Full Abstract of AntiPS/3G4 AACR Presentation (3-28-2004)
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Abstract #1498
Anti-phosphatidylserine monoclonal antibody, 3G4, enhances the anti-tumor effects of Docetaxel against human breast cancer
Xianming Huang, Mary Bennett, Jin He, Linda Watkins, Philip Thorpe. UT SW Med. Center at Dallas
Phosphatidylserine (PS) is an anionic phospholipid that resides almost exclusively on the inner leaflet of the plasma membrane of mammalian cells under normal conditions. We have demonstrated that PS is selectively expressed on the outer leaflet of tumor vascular endothelium but not in normal vessels, possibly due in part to exposure to stress conditions in the tumor microenvironment, making PS an excellent candidate for tumor vascular targeting. We have developed a monoclonal anti-PS antibody, 3G4. When injected into tumor bearing mice, 3G4 localize specifically to tumor endothelium. In preclinical studies, 3G4 alone significantly inhibits tumor growth in a variety of rodent tumor models. Up to 50% regressions were seen in syngeneic and human tumors, including human breast carcinomas. Docetaxel is the most effective single cytotoxic drugs against breast cancer. It binds to microtubule and inhibits microtubule depolymerization, results in disrupted cell mitosis and proliferation and induces apoptosis, therefore PS exposure. In this study, we evaluated whether 3G4 can enhance the therapeutic effect of Docetaxel in an orthotopic human MDA-MB-435 breast tumors model. In vitro, docetaxel increased PS exposure on endothelial cells. In vivo, docetaxel significantly increased PS exposure on tumor vessels, 56% tumor blood vessels were PS positive in docetaxel treated group compared with 35% in control group. Tumor growth was inhibited by 93% in the combination treated group, as compared with 68% and 60% in groups treated with docetaxel and 3G4 alone, respectively (P<0.01). Histological examination revealed large numbers of macrophages attached to the tumor endothelium and infiltration of macrophages into the tumor interstitium. Vascular damage to tumor vessels was seen. In vitro studies showed that 3G4 enhanced the phagocytosis of PS-expressing cells by murine macrophages. These studies indicate that as an adjuvant therapy, 3G4 could significantly enhance the therapeutic efficacy of Docetaxel in breast cancer patients, provide a more effective therapy for breast cancer.
Presenter: Xianming Huang
Affiliation: UT SW Med. Center at Dallas
E-mail: xianming.huang@utsouthwestern.edu |
