Enhancement of antibody-mediated immune responses
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.
1. A method of enhancing cytotoxicity elicited by a therapeutic antibody in a subject, which method comprises disrupting activation of SHIP by Fc-gamma-receptor IIB (FcγRIIB) caused by binding of the antibody to FcγRIIB, wherein the disrupting is accomplished by modifying the Fc region of the antibody to reduce its affinity for FcγRIIB, thereby inhibiting binding of the antibody to FcγRIIB in the subject, wherein the Fc region of the antibody is at least 80% homologous with a native Fc region, and wherein said therapeutic antibody binds activating Fc-receptors with at least the same affinity as the wildtype antibody.
2. The method according to claim 1 , wherein the antibody is an anti-tumor antibody.
3. The method according to claim 2 , wherein the antibody is specific for a tumor cell growth receptor.
4. The method according to claim 3 , wherein the antibody is specific for a HER2/neu growth factor receptor.
5. The method according to claim 1 , wherein the antibody is specific for a CD20 B cell antigen.
6. The method according to claim 1 , wherein the subject expresses human Fc receptors.
7. The method according to claim 1 , wherein the wherein the Fc region of the antibody is at least 90% homologous with a native Fc region.
8. The method according to claim 1 , wherein the wherein the Fc region of the antibody is at least 95% homologous with a native Fc region.
9. The method according to claim 1 , wherein the wherein the Fc region of the antibody comprises 1 amino acid substitution compared to the native Fc region.
10. The method according to claim 1 , wherein the wherein the Fc region of the antibody comprises 1-5 amino acid substitutions compared to the native Fc region.
11. The method according to claim 9 , wherein the wherein the Fc region of the antibody consists of 1 amino acid substitution compared to the native Fc region.
12. The method according to claim 9 , wherein the antibody is specific for a HER2/neu growth factor receptor.
13. The method according to claim 9 , wherein the antibody is specific for a CD20 B cell antigen.
14. The method according to claim 1 , wherein the wherein the Fc region of the antibody comprises 1 amino acid addition compared to the native Fc region.
15. The method according to claim 1 , wherein the wherein the Fc region of the antibody comprises 1-5 amino acid additions compared to the native Fc region.
16. The method according to claim 14 , wherein the wherein the Fc region of the antibody consists of 1 amino acid addition compared to the native Fc region.
17. The method according to claim 14 , wherein the antibody is specific for a HER2/neu growth factor receptor.
18. The method according to claim 14 , wherein the antibody is specific for a CD20 B cell antigen.
19. The method according to claim 1 , wherein the wherein the Fc region of the antibody comprises at least 1 amino acid deletion compared to the native Fc region.
20. The method according to claim 19 , wherein the wherein the Fc region of the antibody consists of 1 amino acid deletion compared to the native Fc region.
21. The method according to claim 19 , wherein the antibody is specific for a HER2/neu growth factor receptor.
22. The method according to claim 19 , wherein the antibody is specific for a CD20 B cell antigen.
23. A method of enhancing cytotoxicity elicited by a therapeutic antibody in a subject, which method comprises disrupting activation of SHIP by Fc-gamma-receptor IIB (FcγRIIB) caused by binding of the antibody to FcγRIIB, wherein the disrupting is accomplished by modifying the Fc region of the antibody to reduce its affinity for FcγRIIB, thereby inhibiting binding of the antibody to FcγRIIB in the subject wherein the Fc region of the antibody is at least 80% homologous with a native Fc region, and wherein said therapeutic antibody retains binding to FcRIIA and FcRIIIA.
24. The method of claim 23 wherein said retained binding is unchanged or enhanced as compared to the wildtype antibody.
25. A method of enhancing cytotoxicity elicited by a therapeutic antibody in a subject which method comprises disrupting activation of SHIP by Fc-gamma-receptor IIB (FcγRIIB) caused by binding of the antibody to FcγRIIB, wherein the disrupting is accomplished by modifying the Fc region of the antibody to reduce its affinity for FcγRIIB, thereby inhibiting binding of the antibody to FcγRIIB in the subject wherein the Fc region of the antibody is at least 80% homologous with a native Fc region, and wherein said therapeutic antibody that has reduced affinity for FcγRIIB has unchanged affinity for stimulatory FcRs, FcRI or FCRIII.
26. A method of enhancing cytotoxicity elicited by a therapeutic antibody in a subject, which method comprises disrupting activation of SHIP by Fc-gamma-receptor IIB (FcγRIIB) caused by binding of the antibody to FcγRIIB, wherein the disrupting is accomplished by modifying the Fc region of the antibody to reduce its affinity for FcγRIIB, thereby inhibiting binding of the antibody to FcγRIIB in the subject, wherein the Fc region of the antibody is at least 80% homologous with a native Fc region, and wherein said therapeutic antibody that has reduced affinity for FcγRIIB has enhanced affinity for stimulatory FcRs, FcRI or FCRIII.
27. The method according to claim 23 , wherein the antibody is an anti-tumor antibody.
28. The method according to claim 23 , wherein the antibody is specific for a tumor cell growth receptor.
29. The method according to claim 23 , wherein the antibody is specific for a HER2/neu growth factor receptor.
30. The method according to claim 23 , wherein the antibody is specific for a CD20 B cell antigen.
31. The method according to claim 23 , wherein the subject expresses human Fc receptors.
32. The method according to claim 23 , wherein the wherein the Fc region of the antibody is at least 90% homologous with a native Fc region.
33. The method according to claim 23 , wherein the wherein the Fc region of the antibody is at least 95% homologous with a native Fc region.
34. The method according to claim 23 , wherein the wherein the Fc region of the antibody comprises 1 amino acid substitution compared to the native Fc region.
35. The method according to claim 23 , wherein the wherein the Fc region of the antibody comprises 1-5 amino acid substitutions compared to the native Fc region.
36. The method according to claim 23 , wherein the wherein the Fc region of the antibody consists of 1 amino acid substitution compared to the native Fc region.
37. The method according to claim 23 , wherein the wherein the Fc region of the antibody comprises 1 amino acid addition compared to the native Fc region.
38. The method according to claim 23 , wherein the wherein the Fc region of the antibody comprises 1-5 amino acid additions compared to the native Fc region.
39. The method according to claim 23 , wherein the wherein the Fc region of the antibody consists of 1 amino acid addition compared to the native Fc region.
40. The method according to claim 23 , wherein the wherein the Fc region of the antibody comprises at least 1 amino acid deletion compared to the native Fc region.
41. The method according to claim 23 , wherein the wherein the Fc region of the antibody consists of 1 amino acid deletion compared to the native Fc region.