This proposal seeks to generate monoclonal antibodies against receptors for growth factors and hormones and to test them in cell culture and in model experimental animal systems, in preparation for Phase I clinical trials. The participants in this coopoerative agreement include basic scientists and clinical investigators from the University of California at San Diego, the Salk Institute, Memorial Sloan-Kettering Cancer Center and researchers at Hybritech, Inc. Close productive collaborations already exist between these scientists in studies with monoclonal antibodies against antigens on normal and malignant human cells. Each participant currently is receiving support from the National Cancer Institute, for basic and/or clinical research involving monoclonal antibodies. Section 1 presents an overview and an administrative budget. Section 2 deals with production of murine anti-human transferrin receptor monoclonal antibodies as well as rat anti-mouse transferrin receptor antibodies. In Section 3, monoclonal antibodies will be raised against the receptors for EGF and insulin. Both mouse anti-human receptor and rat anti-mouse receptor antibodies will be studied. Section 4 is a project in which ricin conjugates to antireceptor antibodies are produced. Section 5 describes assays screening for antiproliferative activity against normal and malignant cells and for binding to normal tissues. Section 6 describes a core, providing tests of anti-tumor efficacy against human turmo xenografts in athymic mice. Section 7 provides a core for a scale up of production of candidate monoclonal antibodies. It is our intention that these experiments will lead to future Phase 1 clinical trials, with antibodies which show promise of anti-tumor activity in vivo and which do not show serious toxicity in the invivo rat anti-murine receptor experiments. The research components which comprise this Cooperative Agreement will make it possible to evaluate the potential utility of antireceptor monoclonal antibodies in cancer therapy, using a sequence of screens and tests designed to be comparable to the NCE, DIC standard preclinical screen for chemotherapeutic agents.
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