Therapeutic CD47 antibodies

• US 10,676,524 B2
• Filed: 10/03/2017
• Issued: 06/09/2020
• Est. Priority Date: 12/12/2012
• Status: Active Grant

• Current Assignee: Arch Oncology, Inc.
• Original Assignee: Arch Oncology, Inc.
• Inventors: Frazier, William A., Manning, Pamela T., Frey, Gerhard, Chang, Hwai Wen
• Primary Examiner(s): Roark, Jessica H
• Application Number:
  US15/723,534
• Publication Number:
  US 20180057592A1
• Time in Patent Office: 980 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• 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 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of 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

Abstract

Provided are monoclonal antibodies and antigen-binding fragments thereof that bind to CD47 of multiple mammalian species, block the binding of SIRPalpha and TSP1 to CD47, promote phagocytosis of susceptible cancer cells, and reverse TSP1 inhibition of nitric oxide signaling, as well as monoclonal antibodies and antigen binding fragments thereof that compete with the former for binding to CD47 and that exhibit similar biological activities. Also provided are combinations of any of the foregoing. Such antibody compounds are variously effective in 1) treating tissue ischemia and ischemia-reperfusion injury (IRI) in the setting of organ preservation and transplantation, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, and other instances of surgery and/or trauma in which IRI is a component of pathogenesis; 2) in treating autoimmune and inflammatory diseases; and 3) as anti-cancer agents for treating susceptible cancer cells, promoting their phagocytic uptake and clearance.

Claims

1. A monoclonal antibody, or antigen-binding fragment thereof, that specifically binds CD47, wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises three light chain complementarity determining regions (LCDRs 1-3) and three heavy chain complementarity determining regions (HCDRs 1-3), wherein:

LCDR1 comprises the amino acid sequence RSSQSLVHSNGNTYLH (SEQ ID NO;

1);

LCDR2 comprises the amino acid sequence KVSYRFS (SEQ ID NO;

2); and

LCDR3 comprises the amino acid sequence SQNTHVPRT (SEQ ID NO;

3);

HCDR1 comprises the amino acid sequence GYTFTNYYVF (SEQ ID NO;

4);

HCDR2 comprises the amino acid sequence DINPVNGDTNFNEKFKN (SEQ ID NO;

5); and

HCDR3 comprises the amino acid sequence GGYTMDY (SEQ ID NO;

6); and

wherein the monoclonal antibody, or antigen-binding fragment thereof, further comprises a light chain constant domain of SEQ ID NO;

117; and

wherein the monoclonal antibody, or antigen-binding fragment thereof, further comprises a heavy chain constant domain selected from among SEQ ID NO;

118, SEQ ID NO;

119, SEQ ID NO;

120, and SEQ ID NO;

121.

2. The monoclonal antibody, or antigen-binding fragment thereof of claim 1, which is chimeric or humanized.

3. The monoclonal antibody, or antigen-binding fragment thereof of claim 1, which specifically binds human, rat, mouse, and pig CD47.

4. The monoclonal antibody, or antigen-binding fragment thereof of claim 1, which comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR and said HCVR comprise, respectively, amino acid sequences selected from among the following combinations of LCVRs and HCVRs:

SEQ ID NO;

7 and SEQ ID NO;

57;

SEQ ID NO;

8 and SEQ ID NO;

58;

SEQ ID NO;

9 and SEQ ID NO;

59;

SEQ ID NO;

10 and SEQ ID NO;

60;

SEQ ID NO;

11 and SEQ ID NO;

61;

SEQ ID NO;

12 and SEQ ID NO;

62;

SEQ ID NO;

13 and SEQ ID NO;

63;

SEQ ID NO;

14 and SEQ ID NO;

64;

SEQ ID NO;

15 and SEQ ID NO;

65;

SEQ ID NO;

16 and SEQ ID NO;

66;

SEQ ID NO;

17 and SEQ ID NO;

67;

SEQ ID NO;

18 and SEQ ID NO;

68;

SEQ ID NO;

19 and SEQ ID NO;

69;

SEQ ID NO;

20 and SEQ ID NO;

70;

SEQ ID NO;

21 and SEQ ID NO;

71;

SEQ ID NO;

22 and SEQ ID NO;

72;

SEQ ID NO;

23 and SEQ ID NO;

73;

SEQ ID NO;

24 and SEQ ID NO;

74;

SEQ ID NO;

25 and SEQ ID NO;

75;

SEQ ID NO;

26 and SEQ ID NO;

76;

SEQ ID NO;

27 and SEQ ID NO;

77;

SEQ ID NO;

28 and SEQ ID NO;

78;

SEQ ID NO;

29 and SEQ ID NO;

79;

SEQ ID NO;

30 and SEQ ID NO;

80; and

SEQ ID NO;

31 and SEQ ID NO;

81.