Human Monoclonal Antibodies Against CD20

Abstract

Isolated human monoclonal antibodies which bind to and inhibit human CD20, and related antibody-based compositions and molecules, are disclosed. The human antibodies can be produced by a transfectoma or in a non-human transgenic animal, e.g., a transgenic mouse, capable of producing multiple isotypes of human monoclonal antibodies by undergoing V-D-J recombination and isotype switching. Also disclosed are pharmaceutical compositions comprising the human antibodies, non-human transgenic animals and hybridomas which produce the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.

1 - 102 . (canceled) 
     
     
         103 . A method of treating or preventing an autoimmune disease in a subject, comprising administering to the subject an isolated human monoclonal anti-CD20 antibody or an antigen-binding fragment thereof in an amount effective to treat or prevent the autoimmune disease,
 wherein the antibody or antigen-binding fragment binds to human CD20 and comprises a heavy chain variable region (V H ) comprising CDRs 1-3 and a light chain variable region (V L ) comprising CDRs 1-3, wherein:   (i) the V H  CDR1 amino acid sequence comprises the sequence of SEQ ID NO: 13; the V H  CDR2 amino acid sequence comprises the sequence of SEQ ID NO: 14; the V H  CDR3 amino acid sequence comprises the sequence of SEQ ID NO: 15; the V L  CDR1 amino acid sequence comprises the sequence of SEQ ID NO: 16; the V L  CDR2 amino acid sequence comprises the sequence of SEQ ID NO: 17; and the V L  CDR3 amino acid sequence comprises the sequence of SEQ ID NO: 18;   (ii) the V H  CDR1 amino acid sequence comprises the sequence of SEQ ID NO: 19; the V H  CDR2 amino acid sequence comprises the sequence of SEQ ID NO: 20; the V H  CDR3 amino acid sequence comprises the sequence of SEQ ID NO: 21; the V L  CDR1 amino acid sequence comprises the sequence of SEQ ID NO: 22; the V L  CDR2 amino acid sequence comprises the sequence of SEQ ID NO: 23; and the V L  CDR3 amino acid sequence comprises the sequence of SEQ ID NO: 24; or   (iii) the V H  CDR1 amino acid sequence comprises the sequence of SEQ ID NO: 25; the V H  CDR2 amino acid sequence comprises the sequence of SEQ ID NO: 26; the V H  CDR3 amino acid sequence comprises the sequence of SEQ ID NO: 27; the V L  CDR1 amino acid sequence comprises the sequence of SEQ ID NO: 28; the V L  CDR2 amino acid sequence comprises the sequence of SEQ ID NO: 29; and the V L  CDR3 amino acid sequence comprises the sequence of SEQ ID NO: 30.   
     
     
         104 . The method of  claim 103 , wherein the antibody or antigen-binding fragment comprises:
 (i) a V H  amino acid sequence comprising the sequence of SEQ ID NO: 2; and a V L  amino acid sequence comprising the sequence of SEQ ID NO: 4;   (ii) a V H  amino acid sequence comprising the sequence of SEQ ID NO: 6; and a V L  amino acid sequence comprising the sequence of SEQ ID NO: 8; or   (iii) a V H  amino acid sequence comprising the sequence of SEQ ID NO: 10; and a V L  amino acid sequence comprising the sequence of SEQ ID NO: 12.   
     
     
         105 . The method of  claim 103 , wherein the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant region. 
     
     
         106 . The method of  claim 103 , wherein the antibody or antigen-binding fragment comprises an Ig kappa light chain constant region. 
     
     
         107 . The method of  claim 103 , wherein the antibody or antigen-binding fragment comprises a V H  CDR1 amino acid sequence comprising the sequence of SEQ ID NO: 13; a V H  CDR2 amino acid sequence comprising the sequence of SEQ ID NO: 14; a V H  CDR3 amino acid sequence comprising the sequence of SEQ ID NO: 15; a V L  CDR1 amino acid sequence comprising the sequence of SEQ ID NO: 16; a V L  CDR2 amino acid sequence comprising the sequence of SEQ ID NO: 17; and a V L  CDR3 amino acid sequence comprising the sequence of SEQ ID NO: 18. 
     
     
         108 . The method of  claim 107 , wherein the antibody or antigen-binding fragment comprises a V H  amino acid sequence comprising the sequence of SEQ ID NO: 2; and a V L  amino acid sequence comprising the sequence of SEQ ID NO: 4. 
     
