ENGINEERED ANTI-IL-23P19 ANTIBODIES

• US 20100272731A1
• Filed: 02/21/2008
• Published: 10/28/2010
• Est. Priority Date: 02/23/2007
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Liu, Yan-Hui, Ingram, Richard N., Beyer, Brian M., Presta, Leonard G., Orth, Peter
• Granted Patent: US 8,293,883 B2
• Time in Patent Office: Days
• US Class Current: 424/158.100
• 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 17/06 Antipsoriatics
• 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 27/02 Ophthalmic agents
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07K 14/54 : Interleukins [IL]
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/565 : 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

Abstract

Engineered antibodies to human IL-23p19 are provided, as well as uses thereof, e.g., in treatment of inflammatory, autoimmune, and proliferative disorders.

Claims

1. A binding compound that binds to human IL-23p19 comprising:

a) an antibody light chain variable domain, or antigen binding fragment thereof, comprising one or more CDR sequences selected from the group consisting of SEQ ID NOs;

32-46; and

b) an antibody heavy chain variable domain, or antigen binding fragment thereof, comprising one or more CDR sequences selected from the group consisting of SEQ ID NOs;

15-31.

7. The binding compound of claim 1 comprising:

a) an antibody light chain variable domain, or antigen binding fragment thereof, comprising three CDR sequences selected from the group consisting of SEQ ID NOs;

32-46; and

b) an antibody heavy chain variable domain, or antigen binding fragment thereof, comprising three CDR sequences selected from the group consisting of SEQ ID NOs;

15-31.

10. The binding compound of claim 1 comprising:

a) a light chain variable domain, or antigen binding fragment thereof, comprising;

at least one CDRL1 from the group consisting of SEQ ID NOs;

32-36;

at least one CDRL2 from the group consisting of SEQ ID NOs;

37-41; and

at least one CDRL3 from the group consisting of SEQ ID NOs;

42-46; and

b) a heavy chain variable domain, or antigen binding fragment thereof, comprising;

at least one CDRH1 from the group consisting of SEQ ID NOs;

15-19;

at least one CDRH2 from the group consisting of SEQ ID NOs;

20-26; and

at least one CDRH3 from the group consisting of SEQ ID NOs;

27-31.

2-6. -6. (canceled)

8-9. -9. (canceled)

11-12. -12. (canceled)

13. A binding compound that binds to human IL-23, comprising:

a) a light chain variable domain, or antigen binding fragment thereof, comprising CDRL1, CDRL2 and CDRL3, wherein;

CDRL1 comprises the sequence of SEQ ID NO;

36 or a variant thereof;

CDRL2 comprises the sequence of SEQ ID NO;

41 or a variant thereof; and

CDRL3 comprises the sequence of SEQ ID NO;

46 or a variant thereof; and

b) a heavy chain variable domain, or antigen binding fragment thereof, comprising CDRH1, CDRH2 and CDRH3, wherein;

CDRH1 comprises the sequence of SEQ ID NO;

19 or a variant thereof;

CDRH2 comprises a sequence selected from the group consisting of SEQ ID NOs;

24-26 or a variant thereof; and

CDRH3 comprises the sequence of SEQ ID NO;

31 or a variant thereof;

wherein each variant comprises up to five conservatively modified amino acid substitutions.

14. The binding compound of claim 13 wherein:

a) the light chain variable domain, or antigen binding fragment thereof, comprises residues 1-108 of SEQ ID NO;

14; and

b) the heavy chain variable domain, or antigen binding fragment thereof, comprises residues 1-116 of a sequence selected from the group consisting of SEQ ID NOs;

6-8.

19. The binding compound of claim 14 comprising a light chain and a heavy chain, wherein:

a) the light chain comprises the sequence of SEQ ID NO;

14; and

b) the heavy chain comprises a sequence selected from the group consisting of SEQ ID NOs;

6-8.

43. The binding compound of claim 19 wherein the heavy chain comprises the sequence of SEQ ID NO:

7.

