This project is designed to test three hypotheses with regard to the development of humanized monoclonal antibody (huAb)-based therapies of epithelial cancers: (1) Can mAbs against restricted differentiation antigens be used for selective delivery of therapeutic amounts of radioisotopes or toxic agents? (ii) Can mAbs with biological effector functions (including immune tumor cell lysis) focus the destructive effect of an inflammatory reaction at the tumor site? (iii) Can restricted tumor stromal antigens such as fibroblast activation protein (FAP) and endosialin serve as therapeutic targets in epithelial cancers? Past studies with mouse mAbs have identified several antigenic systems of colon, kidney, and breast cancers that hold promise for immunotherapeutic approaches because some are highly expressed in tumor tissues but show only limited normal tissue expression; some are efficient targets for complement-mediated cytotoxicity; and some have shown selective tumor targeting in phase I biodistribution/dosimetry studies in patients. However, the clinical utility of mouse mAbs in the therapy of epithelial cancers is limited by the induction of human antimouse antibody (HAMA) responses that prevent prolong and/or repeat treatment. The use of chimeric (chAb) and humanized (huAb) versions of available mAbs offers a powerful method for overcoming these shortcomings and for exploring the therapeutic potential of mAb conjugates with radioisotopes or drugs and mAbs with intrinsic cytotoxic or inflammatogenic properties.
Aim I focuses on the use of two mAbs, huAb A33 and chAb G250, against highly restricted antigens of colon and kidney cancers as carriers for radioisotopes and drugs. Moreover, A33 serves as a prototype for target antigens with prominent internalization characteristics, allowing the use of mAb-conjugates with Auger electron-emitting isotopes and drugs with intracellular sites of action.
Aim II explores the use of an immune cytotoxic anti-Le/y mAb, huAb S193, in patients with colon and breast cancer, and initial evaluation of an immune cytotoxic IgM, mAb F31, in patients with kidney cancer. (The assessment of immune cytotoxic and inflammatogenic effects in these patients will be conducted in conjunction with Projects by Drs. Scheinberg and Houghton.) Aim III represents a novel concept for the imaging and therapy of epithelial cancers that employs huAbs against restricted antigens of reactive tumor stromal fibroblasts (huAb F19, anti-FAP) and tumor capillary endothelial cells (huAb FB5, anti-endosialin). These targets are particularly attractive because the stromal compartment is critical for the growth of epithelial cancers, and stromal targets may be readily accessible to circulating mAbs. The proposed phase I and II trials will follow a general study design previously developed for mouse mAbs, with emphasis on biodistribution studies (external imaging, biopsy-based dosimetry, autoradiography) and dosimetry development (in conjunction with the Nuclear Medicine Core). These studies may lead to safe and effective immunotherapies for patients with epithelial cancers.
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