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 VH4-34 antibody 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 cytotoxic agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells.
2. The method of claim 1 , wherein the mammal is a human.
3. The method of claim 1 , wherein the mammal is a nonhuman mammal.
4. The method of claim 1 , wherein the hyperproliferating B cells are stimulated into a hyperproliferating condition by growth factors, cytokines, or Epstein Barr Virus infection.
5. The method of claim 1 , wherein the second cytotoxic agent is a chemotherapeutic agent, a radioactive isotope, a cytotoxic antibody, an immunoconjugate, a ligand conjugate, an immunosuppressant, a cell growth regulator or inhibitor, a toxin, or mixtures thereof.
6. The method of claim 5 , wherein the chemotherapeutic agent is vincristine, daunorubicin, L-asparaginase, or colchicine.
7. The method of claim 1 , wherein the condition characterized by a hyperproliferation of B cells is lymphoid cancer.
8. The method of claim 1 , wherein the viability of hyperproliferating B cells is reduced to 42 percent.
9. The method of claim 1 , wherein the viability of hyperproliferating B cells is reduced to 30 percent.
10. The method of claim 1 , wherein said cell membrane wounding VH4-34 antibody is administered at a dosage of 1.25 mg/kg bodyweight.
11. A method of killing neoplastic B cells in a mammal, comprising administering to neoplastic B cells a cytotoxic amount of a cell membrane wounding VH4-34 antibody that binds to the CDIM epitope on the surface of the neoplastic 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 cytotoxic agent to enter said neoplastic B cells to synergistically reduce the viability of the neoplastic B cells.
12. The method of claim 11 , wherein the mammal is a human.
13. The method of claim 11 , wherein the mammal is a nonhuman mammal.
14. The method of claim 11 , wherein the neoplastic B cells are stimulated into a hyperproliferating condition by growth factors, cytokines, or Epstein Barr Virus infection.
15. The method of claim 11 wherein the second cytotoxic agent is a chemotherapeutic agent, a radioactive isotope, a cytotoxic antibody, an immunoconjugate, a ligand conjugate, an immunosuppressant, a cell growth regulator or inhibitor, a toxin, or mixtures thereof.
16. The method of claim 11 , wherein the second cytotoxic agent is vincristine, daunorubicin, L-asparaginase, or colchicine.
17. The method of claim 11 , wherein the mammal has lymphoid cancer.
18. The method of claim 11 , wherein the viability of neoplastic B cells is reduced to 42 percent.
19. The method of claim 11 , wherein the viability of neoplastic B cells is reduced to 30 percent.
20. The method of claim 11 , wherein said cell membrane wounding VH4-34 antibody is administered at a dosage of 1.25 mg/kg bodyweight.