     
         109 . The method of  claim 107 , wherein the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant region and an Ig kappa light chain constant region. 
     
     
         110 . The method of  claim 103 , wherein the antibody or antigen-binding fragment is an intact antibody. 
     
     
         111 . The method of  claim 110 , wherein the antibody or antigen-binding fragment is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, an IgG4 antibody, an IgM antibody, an IgA1 antibody, an IgA2 antibody, a secretory IgA antibody, an IgD antibody, or an IgE antibody. 
     
     
         112 . The method of  claim 103 , wherein the antibody or antigen-binding fragment is an antibody fragment or a single chain antibody. 
     
     
         113 . The method of  claim 103 , wherein the antibody or antigen-binding fragment is linked to an additional therapeutic agent. 
     
     
         114 . The method of  claim 113 , wherein the additional therapeutic agent is an anti-inflammatory agent or an immunosuppressive agent. 
     
     
         115 . The method of  claim 103 , wherein the antibody or antigen-binding fragment is present in a bispecific molecule, wherein the bispecific molecule has binding specificity for human CD20 and for a human effector cell. 
     
     
         116 . The method of  claim 115 , wherein the bispecific molecule has binding specificity for human CD20 and for a human Fc receptor or a T cell receptor. 
     
     
         117 . The method of  claim 103 , wherein treatment comprises killing B cells which express CD20. 
     
     
         118 . The method of  claim 103 , wherein treatment comprises killing B cells which produce antibodies against autoantigens. 
     
     
         119 . The method of  claim 103 , wherein the autoimmune disease is multiple sclerosis, psoriasis, psoriatic arthritis, dermatitis, systemic scleroderma, systemic sclerosis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, glomerulonephritis, eczema, asthma, atherosclerosis, leukocyte adhesion deficiency, Raynaud's syndrome, Sjögren's syndrome, juvenile onset diabetes, Reiter's disease, Behçet's disease, immune complex nephritis, IgA nephropathy, IgM polyneuropathy, immune-mediated thrombocytopenia, hemolytic anemia, myasthenia gravis, lupus nephritis, systemic lupus erythematosus, rheumatoid arthritis (RA), atopic dermatitis, pemphigus, Graves' disease, Hashimoto's thyroiditis, Wegener's granulomatosis, Omenn's syndrome, chronic renal failure, acute infectious mononucleosis, HIV, or a herpes virus associated disease. 
     
     
         120 . The method of  claim 103 , wherein the autoimmune disease is multiple sclerosis. 
     
     
         121 . The method of  claim 107 , wherein the autoimmune disease is an inflammatory disorder. 
     
     
         122 . The method of  claim 121 , wherein the autoimmune disease and/or inflammatory disorder is multiple sclerosis, systemic sclerosis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, juvenile onset diabetes, immune-mediated thrombocytopenia, hemolytic anemia, myasthenia gravis, rheumatoid arthritis (RA), or pemphigus vulgaris. 
     
     
         123 . The method of  claim 121 , wherein the autoimmune disease and/or inflammatory disorder is multiple sclerosis. 
     
     
         124 . The method of  claim 103 , wherein the antibody or antigen-binding fragment is administered with a pharmaceutically acceptable carrier. 
     
     
         125 . The method of  claim 103 , wherein the antibody or antigen-binding fragment is administered with an additional therapeutic agent. 
     
     
         126 . The method of  claim 125 , wherein the additional therapeutic agent is an anti-inflammatory agent or an immunosuppressive agent. 
     
     
         127 . The method of  claim 125 , wherein the additional therapeutic agent is a steroidal drug, a nonsteroidal anti-inflammatory drug (NSAID), a disease-modifying anti-rheumatic drug (DMARD), a pyrimidine synthesis inhibitor, an IL-1 receptor blocking agent, a TNF-α blocking agent, cyclosporine, or azathioprine. 
     
     
         128 . The method of  claim 125 , wherein the additional therapeutic agent is an anti-CD25 antibody, an anti-IL6R antibody, an anti-IL8 antibody, an anti-IL15 antibody, an anti-IL15R antibody, an anti-CD4 antibody, an anti-CD11a antibody, an anti-alpha-4/beta-1 integrin (VLA4) antibody, a CTLA4-Ig, an anti-C3b(i) antibody, a cytokine, or a chemokine.