Internalizing Anti-CD74 Antibodies and Methods of Use

Abstract

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 cancer that expresses CD74, comprising administering to a subject at least one naked humanized, human or chimeric anti-CD74 antibody or antigen-binding fragment thereof. 
     
     
         2 . The method of  claim 1 , wherein administering said naked anti-CD74 antibody or fragment thereof is effective to treat the cancer. 
     
     
         3 . The method of  claim 2 , wherein administering said naked anti-CD74 antibody or fragment thereof is effective to treat the cancer in the absence of any other administered antibody or fragment thereof. 
     
     
         4 . The method of  claim 2 , wherein administering said naked anti-CD74 antibody or fragment thereof is effective to treat the cancer in the absence of any other administered therapeutic agent. 
     
     
         5 . The method of  claim 1 , wherein the anti-CD74 antibody or fragment thereof is rapidly internalized. 
     
     
         6 . The method of  claim 5 , wherein 8×10 6  antibody molecules per cell per day are internalized. 
     
     
         7 . The method of  claim 5 , wherein 70% of anti-CD74 antibody bound to the surface of Raji cells is internalized and catabolized within three hours. 
     
     
         8 . The method of  claim 1 , wherein said anti-CD74 antibody or fragment thereof induces apoptosis of cancer cells. 
     
     
         9 . The method of  claim 1 , wherein the naked anti-CD74 antibody or fragment thereof is administered before, during or after the administration of at least one therapeutic agent. 
     
     
         10 . The method of  claim 9 , wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, an immunoconjugate, a fusion protein, a drug, a toxin, an antisense oligonucleotide, a boron compound, an immunomodulator, a hormone, a cytotoxic agent, an enzyme, an RNase, a recombinant RNase and a radionuclide. 
     
     
         11 . The method of  claim 10 , wherein said second antibody, second antibody fragment or immunoconjugate is reactive with a B-cell or T-cell antigen other than CD74. 
     
     
         12 . The method of  claim 11 , wherein said antigen is selected from the group consisting of CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD80, CD126, B7, MUC1, Ia, HM1.24, tenascin and mature HLA-DR dimer. 
     
     
         13 . The method of  claim 12 , wherein said antigen is CD19, CD20 or CD22. 
     
     
         14 . The method of  claim 10 , wherein the drug 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 antimitotic agent, an antiangiogenic agent, an apoptotic agent, 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. 
     
     
         15 . The method of  claim 10 , wherein the drug is selected from the group consisting of doxorubicin, methotrexate, taxol, CPT-11, cyclophosphamide, etoposide, carmustine, vincristine, procarbazine, prednisone, bleomycin, leucovorin, phenyl butyrate, bryostatin-1 and dexamethasone. 
     
     
         16 . The method of  claim 10 , wherein the toxin is selected from the group consisting of ricin, abrin, ribonuclease (RNase), DNase I,  Staphylococcal  enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin,  Pseudomonas  exotoxin and  Pseudomonas  endotoxin. 
     
     
         17 . The method of  claim 10 , wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor, an interferon (IFN), an interleukin (IL) a tumor necrosis factor (TNF). 
     
     
         18 . The method of  claim 17 , wherein the immunomodulator is selected from the group consisting of IFN-α, IFN-β, IFN-γ, erythropoietin, thrombopoietin, IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, IL-21, TNF-α, TNF-β, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) and the stem cell growth factor designated “S1 factor”. 
     
     
         19 . The method of  claim 6 , wherein the radionuclide is selected from the group consisting of  225 Ac,  18 F,  68 Ga,  67 Ga,  90 Y,  86 Y,  111 In,  131 I,  125 I,  123 I,  99m Tc,  94m Tc,  186 Re,  188 re,  177 Lu,  62 Cu,  64 Cu,  67 Cu,  212 Bi,  213 Bi,  32 P,  11 C,  13 N,  15 O,  76 Br and  211 At. 
     
     
         20 . The method of  claim 1 , wherein said cancer is selected from the group consisting of a solid tumor, non-Hodgkin's lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, a B-cell malignancy and a T-cell malignancy. 
     
     
         21 . The method of  claim 20 , wherein said solid tumor is selected from the group consisting of melanoma, carcinoma and sarcoma. 
     
     
         22 . The method of  claim 21 , wherein said solid tumor is selected from the group consisting of renal cancer, lung cancer, breast cancer, bladder cancer, pancreatic cancer, prostate cancer, intestinal cancer, stomach cancer, gastrointestinal cancer, melanoma and glioma. 
     
     
         23 . The method of  claim 20 , wherein said B-cell malignancy is selected from the group consisting of non-Hodgkin's lymphoma, Hodgkin's lymphoma, indolent forms of B-cell lymphomas, aggressive forms of B-cell lymphomas, B-cell leukemias, chronic lymphocytic leukemia, acute lymphocytic leukemia, dendritic cell leukemia and multiple myeloma. 
     
     
         24 . The method of  claim 1 , wherein said naked anti-CD74 antibody or fragment thereof is administered intravenously, intramuscularly, subcutaneously or parenterally. 
     
