Novel radioimmunoconjugates for targeted alpha-particle therapy of metastatic prostatic cancer

转移性去势抵抗性前列腺癌（mCRPC）仍然无法治愈。 一旦患者的进展超过enzalutamide和阿比特龙，则多西他赛以外的选择有限。 另一方面，mCRPC是放射免疫疗法（RIT）的合适靶标，特别是使用短程、高线性能量转移α-发射体（例如，212 Pb），基于小的传播模式，包括骨髓和淋巴结，通常接受高水平循环抗体的部位。 鉴于最近批准的α粒子223 Ra用于治疗前列腺癌骨转移的安全性和有效性，α粒子放疗联合特异性靶向肿瘤细胞的抗体对于针对mCRPC的治疗开发具有很大的希望。 快速内化到肿瘤细胞中的抗体具有改善的肿瘤靶向效率。 我们已经鉴定了一组选自噬菌体展示文库的针对人前列腺癌组织的单链抗体（scFv）。 用99 mTc标记的一种抗体的体内研究已经显示出优异的肿瘤特异性靶向，在mCRPC的临床前模型中具有高肿瘤摄取和肿瘤/非靶比。 此后，我们将靶抗原鉴定为CD 46，其为先天免疫的负调节因子。 mCRPC临床数据分析显示，mCRPC均匀过度表达CD 46，并且在enzalutamide和阿比特龙耐药患者中进一步上调。 CD 46是一种令人兴奋的新细胞表面抗原，可用于针对mCRPC的治疗开发。 我们假设，从我们的新型抗CD 46内化人scFv衍生的优化抗体形式将改善体内肿瘤靶向;当用新兴的α粒子同位素（212 Pb）标记时，CD 46抗体将被开发成用于mCRPC的新型RIT。 本项目的目标是开发一系列由抗体片段和全长抗体组成的新型抗体形式，用α发射体标记它们，确定RIT的优化形式。 通过肿瘤细胞特异性结合和内化的体外评价以及肿瘤靶向和辐射剂量测定的体内测定，将评价先导抗体在局部和播散/转移性mCRPC细胞系异种移植模型中的疗效和毒性，并进一步在mCRPC患者源性异种移植模型中进行评价。 如果成功实施，我们的研究将确定一种用于mCRPC治疗开发的主要RIT药物，解决对enzalutamide和阿比特龙无应答或耐药患者的迫切需求。

Metastatic castration resistant prostate cancer (mCRPC) remains incurable. Once patients have progressed beyond enzalutamide and abiraterone, there are limited options other than docetaxel. On the other hand, mCRPC is an appropriate target for radioimmunotherapy (RIT), especially with short-range, high linear energy transfer alpha-emitters (e.g., 212Pb), based on the pattern of small spreads, including bone marrow and lymph nodes, sites that typically receive high levels of circulating antibody. Given the demonstrated safety and efficacy of recently approved alpha-particle 223Ra for treatment of bone metastases in prostate cancer, alpha-particle radiotherapy combined with antibody specifically targeting to tumor cells hold great promise for therapy development against mCRPC. Antibodies that are rapidly internalized into tumor cells have improved tumor targeting efficiency. We have identified a panel of single chain antibodies (scFvs) selected from phage display libraries against human prostate cancer tissues. In vivo studies of one antibody labeled with 99mTc have shown excellent tumor specific targeting with high tumor uptake and tumor/non- target ratio in preclinical models of mCRPC. We have since identified the target antigen as CD46, a negative regulator of the innate immunity. Analysis of mCRPC clinical data shows that CD46 is homogeneously overexpressed by mCRPC and further upregulated in patients who are resistant to enzalutamide and abiraterone. CD46 is an exciting new cell surface antigen for therapy development against mCRPC. We hypothesize that optimized antibody formats, derived from our novel anti-CD46 internalizing human scFv, will improve tumor targeting in vivo; and when labeled with the emerging alpha-particle isotope (212Pb), CD46 antibody will be developed into a novel RIT for mCRPC. The goal of this project is to develop a series of novel antibody formats composed of antibody fragments and full-length antibodies, labeled them with alpha emitters, identified the optimized format for RIT. Through in vitro evaluation of tumor cell- specific binding and internalization and in vivo determination of tumor targeting and radiation dosimetry, the lead antibody will be evaluated for efficacy and toxicity in both localized and disseminated/metastatic mCRPC cell line xenograft models, and further in mCRPC patient-derived xenograft models. If successfully carried out, our study will identify a lead RIT agent for therapeutic development against mCRPC, addressing a dire need for patients who are either non-responsive or have developed resistant to enzalutamide and abiraterone.