Antibody induced cell membrane wounding
Compositions and methods for inducing cell membrane wounding, cell permeabilization and cell killing are provided. The composition comprises a polyvalent agent that binds to a highly expressed cell surface antigen present on the surface of a cell. Preferably, the cell surface antigen is associated with the cytoskeleton of the cell. A preferred polyvalent agent is an IgM, and enhanced cell wounding and killing can be provided by the addition of a crosslinking agent. At sublethal concentrations in vivo, the cell wounding antibodies permeabilize cells and dramatically enhance response to chemotherapeutic agents, even in patients refractory to the chemotherapeutic agents.
1. A method of treating a mammal suffering from a condition characterized by hyperproliferation of B cells, wherein said hyperproliferating B-cells are cancer cells, comprising administering a cell membrane-wounding VH4-34antibody that binds to the CDIM epitope on the surface of B cells, in combination with a second cytotoxic agent, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage that was determined to cause membrane pores that allow the second agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells, wherein the VH4-34 antibody is an IgM.
2. A method of treating a mammal suffering from a condition characterized by hyperproliferation of B cells, wherein said hyperproliferating B-cells are cancer cells, comprising administering a cell membrane-wounding VH4-34antibody that binds to the CDIM epitope on the surface of B cells, in combination with a second agent, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage that was determined to cause membrane pores that allow the second agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells, wherein said second agent is a cytotoxic agent that interferes with the polymerization or depolymerization of microtubules.
3. The method of claim 2 , wherein the cytotoxic agent that interferes with the polymerization or depolymerization of microtubules is a taxane, vinca alkaloid or colchicine, or mixtures thereof.
4. The method of claim 3 , wherein the vinca alkaloid is vinblastine, vincristine, vindesine, or vinorelbine, or mixtures thereof.
5. The method of claim 4 , wherein the taxane is paclitaxel, or docetaxel, or mixtures thereof.
6. A method of treating a mammal suffering from a condition characterized by hyperproliferation of B cells, wherein said hyperproliferating B-cells are cancer cells, comprising administering a cell membrane-wounding VH4-34antibody that binds to the CDIM epitope on the surface of B cells, in combination with a second cytotoxic agent, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage that was determined to cause membrane pores that allow the second agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells, wherein the second agent is a cytotoxic antibody.
7. The method of claim 6 , wherein the antibody has specific binding for CD11a, CD19, CD20, CD21, CD22, CD25, CD34, CD37, CD38, CD40, CD45, CD52, CD80, CD 86, IL-4R, IL-6R, IL-8R, IL-13R, integrin (VLA4), BLYS receptor, cell surface idiotypic Ig, or mixtures thereof.
8. The method of claim 6 , wherein the antibody is rituximab, or anti-CD52.
9. The method of claim 2 , wherein the condition characterized by a hyperproliferation of B cells is lymphoid cancer.
10. The method of claim 9 , wherein the lymphoid cancer is acute or chronic leukemia, or lymphoma, of B-cell origin.
11. The method of claim 10 , wherein the lymphoid cancer is acute lymphocytic leukemia (ALL), non-Hodgkins lymphoma (NHL), Burkitt's lymphoma, B progenitor ALL, adult ALL, or chronic lymphocytic leukemia (CLL).
12. The method of claim 2 , wherein the viability of hyperproliferating B cells is reduced to about 42 percent.
13. The method of claim 2 , wherein the viability of hyperproliferating B cells is reduced to about 30 percent.
14. The method of claim 2 , wherein said cell membrane wounding VH4-34 antibody is administered at a dosage of about 1.25 mg/kg bodyweight.
15. The method of claim 6 , wherein the condition characterized by a hyperproliferation of B cells is lymphoid cancer.
16. The method of claim 15 , wherein the lymphoid cancer is acute or chronic leukemia, or lymphoma, of B-cell origin.
17. The method of claim 16 , wherein the lymphoid cancer is acute lymphocytic leukemia (ALL), non-Hodgkins lymphoma (NHL), Burkitt's lymphoma, B progenitor ALL, adult ALL, or chronic lymphocytic leukemia (CLL).
18. The method of claim 6 , wherein the viability of hyperproliferating B cells is reduced to about 42 percent.
19. The method of claim 6 , wherein the viability of hyperproliferating B cells is reduced to about 30 percent.
20. The method of claim 6 , wherein said cell membrane wounding VH4-34 antibody is administered at a dosage of about 1.25 mg/kg bodyweight.