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

Caroline Rousseau; Pierre Baumgartner; Marie-Françoise Heymann; Manon Taupin; Maïwenn Geffroy; Jean-François Chatal; Gaëlle Gautier; Nadia Allam; Joëlle Gaschet; Romain Eychenne; François Guérard; Jean-François Gestin; Nicolas Varmenot; Michel Chérel

doi:10.3390/cancers17071190

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

Cancers (Basel). 2025 Mar 31;17(7):1190. doi: 10.3390/cancers17071190.

Authors

Caroline Rousseau^{1

2}, Pierre Baumgartner¹, Marie-Françoise Heymann^{1

3}, Manon Taupin^{1

4}, Maïwenn Geffroy¹, Jean-François Chatal⁵, Gaëlle Gautier⁶, Nadia Allam¹, Joëlle Gaschet^{1

2}, Romain Eychenne^{2

7}, François Guérard², Jean-François Gestin^{1

2}, Nicolas Varmenot^{1

2

7}, Michel Chérel^{1

2}

Affiliations

¹ Institut de Cancérologie de l'Ouest, F-44800 Saint-Herblain, France.
² Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France.
³ Research Pathology Platform, Tumor Heterogeneity and Precision Medicine, F-44800 Saint-Herblain, France.
⁴ Research Pathology Platform, F-44800 Saint-Herblain, France.
⁵ Atonco, Pôle Bio-Ouest Laennec, Rue du Moulin de la Rousselière, F-44800 Saint-Herblain, France.
⁶ Chelatec, 1 Rue Aronnax, F-44817 Saint-Herblain, France.
⁷ Groupement d'Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint-Herblain, France.

Abstract

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.

Keywords: PET/CT; [211At]At; [89Zr]Zr-girentuximab; carbonic anhydrase IX; dosimetry; non-muscle-invasive bladder cancer; radioimmunotherapy.