Anthracycline-Antibody Conjugates for Cancer Therapy

Abstract

The invention relates to therapeutic conjugates with the ability to target various antigens. The conjugates contain a targeting antibody or antigen binding fragment thereof and an anthracycline chemotherapeutic drug. The targeting antibody and the chemotherapeutic drug are linked via a linker comprising a hydrazide moiety.

What is claimed is: 
     
         1 . A method of treating a CD74-expressing cancer, comprising administering to a human subject with a CD74-expressing cancer a conjugate of an anthracycline drug and a humanized anti-CD74 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof comprises human antibody framework (FR) and constant region sequences, wherein the humanized anti-CD74 antibody competes for binding to CD74 with an LL1 antibody comprising the light chain complementarity determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH, SEQ ID NO:1), CDR2 (TVSNRFS, SEQ ID NO:2) and CDR3 (SQSSHVPPT, SEQ ID NO:3) and heavy chain CDR1 (NYGVN, SEQ ID NO:4), CDR2 (WINPNTGEPTFDDDFKG, SEQ ID NO:5), and CDR3 (SRGKNEAWFAY, SEQ ID NO:6). 
     
     
         2 . The method of  claim 1 , wherein the humanized anti-CD74 antibody comprises one or more substituted FR residues selected from the group consisting of light chain variable region amino acid residues 2, 3, 4, 46, 87 and 100 of SEQ ID NO:11 and heavy chain variable region amino acid residues 5, 37, 38, 46, 68, 91 and 93 of SEQ ID NO:8. 
     
     
         3 . The method of  claim 2 , wherein the humanized anti-CD74 antibody comprises all of the light chain variable region amino acid residues 2, 3, 4, 46, 87 and 100 of SEQ ID NO:11 and heavy chain variable region amino acid residues 5, 37, 38, 46, 68, 91 and 93 of SEQ ID NO:8. 
     
     
         4 . The method of  claim 3 , wherein the humanized anti-CD74 antibody comprises the variable region amino acid sequences of SEQ ID NO:9 and SEQ ID NO:12. 
     
     
         5 . The method of  claim 1 , wherein the humanized antibody comprises human antibody constant region sequences selected from the group consisting of IgG1, IgG2, IgG3 and IgG4. 
     
     
         6 . The method of  claim 1 , wherein said anthracycline drug is selected from the group consisting of daunorubicin, doxorubicin, epirubicin, 2-pyrrolinodoxorubicin, morpholino-doxorubicin, and cyanomorpholino-doxorubicin. 
     
     
         7 . The method of  claim 6 , wherein said anthracycline drug is linked to the antibody through the 13-keto moiety. 
     
     
         8 . The method of  claim 1 , wherein the anthracycline drug is conjugated to the antibody or fragment thereof with 4-(N-maleimidomethyl)cyclohexane-1-carboxyl hydrazide. 
     
     
         9 . The method of  claim 1 , wherein the cancer is selected from the group consisting of B-cell lymphoma, B-cell leukemia, multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, colon cancer, pancreatic cancer and melanoma. 
     
     
         10 . The method of  claim 1 , further comprising administering a therapeutic agent selected from the group consisting of a second antibody, a second antibody fragment, a drug, a toxin, an enzyme, a hormone, an immunomodulator, an antisense oligonucleotide, a boron compound, a photoactive agent and a radioisotope. 
     
     
         11 . 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 and a colony stimulating factor. 
     
     
         12 . The method of  claim 11 , wherein the immunomodulator is selected from the group consisting of interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL18, IL-21), G-CSF, GM-CSF, interferon-α, interferon-β, interferon-γ, TNF-α, erythropoietin and thrombopoietin. 
     
     
         13 . The method of  claim 10 , wherein the second antibody or antibody fragment binds to a tumor-associated antigen selected from the group consisting of CD74, CD22, EGP-1 (Trop-2), EGP-2, CEACAM5, colon-specific antigen-p mucin (CSAp), carbonic anhydrase IX, HER-2/neu, CD19, CD20, CD21, CD23, CD25, CD30, CD33, CD37, CD40, CD45, CD66, NCA90, NCA95, CD80, alpha-fetoprotein (AFP), VEGF, EGF receptor, P1GF, MUC1, MUC2, MUC3, MUC4, MUC5ac, PSMA, HCG, HLA-D-DR, Ia, A3, A33, Ep-CAM, KS-1, Le(y), PSA, tenascin, folate receptor, Tn antigen, Thomas-Friedenreich antigens, tumor angiogenesis antigens, Ga 733, IL-2, and MAGE.