Introduction: Recently, alpha-emitting radionuclides like astatine-211 have offered promising results in clinical development. Non-muscle-invasive bladder cancer (NMIBC) presents a need for novel therapies. One promising approach is radioimmunotherapy targeting Carbonic Anhydrase IX (CA-IX), which is supported by preclinical and clinical evidence. The aim of our preclinical and clinical studies was to evaluate the [211At]At-anti-CA-IX antibody (ATO-101™) for future use in NMIBC patient care. Methods: The anti-CA-IX antibody, girentuximab (TLX250), was labeled with lutetium-177 and astatine-211 for in vitro studies. Affinity constant measurements of [211At]At-girentuximab in RT-112 cells were taken, and toxicity evaluations were conducted in vitro and in healthy mice. Additionally, a clinical proof-of-concept study, PERTINENCE, that used [89Zr]Zr-girentuximab for PET/CT imaging in bladder cancer patients was conducted. Results: The measurement of the affinity constant of [211At]At-girentuximab in RT112 cells revealed high binding affinity and significant cytotoxicity compared to [177Lu]Lu-girentuximab. Biodistribution studies in healthy mice indicated low systemic radioactivity uptake, and a bladder post-instillation examination showed no abnormalities in bladder mucosa, suggesting safety. In the PERTINENCE study, which involved patients with NMIBC tumors expressing CA-IX, [89Zr]Zr-girentuximab PET/CT showed no extravesical leakage. Wall bladder uptake spots correlated with recurrence or inflammatory reaction. A dosimetric study suggested the potential efficacy and favorable safety profile of intravesical alpha therapy with the [211At]At-anti-CA-IX antibody (ATO-101™) in NMIBC treatment. Conclusions: Preclinical and clinical data demonstrate the promising therapeutic role of211At-targeted alpha agents in NMIBC, and the [211At]At-anti-CA-IX antibody (ATO-101™) could fulfill this role. A phase I FIH clinical trial is in preparation, and results are expected within the next years.
引言：近年来，α发射放射性核素如砹-211在临床开发中展现出良好前景。非肌层浸润性膀胱癌（NMIBC）亟需新型疗法。靶向碳酸酐酶IX（CA-IX）的放射免疫疗法是一种前景广阔的治疗策略，其有效性已获得临床前及临床证据支持。本研究通过临床前及临床研究，旨在评估[211At]At-抗CA-IX抗体（ATO-101™）在未来NMIBC临床治疗中的应用潜力。 方法：将抗CA-IX抗体吉仑妥昔单抗（TLX250）分别用镥-177和砹-211标记进行体外研究。在RT-112细胞中测定[211At]At-吉仑妥昔单抗的亲和常数，并在体外及健康小鼠体内进行毒性评估。同时开展了临床概念验证研究PERTINENCE，使用[89Zr]Zr-吉仑妥昔单抗对膀胱癌患者进行PET/CT成像。 结果：RT112细胞中[211At]At-吉仑妥昔单抗的亲和常数测定显示，相较于[177Lu]Lu-吉仑妥昔单抗，其具有更高的结合亲和力与显著细胞毒性。健康小鼠生物分布研究表明全身放射性摄取较低，膀胱灌注后检查显示膀胱黏膜无异常，提示其安全性。在针对CA-IX阳性NMIBC患者的PERTINENCE研究中，[89Zr]Zr-吉仑妥昔单抗PET/CT未显示膀胱外渗漏现象。膀胱壁摄取点与肿瘤复发或炎症反应相关。剂量学研究提示膀胱内α疗法使用[211At]At-抗CA-IX抗体（ATO-101™）治疗NMIBC可能具有良好疗效与安全性。 结论：临床前及临床数据表明211At靶向α制剂在NMIBC治疗中具有广阔前景，[211At]At-抗CA-IX抗体（ATO-101™）有望成为理想治疗选择。目前正在筹备首次人体I期临床试验，预计未来数年内可获得研究结果。
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