Preclinical and Clinical Feasibility Studies as the First Step Before Forthcoming Intravesical Instillation of [211At]At-anti-CA-IX Antibody (ATO-101™) Study in Patients with Non-Muscle-Invasive Bladder Cancer Unresponsive to Standard of Care

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 of 211At-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.