Pb-212 Peptide Receptor Targeted Prostate Cancer Therapy

这项临床前研究计划的总体目标是开发和评估靶向阿尔法的疗效。 使用靶向蛙皮素受体的阿尔法放射标记多肽拮抗剂的治疗(TAT) (BB2r)在人前列腺癌中表达。该研究计划有四个具体的技术目标： ~(212)Pb-RM2的合成与验证：本目标的目标是建立和优化方法 用于从商业上获得的~(212)Pb开始高产率和高纯度地合成~(212)Pb-RM2 224Ra/212Pb放射性核素发生器。利用自动化放射化学技术，常规的SOP将被 为高效生产临床级212Pb-RM2而开发。这也将需要制定程序 评估质量控制，以确保最终产品符合FDA的pH、无菌和 细菌内毒素。 评估212Pb-RM2的体外疗效：将通过以下小组评估212Pb-RM2的效用 代表雄激素依赖/非依赖性光谱的人PC细胞系以及一组 对多西紫杉醇、苯扎鲁胺和阿比特龙耐药的化疗耐药细胞株。几个 在这项研究过程中，将建立化疗耐药细胞系。TAT对各细胞的影响 将通过评估细胞毒性、克隆形成能力、DNA损伤和修复、细胞凋亡、细胞周期和 靶向受体(BB2r)、雄激素受体(AR)和最普遍的 PC中雄激素受体剪接变异体(ARV7)。 对~(212)Pb-RM2体内疗效的评价：最初，将对~(212)Pb-RM2的体内稳定性进行评估 然后根据212Pb-RM2确定单个器官、组织和肿瘤的辐射剂量学 使用前列腺癌异种移植模型获得的药代动力学数据。最大耐受量(MTD) 在进行疗效评价前，先测定212Ph-RM2。雇佣了一系列 CRPC异种移植模型(侧翼、胫骨和全身)，212Pb-RM2控制和缩小病灶的效果 此外，还将评估PC的系统性增长。将使用68Ga-RM2同时进行PET成像以评估 与BB2r靶向治疗同时表达BB2r以验证成像生物标记物的准确性 治疗效果的衡量标准。 执行FDA IND支持研究：这些研究的数据将用于为医生做准备 赞助IND向FDA提交TAT试剂212Pb-RM2。这一目标将继续实现。 资助期的过程，将包括获得商业化制备的cGMP产品，确定 内脏辐射剂量测定，获得商业单种毒理学评价数据，进展 并完善了常规自动化临床制剂212Pb-RM2的标准操作程序， 以及所需的制备产品放大运行的性能，以证明可以制备212Pb-RM2 在数量和纯度上满足预期的临床需求。

The overall goal of this preclinical research program is to develop and evaluate the efficacy of targeted alpha therapy (TAT) using an alpha emitting radiolabeled peptide antagonist which targets the bombesin receptor (BB2r) expressed in human prostate cancer. The research program has four specific technical objectives:  Synthesis & Validation of 212Pb-RM2: The goals of this objective are to establish and optimize methods for synthesizing 212Pb-RM2 in high yield and purity starting with 212Pb obtained from commercially available 224Ra/212Pb radionuclide generators. Utilizing automated radiochemistry technology, routine SOP’s will be developed for the efficient production of clinical grade 212Pb-RM2. This will also entail developing procedures for assessing the quality control to assure that the final product meets FDA requirements for pH, sterility, and bacterial endotoxins.  Evaluate Efficacy of 212Pb-RM2 In Vitro: The utility of 212Pb-RM2 will be assessed across a panel of human PC cell lines representing the spectrum of androgen dependence/independence as well as a panel of chemotherapy resistant cell lines that are resistant to docetaxel, enzalutamide, and abiraterone. Several chemotherapy resistant cell lines will be created during the course of this study. The effects of TAT on each cell line will be evaluated by assessing cytotoxicity, clonogenicity, DNA damage & repair, apoptosis, cell cycle, and protein expression of the targeted receptor, (BB2r), the androgen receptor (AR), and the most prevalent androgen receptor splice variant in PC,(ARV7).  Evaluate Efficacy of 212Pb-RM2 In Vivo: Initially, the in vivo stability of 212Pb-RM2 will be assessed followed by determination of individual organ, tissue, and tumor radiation dosimetry based on 212Pb-RM2 pharmacokinetic data obtained using prostate cancer xenograft models. The maximum tolerated dose (MTD) of 212Pb-RM2 will be determined prior to performance of therapeutic efficacy evaluation. Employing a series of CRPC xenograft models (flank, tibial, and systemic), the efficacy of 212Pb-RM2 in controlling and reducing focal and systemic PC growth will be evaluated. Concurrent PET imaging using 68Ga-RM2 will be performed to assess BB2r expression concurrent with BB2r targeted treatment to validate the imaging biomarker as an accurate measure of treatment efficacy.  Perform FDA IND Enabling Studies: Data from these studies will be used to prepare a physician sponsored IND for submission to the FDA of the TAT agent, 212Pb-RM2. This objective will be carried out over the course of the funding period and will include obtaining commercially prepared cGMP product, determining internal organ radiation dosimetry, obtaining commercial single species toxicology evaluation data, development and refinement of a standard operating procedure for the routine automated clinical preparation of 212Pb-RM2, and performance of required preparative product scale-up runs to demonstrate that 212Pb-RM2 can be prepared in quantities and purity necessary to meet expected clinical demands.