Non-antigenic toxin-conjugate and fusion protein of internalizing receptor system

Abstract

A conjugate of a toxin and a cytokine, and a fusion protein comprising a bispecific antibody that has a first specificity for a cell marker specific to a malignant cell and a second specificity for a region of IL-15α, each optionally further comprising a radionuclide, are useful therapeutic reagents for treating leukemias and lymphomas.

1 . A conjugate of a non-immunogenic toxin or therapeutic radionuclide and a cell-specific cytokine.  
     
     
         2 . A conjugate as claimed in  claim 1 , wherein said toxin is an RNase.  
     
     
         3 . A conjugate as claimed in  claim 1 , wherein said cytokine is IL-15.  
     
     
         4 . A conjugate as claimed in  claim 3 , wherein said toxin is onconase.  
     
     
         5 . A conjugate as claimed in  claim 4 , which additionally comprises a diagnostic radionuclide.  
     
     
         6 . A composition comprising a conjugate according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         7 . A composition as claimed in  claim 6 , additionally comprising a diagnostic radionuclide conjugated to said cytokine.  
     
     
         8 . A fusion protein comprising a bispecific antibody that has a first specificity for a cell marker specific to a malignant cell and a second specificity for a region of IL-15α.  
     
     
         9 . A fusion protein as claimed in  claim 8 , wherein said bispecific antibody is a scF v .  
     
     
         10 . A fusion protein as claimed in  claim 9 , wherein said scF v  is a fusion of two individual scF v  molecules.  
     
     
         11 . A fusion protein as claimed in  claim 8 , wherein said cell marker is a B-cell restricted antigen.  
     
     
         12 . A fusion protein as claimed in  claim 11 , wherein said cell marker is CD20.  
     
     
         13 . A fusion protein as claimed in  claim 8 , wherein said region of IL-15α is an extracellular domain of IL-15α.  
     
     
         14 . A composition comprising a fusion protein according to  claim 8  and a pharmaceutically acceptable carrier.  
     
     
         15 . A kit comprising a conjugate of onconase and IL-15, and a fusion protein comprising a bispecific antibody that has a first specificity for a cell marker specific to a malignant cell and a second specificity for a region of IL-15α.  
     
     
         16 . A method of treating a malignancy, comprising the steps of: 
 first administering to a subject having a malignancy a fusion protein comprising a bispecific antibody that has a first specificity for a cell marker specific to a malignant cell and a second specificity for a region of IL-15α, and then administering to said subject therapeutically effective amount of a conjugate of onconase and IL-15.    
     
     
         17 . A method as claimed in  claim 16 , additionally comprising a step of administering at least one of chemotherapy and radiation therapy in an amount sufficient to prevent tumor cells from activating DNA-repair mechanisms.  
     
     
         18 . A method as claimed in  claim 16 , wherein said cell marker is a B-cell restricted antigen and said subject has a B-cell malignancy.  
     
     
         19 . A method as claimed in  claim 18 , wherein said cell marker is CD20 and said subject has B-cell lymphocytic leukemia, non-Hodgkin's lymphoma, hairy cell leukemia or acute myelogenous leukemia.