Antibodies with altered effector functions

• US 20050152894A1
• Filed: 09/03/2004
• Published: 07/14/2005
• Est. Priority Date: 09/05/2003
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Reilly, Dorothea, Weikert, Stefanie, Krummen, Lynne A.
• Application Number:
  US10/934,087
• Publication Number:
  US 20050152894A1
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6873 the antibody targeting an immunoglobulin; the antibody being an anti-idiotypic antibody
• 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 1/18 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 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 27/06 Antiglaucoma agents or miotics
• 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 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• 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 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 37/06 : 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 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• 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 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/00 : Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/283 : against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2866 : against receptors for cytokines, lymphokines, interferons
• 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 16/4241 : against anti-human or anti-animal Ig
• CPC Class Codes: C07K 2317/53 : Hinge
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]

Abstract

The invention provides antibodies with altered effector functions, and methods of using these antibodies in the treatment of various diseases. The invention further provides compositions, kits and articles of manufacture for practicing methods of the invention.

Claims

1. A method of treating a disease comprising administering to a subject having the disease an antibody effective in treating the disease, wherein said antibody comprises a variant heavy chain hinge region incapable of inter-heavy chain disulfide linkage, and wherein the antibody is produced in a eukaryotic host cell culture.

2. The method of claim 1, wherein the antibody has reduced antibody-dependent cellular cytotoxicity (ADCC) compared to a wild type antibody.

3. The method of claim 1, wherein said variant heavy chain hinge region lacks a cysteine residue capable of forming a disulfide linkage.

4. The method of claim 3, wherein said disulfide linkage is intermolecular.

5. The method of claim 4, wherein said intermolecular disulfide linkage is between cysteines of two immunoglobulin heavy chains.

6. The method of claim 2, wherein a hinge region cysteine residue that is normally capable of forming a disulfide linkage is deleted.

7. The method of claim 2, wherein a hinge region cysteine residue that is normally capable of forming a disulfide linkage is substituted with another amino acid.

8. The method of claim 7, wherein said cysteine residue is substituted with serine.

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

10. The method of claim 9, wherein said full-length antibody comprises a heavy chain and a light chain.

11. The method of claim 1, wherein said antibody is humanized.

12. The method of claim 1, wherein said antibody is human.

13. The method of claim 1, wherein said antibody is an antibody fragment.

14. The method of claim 13 wherein said antibody fragment is an Fc fusion polypeptide.

15. The method of claim 1, wherein said antibody comprises a heavy chain constant domain and a light chain constant domain.

16. The method of claim 1, wherein the antibody is of an isotype selected from the group consisting of IgG, IgA and IgD.

17. The method of claim 16, wherein the antibody is an IgG.

18. The method of claim 17, wherein the antibody is an IgG1.

19. The method of claim 16, wherein the antibody is an IgG2.

20. The method of claim 1, wherein the antibody is a therapeutic antibody.

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

22. The method of claim 1, wherein the antibody is an antagonistic antibody.

23. The method of claim 1, wherein the antibody is a diagnostic antibody.

24. The method of claim 1, wherein the antibody is a blocking antibody.

25. The method of claim 1, wherein the antibody is a neutralizing antibody.

26. The method of claim 1, wherein the antibody is capable of binding to a tumor antigen.

41. The method of claim 1 wherein the antibody is conjugated with a heterologous moiety.

42. The method of claim 41, wherein said heterologous moiety is a cytotoxic agent.

43. The method of claim 42, wherein said cytotoxic agent is selected from the group consisting of a radioactive isotope, a chemotherapeutic agent and a toxin.

44. The method of claim 43, wherein the toxin is selected from the group consisting of calichemicin, maytansine and trichothene.

47. The method of claim 1, wherein the antibody exhibits substantially similar pharmacokinetic values as its wild type counterpart which comprises wild type ADCC activity.

48. The method of claim 1, wherein the ADCC activity is measured in vitro.

49. The method of claim 1, wherein the eukaryotic host cell is a mammalian host cell.

50. The method of claim 49, wherein the host cell is a Chinese hamster ovary (CHO) cell.

51. The method of claim 1, wherein the antibody has substantially reduced complement dependent cytotoxicity compared to its wild type counterpart antibody.

52. The method of claim 1, wherein the antibody comprises substantially reduced binding to a complement protein compared to its wild type counterpart antibody.

53. The method of claim 52, wherein the complement is C1q.

54. The method of claim 1, wherein the disease is a tumor or cancer.

55. The method of claim 1, wherein the disease is an immunological discorder.

56. The method of claim 55, wherein the immunological disorder is autoimmune.

27-40. -40. (canceled)

45-46. -46. (canceled)

57-60. -60. (canceled)