NEW BCAS FOR RADIOIMMUNOTHERAPY WITH RADIOMETALS

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The overall goal of this project is to develop new bifunctional chelating agents (BCAs) for the radiolabeling of monoclonal antibodies (MAbs) with radiometals other than 90Y for radioimmunotherapy in animal studies and ultimately clinically. We are proposing to study in this application a novel family of BCAs for radiolabeling of MAb CC49. The MAb CC49 is a well characterized reagent reactive with human adenocarcinomas and is being used in clinical phase and phase Il localization and therapy trials by us and other investigators. Therefore, the animal studies proposed in this application will elucidate the therapeutic efficacy, stability and other characteristics of BCA radiometal labeled conjugates, with the long term goal of their use in human clinical therapy trials. The specific aims are 1) To optimize the ability of trisuccin, a new hydroxamic acid based BCA to bind various radioactive metals to monoclonal antibodies for radioimmunoimaging and radioimmunotherapy, 2) To expand this "family" of hydroxamic acid-based BCAs to provide alternative or improved radioisotope linking strategies, 3) To radiolabel the MAb CC49 with 99mTc, 186Re and 67Cu using trisuccin and other hydroxamic acid-based BCAs, 4) To characterize the immunoreactivity, the in vitro and in vivo stability of hydroxamic acid chelated monoclonal antibodies labeled with the above radioisotopes. 5) To compare the tumor localization and biodistribution of radioisotopes linked to MAb CC49 via hydroxamic acid BCAs versus 99mTc and 186Re-MAG2-GABA-labeled CC49, and 6) To compare radioimmunotherapy effects of radiolabeled CC49 when radioisotopes are linked by hydroxamic acid based BCAs versus 99mTc and 186Re-MAG2-GABA- labeled CC49. Standard analytical and biochemical techniques will be used to demonstrate the purity of the hydroxamic acid compounds synthesized. Stability and pharmacokinetic studies will be carried out in rabbits. The biodistribution and therapy studies will be carried out in athymic nude mice bearing subcutaneous human colon cancer xenografts. The eventual goal of this project is to produce a better radioimmunotherapeutic agent for treatment of human malignancies.