Claims for Patent: 8,747,857

Summary for Patent: 8,747,857

Title:	Calicheamicin derivative-carrier conjugates
Abstract:	Methods for preparing monomeric cytotoxic drug/carrier conjugates with a drug loading significantly higher than in previously reported procedures and with decreased aggregation and low conjugate fraction (LCF) are described. Cytotoxic drug derivative/antibody conjugates, compositions comprising the conjugates and uses of the conjugates are also described. Monomeric calicheamicin derivative/anti-CD22 antibody conjugates, compositions comprising the conjugates and uses of the conjugates are also described.
Inventor(s):	Kunz; Arthur (New City, NY), Moran; Justin Keith (Valley Cottage, NY), Rubino; Joseph Thomas (Towaco, NJ), Jain; Neera (New City, NY), Vidunas; Eugene Joseph (Middletown, NY), Simpson; John McLean (Upper Nyack, NY), Merchant; Nishith (Palisades Park, NJ), Dijoseph; John Francis (Woodbridge, NJ), Ruppen; Mark Edward (Garnerville, NY), Damle; Nitin Krishnaji (Upper Saddle River, NJ), Robbins; Paul David (Derwood, MD), Popplewell; Andrew George (Middlesex, GB)
Assignee:	Wyeth Holdings LLC (Madison, NJ)
Application Number:	10/699,874
Patent Claims:	1. A method of treating a subject with a B-cell malignancy that expresses CD22 antigen, the method comprising administering to the subject a therapeutically effective dose of a composition comprising a monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate, wherein the anti-CD22 antibody of the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate comprises a light chain variable region having the sequence set forth in SEQ ID NO: 19 and a heavy chain variable region having the sequence set forth in SEQ ID NO: 27. 2. The method of claim 1, wherein the anti-CD22 antibody is selected from the group consisting of a monoclonal antibody, a chimeric antibody, a human antibody, a humanized antibody, a single chain antibody, and a biologically active antibody fragment, wherein the biologically active antibody fragment is a Fab, a modified Fab, Fab', F(ab').sub.2 or Fv. 3. The method of claim 1, wherein the anti-CD22 antibody is a humanized antibody. 4. The method of claim 1, wherein the cytotoxic drug of the monomeric cytotoxic drug derivative is calicheamicin, gamma calicheamicin or N-acetyl gamma calicheamicin. 5. The method of claim 4, wherein the monomeric cytotoxic drug derivative is functionalized with 3-mercapto-3-methyl butanoyl hydrazide and conjugated to the anti-CD22 antibody via a hydrolyzable linker that is capable of releasing the cytotoxic drug from the conjugate after binding and entry into target cells. 6. The method of claim 1, wherein the therapeutically effective dose of the composition is administered subcutaneously, intraperitoneally, intravenously, intraarterially, intramedullarly, intrathecally, transdermally, transcutaneously, intranasally, topically, enterally, intravaginally, sublingually or rectally. 7. The method of claim 1, wherein the therapeutically effective dose of the composition is administered intravenously. 8. The method of claim 1, wherein the subject is a human subject. 9. The method of claim 1, wherein the B-cell malignancy is a leukemia, a lymphoma or a Non-Hodgkin's lymphoma. 10. The method of claim 1, comprising administering the therapeutically effective dose of the composition with one or more bioactive agents. 11. The method of claim 10, wherein one of the one or more bioactive agents is an antibody. 12. The method of claim 11, wherein the antibody is directed against a cell surface antigen expressed on B-cell malignancies. 13. The method of claim 12, wherein the cell surface antigen expressed on B-cell malignancies is CD19, CD20 or CD33. 14. The method of claim 11, wherein the antibody is rituximab. 15. The method of claim 11, wherein the therapeutically effective dose of the composition is administered together with an antibody directed against a cell surface antigen expressed on B-cell malignancies and optionally one or more combinations of cytotoxic agents, wherein the one or more combinations of cytotoxic agents is selected from: A. CHOPP (cyclophosphamide, doxorubicin, vincristine, prednisone, and procarbazine); B. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); C. COP (cyclophosphamide, vincristine, and prednisone); D. CAP-BOP (cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone); E. m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and leucovorin); F. ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, mechloethamine, vincristine, prednisone, and procarbazine); G. ProMACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, cytarabine, bleomycin, and vincristine); H. MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, and leucovorin); I. MOPP (mechloethamine, vincristine, prednisone, and procarbazine); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); K. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABV (adriamycin/doxorubicin, bleomycin, and vinblastine); L. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); M. ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); N. IMVP-16 (ifosfamide, methotrexate, and etoposide); O. MIME (methyl-gag, ifosfamide, methotrexate, and etoposide); P. DHAP (dexamethasone, high-dose cytarabine, and cisplatin); Q. ESHAP (etoposide, methylpredisolone, high-dose cytarabine, and cisplatin); R. CEPP(B) (cyclophosphamide, etoposide, procarbazine, prednisone, and bleomycin); S. CAMP (lomustine, mitoxantrone, cytarabine, and prednisone); T. CVP-1 (cyclophosphamide, vincristine, and prednisone); U. ESHOP (etoposide, methylpredisolone, high-dose cytarabine, vincristine and cisplatin); V. EPOCH (etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone); W. ICE (ifosfamide, cyclophosphamide, and etoposide); X. CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin); and Y. P/DOCE (epirubicin or doxorubicin, vincristine, cyclophosphamide, and prednisone). 16. A method of treating a subject with a B-cell malignancy that expresses CD22 antigen, the method comprising administering to the subject a therapeutically effective dose of a composition comprising a monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate, wherein the anti-CD22 antibody of the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate comprises a light chain having the sequence set forth in SEQ ID NO: 28 and a heavy chain having the sequence set forth in SEQ ID NO: 30. 17. The method of claim 16, wherein the anti-CD22 antibody is a biologically active antibody fragment, wherein the biologically active antibody fragment is a Fab, a modified Fab, Fab', or F(ab').sub.2. 18. The method of claim 16, wherein the cytotoxic drug of the monomeric cytotoxic drug derivative is calicheamicin, gamma calicheamicin or N-acetyl gamma calicheamicin. 19. The method of claim 18, wherein the calichcamicin monomeric cytotoxic drug derivative is functionalized with 3-mercapto-3-methyl butanoyl hydrazide and conjugated to the anti-CD22 antibody via a hydrolyzable linker that is capable of releasing the cytotoxic drug from the conjugate after binding and entry into target cells. 20. The method of claim 16, wherein the therapeutically effective dose of the composition is administered subcutaneously, intraperitoneally, intravenously, intraarterially, intramedullarly, intrathecally, transdermally, transcutaneously, intranasally, topically, enterally, intravaginally, sublingually or rectally. 21. The method of claim 16, wherein the therapeutically effective dose of the composition is administered intravenously. 22. The method of claim 16, wherein the subject is a human subject. 23. The method of claim 16, wherein the B-cell malignancy is a leukemia, a lymphoma or a Non-Hodgkin's lymphoma. 24. The method of claim 16, comprising administering the therapeutically effective dose of the composition with one or more bioactive agents. 25. The method of claim 24, wherein one of the one or more bioactive agents is an antibody. 26. The method of claim 25, wherein the antibody is directed against a cell surface antigen expressed on B-cell malignancies. 27. The method of claim 26, wherein the cell surface antigen expressed on B-cell malignancies is CD19, CD20 or CD33. 28. The method of claim 25, wherein the antibody is rituximab. 29. The method of claim 25, wherein the therapeutically effective dose of the composition is administered together with an antibody directed against a cell surface antigen expressed on B-cell malignancies and optionally one or more combinations of cytotoxic agents, wherein the one or more combinations of cytotoxic agents is selected from: A. CHOPP (cyclophosphamide, doxorubicin, vincristine, prednisone, and procarbazine); B. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); C. COP (cyclophosphamide, vincristine, and prednisone); D. CAP-BOP (cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone); E. m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and leucovorin); F. ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, mechloethamine, vincristine, prednisone, and procarbazine); G. ProMACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, cytarabine, bleomycin, and vincristine); H. MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, and leucovorin); I. MOPP (mechloethamine, vincristine, prednisone, and procarbazine); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); K. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABV (adriamycin/doxorubicin, bleomycin, and vinblastine); L. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); M. ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); N. IMVP-16 (ifosfamide, methotrexate, and etoposide); O. MIME (methyl-gag, ifosfamide, methotrexate, and etoposide); P. DHAP (dexamethasone, high-dose cytarabine, and cisplatin); Q. ESHAP (etoposide, methylpredisolone, high-dose cytarabine, and cisplatin); R. CEPP(B) (cyclophosphamide, etoposide, procarbazine, prednisone, and bleomycin); S. CAMP (lomustine, mitoxantrone, cytarabine, and prednisone); T. CVP-1 (cyclophosphamide, vincristine, and prednisone); U. ESHOP (etoposide, methylpredisolone, high-dose cytarabine, vincristine and cisplatin); V. EPOCH (etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone); W. ICE (ifosfamide, cyclophosphamide, and etoposide); X. CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin); and Y. P/DOCE (epirubicin or doxorubicin, vincristine, cyclophosphamide, and prednisone). 30. A method of treating a subject with a B-cell malignancy that expresses CD22 antigen, the method comprising administering to the subject a therapeutically effective dose of a composition comprising a monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate, wherein the anti-CD22 antibody of the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate comprises SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, residues 50-66 of SEQ ID NO: 23 or residues 50-66 of SEQ ID NO: 27 for CDR-H2, SEQ ID NO: 3for CDR-H3, SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5 for CDR-L2, and SEQ ID NO: 6 for CDR-L3. 31. The method of claim 30, wherein the anti-CD22 antibody is selected from a group consisting of a monoclonal antibody, a chimeric antibody, a human antibody, a humanized antibody, a single chain antibody, and a biologically active antibody fragment, wherein the biologically active antibody fragment is a Fab, a modified Fab, Fab', F(ab').sub.2 or Fv. 32. The method of claim 30, wherein the anti-CD22 antibody is a humanized antibody. 33. The method of claim 32, wherein the humanized antibody comprises a variable domain comprising human acceptor framework regions. 34. The method of claim 32, wherein the anti-CD22 antibody comprises a heavy chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 21 and SEQ ID NO: 22, wherein residues at one or more of positions 1, 28, 48, 72 and 97 of SEQ ID NO: 21 are replaced by glutamate, arginine, isoleucine, alanine, and threonine, respectively. 35. The method of claim 32, wherein the anti-CD22 antibody comprises a heavy chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 21 and SEQ ID NO: 22, wherein residues at one or more of positions 1, 28, 48, 68, 70, 72 and 97 of SEQ ID NO: 21 are replaced by glutamate, arginine, isoleucine, alanine, leucine, alanine, and threonine, respectively. 36. The method of claim 32, wherein the anti-CD22 antibody comprises a light chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 17 and SEQ ID NO: 18, wherein residues at one or more of positions 2, 4, 42, 43, 50 and 65 of SEQ ID NO: 17 are replaced by valine, valine, leucine, histidine, glutamine, and aspartate, respectively. 37. The method of claim 32, wherein the anti-CD22 antibody comprises a light chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 17 and SEQ ID NO: 18, wherein residues at one or more of positions 2, 3, 4, 42, 43, 50 and 65 of SEQ ID NO: 17 are replaced by valine, valine, valine, leucine, histidine, glutamine, and aspartate, respectively. 38. The method of claim 30, wherein the cytotoxic drug of the monomeric cytotoxic drug derivative is calicheamicin, gamma calicheamicin or N-acetyl gamma calicheamicin. 39. The method of claim 38, wherein the monomeric cytotoxic drug derivative is functionalized with 3-mercapto-3-methyl butanoyl hydrazide and conjugated to the anti-CD22 antibody via a hydrolyzable linker that is capable of releasing the cytotoxic drug from the conjugate after binding and entry into target cells. 40. The method of claim 30, wherein the therapeutically effective dose of the composition is administered subcutaneously, intraperitoneally, intravenously, intraarterially, intramedullarly, intrathecally, transdermally, transcutaneously, intranasally, topically, enterally, intravaginally, sublingually or rectally. 41. The method of claim 30, wherein the therapeutically effective dose of the composition is administered intravenously. 