     
         25 . The method of  claim 1 , wherein said naked anti-CD74 antibody or fragment thereof is a chimeric or humanized antibody or fragment thereof comprising the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:19), CDR2 (TVSNRFS; SEQ ID NO:20), and CDR3 (SQSSHVPPT; SEQ ID NO:21) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:22), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:23), and CDR3 (SRGKNEAWFAY; SEQ ID NO:24). 
     
     
         26 . The method of  claim 1 , wherein said naked anti-CD74 antibody or fragment thereof competes for binding to CD74 with a monoclonal LL1 antibody comprising the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:19), CDR2 (TVSNRFS; SEQ ID NO:20), and CDR3 (SQSSHVPPT; SEQ ID NO:21) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:22), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:23), and CDR3 (SRGKNEAWFAY; SEQ ID NO:24). 
     
     
         27 . A method for treating a cancer that expresses CD74, comprising administering to a subject at least one first immunoconjugate comprising a humanized, human or chimeric anti-CD74 antibody or antigen-binding fragment thereof conjugated to a therapeutic agent, wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, a second immunoconjugate, a fusion protein, a drug, an antisense oligonucleotide, a boron compound, an immunomodulator, a hormone and an enzyme. 
     
     
         28 . The method of  claim 27 , wherein said second antibody, second antibody fragment or second immunoconjugate is reactive with a B-cell or T-cell antigen other than CD74. 
     
     
         29 . The method of  claim 28 , wherein said antigen is selected from the group consisting of CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD80, CD126, B7, MUC1, Ia, HM1.24, tenascin and mature HLA-DR dimer. 
     
     
         30 . The method of  claim 29 , wherein said antigen is CD19, CD20 or CD22. 
     
     
         31 . The method of  claim 27 , wherein the drug 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 antimitotic agent, an antiangiogenic agent, an apoptotic agent, 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. 
     
     
         32 . The method of  claim 27 , wherein the drug is selected from the group consisting of doxorubicin, methotrexate, taxol, CPT-11, cyclophosphamide, etoposide, carmustine, vincristine, procarbazine, prednisone, bleomycin, leucovorin, phenyl butyrate, bryostatin-1 and dexamethasone. 
     
     
         33 . The method of  claim 27 , wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor, an interferon (IFN), an interleukin (IL) a tumor necrosis factor (TNF). 
     
     
         34 . The method of  claim 27 , wherein the immunomodulator is selected from the group consisting of IFN-α, IFN-β, IFN-γ, erythropoietin, thrombopoietin, IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, IL-21, TNF-α, TNF-β, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) and the stem cell growth factor designated “S1 factor”. 
     
     
         35 . The method of  claim 27 , wherein the anti-CD74 antibody or fragment thereof is rapidly internalized. 
     
     
         36 . The method of  claim 35 , wherein 8×10 6  antibody molecules per cell per day are internalized. 
     
     
         37 . The method of  claim 35 , wherein 70% of anti-CD74 antibody bound to the surface of Raji cells is internalized and catabolized within three hours. 
     
     
         38 . The method of  claim 27 , further comprising administering to the subject at least one other therapeutic agent. 
     
     
         39 . The method of  claim 27 , wherein said cancer is selected from the group consisting of a solid tumor, non-Hodgkin's lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, a B-cell malignancy and a T-cell malignancy. 
     
     
         40 . The method of  claim 39 , wherein said solid tumor is selected from the group consisting of melanoma, carcinoma and sarcoma. 
     
     
         41 . The method of  claim 40 , wherein said solid tumor is selected from the group consisting of renal cancer, lung cancer, breast cancer, bladder cancer, pancreatic cancer, prostate cancer, intestinal cancer, stomach cancer, gastrointestinal cancer, melanoma and glioma. 
     
     
         42 . The method of  claim 39 , wherein said B-cell malignancy is selected from the group consisting of non-Hodgkin's lymphoma, Hodgkin's lymphoma, indolent forms of B-cell lymphomas, aggressive forms of B-cell lymphomas, B-cell leukemias, chronic lymphocytic leukemia, acute lymphocytic leukemia, dendritic cell leukemia and multiple myeloma. 
     
     
         43 . The method of  claim 27 , wherein said first immunoconjugate is administered intravenously, intramuscularly, subcutaneously or parenterally. 
     
     
         44 . The method of  claim 27 , wherein said anti-CD74 antibody or fragment thereof is a chimeric or humanized antibody or fragment thereof comprising the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:19), CDR2 (TVSNRFS; SEQ ID NO:20), and CDR3 (SQSSHVPPT; SEQ ID NO:21) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:22), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:23), and CDR3 (SRGKNEAWFAY; SEQ ID NO:24). 
     
     
         45 . The method of  claim 27 , wherein said anti-CD74 antibody or fragment thereof competes for binding to CD74 with a monoclonal LL1 antibody comprising the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:19), CDR2 (TVSNRFS; SEQ ID NO:20), and CDR3 (SQSSHVPPT; SEQ ID NO:21) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:22), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:23), and CDR3 (SRGKNEAWFAY; SEQ ID NO:24).