Project-1 will further develop and help evaluate clinically new immunoliposomal agents that target HER2-positive breast tumor cells in order to improve the survival of women with advanced breast cancer. The growth factor receptor tyrosine kinase encoded by the protooncogene HER2 (c-erbB-2/neu) represents an attractive target for therapy because its amplification and overexpression occur early in the development of breast cancer, resulting in aggressive disease resistant to systemic therapy. Several anti-HER2 antibodies, including a humanized monoclonal (rhuMAbHER2; Genentech, Inc.) showing clinical promise in patients with metastatic and chemotherapy-resistant HER2-positive breast cancer, are known to produce in vivo tumoristatic effects that become tumoricidal when administered in synergistic combination with either doxorubicin, cisplatin, or taxol. This project will proceed with the development of a first-generation tumoricidal immunoliposomal agent (l-L-dox) composed of humanized anti- HER2 monoclonal fragments, rhuMAbHER-Fab', expressed on the surface of liposomes (conventional or sterically stabilized) encapsulated with doxorubicin. Progress to date indicates that some but not all I-L-dox formulations exhibit in vitro membrane binding, intracellular uptake, and toxicity that is specific to HER2-positive breast cancer cells. Furthermore, preliminary in vivo studies suggest that when these I-L-dox formulations are administered i.v. or i.p. into SCID mice bearing HER2- positive BT-474 breast tumor xenografts, the immunoliposomes and their contents accumulate within the tumors and produce enhanced antitumor effects relative to treatment with free doxorubicin. Over the next project interval, emphasis will be given to the completion of in vivo preclinical studies and the initiation of a Phase-I clinical trial (conducted by the SPORE's Clinical Core) using the most effective preclinical formulation of I-L-dox. Collaborations have been established to facilitate the translational development toward ND approval of I-L-dox and to complete the pharmacokinetic, toxicologic, and efficacy testing necessary to demonstrate that tumor-targeting by anti-HER2 immunoliposomes enhances the therapeutic index of an established breast cancer agent like doxorubicin. With confirmatory in vivo evidence for the targeting advantages of I-L- dox, increased attention will be given to the encapsulation of a Pt(II) or taxane derivative to initiate preclinical development of an additional tumoricidal anti-HER2 immunoliposomal agent. Furthermore, feasibility testing will begin on a second-generation of targeted therapeutics designed to exploit the novel property that anti-HER2 immunoliposomes (unlike untargeted conventional or sterically stabilized Iiposomes) deliver their contents beyond the coated pit-lysosome pathway and into the cytoplasm of HER2-positive breast cancer cells. This unique intracellular delivery potential of anti-HER2 immunoliposomes makes possible future development of alternative (non-chemotherapy-based) treatment approaches such as HER2-targeted breast cancer gene therapy.
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