Immunotherapy of b cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins

Abstract

The invention is directed to a method for treating a treating and diagnosing a B cell-related disease, T cell-related disease or an autoimmune disease in a mammal by concurrently or sequentially administering to the mammal a therapeutic composition that comprises a pharmaceutically acceptable vehicle and at least one conjugated antibody, wherein predosing with a non-radiolabeled antibody is not performed.

1 . A combination comprising either
 (i) a conjugated anti-CD74 antibody or antigen-binding fragment thereof and an unconjugated anti-CD20 antibody or antigen-fragment thereof, or   (ii) a conjugated anti-CD20 antibody or antigen-binding fragment thereof and an unconjugated anti-CD74 antibody or antigen binding fragment thereof.   
   
   
       2 . The combination of  claim 1 , wherein the conjugated anti-CD20 antibody or anti-CD20 antibody antigen-binding fragment thereof is a humanized A20 (hA20) antibody or antibody antigen-binding fragment thereof. 
   
   
       3 . The combination of  claim 1 , wherein the conjugated antibody or antibody fragment and the unconjugated antibody or antibody fragment form a fusion protein. 
   
   
       4 . The combination of  claim 1 , wherein the conjugated antibody or antibody fragment and the unconjugated antibody or antibody fragment form a bispecific antibody. 
   
   
       5 . The combination of  claim 1 , wherein said conjugated and unconjugated antibody or antibody antigen-binding fragment thereof is a human or humanized antibody or antigen-binding fragment thereof. 
   
   
       6 . The combination of  claim 1 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to a therapeutic agent selected from the group consisting of a drug, a toxin, an immunomodulator, a chelator, a boron compound, a photoactive agent, and a radionuclide. 
   
   
       7 . The combination of  claim 1 , wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to 90Y-DOTA. 
   
   
       8 . The combination of  claim 1 , wherein the conjugated or unconjugated antibody or antibody antigen-binding fragment is an antibody fragment selected from the group consisting of F(ab) 2 , Fab, Fv, sFv, scFv and diabody. 
   
   
       9 . The combination of  claim 6 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to a drug which possesses the pharmaceutical property selected from the group consisting of an antimitotic agent, an alkylating agent, an antimetabolite agent, an antiangiogenic agent, an apoptotic agent, an alkaloid agent, an antibiotic and combinations thereof. 
   
   
       10 . The combination of  claim 9 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to a drug is selected from the group consisting of a nitrogen mustard, an ethylenimine, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, an anthracycline, a taxane, a COX-2 inhibitor, a pyrimidine analog, a purine analog, an antibiotic, an enzyme, an epipodophyllotoxin, a platinum coordination complex, a vinca alkaloid, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, an endostatin, a taxol, a camptothecin, a doxorubicin, and a combination thereof. 
   
   
       11 . The combination of  claim 6 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to a drug is selected from the group consisting of cyclophosphamide, etoposide, vincristine, procarbazine, prednisone, carmustine, doxorubicin, methotrexate, bleomycin, dexamethasone, phenyl butyrate, bryostatin-1, and leucovorin. 
   
   
       12 . The combination of  claim 6 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to a toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin,  Pseudomonas  exotoxin, and  Pseudomonas  endotoxin. 
   
   
       13 . The combination of  claim 6 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to an immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic growth factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin and a combination thereof. 
   
   
       14 . The combination of  claim 6 , wherein said conjugated antibody or antibody antigen-binding fragment thereof is conjugated to an immunomodulator selected from the group consisting of IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, G-CSF, GM-CSF, interferon-α, -β or -γ, TNF-α and “S1 factor”. 
   
   
       15 . The combination of  claim 6 , wherein said radionuclide is bound to said chelator is selected from the group consisting of DTPA, DOTA, TETA or NOTA. 
   
   
       16 . The combination of  claim 6 , wherein said therapeutic agent is selected from the group consisting of tumor necrosis factor, a hematopoietic growth factor, colony stimulating factor, interferon, and stem cell growth factor. 
   
   
       17 . The combination of  claim 6 , wherein said therapeutic agent is a radionuclide. 
   
   
       18 . The combination of  claim 6 , wherein said therapeutic agent is used in photodynamic therapy or neutron capture procedures. 
   
   
       19 . A method for treating an autoimmune disease, comprising administering to a human a therapeutic combination comprising:
 (a) a pharmaceutically acceptable vehicle containing a conjugated anti-CD74 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable vehicle containing an unconjugated anti-CD20 antibody or antigen-binding fragment thereof, or   (b) a pharmaceutically acceptable vehicle containing a conjugated anti-CD20 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable vehicle containing an unconjugated anti-CD74 antibody or antigen binding fragment thereof,   
     wherein said conjugated and unconjugated antibody or fragment thereof in (a) or (b) are administered concurrently or sequentially. 
   
   
       20 . A method according to  claim 19 , wherein said autoimmune disease is selected from the group consisting of acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, 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, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis ubiterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, psoriasis, and fibrosing alveolitis.