immune responses mediated by activated lymphocytes in a subject comprising the administration of an anti-PD-1 specific antibody according to claim 41 to a subject, said anti-PD-1 specific antibody having the binding specificity of the antibody produced by the hybridoma clone 19.

54. The method according to claim 53, wherein an additional PD-1 specific monoclonal antibody that binds to an epitope that is distinct and non-overlapping to the epitope bound by an antibody produced by clone 19.

55. The method according to claim 54, wherein said additional PD-1 specific monoclonal antibody binds to the same epitope as the antibody produced by clone 10.

56. The method according to claim 54, wherein said antibody is the antibody produced by clone 2.

57. A method of treating allergies, rheumatoid arthritis, type I diabetes mellitus, multiple sclerosis, inflammatory bowel disease, Crohn'"'"'s disease, systemic lupus erythematosus, tissue, skin and organ transplant rejection or graft-versus-host disease (GVHD) comprising the administration of an anti-PD-1 specific antibody according to claim 41 to a subject having said disease, said anti-PD-1 specific antibody having the binding specificity of the antibody produced by clone 19.

58. The method according to claim 57, wherein an additional PD-1 specific monoclonal antibody that binds to an epitope that is distinct and non-overlapping to the epitope bound by an antibody produced by clone 19.

59. The method according to claim 58, wherein said additional PD-1 specific monoclonal antibody binds to the same epitope as the antibody produced by clone 10.

60. The method according to claim 58, wherein said antibody is the antibody produced by clone 2.

61. The antibody according to claim 41, wherein said antibody comprises.

a) SEQ ID NO:

27 (light chain CDR1), SEQ ID NO;

28 (light chain CDR2), SEQ ID NO;

29 (light chain CDR3), SEQ ID NO;

30 (heavy chain CDR1), SEQ ID NO;

31 (heavy chain CDR2) and SEQ ID NO;

32 (heavy chain CDR3);

or

b) SEQ ID NO;

27 (light chain CDR1), SEQ ID NO;

28 (light chain CDR2), SEQ. ID NO;

29 (light chain CDR3), amino acids 6-10 of SEQ ID NO;

30 (heavy chain CDR1), SEQ ID NO;

31 (heavy chain CDR2) and SEQ ID NO;

32 (heavy chain CDR3).

44. An isolated polypeptide comprising SEQ ID NO:

12, SEQ ID NO;

14, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, amino acids 6-10 of SEQ ID NO;

30, SEQ ID NO;

31 or SEQ ID NO;

32.

45. An isolated nucleic acids, vector or host cell selected from:

a) one or more isolated nucleic acid encoding a polypeptide according to claim 44;

b) a vector comprising a nucleic acid according to a);

or

c) an isolated host cell comprising a vector according to a) or b).

46. An isolated polypeptide comprising:

a) one or more heavy chain CDR sequences selected from SEQ ID NO;

30, amino acids 6-10 of SEQ ID NO;

30, SEQ ID NO;

31 or SEQ ID NO;

32;

b) one or more light chain CDR sequences selected from SEQ ID NO;

27, SEQ ID NO;

28 or SEQ ID NO;

29;

c) SEQ ID NO;

30 and SEQ ID NO;

31;

SEQ ID NO;

30 and SEQ ID NO;

32;

SEQ ID NO;

31 and SEQ ID NO;

32;

SEQ ID NO;

30, SEQ ID NO;

31 and SEQ ID NO;

32;

amino acids 6-10 of SEQ ID NO;

30 and SEQ ID NO;

31;

amino acids 6-10 of SEQ ID NO;

30 and SEQ ID NO;

32;

SEQ ID NO;

31 and SEQ ID NO;

32;

or amino acids 6-10 of SEQ ID NO;

30, SEQ ID NO;

31 and SEQ ID NO;

32;

d) two or all three light chain CDR sequences selected from SEQ ID NO;

27, SEQ NO;

28 or SEQ ID NO;

29;

e) an antibody, said antibody comprising one or more heavy chain CDR sequences selected from SEQ ID NO;

30, amino acids 6-10 of SEQ ID NO;

30, SEQ ID NO;

31 or SEQ ID NO;

32, said antibody binding to PD-1;

f) an antibody, said antibody comprising one or more light chain CDR sequences selected from SEQ ID NO;

27, SEQ ID NO;

28 or SEQ ID NO;

29, said antibody binding to PD-1;

g) an antibody, said antibody comprising SEQ ID NO;

30 and SEQ ID NO;

31;

SEQ ID NO;

30 and SEQ ID NO;

32;

SEQ ID NO;

31 and SEQ ID NO;

32;

SEQ ID NO;

30, SEQ ID NO;

31 and SEQ ID NO;

32;

amino acids 6-10 of SEQ ID NO;

30 and SEQ ID NO;

31;

amino acids 6-10 of SEQ ID NO;

30 and SEQ ID NO;

32;

SEQ ID NO;

31 and SEQ ID NO;

32;

or amino acids 6-10 of SEQ ID NO;

30, SEQ ID NO;

31 and SEQ ID NO;

32, and binding to PD-1;

or

h) an antibody, said antibody comprising two or all three light chain CDR sequences selected from SEQ ID NC);

27, SEQ ID NO;

28 or SEQ ID NO;

29.

47. An isolated nucleic acid, vector or host cell selected from:

a) an isolated nucleic acid encoding a polypeptide or an antibody according to claim 46;

b) a vector comprising a nucleic acid according to claim a);

c) a host cell comprising a vector or nucleic acid according to a) or b).