Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells

Abstract

A chimeric LL2 monoclonal antibody is described in which the complementarity determining regions (CDRs) of the light and heavy chains of the murine LL2 anti-B-lymphoma, anti-leukemia cell monoclonal antibody has been recombinantly joined to the human kappa and IgG 1 constant region domains, respectively, which retains the immunospecificity and B-cell lymphoma and leukemia cell internalization capacity of the parental murine LL2 monoclonal antibody, and which has the potential of exhibiting reduced human anti-mouse antibody production activity. A humanized LL2 monoclonal antibody is described in which the CDRs of the light and heavy chains have been recombinantly joined to a framework sequence of human light and heavy chains variable regions, respectively, and subsequently linked to human kappa and IgG 1 constant region domains, respectively, which retains the immunospecificity and B-lymphoma and leukemia cell internalization capacities of the parental murine and chimeric LL2 monoclonal antibodies, and which has the potential for exhibiting reduced human anti-mouse antibody production activity. Vectors for producing recombinant chimeric and humanized chimeric monoclonal antibodies are provided. Isolated DNAs encoding the amino acid sequences of the LL2 variable light and heavy chain and CDR framework regions are described. Conjugates of chimeric and humanized chimeric LL2 antibodies with cytotoxic agents or labels find use in therapy and diagnosis of B-cell lymphomas and leukemias.

We claim:  
     
         1 . An immunoconjugate comprising an antibody or a fragment thereof specific for B-cells which is conjugated to Y-90 through a DTPA chelating agent.  
     
     
         2 . The immunoconjugate of  claim 1 , wherein the DTPA chelating agent is aminohexyl DTPA.  
     
     
         3 . The immunoconjugate of  claim 1 , wherein at least 47.3% of Y-90 is chelated.  
     
     
         4 . The immunoconjugate of  claim 1 , wherein the immunoconjugate is internalizing.  
     
     
         5 . The immunoconjugate of  claim 4 , wherein conjugation through the DPTA chelating agent to Y-90 does not reduce binding to B-cells or internalization function relative to the unconjugated antibody.  
     
     
         6 . A method of treating B-cell lymphoma and lymphocytic leukemia comprising administering an immunoconjugate as claimed in  claim 1  to a subject suffering from B-cell lymphoma or lymphocytic leukemia.  
     
     
         7 . A method of treating B-cell lymphoma and lymphocytic leukemia comprising administering an immunoconjugate as claimed in  claim 2  to a subject suffering from B-cell lymphoma or lymphocytic leukemia.  
     
     
         8 . A method of treating B-cell lymphoma and lymphocytic leukemia comprising administering an immunoconjugate as claimed in  claim 3  to a subject suffering from B-cell lymphoma or lymphocytic leukemia.  
     
     
         9 . A method of treating B-cell lymphoma and lymphocytic leukemia comprising administering an immunoconjugate as claimed in  claim 4  to a subject suffering from B-cell lymphoma or lymphocytic leukemia.  
     
     
         10 . A method of treating B-cell lymphoma and lymphocytic leukemia comprising administering an immunoconjugate as claimed in  claim 5  to a subject suffering from B-cell lymphoma or lymphocytic leukemia.