15. A binding compound that binds to human IL-23, comprising:

a) a light chain variable domain, or antigen binding fragment thereof, comprising CDRL1, CDRL2 and CDRL3, wherein;

CDRL1 comprises the sequence of SEQ ID NO;

36;

CDRL2 comprises the sequence of SEQ ID NO;

41; and

CDRL3 comprises the sequence of SEQ ID NO;

46; and

b) a heavy chain variable domain, or antigen binding fragment thereof, comprising CDRH1, CDRH2 and CDRH3, wherein;

CDRH1 comprises the sequence of SEQ ID NO;

19;

CDRH2 comprises a sequence selected from the group consisting of SEQ ID NOs;

24-26; and

CDRH3 comprises the sequence of SEQ ID NO;

31.

27. An isolated nucleic acid encoding at least one of the light chain variable domain or heavy chain variable domain of the binding compound of claim 15.

28. An expression vector comprising the nucleic acid of claim 27 operably linked to control sequences that are recognized by a host cell when the host cell is transfected with the vector.

29. A host cell comprising the expression vector of claim 28.

30. A method of producing a polypeptide comprising:

culturing the host cell of claim 29 in culture medium under conditions wherein the nucleic acid sequence is expressed, thereby producing polypeptides comprising at least one of the light and heavy chain variable domains; and

recovering the polypeptide or polypeptides from the host cell or culture medium.

31. The binding compound of claim 15, further comprising a heavy chain constant region comprising a γ

1 human heavy chain constant region or a variant thereof, wherein the constant region variant comprises up to 20 conservatively modified amino acid substitutions.

32. The binding compound of claim 15, further comprising a heavy chain constant region comprising a γ

4 human heavy chain constant region or a variant thereof, wherein the constant region variant comprises up to 20 conservatively modified amino acid substitutions.

33. The binding compound of claim 15, wherein the binding compound is an antibody fragment selected from the group consisting of Fab, Fab′

, Fab′

-SH, Fv, scFv, F(ab′

)₂, and a diabody.

34. A method of suppressing an immune response in a human subject comprising administering to a subject in need thereof an antibody specific for IL-23, or a antigen binding fragment thereof, in an amount effective to block the biological activity of IL-23, wherein the antibody is the antibody of claim 15.

35. The method of claim 34, wherein the immune response is an inflammatory response.

36. The method of claim 35, wherein the subject has a disorder selected from the group consisting of arthritis, psoriasis and inflammatory bowel disease.

37. The method of claim 34, wherein the immune response is an autoimmune response.

38. The method of claim 37, wherein the subject has a disorder selected from the group consisting of multiple sclerosis, systemic lupus erythematosus and diabetes.

39. The method of claim 34, wherein the subject has cancer and the immune response is a Th17 response.

41. A pharmaceutical composition comprising the binding compound of claim 15 in combination with a pharmaceutically acceptable carrier or diluent.

16-18. -18. (canceled)

20. (canceled)

21. A binding compound that binds to human IL-23, comprising:

a) an antibody light chain variable domain, or antigen binding fragment thereof, consisting essentially of the sequence of residues 1-108 of SEQ ID NO;

14; and

b) an antibody heavy chain variable domain, or antigen binding fragment thereof, consisting essentially of residues 1-116 of a sequence selected from the group consisting of SEQ ID NOs;

6-8.

44. The binding compound of claim 21 wherein the heavy chain variable domain, or antigen binding fragment thereof, comprises residues 1-116 of SEQ ID NO:

7.

22. (canceled)

23. A binding compound that binds to human IL-23 at an epitope comprising residues 20-30 or residues 82-110 of SEQ ID NO:

47.

24. The binding compound of claim 23, wherein the binding compound binds to an epitope comprising residues 20-30 and residues 82-110 of SEQ ID NO:

47.

25. The binding compound of claim 24, wherein the binding compound binds to an epitope comprising residues K20, T23, W26, S27, P30, E82, S95, L96, L97, P98, D99, P101, G103, Q104, H106, A107 and L110 of SEQ ID NO:

47.

26. An antibody, or antigen binding fragment thereof, that is able to block binding of a binding compound comprising:

a) an antibody light chain comprising the sequence of SEQ ID NO;

14; and

b) an antibody heavy chain comprising a sequence selected from the group consisting of SEQ ID NOs;

6-8,

to human IL-23 in a cross-blocking assay.

40. (canceled)

42. (canceled)

44-1. An antibody, or antigen binding fragment thereof, that is able to block the binding of human IL-23R to the antibody deposited with ATCC under accession number PTA-7803 in a cross-blocking assay.