42. The method of claim 30, wherein the subject is a human subject. 43. The method of claim 30, wherein the B-cell malignancy is a leukemia, a lymphoma or a Non-Hodgkin's lymphoma. 44. The method of claim 30, comprising administering the therapeutically effective dose of the composition with one or more bioactive agents. 45. The method of claim 44, wherein one of the one or more bioactive agents is an antibody. 46. The method of claim 45, wherein the antibody is directed against a cell surface antigen expressed on B-cell malignancies. 47. The method of claim 46, wherein the cell surface antigen expressed on B-cell malignancies is CD19, CD20 or CD33. 48. The method of claim 45, wherein the antibody is rituximab. 49. The method of claim 45, wherein the therapeutically effective dose of the composition is administered together with an antibody directed against a cell surface antigen expressed on B-cell malignancies and optionally one or more combinations of cytotoxic agents, wherein the one or more combinations of cytotoxic agents is selected from: A. CHOPP (cyclophosphamide, doxorubicin, vincristine, prednisone, and procarbazine); B. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); C. COP (cyclophosphamide, vincristine, and prednisone); D. CAP-BOP (cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone); E. m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and leucovorin); F. ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, mechloethamine, vincristine, prednisone, and procarbazine); G. ProMACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, cytarabine, bleomycin, and vincristine); H. MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, and leucovorin); I. MOPP (mechloethamine, vincristine, prednisone, and procarbazine); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); K. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABV (adriamycin/doxorubicin, bleomycin, and vinblastine); L. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); M. ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); N. IMVP-16 (ifosfamide, methotrexate, and etoposide); O. MIME (methyl-gag, ifosfamide, methotrexate, and etoposide); P. DHAP (dexamethasone, high-dose cytarabine, and cisplatin); Q. ESHAP (etoposide, methylpredisolone, high-dose cytarabine, and cisplatin); R. CEPP(B) (cyclophosphamide, etoposide, procarbazine, prednisone, and bleomycin); S. CAMP (lomustine, mitoxantrone, cytarabine, and prednisone); T. CVP-1 (cyclophosphamide, vincristine, and prednisone); U. ESHOP (etoposide, methylpredisolone, high-dose cytarabine, vincristine and cisplatin); V. EPOCH (etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone); W. ICE (ifosfamide, cyclophosphamide, and etoposide); X. CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin); and Y. P/DOCE (epirubicin or doxorubicin, vincristine, cyclophosphamide, and prednisone). 50. A method of treating a subject with a B-cell malignancy that expresses CD22 antigen, the method comprising administering to the subject a therapeutically effective dose of a composition comprising a monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate, wherein the anti-CD22 antibody of the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate comprises a light chain variable region having the sequence set forth in SEQ ID NO: 7 and a heavy chain variable region having the sequence set forth in SEQ ID NO: 8. 51. The method of claim 50, wherein the anti-CD22 antibody is selected from a group consisting of a monoclonal antibody, a chimeric antibody, a single chain antibody, and a biologically active antibody fragment, wherein the biologically active antibody fragment is a Fab, a modified Fab, Fab', F(ab').sub.2 or Fv. 52. The method of claim 50, wherein the anti-CD22 antibody is a chimeric antibody. 53. The method of claim 50, wherein the cytotoxic drug of the monomeric cytotoxic drug derivative is calicheamicin, gamma calicheamicin or N-acetyl gamma calicheamicin. 54. The method of claim 53, wherein the monomeric cytotoxic drug derivative is functionalized with 3-mercapto-3-methyl butanoyl hydrazide and conjugated to the anti-CD22 antibody via a hydrolyzable linker that is capable of releasing the cytotoxic drug from the conjugate after binding and entry into target cells. 55. The method of claim 50, wherein the therapeutically effective dose of the composition is administered subcutaneously, intraperitoneally, intravenously, intraarterially, intramedullarly, intrathecally, transdermally, transcutaneously, intranasally, topically, enterally, intravaginally, sublingually or rectally. 