Carbonic Anhydrase IX-Targeted α-Radionuclide Therapy with 225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model

• Published in: Pharmaceuticals
• Main Authors: Robin I. J. Merkx, Mark Rijpkema, Gerben M. Franssen, Annemarie Kip, Bart Smeets, Alfred Morgenstern, Frank Bruchertseifer, Eddie Yan, Michael P. Wheatcroft, Egbert Oosterwijk, Peter F. A. Mulders, Sandra Heskamp
• Format: Article
• Language: English
• Published: MDPI AG 2022-05-01
• Subjects: radioimmunotherapy; RCC; actinium-225; CAIX; G250
• Online Access: https://www.mdpi.com/1424-8247/15/5/570
• ISSN: 1424-8247

In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (²²⁵Ac) or the β^--emitter lutetium-177 (¹⁷⁷Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [²²⁵Ac] Ac-DOTA-hG250 (²²⁵Ac-hG250) or 30 µg [¹⁷⁷Lu] Lu-DOTA-hG250 (¹⁷⁷Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of ²²⁵Ac-hG250; 13 MBq of ¹⁷⁷Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for ²²⁵Ac-hG250 and ¹⁷⁷Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq ²²⁵Ac-hG250, 25 kBq ²²⁵Ac-hG250, and 13 MBq ¹⁷⁷Lu-hG250 compared to untreated control (<i>p</i> < 0.05). Non-tumor-bearing mice that received single-dose treatment with 15 or 25 kBq ²²⁵Ac-hG250 showed weight loss at the end of the experiment (day 126), and immunohistochemical analysis suggested radiation-induced nephrotoxicity. These results demonstrate the therapeutic potential of CAIX-targeted α-therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity.