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    A Novel Vascular Targeting Antibody, 3G4, Enhances the Therapeutic Efficacy of Docetaxel Against Drug Resistant Breast Cancer and Metastases

    Scientific Abstract:
    A novel vascular targeting antibody, 3G4, enhances the therapeutic efficacy of docetaxel against drug resistant breast cancer and metastases Background: A therapeutic monoclonal antibody, 3G4, directed against tumor vasculature was generated in this laboratory. A chimeric version is scheduled to enter Phase I clinical trials in late 2004. The antibody recognizes phosphatidylserine (PS), a specific marker of tumor vessels. When injected into tumor-bearing mice, 3G4 localizes specifically to tumor blood vessels, induces damage to tumor vessels and suppresses tumor growth in multiple tumor types. When combined with docetaxel, results were even more remarkable. In an orthotopic human breast tumor model in mice, the combination of 3G4 and docetaxel inhibited tumor growth by 93%, as compared with 60% and 68%, decreased tumor burden in the liver and lungs by more than 90%, as compared with 45% and 56%, for 3G4 and docetaxel alone, respectively. Importantly, the combination is no more toxic than is docetaxel alone. Objective/Hypothesis: We hypothesize that combining 3G4 with docetaxel will have high efficacy in the treatment of primary human breast tumors and their metastases. Also, since 3G4 targets the stable tumor endothelium rather than tumor cells themselves, we hypothesize that the therapy will be effective against drug resistant breast tumors. Specific Aims: 1) To assess the efficacy and safety of the combination of 3G4 and docetaxel against MDA-MB-435, T0.1 taxol-resistant human breast tumor and 4T1 syngeneic mouse mammary tumor. 2) To assess the anti-metastatic effect of the combination. 3) To dissect the mechanisms of the antitumor effect. Study Design: Optimal dosing schedules will be determined in mice bearing orthotopic breast tumors and taxol-resistant variants. The spontaneous metastatic model will be established using a luciferase labeled MDA-MB-435-luc cell line. Experimental metastatic models will be setup by iv injection of breast tumor cells. To dissect the mechanisms, vascular damage will be assessed by measuring microvessel density and functional vascular volume in tumors. Metastases will be assessed by non-invasive imaging and quantified by luciferase assay. Potential Outcomes and Benefits of the Research: The proposed studies could ultimately lead to the development of a new and more effective strategy for the treatment of human breast tumors. Since 3G4 is already chimerized and close to clinical trials, it should be possible to take the 3G4/docetaxel combination rapidly into clinical trials in breast cancer patients.

    Lay Abstract:
    A novel vascular targeting antibody, 3G4, enhances the therapeutic efficacy of docetaxel against drug resistant breast cancer and metastases Antiangiogenic agents that attack tumor blood vessels and starve tumors of oxygen and nutrients have shown promising clinical activity, especially when combined with chemotherapeutic drugs. The goal of the present study is to explore our finding that a novel vascular targeting antibody, 3G4, markedly improves the therapeutic efficacy of docetaxel, a key drug for treating breast cancer. The target for 3G4 is phosphatidylserine (PS), a recently identified specific marker of tumor vasculature. We found that 3G4, as a single agent, suppresses tumor growth by 60% to 75% in two different human breast tumor models in mice. When combined with docetaxel, results were even more remarkable. In a human breast tumor model in mice, 3G4 plus docetaxel inhibited tumor growth by 93%, as compared with 60% and 68% for 3G4 and docetaxel, respectively. The combination therapy decreased tumor burden in the liver and lungs by more than 90%, as compared with 45% and 56% decrease for 3G4 and docetaxel, respectively. The combination was also effective against drug resistant breast tumors. Importantly, the combination is no more toxic to mice than is docetaxel alone. The hypothesis underlying the proposed studies is that combining 3G4 with docetaxel will lead to significantly enhanced therapeutic effects for the treatment of human breast tumors. We propose to examine the antitumor effect in three different breast tumor models, including drug resistant breast tumors, each represents different clinical settings of human breast cancer. We will then evaluate the efficacy of the combined therapy on tumor metastasis. Finally, we will attempt to clarify the mechanism. A human-mouse chimeric version of 3G4, which has similar preclinical activities to murine 3G4, has been made in gram-quantities by a pharmaceutical company and is scheduled to enter Phase I clinical trials in cancer patients at the end of 2004. The chimeric 3G4 is safe in monkeys, atherosclerotic rabbits and rodents even at dose ten-fold higher than the calculated therapeutic dose. The proposed studies could ultimately lead to the development a new and more effective strategy for the treatment of human breast tumors. Since 3G4 is already chimerized and close to clinical trials, it should be possible to take the 3G4/docetaxel combination rapidly into clinical trials in breast cancer patients.