56. The method of claim 50, wherein the therapeutically effective dose of the composition is administered intravenously. 57. The method of claim 50, wherein the subject is a human subject. 58. The method of claim 50, wherein the B-cell malignancy is a leukemia, a lymphoma or a Non-Hodgkin's lymphoma. 59. The method of claim 50, comprising administering the therapeutically effective dose of the composition of the monomeric cytotoxic drug derivative/anti-CD22-antibody conjugate with one or more bioactive agents. 60. The method of claim 59, wherein one of the one or more bioactive agents is an antibody. 61. The method of claim 60, wherein the antibody is directed against a cell surface antigen expressed on B-cell malignancies. 62. The method of claim 61, wherein the cell surface antigen expressed on B-cell malignancies is CD19, CD20 or CD33. 63. The method of claim 60, wherein the antibody is rituximab. 64. The method of claim 60, wherein the therapeutically effective dose of the composition is administered together with an antibody directed against a cell surface antigen expressed on B-cell malignancies and optionally one or more combinations of cytotoxic agents, wherein the one or more combinations of cytotoxic agents is selected from: A. CHOPP (cyclophosphamide, doxorubicin, vincristine, prednisone, and procarbazine); B. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); C. COP (cyclophosphamide, vincristine, and prednisone); D. CAP-BOP (cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone); E. m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and leucovorin); F. ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, mechloethamine, vincristine, prednisone, and procarbazine); G. ProMACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, cytarabine, bleomycin, and vincristine); H. MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, and leucovorin); I. MOPP (mechloethamine, vincristine, prednisone, and procarbazine); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); K. KMOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABV (adriamycin/doxorubicin, bleomycin, and vinblastine); L. MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABVD (adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine); M. ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); N. IMVP-16 (ifosfamide, methotrexate, and etoposide); O. MIME (methyl-gag, ifosfamide, methotrexate, and etoposide); P. DHAP (dexamethasone, high-dose cytarabine, and cisplatin); Q. ESHAP (etoposide, methylpredisolone, high-dose cytarabine, and cisplatin); R. CEPP(B) (cyclophosphamide, etoposide, procarbazine, prednisone, and bleomycin); S. CAMP (lomustine, mitoxantrone, cytarabine, and prednisone); T. CVP-1 (cyclophosphamide, vincristine, and prednisone); U. ESHOP (etoposide, methylpredisolone, high-dose cytarabine, vincristine and cisplatin); V. EPOCH (etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone); W. ICE (ifosfamide, cyclophosphamide, and etoposide); X. CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin); and Y. P/DOCE (epirubicin or doxorubicin, vincristine, cyclophosphamide, and prednisone). 65. A method of treating a subject with aggressive lymphomas that expresses CD22 antigen comprising administering to the subject a patient in need of said treatment a therapeutically effective dose of a composition comprising a monomeric calicheamicin derivative anti-CD22 antibody conjugate together with one or more bioactive agents, wherein the monomeric calicheamicin derivative-anti-CD22 antibody conjugate comprises calicheamicin, gamma calicheamicin or N-acetyl gamma calicheamicin functionalized with 3-mercapto-3-methyl butanoyl hydrazide and an anti-CD22 antibody comprising SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2, ef SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, residues 50-66 of SEQ ID NO: 23 or residues 50-66 of SEQ ID NO:27 for CDR-H2, SEQ ID NO: 3for CDR-H3, SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5 for CDR-L2, and SEQ ID NO: 6 for CDR-L3. 66. The method of claim 65, wherein the anti-CD22 antibody comprises a variable domain comprising human acceptor framework regions. 67. The method of claim 65, wherein the anti-CD22 antibody comprises a heavy chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 21 and SEQ ID NO: 22, wherein residues at one or more of positions 1, 28, 48, 72 and 97 f SEQ ID NO: 21 are replaced by glutamate, arginine, isoleucine, alanine, and threonine, respectively. 