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

转移性去势抵抗前列腺癌(MCRPC)仍然无法治愈。一旦患者超越了苯扎鲁胺和阿比特龙，除了多西紫杉醇之外，还有有限的选择。另一方面，mCRPC是放射免疫治疗(RIT)的合适靶点，特别是对于短程、高线性能量转移的阿尔法发射体(例如，212Pb)，基于小扩散的模式，包括骨髓和淋巴结，这些部位通常会收到高水平的循环抗体。鉴于最近批准的α-粒子223Ra治疗前列腺癌骨转移的安全性和有效性，α-粒子放射治疗和针对肿瘤细胞的特异性抗体在治疗mCRPC方面具有很大的发展前景。快速内化到肿瘤细胞中的抗体提高了肿瘤靶向效率。我们已经鉴定了一组从噬菌体展示文库中挑选出来的抗人前列腺癌组织的单链抗体(ScFv)。体内研究表明，99mTC标记的抗体具有良好的肿瘤特异性靶向性，在临床前的mCRPC模型中具有很高的肿瘤摄取率和肿瘤/非靶点比率。自那以后，我们确定目标抗原是CD46，一种天然免疫的负调节因子。对mCRPC临床数据的分析表明，mCRPC均一性过表达CD46，在对苯扎鲁胺和阿比特龙耐药的患者中CD46进一步上调。CD46是一种令人兴奋的新型细胞表面抗原，可用于治疗mCRPC。我们假设，优化的抗体形式，源自我们新的抗CD46内化人单链抗体，将提高体内的肿瘤靶向性；当标记新出现的α粒子同位素(212Pb)时，CD46抗体将发展成为一种新的mCRPC的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，并用α发射体标记它们，确定适合RIT的最佳形式。通过肿瘤细胞特异性结合和内化的体外评估以及体内肿瘤靶向和辐射剂量学的测定，铅抗体将在局部和播散/转移性mCRPC细胞系异种移植模型中以及进一步在mCRPC患者来源的异种移植模型中进行疗效和毒性评估。如果成功进行，我们的研究将确定针对mCRPC的治疗开发的主要RIT试剂，满足对苯扎鲁胺和阿比特龙无反应或已产生抗药性的患者的迫切需求。

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.