Anionic phospholipids, such as phosphatidylserine (PS), are largely absent from the surface of most cells under normal conditions. Anionic phospholipids become exposed on tumor blood vessels in response to stress conditions in the tumor microenvironment. To target cell surface anionic phospholipids, we have raised monoclonal antibodies that recognize anionic phospholipids. Some of the antibodies bind directly to the lipids 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 following 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, 3G4, results in 50-90% tumor growth retardation. 3G4 enhances the antitumor effects of common radio- and chemo-therapeutic strategies. In vitro and in vivo studies indicate that 3G4 acts by provoking innate autoimmune reactions that destroy tumor blood vessels. In addition, the antibody appears to negate PS-mediated immunosuppressive signals generated by the vascular endothelium and received by monocytes/macrophages. A chimeric version of 3G4, called bavituximab, has been produced. Phase I clinical trials in cancer patients are in progress.
Bavituximab also has potential as a broad spectrum antiviral agent for the treatment of infections caused by enveloped viruses, including viruses such as hepatitis C virus and hemorrhagic fever viruses. We have found that PS becomes exposed on the external surface of virally infected cells, probably because elevations in intracellular calcium activate PS exporters and inhibit PS importers. The virions thus pick up randomized phospholipid envelopes as they egress through the plasma membrane or membranes of intracellular vesicles. The envelopes of multiple virus families have PS on their external surface. Bavituximab treatment of guinea pigs with advanced Lassa fever-related virus infections gives 50% survival of the animals. Bavituximab treatment of mice with lethal murine cytomegalovirus infections gives 100% survival. Animals that survive gain weight steadily and do not display physical signs of disease. No observable toxicities are associated with bavituximab therapy. Bavituximab achieves its protective effects by directing host cells to kill the virally-infected cells and by causing opsonization and clearance of virions from the bloodstream. Phase I clinical trials are in progress in which patients with refractory hepatitis C virus infections are being treated with bavituximab. The treatment has been well tolerated at all dose levels and reductions in viral RNA of 50 to 97% have beed observed. The trials are being extended to other viruses.
RESEARCH INTERESTS
Vascular targeting agents
Angiogenesis and anti-angiogenic therapeutics
Anti-viral therapeutics
Immunotoxins
RECENT PUBLICATIONS
PE Thorpe, "Vascular targeting agents as cancer therapeutics" Clinical Cancer Research, Volume 10:415-427, January 2004
Ran S, He J, Huang X, Soares M, Scothorn D, Thorpe PE, "Antitumor effects of a monoclonal antibody directed against anionic phospholipids on the surface of tumor blood vessels in mice" Clinical Cancer Research, 11:1551-1562, 2005
Huang X, Bennett M, Thorpe PE, "A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice" Cancer Research, 65:4408-4416, 2005
Huang X, Bennett M, Thorpe PE, "Antitumor effects and lack of side-effects in mice of an immunotoxin directed against human and mouse prostate specific membrane antigen" Prostate, 9999:1-11, 2004
Castro-Rivera E, Ran S, Thorpe PE, Minna JD, "Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer whereas VEGF-165 antagonizes this effect" Proceedings of the National Academies of Science (USA), 101:11432-11437, 2004
SIGNIFICANT PUBLICATIONS
Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE, "Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature" Science, 275:547-550, 1997
Brekken RA, King SW, Thorpe PE, "Vascular endothelial growth factor as a marker of tumor endothelium" Cancer Research, 58:1952-1959, 1998
Ran S, Downes A, Thorpe PE, "Increased exposure of anionic phospholipids on the surface of tumor blood vessels" Cancer Research, 62:6132-6140, 2002
Veenendaal LM, Jin H, Ran S, Cheung L, Navone N, Marks JW, Thorpe PE, Walterberger J, Rosenblum MG, "In vitro and in vivo studies of a VEGF-121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors" Proceedings of the National Academies of Science (USA), 99:7866-7871, 2002
Burrows FJ, Thorpe PE, "Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature" Proceedings of the National Academies of Science (USA), 90:8996-9000, 1993
Point and right click (click and hold for Mac users) your mouse onand select "Save this link (or target) as..." option to save the file to your local computer.
