Human Antibodies to PD-1

• US 20150203579A1
• Filed: 01/23/2015
• Published: 07/23/2015
• Est. Priority Date: 01/23/2014
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Papadopoulos, Nicholas J., Murphy, Andrew J., Thurston, Gavin, Ioffe, Ella, Burova, Elena
• Granted Patent: US 9,987,500 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 31/12 Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/31 : multispecific
• 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

Abstract

The present invention provides antibodies that bind to the T-cell co-inhibitor programmed death-1 (PD-1) protein, and methods of use. In various embodiments of the invention, the antibodies are fully human antibodies that bind to PD-1. In certain embodiments, the present invention provides multi-specific antigen-binding molecules comprising a first binding specificity that binds to PD-1 and a second binding specificity that binds to an autoimmune tissue antigen, another T-cell co-inhibitor, an Fc receptor, or a T-cell receptor. In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing PD-1 activity, thus providing a means of treating a disease or disorder such as cancer or a chronic viral infection. In other embodiments, the antibodies are useful for enhancing or stimulating PD-1 activity, thus providing a means of treating, for example, an autoimmune disease or disorder.

Claims

1-56. -56. (canceled)

57. An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human programmed death-1 (PD-1) protein, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) sequence selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, and 314; and

three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) sequence selected from the group consisting of SEQ ID NOs;

10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, and 202.

58. The isolated antibody or antigen-binding fragment thereof of claim 57, comprising:

(a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, and 316;

(b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, and 318;

(c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 312, and 320;

(d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, and 204;

(e) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, and 206; and

(f) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, and 208.

59. The isolated antibody or antigen-binding fragment thereof of claim 58, wherein the HCVR/LCVR amino acid sequence pair is selected from the group consisting of SEQ ID NOs:

2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/202, 218/202, 226/202, 234/202, 242/202, 250/202, 258/202, 266/202, 274/202, 282/202, 290/202, 298/186, 306/186 and 314/186.

60. The isolated antibody or antigen-binding fragment thereof of claim 59, wherein the antibody has one or more of the following properties:

(a) blocks human PD-1 protein binding to PD-L1 with an IC₅₀ of less than 3 nM as measured in a competition sandwich ELISA assay at 25°

C.;

(b) binds monomeric human PD-1 with a binding dissociation equilibrium constant (K_D) of less than about 50 nM as measured in a surface plasmon resonance assay at 37°

C.;

(c) binds monomeric human PD-1 with a K_D less than about 12 nM in a surface plasmon resonance assay at 25°

C.;

(d) binds monomeric cynomolgus PD-1 with a K_D less than about 8.5 nM in a surface plasmon resonance assay at 25°

C.;

(e) binds monomeric human PD-1 with a dissociative half-life (t%) of greater than about 6.3 minutes as measured in a surface plasmon resonance assay at 25°

C.; and

(f) binds monomeric human PD-1 with a dissociative half-life (t%) of greater than about 0.9 minutes as measured in a surface plasmon resonance assay at 37°

C.

61. The isolated antibody or antigen-binding fragment of claim 60, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

330, 332, 334 and 336.

62. The isolated antibody or antigen-binding fragment of claim 60, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

331, 333, 335 and 337.

63. The isolated antibody or antigen-binding fragment of claim 60, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain/light chain amino acid sequence pair selected from the group consisting of SEQ ID NOs:

330/331, 332/333, 334/335 and 336/337.

73. A pharmaceutical composition comprising an isolated human monoclonal antibody or antigen-binding fragment thereof that binds PD-1 according to claim 57, and a pharmaceutically acceptable carrier or diluent.

74. A method of inhibiting a tumor in a subject comprising administering the pharmaceutical composition of claim 73 to a subject in need thereof.

75. The method of claim 74, wherein the tumor is selected from the group consisting of brain cancer, renal cell carcinoma, ovarian cancer, prostate cancer, colon cancer, non-small-cell lung cancer, squamous cell carcinoma of head and neck, colorectal cancer, and melanoma.

76. The method of claim 74, wherein the pharmaceutical composition is administered subcutaneously, intravenously, intradermally, intraperitoneally, orally, intramuscularly or intracranially.

77. The method of claim 74, wherein the pharmaceutical composition is administered to the subject in combination with a second therapeutic agent.

78. The method of claim 77, wherein the second therapeutic agent is selected from the group consisting of radiation therapy, a chemotherapeutic agent, a cytotoxic agent, a vascular endothelial growth factor (VEGF) antagonist, a second antibody to PD-1, an antibody to PD-L1, an antibody to a second T-cell co-inhibitor, an antibody to a tumor specific antigen, a NSAID, a corticosteroid, and a dietary supplement such as an antioxidant.

79. The method of claim 74, wherein the antibody or antigen-binding fragment is administered at a dose of about 0.1 mg/kg of body weight to about 60 mg/kg of body weight of the subject.

80. A method for inhibiting a tumor in a subject comprising administering the pharmaceutical composition of claim 73 to the subject in need thereof.

81. The method of claim 80, wherein the pharmaceutical composition is administered in combination with a VEGF antagonist.

82. The method of claim 81, wherein the VEGF antagonist is selected from the group consisting of an anti-VEGF antibody, a small molecule kinase inhibitor of VEGF receptor and a VEGF-inhibiting fusion protein.

64. An isolated antibody or antigen-binding fragment thereof that binds to the same epitope on human PD-1 protein as an antibody or antigen-binding fragment thereof which comprises three CDRs of a HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, and 314; and

three CDRs of a LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs;

10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, and 202.

65. An isolated antibody or antigen-binding fragment thereof that competes for binding to human PD-1 protein with a reference antibody or antigen-binding fragment thereof which comprises the CDRs of a HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, and 314; and

the CDRs of a LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs;

10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, and 202.

66. The isolated antibody or antigen-binding fragment of claim 65, wherein the reference antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

330, 332, 334 and 336.

67. The isolated antibody or antigen-binding fragment of claim 65, wherein the reference antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

331, 333, 335 and 337.

68. The isolated antibody or antigen-binding fragment of claim 65, wherein the reference antibody or antigen-binding fragment thereof comprises a heavy chain/light chain amino acid sequence pair selected from the group consisting of SEQ ID NOs:

330/331, 332/333, 334/335 and 336/337.

69. An isolated human monoclonal antibody or antigen-binding fragment thereof that blocks PD-1 binding to PD-L1, as measured by a competition sandwich ELISA assay at 25°

C.

70. The isolated antibody or antigen-binding fragment of claim 69 comprising the CDRs of a HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs:

18, 34, 50, 66, 82, 114, 130, 162, 178, 194, 210, 218, 226, 234, 242, 258, 266, 274, 282, 290, 298, 306 and 314; and

the CDRs of a LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs;

26, 42, 58, 74, 90, 122, 138, 170, 186, and 202.

71. An isolated antibody or antigen-binding fragment thereof that binds human PD-1, wherein the antibody or antigen-binding fragment thereof enhances PD-1 binding to PD-L1, as measured by a competition sandwich ELISA assay at 25°

C.

72. The isolated antibody or antigen-binding fragment thereof of claim 71, wherein the antibody comprises the CDRs of a HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 98, and 250; and

the CDRs of a LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs;

10, 106, and 202.