Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents
View Patent ↗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 enhancing the immune destruction of a tumor in a mammal, the method comprising the steps of:
pre-treating a mammal with a cytotoxic agent; and
administering an immunocytokine comprising an antibody binding site and interleukin-2 wherein the pre-treating step enhances the immune destruction of the tumor.
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 antibody binding site comprises, in an amino-terminal to carboxy-terminal direction, an immunoglobulin variable region and a CH2 domain.
5. The method of claim 4 , wherein the antibody binding site further comprises a CH3 domain attached to the carboxy terminal end of the CH2 domain.
6. 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) interleukin-2.
7. The method of claim 6 , wherein the antibody binding site further comprises a CH3 domain interposed between the CH2 domain and interleukin-2.
8. The method of claim 1 , wherein said cytotoxic agent is a taxane.
9. The method of claim 8 , wherein said taxane is selected from the group consisting of paclitaxel, docetaxel and 10-deacetyl Baccatin III.
10. The method of claim 1 , wherein said cytotoxic agent is an alkylating chemotherapeutic agent.
11. The method of claim 10 , wherein said alkylating chemotherapeutic agent is selected from the group consisting of cyclophosphamide and carboplatin.
12. The method of claim 1 , wherein two or more different cytotoxic agents are administered to said mammal.
13. The method of claim 1 , wherein two or more different immunocytokines are administered to said mammal.
14. The method of claim 1 , wherein the mammal is pre-treated with the cytotoxic agent for between about 4 hours and about 72 hours.
15. The method of claim 14 , wherein the mammal is pre-treated with the cytotoxic agent for about 24 hours.
16. The method of claim 14 , wherein the mammal is pre-treated with the cytotoxic agent for 72 hours.
17. The method of claim 1 , wherein the cytotoxic agent enhances a T-cell immune response.