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

项目摘要和摘要 这项建议的主要目标是优化我们有前途的CD46定向放射免疫治疗方法和 利用最新的转移性肿瘤模型，系统地测试其治疗效果和毒性。 治疗效果和毒性的读数将包括组织学、代谢学和微型剂量学。 分析。我们的初步数据和之前的出版物显示了CD46指导的巨大前景 放射免疫疗法。中心假设是我们的建议是优化的CD46导向 放射免疫疗法可以在相对保留正常组织的情况下有效地治疗前列腺癌。 毒性。这一假设将在相关的原位和播散性转移模型中进行验证，使用读数 包括组织学、代谢组学和微尺度剂量学分析。 在PAR-22-139的指导下，我们组建了一支包括核医学在内的多学科多PI团队 内科医生、癌症新陈代谢和动物模型开发专家、物理学家、放射化学家、专家 在抗体药物开发方面，以及病理学家。在目标1中，我们开发了用于抗体的新型双功能螯合剂 标记以最大限度地实现治疗性225 Ac的肿瘤递送。在目标2中，我们系统地测试了优化的 临床相关转移性前列腺癌模型中的放射免疫治疗药物。在目标3中，我们开发了一个 结合代谢学、组织学和微尺度剂量学的多部分治疗和毒理学读数 分析。总体而言，本提案中开发的方法有望推动CD46定向 放射免疫治疗，并将对整个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.