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 an immune system disease, comprising administering to a subject with an immune system disease a therapeutic composition comprising at least one humanized, human or chimeric anti-CD74 antibody or antigen-binding fragment thereof or a fusion protein comprising a humanized, human or chimeric anti-CD74 antibody or antigen-binding fragment thereof. 
     
     
         2 . The method of  claim 1 , wherein said anti-CD74 antibody or fragment thereof or fusion protein is a naked antibody or fragment or fusion protein. 
     
     
         3 . The method of  claim 2 , wherein administering said naked anti-CD74 antibody or fragment thereof or fusion protein is effective to treat the immune system disease. 
     
     
         4 . The method of  claim 3 , wherein administering said naked anti-CD74 antibody or fragment thereof or fusion protein is effective to treat the immune system disease in the absence of any other administered antibody, antibody fragment or fusion protein. 
     
     
         5 . The method of  claim 2 , wherein the naked anti-CD74 antibody or fragment thereof or fusion protein is administered before, during or after the administration of at least one therapeutic agent used to treat the immune system disease. 
     
     
         6 . The method of  claim 5 , wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, a second 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, a radionuclide and an immunoconjugate. 
     
     
         7 . The method of  claim 1 , wherein said anti-CD74 antibody or fragment thereof or fusion protein is conjugated to at least one therapeutic agent. 
     
     
         8 . The method of  claim 7 , wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, a second 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, a radionuclide and an immunoconjugate. 
     
     
         9 . The method of  claim 8 , wherein the drug is selected from the group consisting of a vinca alkaloid, an anthracycline, an epidophyllotoxin, a taxane, an antimetabolite, an alkylating agent, an antibiotic, a COX-2 inhibitor, an antimitotic agent, an antiangiogenic agent, an apoptotoic agent, doxorubicin, methotrexate, taxol, CPT-11, a camptothecan, nitrogen mustard, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a pyrimidine analog, a purine analog and a platinum coordination complex. 
     
     
         10 . The method of  claim 9 , wherein the drug is doxorubicin. 
     
     
         11 . The method of  claim 8 , 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. 
     
     
         12 . The method of  claim 8 , 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), IFN-α, IFN-β, IFN-γ, erythropoietin, thrombopoietin, interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, IL-21, a tumor necrosis factor, granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). 
     
     
         13 . The method of  claim 8 , 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, 67Cu,  212 Bi,  213 Bi,  32 P,  11 C,  13 N,  15 O,  76 Br and  211 At. 
     
     
         14 . The method of  claim 8 , wherein said second antibody, second antibody fragment or second fusion protein is reactive with a B-cell or T-cell antigen other than CD74. 
     
     
         15 . The method of  claim 14 , 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. 
     
     
         16 . The method of  claim 1 , wherein said immune system disease is selected from the group consisting of an immune dysregulation disease, an autoimmune disease, a Class III autoimmune disease, organ graft rejection and graft versus host disease. 
     
     
         17 . The method of  claim 1 , wherein said antibody or fragment thereof or antibody fusion protein is administered intravenously, intramuscularly, subcutaneously or parenterally. 
     
     
         18 . The method of  claim 16 , wherein the autoimmune disease is selected from the group consisting of immune-mediated thrombocytopenia, acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sjogren's syndrome, multiple sclerosis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis obliterans, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pamphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis and fibrosing alveolitis. 
     
     
         19 . The method of  claim 1 , wherein the anti-CD74 antibody or fragment thereof or fusion protein is a chimeric or humanized 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). 
     
     
         20 . A method of delivering a therapeutic or diagnostic agent to a subject with an immune system disease comprising administering to a subject with an immune system disease an immunoconjugate comprising at least one humanized, human or chimeric anti-CD74 antibody or antigen-binding fragment thereof or a fusion protein comprising a humanized, human or chimeric anti-CD74 antibody or antigen-binding fragment thereof, wherein the immunoconjugate comprises at least one therapeutic or diagnostic agent. 
     
     
         21 . The method of  claim 20 , wherein the anti-CD74 antibody or fragment thereof or fusion protein is a chimeric or humanized 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). 
     
     
         22 . The method of  claim 20 , wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, a second 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, a radionuclide and an immunoconjugate. 
     
     
         23 . A method of delivering a therapeutic or diagnostic agent to a subject with an immune system disease comprising:
 a) administering to a subject with an immune system disease a bispecific or multispecific antibody comprising at least one anti-CD74 antibody or antigen-binding fragment thereof and at least one antibody or antibody fragment that binds to a hapten; and   b) administering to the subject a targetable conjugate comprising one or more copies of the hapten, wherein the targetable conjugate is attached to at least one therapeutic or diagnostic agent.   
     
     
         24 . The method of  claim 23 , wherein the anti-CD74 antibody or fragment thereof or fusion protein is a chimeric or humanized 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). 
     
     
         25 . The method of  claim 23 , wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, a second 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, a radionuclide and an immunoconjugate.