Enhancement of antibody-mediated immune responses

• US 20010036459A1
• Filed: 04/13/2001
• Published: 11/01/2001
• Est. Priority Date: 04/13/2000
• Status: Active Grant

• Current Assignee: Rockefeller University
• Original Assignee: Rockefeller University
• Inventors: Ravetch, Jeffrey V.
• Granted Patent: US 7,416,726 B2
• Time in Patent Office: Days
• US Class Current: 424/143.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/72 Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is related to enhancing the function of anti-tumor antibodies by regulating FcγRIIB-mediated activity. In particular, disrupting SHIP activation by FcγRIIB enhances cytotoxicity elicited by a therapeutic antibody in vivo in a human. The invention further provides an antibody, e.g., an anti-tumor antibody, with a variant Fc region that results in binding of the antibody to FcγRIIB with reduced affinity. A variety of transgenic mouse models demonstrate that the inhibiting FcγRIIB molecule is a potent regulator of cytotoxicity in vivo.

Claims

1. A method for enhancing cytotoxicity elicited by a therapeutic antibody in vivo in a subject, which method comprises disrupting activation of SHIP by Fc-gamma-receptor IIB (Fcγ

RIIB).

2. The method according to

claim 1

, wherein the SHIP activation by Fcγ

RIIB results from antibody binding to Fcγ

RIIB.

3. The method according to

claim 2

, wherein antibody binding is inhibited by a competitive inhibitor.

4. The method according to

claim 2

, wherein antibody binding is inhibited by modifying the Fc portion of the antibody to reduce its affinity for Fcγ

RIIB.

5. The method according to

claim 1

, wherein SHIP activation by Fcγ

RIIB is disrupted by inhibiting the expression of Fcγ

RIIB.

6. The method according to

claim 5

, wherein Fcγ

RIIB expression is disrupted with an antisense nucleic acid specific for the γ

IIB chain mRNA.

7. The method according to

claim 5

, wherein Fcγ

RIIB expression is disrupted with an intracellular antibody specific for the γ

IIB chain.

8. The method according to

claim 1

, wherein SHIP activation is inhibited by an inositol phosphatase inhibitor.

9. The method according to

claim 1

, wherein SHIP activation is inhibited by inhibiting SHIP expression.

10. The method according to

claim 1

, wherein the antibody is an anti-tumor antibody.

11. The method according to

claim 10

, wherein the antibody is specific for a tumor cell growth receptor.

12. The method according to

claim 11

, wherein the antibody is specific for a HER2/neu growth factor receptor.

13. The method according to

claim 11

, wherein the antibody is specific for a CD20 B cell antigen.

14. The method according to

claim 1

, wherein the antibody binds to human activating Fc receptors.

15. The method according to

claim 14

, wherein the subject expresses human Fc receptors.

16. An antibody with a variant Fc region, which antibody binds Fcγ

RIIB with reduced affinity.

17. The antibody of

claim 16

, which binds activating Fc-receptors with at least the same affinity as wildtype antibody.

18. The antibody of

claim 16

, which is an anti-tumor antibody.

19. The antibody of

claim 18

, which is specific for a tumor cell growth receptor.

20. The antibody of

claim 19

, which is specific for a HER2/neu growth factor receptor.

21. The antibody of

claim 19

, which is specific for a CD20 B cell antigen.