The goal of the studies proposed herein is to develop novel argents that can be used for immunotherapy and immunodiagnosis of human adenocarcinomas, particularly those of the pancreas. The reagents under development include tumor vaccine components and new monoclonal antibodies for use as radioimmunoconjugates or for other diagnostic and therapeutic purposes. Studies proposed in Specific Aim 1 investigate immunological parameters that regulate tolerance to a specific tumor antigen (MUC1) and investigate ways of breaking this tolerance and inducing specific responses that reject tumors. MUC1 is highly overexpressed and differentially glycosylated by different human adenocarcinomas (including breast, pancreas, lung, prostate). Immunity and tolerance to MUC1 will be evaluated using an established inbred syngeneic mouse strain, C57B16, and a corresponding C57B16 strain that is transgenic for the human MUC1 gene. The proposed experimental system is designed to characterize the nature (cells or molecules that are involved in regulating the immune status) of anti-MUC1 responses that destroy tumors in normal animal and the nature of the immunological tolerance in transgenic animals. Studies proposed in Specific Aim 2 include the development and testing of novel vaccine formulations of the tumor antigen MUC1. Immunization strategies for breaking immunological tolerance and mounting anti-MUC1 responses that are capable of destroying tumor cells will be investigated. A novel aspect of the vaccine design proposed here is the delivery of a target antigen to antigen presenting cells simultaneous with the delivery of activation signals for those cells by preparing chimerical peptides and/or recombinant proteins that contain 1) an antigenic determinant targeted as a vaccine candidate; and 2) ligands for different receptors on antigen presenting cells. Findings from the proposed experimental system will be used to modify the design of tumor vaccine trails in humans that are ongoing at this institution. Studies proposed in the third specific aim would develop and characterize new monoclonal antibodies against immunologially unexplored domains of MUC1. This experimental design takes into account certain biological properties of MUC1, which suggest that antibodies to some eptiopes on the core protein will have diagnostic and therapeutic utility. Some of these antibodies will be against portions of the protein that remain associated with the cell surface and undergo internalization and are predicted to be of use in radioimmunoconjugate trails; others will be against secreted forms of MUC1 and are predicted to be of use in improving serum diagnostic assays for pancreatic cancer.
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