68. The method of claim 65, wherein the anti-CD22 antibody comprises a heavy chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 21 and SEQ ID NO: 22, wherein residues at one or more of positions 1, 28, 48, 68, 70, 72 and 97 of SEQ ID NO: 21 are replaced by glutamate, arginine, isoleucine, alanine, leucine, alanine, and threonine, respectively. 69. The method of claim 65, wherein the anti-CD22 antibody comprises a light chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 17 and SEQ ID NO: 18, wherein residues at one or more of positions 2, 4, 42, 43, 50 and 65 of SEQ ID NO: 17 are replaced by valine, valine, leucine, histidine, glutamine, and aspartate, respectively. 70. The method of claim 69, wherein the anti-CD22 antibody comprises a light chain variable domain comprising the human acceptor framework regions of SEQ ID NO: 17 and SEQ ID NO: 18, wherein residues at one or more of positions 2, 3, 4, 42, 43, 50, and 65 are of SEQ ID NO: 17 replaced by valine, valine, valine, leucine, histidine, glutamine, and aspartate, respectively. 71. The method of claim 65, wherein one of the one or more bioactive agents is an antibody. 72. The method of claim 71, wherein the antibody is directed against a cell surface antigen expressed on B-cell malignancies. 73. The method of claim 72, wherein the cell surface antigen expressed on B-cell malignancies is CD19, CD20 or CD33. 74. The method of claim 1, wherein the antibody is rituximab. 75. The method of claim 1, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate has the formula ##STR00001## wherein n is 3 to 9. 76. The method of claim 75, wherein the anti-CD22 antibody is in the expression product of a mammalian cell and comprises a light chain consisting of residues 21-239 of SEQ ID NO: 28 and a heavy chain consisting of residues 20-466 of SEQ ID NO: 30. 77. The method of claim 76, wherein the anti-CD22 antibody comprises a light chain consisting of an amino acid sequence resulting from the expression of SEQ ID NO: 29 in a mammalian cell and a heavy chain consisting of an amino acid sequence resulting from the expression of SEQ ID NO: 31 in a mammalian cell. 78. The method of claim 30, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate has the formula ##STR00002## wherein n is 3 to 9. 79. The method of claim 78, wherein the anti-CD22 antibody is the expression product of a mammalian cell and comprises a light chain consisting of residues 21-239 of SEQ ID NO: 28 and a heavy chain consisting of residues 20-466 of SEQ ID NO: 30. 80. The method of claim 79, wherein the anti-CD22 antibody comprises a light chain consisting of an amino acid sequence resulting from the expression of SEQ ID NO: 29 in a mammalian cell and a heavy chain consisting of an amino acid sequence resulting from the expression of SEQ ID NO: 31 in a mammalian cell. 81. The method of claim 9, wherein the leukemia is acute lymphocytic leukemia (ALL). 82. The method of claim 23, wherein the leukemia is acute lymphocytic leukemia (ALL). 83. The method of claim 43, wherein the leukemia is acute lymphocytic leukemia (ALL). 84. The method of claim 58, wherein the leukemia is acute lymphocytic leukemia (ALL). 85. The method of claim 75, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.1 mg/m.sup.2 to 50 mg/m.sup.2. 86. The method of claim 76, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.1 mg/m.sup.2 to 50 mg/m.sup.2. 87. The method of claim 77, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.1 mg/m.sup.2 to 50 mg/m.sup.2. 88. The method of claim 78, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.1 mg/m.sup.2 to 50 mg/m.sup.2. 89. The method of claim 79, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.1 mg/m.sup.2 to 50 mg/m.sup.2. 90. The method of claim 80, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.1 mg/m.sup.2 to 50 mg/m.sup.2. 91. The method of claim 85, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.4 mg/m.sup.2 to 30 mg/m.sup.2. 92. The method of claim 86, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.4 mg/m.sup.2 to 30 mg/m.sup.2. 93. The method of claim 86, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.4 mg/m.sup.2 to 30 mg/m.sup.2. 94. The method of claim 88, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.4 mg/m.sup.2 to 30 mg/m.sup.2. 95. The method of claim 89, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.4 mg/m.sup.2 to 30 mg/m.sup.2. 96. The method of claim 90, wherein the monomeric cytotoxic drug derivative/anti-CD22 antibody conjugate is administered at an effective dose of from 0.4 mg/m.sup.2 to 30 mg/m.sup.2.

Details for Patent 8,747,857

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2022-05-02
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2022-05-02
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2022-05-02