IMMUNOASSAYS FOR DIDEMNINS

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The overall goal of this project is to develop immunoassays capable of detecting didemnins at the nanogram level. Didemnin B is the most potent antitumor, antiviral and cytotoxic member of a family of five cyclic depsipeptides isolated from marine tunicates. This compound is currently in clinical trials as an antitumor agent. Available bioassay and HPLC methods for detecting didemnins in biological matrices lack the precision and sensitivity required for pharmacokinetic and drug metabolism studies. We plan to synthesize well characterized didemnin A derived immunogens which should elicit antibody responses. This will be achieved by coupling didemnin A to immunogenic carriers via its N-methyl-D-leucine side chain to expose the macrocyclic epitope common among all didemnins. Earlier attempts by other investigators failed to develop a radioimmunoassay, possibly because of the strong immunosuppressive action of didemnin B. However, since didemnin A is less potent than didemnin B, careful manipulation of immunization parameters such as choice of immunogenic carrier, immunizing dose, route of immunization, adjuvant type, and prior priming with immunogenic carrier, is expected to evoke humoral immune responses. Phase I efforts will focus on demonstrating the feasibility of developing a generic immunoassay for all didemnins. Phase II will focus on refining the generic assay and develop selective immunoassays for didemnins.