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Last Updated: March 29, 2024

Claims for Patent: 7,981,421


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Summary for Patent: 7,981,421
Title:Combinations of antibodies selective for DR5 and other therapeutic agents
Abstract: An antibody of the invention interacts with human DR5 or with human DR4 to produce agonistic or antagonistic effects downstream of the receptor including inhibition of cell proliferation and apoptosis. Methods and uses for the antibodies, optionally in combination with various therapeutic agents, are detailed, including treatment of apoptosis-related disease and treatment of dysregulated cell growth.
Inventor(s): Zhou; Tong (Birmingham, AL), Ichikawa; Kimihisa (Kanagawa-ken, JP), Kimberly; Robert P. (Birmingham, AL), Koopman; William J. (Indian Springs, AL), Ohsumi; Jun (Kanagawa-ken, JP), LoBuglio; Albert F. (Birmingham, AL), Buchsbaum; Donald J. (Alabaster, AL)
Assignee: The UAB Research Foundation (Birmingham, AL)
Application Number:12/686,659
Patent Claims:1. A method of selectively inducing apoptosis of target cells expressing DR5, comprising contacting the target cells with a monoclonal antibody produced by mouse-mouse hybridoma TRA-8 having ATCC Accession Number PTA-1428 or an antibody having the same epitope specificity as the monoclonal antibody, wherein the antibody is present in amounts sufficient to kill the target cells expressing DR5.

2. The method of claim 1, wherein the method is performed in vivo.

3. The method of claim 1, wherein the method is performed in vitro.

4. The method of claim 1, further comprising providing a second apoptosis-inducing agent or blocking proliferation of target cells by contacting the target cells with a therapeutic quantity of one or more therapeutic agents, wherein the therapeutic agent or agents are present in amounts sufficient to promote apoptosis or to block proliferation.

5. The method of claim 4, wherein the therapeutic agent or agents are selected from the group consisting of chemotherapeutic agents, apoptosis-inducing compounds, members of the TNF family, and second antibodies that promote apoptosis or blocks proliferation of the target cells.

6. The method of claim 5, wherein the chemotherapeutic agents are selected from the group consisting of bleomycin, carboplatin, chlorambucil, cisplatin, colchicine, cyclophosphamide, daunorubicin, actinomycin, diethylstilbestrol, doxorubicin, etoposide, 5-fluorouracil, floxuridine, melphalan, methotrexate, mitomycin, 6-mercaptopurine, teniposide, 6-thioguanine, leflunomide, dactinomycin, tamoxifen, interferon .alpha.-2.beta., glutamic acid, plicamycin, mercaptopurine, carmustine, BCNU, lomustine, CCNU, cytosine araboside, estramustine, hydroxyurea, procarbazine, busulfan, medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, testolactone, mechlorethamine, thiotepa, bethmethasone sodium phosphate, dicarbazine, asparaginase, mitotane, vincristine sulfate, and vinblastine sulfate.

7. The method of claim 5, wherein the members of the TNF family are CD40 ligands, or functional fragments or derivatives thereof.

8. The method of claim 5, wherein the members of the TNF family are Fas ligands or functional fragments or derivatives thereof

9. The method of claim 5, wherein the apoptosis-inducing compounds are selected from the group consisting of bisindolylmaleimide VIII (BisVIII), SN-50 and LY294002.

10. The method of claim 5, wherein the second antibodies are selected from the group consisting of a DR4 antibody, a TNF antibody, a B7 antibody, a CD40 ligand antibody, a CD40 antibody, a CD20 antibody, and a Fas antibody.

11. The method of claim 1, wherein the antibody having the same epitope specificity as the monoclonal antibody comprises a heavy chain comprising a variable region and a light chain comprising a variable region.

12. The method of claim 11, wherein the heavy chain variable region comprises SEQ ID NO:56, SEQ ID NO:31, SEQ ID NO:59, SEQ ID NO: 60, SEQ ID NO:61 or a functional fragment thereof and wherein the light chain variable region comprises SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:46, SEQ ID NO: 74, SEQ ID NO:75, SEQ ID NO:76 or a functional fragment thereof.

13. The method of claim 11, wherein the heavy chain variable region comprises SEQ ID NO:56 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:72 or a functional fragment thereof.

14. The method of claim 11, wherein the heavy chain variable region comprises SEQ ID NO:31 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:46 or a functional fragment thereof.

15. The method of claim 11, wherein the heavy chain variable region comprises SEQ ID NO:59 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:73 or a functional fragment thereof.

16. The method of claim 11, wherein the heavy chain variable region comprises SEQ ID NO:31 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:73 or a functional fragment thereof.

