ANTIBODIES WITH ENHANCED ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY ACTIVITY, METHODS OF THEIR PRODUCTION AND USE

• US 20140046033A1
• Filed: 10/18/2013
• Published: 02/13/2014
• Est. Priority Date: 10/21/2005
• Status: Abandoned Application

• Current Assignee: LFB USA, Inc. (Agence des Participations de l’Etat), Genzyme Corporation (Sanofi )
• Original Assignee: Daniel Schindler
• Inventors: Schindler, Daniel, Meade, Harry M., Edmunds, Timothy, McPherson, John
• Application Number:
  US14/057,243
• Publication Number:
  US 20140046033A1
• Time in Patent Office: Days
• US Class Current: 530/387.3
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/00 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: C07K 16/04 from milk
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/12 isolated from milk
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/72 Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]

Abstract

The invention relates, in part, to antibodies with increased ADCC activity. Methods of producing such antibodies are also provided. The antibodies of the invention are produced in mammary epithelial cells, such as those in a non-human transgenic animal engineered to express and secrete the antibody in its milk. The antibodies or compositions comprising the antibodies can be used to treat disease in which ADCC activity provides a benefit. In one embodiment, therefore, the antibodies or compositions comprising the antibodies can be used to treat cancer, lymphoproliferative disease or autoimmune disease.

Claims

1. A method for enhancing the binding of the Fc region of an IgG antibody or IgG antibodies to an Fcγ

RIII receptor, the method comprising;

modifying the glycosylation of the IgG antibody or antibodies so that the binding of the Fc region of the antibody or antibodies to the Fcγ

RIII receptor is enhanced,

wherein the glycosylation is modified by producing the antibody or antibodies in mammalian mammary epithelial cells.

2. The method of claim 1, wherein the antibody or antibodies are of the isotype IgG1 or IgG2.

3. The method of claim 1, wherein the Fcγ

RIII receptor is on monocytes, macrophages or natural killer cells.

4. The method of claim 1, wherein the mammalian mammary epithelial cells are of a non-human mammal engineered to express the antibody in its milk.

5. The method of claim 1, wherein the antibody is modified such that at least one chain of the antibody does not contain fucose.

6. The method of claim 1, wherein the antibody is modified such that the antibody contains an oligomannose or an additional oligomannose.

7. The method of claim 1, wherein the antibody is modified such that the carbohydrates of the antibody exhibit a high mannose glycosylation pattern.

8. The method of claim 1, wherein the antibody is modified such that at least one chain of the antibody is oligomannose-containing and non-fucosylated.

9. The method of claim 1, wherein the antibody is modified such that the major carbohydrate of the antibody is non-fucosylated.

10. The method of claim 1, wherein the antibody is modified such that the major carbohydrate of the antibody is a non-fucosylated oligomannose.

11. The method of claim 1, wherein the antibody is modified such that the major carbohydrate of the antibody is a non-fucosylated Man5.

12. The method of claim 1, wherein the antibody is modified such that less than 40% of the carbohydrates of the antibody contain fucose.

13. The method of claim 1, wherein the antibodies are modified such that at least 30% of the antibodies have at least one oligomannose.

14. The method of claim 1, wherein at least 60% of the carbohydrates of the antibodies are a non-fucosylated oligomannose and less than 40% of the carbohydrates of the antibodies are fucose-containing.

15. The method of claim 1, wherein the mammary epithelial cells are cells from a goat, sheep, bison, camel, cow, pig, rabbit, buffalo, horse, rat, mouse or llama.

16. The method of claim 15, wherein the transgenic non-human mammal is a goat, sheep, bison, camel, cow, pig, rabbit, buffalo, horse, rat, mouse or llama.

17. The method of claim 1, wherein the antibody is a chimeric antibody, humanized antibody or fully human antibody.

18. The method of claim 1, wherein the antibody is a full-length antibody.

19. The method of claim 1, wherein the full-length antibody comprises a heavy chain and a light chain.

20. The method of claim 1, wherein the antibody is an antibody fragment.

21. The method of claim 1, wherein the antibody is an anti CD137 antibody.

22. A composition comprising antibodies, wherein the antibodies have enhanced binding of the Fc region to an Fcγ

RIII receptor,

wherein the binding of the Fc region to an Fcγ

RIII receptor is enhanced by producing the antibodies in mammalian mammary epithelial cells,

wherein the binding of the Fc region to an Fcγ

RIII receptor is enhanced compared to cell-culture derived antibodies, and

wherein the antibody is of the isotype IgG.

23. The composition of claim 22, wherein the antibodies are of the isotype IgG1 or IgG2.

24. The composition of claim 22, wherein the Fcγ

RIII receptor is on monocytes, macrophages or natural killer cells.

25. The composition of claim 22, wherein the mammalian mammary epithelial cells are of a non-human mammal engineered to express the antibodies in its milk.

26. The composition of claim 22, wherein the antibody is modified such that at least one chain of the antibody does not contain fucose.

27. The composition of claim 22, wherein the antibody is modified such that the antibody contains an oligomannose or an additional oligomannose.

28. The composition of claim 22, wherein the antibody is modified such that the carbohydrates of the antibody exhibit a high mannose glycosylation pattern.

29. The composition of claim 22, wherein the antibody is modified such that at least one chain of the antibody is oligomannose-containing and non-fucosylated.

30. The composition of claim 22, wherein the antibody is modified such that the major carbohydrate of the antibody is non-fucosylated.

31. The composition of claim 22, wherein the antibody is modified such that the major carbohydrate of the antibody is a non-fucosylated oligomannose.

32. The composition of claim 22, wherein the antibody is modified such that the major carbohydrate of the antibody is a non-fucosylated Man5.

33. The composition of claim 22, wherein the antibody is modified such that less than 40% of the carbohydrates of the antibody contain fucose.

34. The composition of claim 22, wherein the antibodies are modified such that at least 30% of the antibodies have at least one oligomannose.

35. The composition of claim 22, wherein at least 60% of the carbohydrates of the antibodies are a non-fucosylated oligomannose and less than 40% of the carbohydrates of the antibodies are fucose-containing.

36. The composition of claim 22, wherein the mammary epithelial cells are cells from a goat, sheep, bison, camel, cow, pig, rabbit, buffalo, horse, rat, mouse or llama.

37. The composition of claim 36, wherein the transgenic non-human mammal is a goat, sheep, bison, camel, cow, pig, rabbit, buffalo, horse, rat, mouse or llama.

38. The composition of claim 22, wherein the antibody is a chimeric antibody, humanized antibody or fully human antibody.

39. The composition of claim 22, wherein the antibody is a full-length antibody.

40. The composition of claim 22, wherein the full-length antibody comprises a heavy chain and a light chain.

41. The composition of claim 22, wherein the antibody is an antibody fragment.

42. The composition of claim 22, wherein the antibody is an anti CD137 antibody.