Systematic evaluation of toxicity and therapeutic efficacy in CD46 directed radioligand therapy

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PROJECT SUMMARY AND ABSTRACT The primary goal of this proposal is to optimize our promising CD46 directed radioimmunotherapy method and to systematically test the therapeutic efficacy and toxicity utilizing state of the art metastatic cancer models. Readouts of therapeutic efficacy and toxicity will include histologic, metabolomic, and microscale dosimetry analysis. Our preliminary data and prior publications demonstrate great promise for CD46 directed radioimmunotherapy. The central hypothesis is our proposal is that optimized CD46 directed radioimmunotherapy will allow for effective prostate cancer treatment with relative sparing of normal tissue toxicity. This hypothesis will be tested in relevant orthotopic and disseminated metastatic models, using readouts including histology, metabolomic, and microscale dosimetry analysis. Guided by PAR-22-139, we have assembled a multidisciplinary multi-PI team including nuclear medicine physicians, specialists in cancer metabolism and animal model development, physicists, radiochemists, experts in antibody drug development, and pathologists. In aim 1, we develop novel bifunctional chelators for antibody labeling to maximize tumoral delivery of the therapeutic 225Ac. In aim 2, we systematically test the optimized radioimmunotherapy agents in clinically relevant metastatic prostate cancer models. In aim 3, we develop a multi-part therapeutic and toxicologic readout incorporating metabolomic, histologic, and microscale dosimetry analysis. Overall, the methods developed in this proposal promise to advance CD46 directed radioimmunotherapy, and will have significant impact upon the field of radiopharmaceutical therapy in general.