ANTI-HUMAN IL-21 MONOCLONAL ANTIBODIES

• US 20120225065A1
• Filed: 05/17/2012
• Published: 09/06/2012
• Est. Priority Date: 12/07/2007
• Status: Active Grant

• Current Assignee: Zymogenetics Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Zymogenetics Incorporated (Bristol-Myers Squibb Company)
• Inventors: JASPERS, Stephen R., RIXON, Mark W., DILLON, Stacey R., RAMSDELL, Frederick J., KREJSA, Cecile M., YI, Eugene C.
• Granted Patent: US 8,361,470 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• 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 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 37/02 : 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• 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 2317/565 : 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 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: Y10S 530/809 : Fused cells, e.g. hybridoma

Abstract

Human anti-human IL-21 monoclonal antibodies and the hybridomas that produce them are presented. Certain of these antibodies have the ability to bind native human IL-21, a mutant recombinant IL-21 protein and/or peptide regions of human IL-21. These human anti-IL-21 antibodies are useful in therapeutic treatment of autoimmune and inflammatory diseases, particularly diseases mediated by T follicular helper cells, B cells T_H cells or T_H17 cells.

Claims

1. A method of treating a subject afflicted with an IL-21-mediated disease, the method comprising administering to said subject an effective amount of an antibody, or antigen binding portion thereof, comprising (a) a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:

61 or a light chain variable region comprising amino acid residues 23 to 129 of SEQ ID NO;

69, or (b) a heavy chain variable region comprising amino acid residues 20 to 145 of SEQ ID NO;

29 or a light chain variable region comprising amino acid residues 21 to 126 of SEQ ID NO;

37, wherein IL-21 activity is inhibited.

2. The method of claim 1, wherein the disease is selected from the group consisting of inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, type I diabetes (IDDM), an autoimmune disease, a T follicular helper cell-mediated or B cell-mediated disease.

3. The method of claim 1, wherein the antibody comprises a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:

61 or a light chain variable region comprising amino acid residues 23 to 129 of SEQ ID NO;

69.

4. The method of claim 1, wherein the antibody comprises a heavy chain variable region comprising amino acid residues 20 to 145 of SEQ ID NO:

29 or a light chain variable region comprising amino acid residues 21 to 126 of SEQ ID NO;

37.

5. The method of claim 1, wherein the antibody comprises (a) a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:

61 and a light chain variable region comprising amino acid residues 23 to 129 of SEQ ID NO;

69, or (b) a heavy chain variable region comprising amino acid residues 20 to 145 of SEQ ID NO;

29 and a light chain variable region comprising amino acid residues 21 to 126 of SEQ ID NO;

37.

6. The method of claim 5, wherein the antibody comprises a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:

61 and a light chain variable region comprising amino acid residues 23 to 129 of SEQ ID NO;

69.

7. The method of claim 5, wherein the antibody comprises a heavy chain variable region comprising amino acid residues 20 to 145 of SEQ ID NO:

29 and a light chain variable region comprising amino acid residues 21 to 126 of SEQ ID NO;

37.

8. The method of claim 1, wherein the Fc portion of the antibody is selected from the group consisting of IgG1, IgG2, and IgG4.

9. The method of claim 1, wherein the Fc portion of the antibody is modified to reduce effector functions.

10. A method of treating a subject afflicted with an IL-21-mediated disease, the method comprising administering to said subject an effective amount of an antibody, or antigen binding portion thereof, comprising (a) a heavy chain variable region comprising the amino acid sequences set forth in SEQ ID NOs:

63, 65, and 67, and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs;

71, 73, and 75, or (b) a heavy chain variable region comprising the amino acid sequences set forth in SEQ ID NOs;

31, 33, and 35 and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs;

39, 41, and 43, wherein IL-21 activity is inhibited.

11. The method of claim 10, wherein the disease is selected from the group consisting of inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, type I diabetes (IDDM), an autoimmune disease, a T follicular helper cell-mediated or B cell-mediated disease.

12. The method of claim 10, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequences set forth in SEQ ID NOs:

63, 65, and 67, and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs;

71, 73, and 75.

13. The method of claim 10, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequences set forth in SEQ ID NOs:

31, 33, and 35 and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs;

39, 41, and 43.

14. The method of claim 10, wherein the Fc portion of the antibody is selected from the group consisting of IgG1, IgG2, and IgG4.

15. The method of claim 10, wherein the Fc portion of the antibody is modified to reduce effector functions.

16. A method of treating a subject afflicted with an IL-21-mediated disease, the method comprising administering to said subject an effective amount of an antibody, or antigen binding portion thereof, which binds to the same epitope as an antibody comprising (a) a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:

61 and a light chain variable region comprising amino acid residues 23 to 129 of SEQ ID NO;

69, or (b) a heavy chain variable region comprising amino acid residues 20 to 145 of SEQ ID NO;

29 and a light chain variable region comprising amino acid residues 21 to 126 of SEQ ID NO;

37, wherein IL-21 activity is inhibited.

17. The method of claim 16, wherein the disease is selected from the group consisting of inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, type I diabetes (IDDM), an autoimmune disease, a T follicular helper cell-mediated or B cell-mediated disease.

18. The method of claim 16, wherein the isolated monoclonal antibody, or antigen-binding fragment thereof, binds to the same epitope as an antibody comprising a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:

61 and a light chain variable region comprising amino acid residues 23 to 129 of SEQ ID NO;

69.

19. The method of claim 16, wherein the isolated monoclonal antibody, or antigen-binding fragment thereof, binds to the same epitope as an antibody comprising a heavy chain variable region comprising amino acid residues 20 to 145 of SEQ ID NO:

29 and a light chain variable region comprising amino acid residues 21 to 126 of SEQ ID NO;

37.