Preclinical Validation of [177Lu]Lu-AKIR001, a CD44v6-Targeted Radiotherapeutic Entering First-in-Human Trials

Targeted radionuclide therapy is an emerging potent therapeutic strategy in oncology. The cell surface antigen CD44v6 is a potential pan-cancer target for radionuclide therapy. This study aimed to evaluate the therapeutic efficacy, biodistribution, dosimetry, and safety profile of AKIR001, an antibody targeting CD44v6 labeled with ¹⁷⁷Lu. Methods: The biodistribution and preclinical dosimetry of [¹⁷⁷Lu]Lu-AKIR001 were calculated in the highly CD44v6-expressing A431 murine xenograft model, with subsequent extrapolation to predict human dosimetry. Therapeutic efficacy was evaluated across 3 xenograft models, 2 with high and 1 with moderate levels of CD44v6, using multiple dosing levels, fractionation regimens, and combinations with cisplatin. Preclinical toxicology was evaluated in a cross-reactive rabbit model and complemented by a PET imaging study using ⁶⁸Ga-labeled AKIR001 in a cynomolgus macaque. Results: Biodistribution studies confirmed the high and selective tumor uptake of [¹⁷⁷Lu]Lu-AKIR001, resulting in favorable dosimetry predictions for clinical application. Therapeutic evaluations demonstrated significant dose-dependent efficacy in all tested xenograft models, with fractionated dosing (2 doses) resulting in complete tumor regression in 80% of the Animals in a radioresistant xenograft model. Biodistribution in rabbits demonstrated low uptake in normal tissues, and a good-laboratory-practice study using an excessive dose of AKIR001 was well tolerated, with no signs of adverse effects. PET imaging in a cynomolgus macaque corroborated these findings. Conclusion: Collectively, these data strongly support the therapeutic efficacy, safety, and dosimetry of [¹⁷⁷Lu]Lu-AKIR001, justifying its advancement into clinical trials. A phase 1 clinical trial of [¹⁷⁷Lu]Lu-AKIR001for CD44v6-positive solid cancers (NCT06639191) is currently recruiting patients.