Methods and compositions for the treatment of proliferative and pathogenic diseases
The invention features proteins including an antibody, or functional derivatives thereof, that bind hCD59 and have the activity of domain 4 of the Streptococcus intermedins intermedilysin (ILY) protein. In order to prevent the independent induction of CDC and ADCC, the antibodies of the invention can bind the same hCD59 epitope as ILYd4 and/or contain modifications that disrupt the interaction between the antibody and complement.
1. An antibody or functional derivative thereof comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a complementarity determining region (CDRL1) comprising the sequence of GASQSVSSSYLA (SEQ ID NO:11), a CDRL2 comprising the sequence of ASSRATGIPD (SEQ ID NO:12), and a CDRL3 comprising the sequence of YGSSPPVT (SEQ ID NO:13); and wherein the heavy chain variable domain comprises a CDRH1 comprising the sequence of SYDIN (SEQ ID NO:14), a CDRH2 comprising the sequence of WMNPNSGNTGYAQKFQG (SEQ ID NO:15), and a CDRH3 comprising the sequence of GKGSGYYNY (SEQ ID NO:16).
2. The antibody or functional derivative thereof of claim 1 , wherein the light chain variable domain of said antibody or functional derivative thereof, comprises the sequence of SEQ ID NO:4 and the heavy chain variable domain comprises the sequence of SEQ ID NO:6.
3. The antibody or functional derivative thereof of claim 1 , wherein said functional derivative of the antibody is selected from a single chain antibody (scFv), a Fv, a Fab, a Fab', or a F(ab') 2 .
4. The antibody or functional derivative thereof of claim 3 , wherein said functional derivative of the antibody does not contain an Fc domain.
5. An antibody or functional derivative thereof comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a CDRL1 comprising the sequence of TGTSSDVGGYNYVS (SEQ ID NO:17), a CDRL2 comprising the sequence of DVSNRPSGVSN (SEQ ID NO:18), and a CDRL3 comprising the sequence of YAGSSTLV (SEQ ID NO:19); and wherein heavy chain variable domain comprises a CDRH1 comprising the sequence of SYDIN (SEQ ID NO:14), a CDRH2 comprising the sequence of WMNPNSGNTGYAQKFQG (SEQ ID NO:15), and a CDRH3 comprising the sequence of GRGFDWLKNFDY (SEQ ID NO:20).
6. The antibody or functional derivative thereof of claim 5 , wherein the light chain variable domain of said antibody or functional derivative thereof, comprises the sequence of SEQ ID NO:8 and the heavy chain variable domain comprises the sequence of SEQ ID NO:10.
7. The antibody or functional derivative thereof of claim 5 , wherein said functional derivative of the antibody is selected from a single chain antibody (scFv), a Fv, a Fab, a Fab', or a F(ab') 2 .
8. The antibody or functional derivative thereof of claim 7 , wherein said functional derivative of the antibody does not contain an Fc domain.
9. A pharmaceutical composition comprising an antibody or functional derivative thereof of claim 1 and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising an antibody or functional derivative thereof of claim 5 and a pharmaceutically acceptable excipient.
11. A kit comprising an antibody or functional derivative thereof of claim 1 and a therapeutic antibody.
12. A kit comprising an antibody or functional derivative thereof of claim 5 and a therapeutic antibody.
13. A method for treating a proliferative disease in a patient in need thereof, said method comprising administering to said patient the antibody or functional derivative thereof of claim 1 and a therapeutic antibody, wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously, or within 14 days of each other, in amounts that together are sufficient to treat said proliferative disease.
14. The method of claim 13 , wherein said therapeutic antibody is selected from the group consisting of rituximab, MT201, 17-1A, herceptin, alemtuzumab, lym-1, bevacizumab, cetuximab, and IL-2 receptor alpha-directed monoclonal antibodies.
15. The method of claim 14 , wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously.
16. The method of claim 15 , wherein said antibody or functional derivative thereof is formulated together with said therapeutic antibody.
17. The method of claim 13 , wherein said proliferative disease is characterized by neoplastic cells expressing CD59.
18. A method for treating a disease caused by a pathogen expressing a CD59- or CD59-like molecule in a patient in need thereof, said method comprising administering to said patient the antibody or functional derivative thereof of claim 1 .
19. The method of claim 18 , further comprising administering a therapeutic antibody against said pathogen, wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously, or within 14 days of each other, in amounts that together are sufficient to treat said pathogenic disease.
20. The method of claim 18 , further comprising administering an antibody specific for a virus selected from the group consisting of human cytomegalovirus (HCMV), human T-cell leukemia virus type 1, HIV-1, simian immunodeficiency virus, Ebola virus, Herpesvirus saimiri virus, influenza virus, and vaccinia virus.
21. The method of claim 19 , wherein said therapeutic antibody is specific for a microbial parasite selected from the group consisting of Naegleria fowleri and Schistosoma manosni.
22. The method of claim 19 , wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously.
23. The method of claim 22 , wherein said antibody or functional derivative thereof is formulated together with said therapeutic antibody.
24. A method for treating a proliferative disease in a patient in need thereof, said method comprising administering to said patient the antibody or functional derivative thereof of claim 5 and a therapeutic antibody, wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously, or within 14 days of each other, in amounts that together are sufficient to treat said proliferative disease.
25. The method of claim 24 , wherein said therapeutic antibody is selected from the group consisting of rituximab, MT201, 17-1A, herceptin, alemtuzumab, lym-1, bevacizumab, cetuximab, and IL-2 receptor alpha-directed monoclonal antibodies.
26. The method of claim 25 , wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously.
27. The method of claim 26 , wherein said antibody or functional derivative thereof is formulated together with said therapeutic antibody.
28. The method of claim 24 , wherein said proliferative disease is characterized by neoplastic cells expressing CD59.
29. A method for treating a disease caused by a pathogen expressing a CD59- or CD59-like molecule in a patient in need thereof, said method comprising administering to said patient the antibody or functional derivative thereof of claim 5 .
30. The method of claim 29 , further comprising administering a therapeutic antibody against said pathogen, wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously, or within 14 days of each other, in amounts that together are sufficient to treat said pathogenic disease.
31. The method of claim 29 , further comprising administering an antibody specific for a virus selected from the group consisting of human cytomegalovirus (HCMV), human T-cell leukemia virus type 1, HIV-1, simian immunodeficiency virus, Ebola virus, Herpesvirus saimiri virus, influenza virus, and vaccinia virus.
32. The method of claim 30 , wherein said therapeutic antibody is specific for a microbial parasite selected from the group consisting of Naegleria fowleri and Schistosoma manosni.
33. The method of claim 30 , wherein said antibody or functional derivative thereof and said therapeutic antibody are administered simultaneously.
34. The method of claim 33 , wherein said antibody or functional derivative thereof is formulated together with said therapeutic antibody.