17. The method of claim 11, wherein the heavy chain variable region comprises one or more complementarity determining regions (CDR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, and wherein the light chain variable region comprises one or more CDRs comprising an amino acid sequence selected from the group consisting of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30.

18. The method of claim 11, wherein the heavy chain variable region comprises a CDR1 comprising SEQ ID NO:25, a CDR2 comprising SEQ ID NO:26, and a CDR3 comprising SEQ ID NO:27, and wherein the light chain variable region comprises a CDR4 comprising SEQ ID NO:28, a CDR5 comprising SEQ ID NO:29, and a CDR6 comprising SEQ ID NO:30.

19. The method of claim 1, wherein the target cells expressing DR5 are cancer cells.

20. The method of claim 1, wherein the target cells expressing DR5 are inflammatory cells.

21. The method of claim 1, wherein the target cells expressing DR5 are activated immune cells.

22. The method of claim 1, further comprising irradiating the target cells.

23. A method of treating an inflammatory or autoimmune disease characterized by target cells expressing DR5 in a subject, comprising (a) administering to the subject a monoclonal antibody produced by mouse-mouse hybridoma TRA-8 having ATCC Accession Number PTA-1428 or an antibody having the same epitope specificity as the monoclonal antibody wherein the antibody is present in amounts sufficient to kill the target cells expressing DR5.

24. The method of claim 23, wherein the method is performed in vivo.

25. The method of claim 23, wherein the method is performed in vitro.

26. The method of claim 23, further comprising providing a second apoptosis-inducing agent or blocking proliferation of target cells by contacting the target cells with a therapeutic quantity of one or more therapeutic agents, wherein the therapeutic agent or agents are present in amounts sufficient to promote apoptosis or to block proliferation.

27. The method of claim 26, wherein the therapeutic agent or agents are selected from the group consisting of chemotherapeutic agents, apoptosis-inducing compounds, members of the TNF family, and second antibodies that promote apoptosis or blocks proliferation of the target cells.

28. The method of claim 27, wherein the chemotherapeutic agents are selected from the group consisting of bleomycin, carboplatin, chlorambucil, cisplatin, colchicine, cyclophosphamide, daunorubicin, actinomycin, diethylstilbestrol, doxorubicin, etoposide, 5-fluorouracil, floxuridine, melphalan, methotrexate, mitomycin, 6-mercaptopurine, teniposide, 6-thioguanine, leflunomide, dactinomycin, tamoxifen, interferon .alpha.-2.beta., glutamic acid, plicamycin, mercaptopurine, carmustine, BCNU, lomustine, CCNU, cytosine araboside, estramustine, hydroxyurea, procarbazine, busulfan, medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, testolactone, mechlorethamine, thiotepa, bethmethasone sodium phosphate, dicarbazine, asparaginase, mitotane, vincristine sulfate, and vinblastine sulfate.

29. The method of claim 27, wherein the members of the TNF family are CD40 ligands, or functional fragments or derivatives thereof.

30. The method of claim 27, wherein the members of the TNF family are Fas ligands, or a functional fragments or derivatives thereof

31. The method of claim 27, wherein the apoptosis-inducing compounds are selected from the group consisting of bisindolylmaleimide VIII (BisVIII), SN-50 and LY294002.

32. The method of claim 27, wherein the second antibodies are selected from the group consisting of a DR4 antibody, a TNF antibody, a B7 antibody, a CD40 ligand antibody, a CD40 antibody, a CD20 antibody, and a Fas antibody.

33. The method of claim 23, wherein the antibody having the same epitope specificity as the monoclonal antibody comprises a heavy chain comprising a variable region and a light chain comprising a variable region.

34. The method of claim 33, wherein the heavy chain variable region comprises SEQ ID NO:56, SEQ ID NO:31, SEQ ID NO:59, SEQ ID NO: 60, SEQ ID NO:61 or a functional fragment thereof and wherein the light chain variable region comprises SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:46, SEQ ID NO: 74, SEQ ID NO:75, SEQ ID NO:76 or a functional fragment thereof.

35. The method of claim 33, wherein the heavy chain variable region comprises SEQ ID NO:56 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:72 or a functional fragment thereof.

36. The method of claim 33, wherein the heavy chain variable region comprises SEQ ID NO:31 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:46 or a functional fragment thereof.

37. The method of claim 33, wherein the heavy chain variable region comprises SEQ ID NO:59 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:73 or a functional fragment thereof.

38. The method of claim 33, wherein the heavy chain variable region comprises SEQ ID NO:31 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:73 or a functional fragment thereof.

