Glycoprotein compositions

• US 20030157108A1
• Filed: 10/22/2002
• Published: 08/21/2003
• Est. Priority Date: 10/25/2001
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Presta, Leonard G.
• Application Number:
  US10/277,370
• Publication Number:
  US 20030157108A1
• Time in Patent Office: Days
• US Class Current: 424/145.1
• 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 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 17/06 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 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• 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 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 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/40 : Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 9/12 : Antihypertensives
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 16/4291 : against IgE
• 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 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]

Abstract

The present invention concerns compositions comprising a glycoprotein having an Fc region, wherein about 80-100% of the glycoprotein in the composition comprises a mature core carbohydrate structure which lacks fucose, attached to the Fc region of the glycoprotein. The preferred glycoprotein is an antibody or immunoadhesin.

Claims

1. A composition comprising a glycoprotein having a Fc region, wherein about 80-100% of the glycoprotein in the composition comprises a mature core carbohydrate structure which lacks fucose, attached to the Fc region of the glycoprotein.

2. The composition of claim 1 wherein the glycoprotein comprises an antibody.

3. The composition of claim 1 wherein the Fc region comprises a human IgG Fc region.

4. The composition of claim 3 wherein the human IgG Fc region comprises a human IgG1, IgG2, IgG3 or IgG4 Fc region.

5. The composition of claim 1 wherein the glycoprotein binds an Fcγ

RIII.

6. The composition of claim 5 wherein the glycoprotein binds the Fcγ

RIII with better affinity, or mediates antibody-dependent cell-mediated cytotoxicity (ADCC) more effectively, than the glycoprotein with a mature core carbohydrate structure including fucose attached to the Fc region of the glycoprotein.

7. The composition of claim 2 wherein the antibody is a chimeric, humanized or human antibody.

8. The composition of claim 2 wherein the antibody binds an antigen selected from the group consisting of a B-cell surface marker, an ErbB receptor, a tumor-associated antigen and an angiogenic factor.

9. The composition of claim 2 wherein the antibody binds CD20, HER2, vascular endothelial growth factor (VEGF), CD40, or prostate stem cell antigen (PSCA).

10. The composition of claim 9 wherein the antibody comprises a humanzed anti-HER2 antibody, a chimeric anti-CD20 antibody and a humanized anti-VEGF antibody.

11. The composition of claim 1 wherein about 90-99% of the glycoprotein in the composition comprises a mature core carbohydrate structure which lacks fucose, attached to the Fc region of the glycoprotein.

12. The composition of claim 1, wherein the glycoprotein has been produced by a chinese hamster ovary (CHO) cell.

13. The composition of claim 12 wherein the CHO cell is a Lec13 cell.

14. The composition of claim 1 wherein the glycoprotein is essentially free of bisecting N-acetylglucosamine (GlcNAc) attached to the mature core carbohydrate structure.

15. The composition of claim 1 wherein the glycoprotein has bisecting N-acetylglucosamine (GlcNAc) attached to the mature core carbohydrate structure.

16. The composition of claim 1 wherein the glycoprotein has one or more galactose residues attached to the mature core carbohydrate structure.

17. The composition of claim 1 wherein the glycoprotein is essentially free of one or more galactose residues attached to the mature core carbohydrate structure.

18. The composition of claim 1 wherein the glycoprotein has one or more sialic acid residues attached to the mature core carbohydrate structure.

19. The composition of claim 1 wherein the glycoprotein is essentially free of one or more sialic acid residues attached to the mature core carbohydrate structure.

20. The composition of claim 1 which is a pharmaceutical preparation.

21. The pharmaceutical preparation of claim 20 further comprising a pharmaceutically acceptable carrier.

22. The composition of claim 1 which is sterile.

23. The composition of claim 1 which is lyophilized.

24. The composition of claim 1 wherein the glycoprotein is an immunoadhesin.

30. An article of manufacture, comprising:

a container;

a label on said container; and

the composition of claim 1 contained within said container.

31. The article of manufacture of claim 30, wherein the label on the container indicates that the composition can be used for the treatment of cancer, autoimmune disease, an inflammatory disorder, infection, or another condition where removal of cells or tissue is desired.

32. A method of treating a mammal comprising administering the composition of claim 1 to the mammal in an amount effective to treat a disease or disorder in the mammal that would benefit from such treatment.

33. The method of claim 32 wherein the mammal is a human.

34. The method of claim 33 wherein the human expresses Fcγ

RIII(F158).

35. The method of claim 32 wherein the disease or disorder is selected from the group consisting of cancer, an autoimmune disease, an inflammatory disorder, infection, or another condition where removal of cells or tissue is desired.

25. A composition comprising a glycoprotein having a Fc region, wherein about 51-100% of the glycoprotein in the composition comprises a mature core carbohydrate structure which lacks fucose, attached to the Fc region of the glycoprotein, and wherein the Fc region comprises an amino acid sequence that differs from a native sequence Fc region.

26. The composition of claim 25 wherein the Fc region comprises an amino acid substitution at any one or more of amino acid positions 256, 290, 298, 312, 326, 330, 333, 334, 360, 378 or 430, utilizing EU numbering for the Fc region residues.

27. The composition of claim 26 wherein the Fc region comprises amino acid substitutions at any two or three of the residues at positions 298, 333 and 334.

28. The composition of claim 27 wherein the Fc region comprises amino acid substitutions at positions 298, 333 and 334.

29. The composition of claim 28 wherein the replacement residues at postitions 298, 333 and 334 are alanine.

36. A host cell comprising nucleic acid encoding a glycoprotein which comprises an Fc region, wherein about 80-100% of the glycoprotein produced by the host cell comprises a mature core carbohydrate structure which lacks fucose, attached to the Fc region of the glycoprotein.

37. The host cell of claim 36 which is a chinese hamster ovary (CHO) cell.

38. A method for producing a glycoprotein comprising culturing the host cell of claim 36 so that the nucleic acid is expressed.

39. The method of claim 38 further comprising recovering the glycoprotein from the host cell culture.

40. The method of claim 39 further comprising conjugating the glycoprotein to a heterologous molecule.

41. The method of claim 40 wherein the heterologous molecule is a cytotoxic agent or an enzyme.