We are interested in creating new drugs that act by homing in on blood vessels in cancers and destroying them. This stops the flow of blood to the cancer, and the cancer cells then die because they are starved of oxygen and nutrients. For this strategy to work, differences had to be found between cancer blood vessels and blood vessels in healthy tissues. We made the remarkable discovery that a fatty lipid molecule, phosphatidylserine, becomes exposed on the outer surface of cancer blood vessels where it can serve as a target for the new drugs.
Chemotherapy or irradiation induces phosphatidylserine exposure on endothelial cells
(L-R: 0 hr, 8 hr, 16 hr, 24 hr)
Phosphatidylserine (PS) is largely absent from the surface of most cells under normal conditions. PS becomes exposed on tumor blood vessels in response to stress conditions in the tumor microenvironment. To target cell surface PS, we raised monoclonal antibodies that recognize anionic phospholipids. Some of the antibodies bind directly to PS while others bind to lipids complexed with beta2-glycoprotein I, a common blood protein. We have found that the antibodies localize specifically to tumor blood vessels after injection into mice bearing various types of solid tumors. In contrast, the antibodies do not localize to blood vessels in normal tissues. Treatment of tumor-bearing mice with one of the antibodies, 2aG4, results in up to 90% tumor growth retardation in multiple tumor models. 2aG4 enhances the antitumor effects of common radio- and chemo-therapeutic strategies. In vitro and in vivo studies indicate that 2aG4 acts by provoking innate immune reactions that destroy tumor blood vessels. In addition, the antibody blocks PS-mediated immunosuppressive signals that would normally prevent immune cells from being able to recognize tumor cells as foreign. The antibody therefore reactivates tumor immunity which further helps to control tumor growth and spread. A semi-human version of 2aG4, called bavituximab, has been produced in collaboration with our pharmaceutical company partners, Peregrine Pharmaceuticals, Inc. Randomized phase IIb studies of bavituximab combined with chemotherapy are in progress in patients suffering from advanced lung or pancreatic cancer. Trials are also underway in patients with liver cancer and breast cancer.
Prolonged survival time and cures in rats bearing orthotopic F98 tumors treated with irradiation and 2aG4