39. The method of claim 33, wherein the heavy chain variable region comprises one or more complementarity determining regions (CDR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, and wherein the light chain variable region comprises on or more CDRs comprising an amino acid sequence selected from the group consisting of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30.

40. The method of claim 33, wherein the heavy chain variable region comprises a CDR1 comprising SEQ ID NO:25, a CDR2 comprising SEQ ID NO:26, and a CDR3 comprising SEQ ID NO:27, and wherein the light chain variable region comprises a CDR4 comprising SEQ ID NO:28, a CDR5 comprising SEQ ID NO:29, and a CDR6 comprising SEQ ID NO:30.

41. The method of claim 23, wherein the target cells expressing DR5 are inflammatory cells.

42. The method of claim 23, wherein the target cells expressing DR5 are activated immune cells.

43. A composition comprising (a) a monoclonal antibody produced by mouse-mouse hybridoma TRA-8 having ATCC Accession Number PTA-1428 or an antibody having the same epitope specificity as the monoclonal antibody and (b) one or more therapeutic agents.

44. The composition of claim 43, wherein the therapeutic agent or agents are selected from the group consisting of chemotherapeutic agents, apoptosis-inducing compounds, members of the TNF family, and second antibodies that promote apoptosis or blocks proliferation of the target cells.

45. The composition of claim 44, wherein the chemotherapeutic agents are selected from the group consisting of bleomycin, carboplatin, chlorambucil, cisplatin, colchicine, cyclophosphamide, daunorubicin, actinomycin, diethylstilbestrol, doxorubicin, etoposide, 5-fluorouracil, floxuridine, melphalan, methotrexate, mitomycin, 6-mercaptopurine, teniposide, leflunomide, dactinomycin, tamoxifen, interferon .alpha.-2.beta., glutamic acid, plicamycin, mercaptopurine, carmustine, BCNU, lomustine, CCNU, cytosine araboside, estramustine, hydroxyurea, procarbazine, busulfan, medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, testolactone, mechlorethamine, thiotepa, bethmethasone sodium phosphate, dicarbazine, asparaginase, mitotane, vincristine sulfate, and vinblastine sulfate.

46. The composition of claim 44, wherein the members of the TNF family are CD40 ligands, or functional fragments or derivatives thereof.

47. The composition of claim 44, wherein the members of the TNF family are Fas ligands, or a functional fragments or derivatives thereof.

48. The composition of claim 44, wherein the apoptosis-inducing compounds are selected from the group consisting bisindolylmaleimide VIII (BisVIII), SN-50 and LY294002.

49. The composition of claim 44, wherein the second antibodies are selected from the group consisting of a DR4 antibody, a TNF antibody, a B7 antibody, a CD40 ligand antibody, a CD40 antibody, a CD20 antibody, and a Fas antibody.

50. The composition of claim 43, wherein the antibody having the same epitope specificity as the monoclonal antibody comprises a heavy chain comprising a variable region and a light chain comprising a variable region.

51. The composition of claim 50, wherein the heavy chain variable region comprises SEQ ID NO:56, SEQ ID NO:31, SEQ ID NO:59, SEQ ID NO: 60, SEQ ID NO:61 or a functional fragment thereof and wherein the light chain variable region comprises SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:46, SEQ ID NO: 74, SEQ ID NO:75, SEQ ID NO:76 or a functional fragment thereof.

52. The composition of claim 50, wherein the heavy chain variable region comprises SEQ ID NO:56 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:72 or a functional fragment thereof.

53. The composition of claim 50, wherein the heavy chain variable region comprises SEQ ID NO:31 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:46 or a functional fragment thereof.

54. The composition of claim 50, wherein the heavy chain variable region comprises SEQ ID NO:59 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:73 or a functional fragment thereof.

55. The composition of claim 50, wherein the heavy chain variable region comprises SEQ ID NO:31 or a functional fragment thereof and the light chain variable region comprises SEQ ID NO:73 or a functional fragment thereof.

56. The composition of claim 50, wherein the heavy chain variable region comprises one or more complementarity determining regions (CDR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, and wherein the light chain variable region comprises on or more CDRs comprising an amino acid sequence selected from the group consisting of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30.

57. The composition of claim 50, wherein the heavy chain variable region comprises a CDR1 comprising SEQ ID NO:25, a CDR2 comprising SEQ ID NO:26, and a CDR3 comprising SEQ ID NO:27, and wherein the light chain variable region comprises a CDR4 comprising SEQ ID NO:28, a CDR5 comprising SEQ ID NO:29, and a CDR6 comprising SEQ ID NO:30.

58. The composition of claim 43, further comprising a pharmaceutically acceptable carrier.

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