This NATIONAL COOPERATIVE DRUG DISCOVERY GROUP (NCDDG) seeks to develop a new form of anticancer therapy utilizing monoclonal antibodies against receptors for essential growth factors, which have the capacity to inhibit receptor activation and function. The participants in the group include laboratory scientists and clinical investigators from Memorial Sloan- Kettering Cancer Center, the Salk Institute, and the University of California at San Diego. There have been close and productive interactions between the program leaders from these three institutions for the past eight years, and this NCDDG has supported our collaboration for the past four years. Each participant is receiving peer reviewed support from the National Cancer Institute for the basic research that has enabled us to design a Drug Discovery Group to explore this potential new form of therapy. Section I presents our overview and our administrative budget. Section II describes research on monoclonal antibodies against the transferrin receptor and a membrane-associated tyrosine against both malignant and normal cells, and further studies of the function and activity of anti-transferrin receptor monoclonal antibodies. In Section IV we are investigating the use of anti-EGF receptor antibodies, antibody fragments and a variety of immunoconjugates as tumor localizing agents and as inhibitors of tumor cell proliferation. Section V is a nude mouse core which provides the animals for the in vivo experiments evaluating the antitumor effects of antireceptor monoclonal antibodies against human tumor xenografts. Section VI is a core laboratory which produces recombinant receptors and candidate monoclonal antibodies. These research components have enabled us to evaluate the potential utility of antireceptor monoclonal antibodies using a sequence of screens and tests designed to be comparable to the NCI, DCT standard preclinical screen for chemotherapeutic agents. The results of this research have enabled us to initiate a Phase I clinical trial with one anti-EGF receptor antibody, and to plan a comparable trial with an antitransferrin receptor antibody.
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