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

项目总结和摘要 该提案的主要目标是优化我们有前途的CD 46定向放射免疫治疗方法， 利用现有技术的转移性癌症模型系统地测试治疗功效和毒性。 疗效和毒性的读数将包括组织学、代谢组学和微尺度剂量测定 分析.我们的初步数据和先前的出版物表明，CD 46定向 放射免疫疗法中心假设是我们的建议是优化的CD 46指导 放射免疫疗法将允许有效的前列腺癌治疗， 毒性这一假设将在相关的原位和播散转移模型中进行检验，使用读数 包括组织学、代谢组学和微尺度剂量测定分析。 在PAR-22-139的指导下，我们组建了一个包括核医学在内的多学科多PI团队 医生，癌症代谢和动物模型开发专家，物理学家，放射化学家，专家 抗体药物开发和病理学家。在目标1中，我们开发新型双功能抗体螯合剂 标记以使治疗性225 Ac的肿瘤递送最大化。在目标2中，我们系统地测试了优化的 放射免疫治疗剂在临床相关转移性前列腺癌模型中的应用。在目标3中，我们开发了一个 结合代谢组学、组织学和微尺度剂量测定的多部分治疗和毒理学读数 分析.总的来说，本提案中开发的方法有望促进CD 46定向 放射免疫疗法，并将对一般的放射药物治疗领域产生重大影响。

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.