Internalizing anti-CD74 antibodies and methods of use
The present invention provides humanized, chimeric and human anti-CD74 antibodies, CD74 antibody fusion proteins, immunoconjugates, vaccines and bispecific that bind to CD74, the major histocompatibility complex (MHC) class-II invariant chain, Ii, which is useful for the treatment and diagnosis of B-cell disorders, such as B-cell malignancies, other malignancies in which the cells are reactive with CD74, and autoimmune diseases, and methods of treatment and diagnosis.
1. A method for treating a CD74-positive multiple myeloma comprising administering to a subject with a CD74-positive multiple myeloma a therapeutic composition comprising at least one humanized or chimeric anti-CD74 antibody or antigen-binding fragment thereof comprising the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:16), CDR2 (TVSNRFS; SEQ ID NO:17), and CDR3 (SQSSHVPPT; SEQ ID NO:18) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:19), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:20), and CDR3 (SRGKNEAWFAY; SEQ ID NO:21), and wherein said anti-CD74 antibody or fragment thereof is a naked antibody or fragment thereof.
2. The method of claim 1 , wherein administering said naked anti-CD74 antibody or fragment thereof is effective to treat the CD74-positive multiple myeloma in the absence of any other administered antibody or fragment thereof.
3. The method of claim 1 , wherein the naked anti-CD74 antibody or antigen-binding fragment thereof is administered before, during or after the administration of at least one therapeutic agent used to treat the CD74-positive multiple myeloma.
4. The method of claim 3 , wherein the therapeutic agent comprises a second antibody, a second antibody fragment, a fusion protein, an immunomodulator, a hormone, a cytotoxic agent, an enzyme, an RNase, a recombinant RNase, a radionuclide, a photoactive agent, a second antibody conjugated to at least one immunomodulator, enzyme, RNase, recombinant RNase, radioactive label, hormone, or cytotoxic agent, or a combination thereof.
5. A method for treating a CD74-positive multiple myeloma comprising administering to a subject with a CD74-positive multiple myeloma a therapeutic composition comprising at least one humanized or chimeric anti-CD74 antibody or antigen-binding fragment thereof, wherein said chimeric, or humanized anti-CD74 antibody comprises the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:16), CDR2 (TVSNRFS; SEQ ID NO:17), and CDR3 (SQSSHVPPT; SEQ ID NO:18) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:19), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:20), and CDR3 (SRGKNEAWFAY; SEQ ID NO:21) and wherein said anti-CD74 antibody or fragment thereof is conjugated to at least one cytotoxic agent selected from the group consisting of a radionuclide, a vinca alkaloid, an anthracycline, an epipodophyllotoxin, a taxane, an antimetabolite, an alkylating agent, an antibiotic, a COX-2 inhibitor, an antiangiogenic agent, an apoptotic agent, doxorubicin, methotrexate, taxol, CPT-11, cyclophosphamide, vincristine, procarbazine, prednisone, bleomycin, dexamethasone, leucovorin, phenyl butyrate, bryostatin-1, a camptothecan, a nitrogen mustard, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a pyrimidine analog, a purine analog and a platinum coordination complex.
6. The method of claim 1 , wherein said antibody or fragment thereof is administered intravenously or intramuscularly at a dose of 20-2000 mg.
7. The method of claim 1 , wherein said antibody or fragment thereof is administered intravenously, intramuscularly, subcutaneously or parenterally.
8. The method of claim 1 , wherein said antibody comprises human IgG1, IgG2a, IgG3 or IgG4 constant regions.
9. The method of claim 5 , wherein the cytotoxic agent is doxorubicin.
10. The method of claim 5 , wherein the cytotoxic agent is an anthracycline.
11. The method of claim 5 , wherein the cytotoxic agent is a radionuclide.
12. The method of claim 5 , wherein the cytotoxic agent is selected from the group consisting of a vinca alkaloid, an anthracycline, an epipodophyllotoxin, a taxane, an antimetabolite, an alkylating agent, an antibiotic, a COX-2 inhibitor, an antiangiogenic agent, an apoptotic agent, doxorubicin, methotrexate, taxol, CPT-11, a camptothecan, a nitrogen mustard, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a pyrimidine analog, a purine analog, and a platinum coordination complex.
13. The method of claim 5 , wherein the antibody or antigen-binding fragment thereof is chimeric.
14. The method of claim 5 , wherein the antibody or antigen-binding fragment thereof is humanized.
15. A method of treating a CD74-positive multiple myeloma comprising administering to a subject with a CD74-positive multiple myeloma a therapeutic composition comprising at least one anti-CD74 antibody or antigen-binding fragment thereof, wherein the anti-CD74 antibody or fragment thereof is conjugated to at least one cytotoxic agent selected from the group consisting of a radionuclide, a vinca alkaloid, an anthracycline, an epipodophyllotoxin, a taxane, an antimetabolite, an alkylating agent, an antibiotic, a COX-2 inhibitor, an antiangiogenic agent, an apoptotic agent, doxorubicin, methotrexate, taxol, CPT-11, cyclophosphamide, vincristine, procarbazine, prednisone, bleomycin, dexamethasone, leucovorin, phenyl butyrate, bryostatin- 1 , a camptothecan, a nitrogen mustard, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a pyrimidine analog, a purine analog and a platinum coordination complex.
16. The method of claim 15 , wherein the cytotoxic agent is an anthracycline.
17. The method of claim 15 , wherein the cytotoxic agent is doxorubicin.
18. The method of claim 15 , wherein the anti-CD74 antibody is chimeric, humanized or human.