Carbonic Anhydrase IX-Targeted Alpha-Radionuclide Therapy with225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model

In this study we compare 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. Methods: BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with [225Ac]Ac-DOTA-hG250 (225Ac-hG250) and MBq [177Lu]Lu-DOTA-hG250 (177Lu-hG250), followed ex vivo biodistrubtion studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, 25 kBq of 225Ac-hG250 or 13 MBq of 177Lu-hG250 or no treatment. Tolerability was evaluated in non-tumor bearing animals. Results: High tumor uptake of both radioimmunoconjugates was observed and reached a maximum at day 7 (212.8 ± 50.2 %ID/g vs. 101.0 ± 18.4 %ID/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 (p<.05). Non-tumor bearing mice that received single-dose treatment with 15 or 25 kBq 225Ac-hG250 showed weight loss at the end of experiment, and immunohistochemical analysis suggested radiation-induced nephrotoxicity. Conclusion: These results demonstrate the therapeutic potency of CAIX-targeted alpha therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity.

MERKX Robin;  RIJPKEMA Mark;  FRANSSEN Gerben;  KIP Annemarie;  SMEETS Bart;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  YAN Eddie;  WHEATCROFT Michael;  OOSTERWIJK Egbert;  MULDERS Peter;  HESKAMP Sandra; 

2022-12-16

MDPI

JRC125926

1424-8247 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC125926,   

10.3390/ph15050570 (online),