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。一旦患者进展到恩杂鲁胺和阿比特龙以外，除了多西紫杉醇之外，选择有限。另一方面，mCRPC是放射免疫治疗（RIT）的合适靶标，特别是短程、高线性能量转移α -发射器（例如，212Pb），基于小扩散的模式，包括骨髓和淋巴结，这些部位通常接受高水平的循环抗体。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粒子放疗联合特异性靶向肿瘤细胞的抗体在治疗mCRPC方面具有很大的前景。快速内化到肿瘤细胞中的抗体提高了肿瘤靶向效率。我们从噬菌体展示文库中选择了一组单链抗体（scFvs）来对抗人类前列腺癌组织。一种标记有99mTc的抗体在临床前mCRPC模型中显示出优异的肿瘤特异性靶向性，具有较高的肿瘤摄取和肿瘤/非靶标比。我们已经确定目标抗原为CD46，一种先天免疫的负调节因子。对mCRPC临床数据的分析显示，在对恩杂鲁胺和阿比特龙耐药的患者中，CD46在mCRPC中同质过表达，并进一步上调。CD46是一种令人兴奋的新的细胞表面抗原，用于治疗mCRPC。我们假设从我们的新型抗cd46内化人scFv衍生的优化抗体格式将改善体内肿瘤靶向性；当CD46抗体被新出现的α粒子同位素（212Pb）标记时，它将发展成为一种新的用于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格式，用α发射体对其进行标记，确定RIT的优化格式。通过对肿瘤细胞特异性结合和内化的体外评估，以及体内肿瘤靶向性和辐射剂量的测定，将对该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进行评估，并进一步在mCRPC患者来源的异种移植模型中进行评估。如果成功进行，我们的研究将确定一种用于mCRPC治疗开发的主要RIT药物，解决对恩杂鲁胺和阿比特龙无反应或产生耐药的患者的迫切需求。

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.