Anti-cd19 antibodies and uses in b cell disorders

Abstract

The invention relates to immunotherapeutic compositions and methods for the treatment of B cell diseases and disorders in human subjects, such as, but not limited to, B cell malignancies and autoimmune diseases and disorders, using therapeutic antibodies that bind to the human CD19 antigen and that preferably mediate human ADCC. The present invention relates to pharmaceutical compositions comprising human or humanized anti-CD19 antibodies of the IgG1 or IgG3 human isotype. The present invention relates to pharmaceutical compositions comprising human or humanized anti-CD19 antibodies of the IgG2 or IgG4 human isotype that preferably mediate human ADCC. The present invention also relates to pharmaceutical compositions comprising chimerized anti-CD19 antibodies of the IgG1, IgG2, IgG3, or IgG4 isotype that mediate human ADCC. In preferred embodiments, the present invention relates to pharmaceutical compositions comprising monoclonal human, humanized, or chimeric anti-CD19 antibodies.

1 - 21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a monoclonal chimerized, human or humanized anti CD19 antibody comprising a sequence having at least 90% identity to amino acids 33 to 37, a sequence having at least 90% identity to amino acids 51 to 68 and a sequence having at least 90% identity to amino acids 101 to 115 of SEQ ID NO:2 and a sequence having at least 85% identity to amino acids amino acids 43 to 58, a sequence having at least 85% identity to amino acids 74 to 80 and a sequence having at least 85% identity to amino acids 113 to 121 of SEQ ID NO:16, or a sequence having at least 90% identity to amino acids 33 to 37, a sequence having at least 90% identity to amino acids 51 to 68 and a sequence having at least 90% identity to amino acids 101 to 114 of SEQ ID NO:4 and a sequence having at least 85% identity to amino acids 44 to 58, a sequence having at least 85% identity to amino acids 74 to 80 and a sequence having at least 85% identity to amino acids 113-121 of SEQ ID NO:18 that (a) is of the IgG1 or IgG3 human isotype, or (b) mediates human antibody-dependent cellular cytotoxicity (ADCC), in a pharmaceutically acceptable carrier. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein a therapeutically effective amount of the monoclonal chimerized anti-CD19 antibody of the IgG1 or IgG3 human isotype is less than about 1 mg/kg of patient body weight. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein a therapeutically effective amount of a monoclonal chimerized anti-CD19 antibody of the IgG1 or IgG3 human isotype is greater than about 2 mg/kg of patient body weight. 
     
     
         25 . The composition of  claim 22 , wherein the anti-CD19 antibody that mediates ADCC is of the IgG1, IgG2, IgG3, or IgG4 human isotype. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein the anti-CD19 antibody has a half-life of at least 4 to 7 days. 
     
     
         27 . The pharmaceutical composition of  claim 22 , wherein the anti-CD19 antibody is detectably labeled, is a naked antibody, is conjugated to a therapeutic compound, is conjugated to a cytotoxic agent, or is conjugated to a diagnostic agent. 
     
     
         28 . The pharmaceutical composition of  claim 22 , wherein the anti-CD19 antibody is bispecific. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the bispecific anti-CD19 antibody has specificity for binding effector cells. 
     
     
         30 . The pharmaceutical composition of  claim 22 , wherein the ADCC function of the anti-CD19 antibody is assessed by measuring the ability of the anti-CD19 antibody to mediate target cell lysis by effector cells in vitro. 
     
     
         31 . The pharmaceutical composition of  claim 22 , wherein the anti-CD19 antibody comprises a heavy chain consisting of a sequence having at least 90% identity to SEQ ID NO:2 or SEQ ID NO:4. 
     
     
         32 . The pharmaceutical composition of  claim 22 , wherein the anti-CD19 antibody comprises the light chain consisting of a sequence having at least 95% amino acid sequence identity to SEQ ID NO:16 or SEQ ID NO:18. 
     
     
         33 . A method of treating a B cell malignancy in a human patient comprising; administering a therapeutically effective regimen of a monoclonal human or humanized anti-CD19 antibody, wherein said antibody comprises a sequence having at least 90% identity to amino acids 33 to 37, a sequence having at least 90% identity to amino acids 51 to 68 and a sequence having at least 90% identity to amino acids 101 to 115 of SEQ ID NO:2 and a sequence having at least 85% identity to amino acids amino acids 43 to 58, a sequence having at least 85% identity to amino acids 74 to 80 and a sequence having at least 85% identity to amino acids 113 to 121 of SEQ ID NO:16, or a sequence having at least 90% identity to amino acids 33 to 37, a sequence having at least 90% identity to amino acids 51 to 68 and a sequence having at least 90% identity to amino acids 101 to 114 of SEQ ID NO:4 and a sequence having at least 85% identity to amino acids 44 to 58, a sequence having at least 85% identity to amino acids 74 to 80 and a sequence having at least 85% identity to amino acids 113-121 of SEQ ID NO:18 that (a) is of the IgG1 or IgG3 human isotype, or (b) mediates human antibody-dependent cellular cytotoxicity (ADCC), in a pharmaceutically acceptable carrier. 
     
     
         34 . The method accordingly to  claim 33 , wherein the anti-CD19 antibody comprises a heavy chain consisting of a sequence having at least 90% identity to SEQ ID NO:2 or SEQ ID NO:4. 
     
     
         35 . The method accordingly to  claim 33 , wherein the antibody comprises the light chain consisting of a sequence having at least 95% identity to SEQ ID NO:16 or SEQ ID NO:18. 
     
     
         36 . The method accordingly to  claim 33 , wherein the antibody is able to deplete circulating B cells. 
     
     
         37 . The method accordingly to  claim 33 , wherein the antibody is able to deplete bone marrow B cells. 
     
     
         38 . The method accordingly to  claim 33 , wherein the B cell malignancy is acute lymphoblastic leukaemia, mantle cell lymphoma, pre-B cell acute lymphoblastic leukaemia, or precursor B cell lymphoblastic lymphoma. 
     
     
         39 . The method accordingly to  claim 33 , wherein the anti-CD19 antibody that mediates ADCC is of the IgG1, IgG2, IgG3, or IgG4 human isotype. 
     
     
         40 . The method accordingly to  claim 33 , wherein the B cell malignancy is treated prior to the administration of the anti-CD19 antibody. 
     
     
         41 . The method accordingly to  claim 33 , wherein the B cell malignancy is treated with a therapy other than an anti-CD19 antibody therapy subsequent to the administration of the anti-CD19 antibody. 
     
     
         42 . The method accordingly to  claim 33 , wherein the treatment for the malignancy is chemotherapy, radioimmunotherapy, toxin therapy, prodrug-activating enzyme therapy, antibody therapy, monocyte or macrophage enhancing therapy, immunoregulatory therapy, tumor neovasculature (statin) therapy, calicheamicin therapy, surgical therapy, or any combination thereof.