Bi-Specific Monovalent Diabodies That are Capable of Binding CD19 and CD3, and Uses Thereof

Abstract

CD19×CD3 bi-specific monovalent diabodies, and particularly, CD19×CD3 bi-specific monovalent Fc diabodies, are capable of simultaneous binding to CD19 and CD3, and are used in the treatment of hematologic malignancies.

1 - 17 . (canceled) 
     
     
         18 . A method of treating a hematologic malignancy associated in a subject in need thereof, said method comprising administering to said subject a covalently associated polypeptide complex, wherein said polypeptide complex comprises a first polypeptide chain and a second polypeptide chain, wherein:
 a) said first polypeptide chain comprises a polypeptide having the amino acid sequence of SEQ ID NO:2 linked to a charged helical domain having the amino acid sequence of SEQ ID NO:12; and   b) said second polypeptide chain comprises a polypeptide having the amino acid sequence of SEQ ID NO:2 linked to a charged helical domain having the amino acid sequence of SEQ ID NO:13;   
       wherein said charged helical domain of said first polypeptide chain and said charged helical domain of said second polypeptide chain are covalently bonded to one another via a disulfide bond. 
     
     
         19 . The method of  claim 18 , wherein the first polypeptide chain further comprises a VH domain of a monoclonal antibody capable of binding to CD3 (VH CD3 ) and the second polypeptide chain further comprises a VL domain of a monoclonal antibody capable of binding to CD3 (VL CD3 ). 
     
     
         20 . The method of  claim 19 , wherein the VL CD3  has the amino acid sequence of SEQ ID NO:25 and the VH CD3  has the amino acid sequence of SEQ ID NO:29. 
     
     
         21 . The method of  claim 18 , wherein the covalently associated polypeptide complex is administered to the subject at a dose of about 0.2 μg/kg, about 2 μg/kg, about 5 μg/kg or about 10 μg/kg. 
     
     
         22 . The method of  claim 18 , wherein the covalently associated polypeptide is administered once weekly. 
     
     
         23 . The method of  claim 18 , wherein the covalently associated polypeptide is administered once weekly for a period of four weeks. 
     
     
         24 . The method of  claim 18 , wherein the covalently associated polypeptide complex is administered to the subject at a dose of about 0.2 μg/kg, about 2 μg/kg, about 5 μg/kg or about 10 μg/kg once weekly for a period of four weeks. 
     
     
         25 . The method of  claim 18 , wherein the covalently associated polypeptide complex is administered to the subject at a dose of about 0.2 μg/kg once weekly for a period of four weeks. 
     
     
         26 . The method of  claim 18 , wherein the covalently associated polypeptide complex is administered to the subject at a dose of about 2 μg/kg once weekly for a period of four weeks. 
     
     
         27 . The method of  claim 18 , wherein the covalently associated polypeptide complex is administered to the subject at a dose of about 5 μg/kg once weekly for a period of four weeks. 
     
     
         28 . The method of  claim 18 , wherein the covalently associated polypeptide complex is administered to the subject at a dose of about 10 μg/kg once weekly for a period of four weeks. 
     
     
         29 . The method of  claim 18 , wherein the first polypeptide chain further comprises a VH domain of a monoclonal antibody capable of binding to CD19 (VH CD19 ) and the second polypeptide chain further comprises a VL domain of a monoclonal antibody capable of binding to CD19 (VL CD19 ). 
     
     
         30 . The method of  claim 18 , wherein the VL CD19  has the amino acid sequence of SEQ ID NO:17 and the VH CD19  has the amino acid sequence of SEQ ID NO:21. 
     
     
         31 . The method of  claim 18 , wherein said hematologic malignancy is selected from the group consisting of: acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), blastic crisis of CML, Abelson oncogene associated with CIVIL (Bcr-ABL translocation), myelodysplastic syndrome (MDS), acute B lymphoblastic leukemia (B-ALL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL), Richter's syndrome, Richter's transformation of CLL, hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), non-Hodgkin lymphomas (NHL), mantel cell leukemia (MCL), small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma. 
     
     
         32 . The method of  claim 18 , wherein the covalently associated polypeptide comprises a monovalent CD3 binding domain and a monovalent CD19 binding domain. 
     
     
         33 . The method of  claim 32 , wherein said monovalent CD19 binding domain cross-reacts with both human and primate CD19, and said monovalent CD3 binding domain cross-reacts with both human and primate CD3.