Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents

Abstract

Disclosed are methods and compositions for treating tumors. Disclosed methods and compositions enhance the uptake of immunocytokines into tumors, and are based on a combination of an immunocytokine with an immunocytokine uptake enhancing agent. Disclosed methods and compositions are particularly useful for reducing tumor size and metastasis in a mammal.

1 . A method of inducing a cytocidal immune response against a tumor in a mammal, the method comprising the steps of administering to a mammal:
 (i) an immunocytokine comprising an antibody binding site and a cytokine; and,   (ii) an immunocytokine uptake enhancing agent that enhances an immune response induced by the immunocytokine.   
     
     
         2 . The method of  claim 1 , wherein the antibody binding site binds to a cancer cell. 
     
     
         3 . The method of  claim 1 , wherein the antibody binding site binds to a tumor specific antigen. 
     
     
         4 . The method of  claim 1 , wherein the immunocytokine uptake enhancing agent is co-administered with the immunocytokine. 
     
     
         5 . The method of  claim 1 , wherein the immunocytokine uptake enhancing agent is administered prior to administration of the immunocytokine. 
     
     
         6 . The method of  claim 1 , wherein the antibody binding site comprises, in an amino-terminal to carboxy-terminal direction, an immunoglobulin variable region, a CH1 domain, and a CH2 domain. 
     
     
         7 . The method of  claim 6 , wherein the antibody binding site further comprises a CH3 domain attached to the carboxy terminal end of the CH2 domain. 
     
     
         8 . The method of  claim 1 , wherein the immunocytokine is a fusion protein comprising, in an amino-terminal to carboxy-terminal direction, (i) the antibody binding site comprising an immunoglobulin variable region capable of binding a cell surface antigen on a preselected cell type, an immunoglobulin CH1 domain, an immunoglobulin CH2 domain, and (ii) the cytokine. 
     
     
         9 . The method of  claim 8 , wherein the antibody binding site further comprises a CH3 domain interposed between the CH2 domain and the cytokine. 
     
     
         10 . The method of  claim 1 , wherein the cytokine of the immunocytokine is selected from the group consisting of a tumor necrosis factor, an interleukin, a colony stimulating factor, and a lymphokine. 
     
     
         11 . The method of  claim 1 , wherein said immunocytokine uptake enhancing agent is a taxane. 
     
     
         12 . The method of  claim 11 , wherein said taxane is selected from the group consisting of Taxol, docetaxel, 10-deacetyl Baccatin III, and derivatives thereof. 
     
     
         13 . The method of  claim 1 , wherein said immunocytokine uptake enhancing agent is an alkylating chemotherapeutic agent. 
     
     
         14 . The method of  claim 13 , wherein said alkylating chemotherapeutic agent is selected from the group consisting of cyclophosphamide, carboplatin, and derivatives thereof. 
     
     
         15 . The method of  claim 1 , wherein two or more different immunocytokine uptake enhancing agents are administered to said mammal. 
     
     
         16 . The method of  claim 1 , wherein two or more different immunocytokines are administered to said mammal. 
     
     
         17 . The method of  claim 1 , wherein said immunocytokine uptake enhancing agent is administered about 24 hours before said immunocytokine. 
     
     
         18 . A composition for inducing an immune response against a tumor in a mammal, the composition comprising:
 (i) an immunocytokine comprising an antibody binding site and a cytokine; and,   (ii) an immunocytokine uptake enhancing agent.   
     
     
         19 . The composition of  claim 18 , wherein the antibody binding site comprises in an amino-terminal to carboxy-terminal direction, an immunoglobulin variable region, a CH1 domain and a CH2 domain. 
     
     
         20 . The composition of  claim 19 , wherein the antibody binding site further comprises a CH3 domain attached to the C-terminal end of the CH2 domain. 
     
     
         21 - 27 . (canceled)