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

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Názov: Preclinical Validation of [177Lu]Lu-AKIR001, a CD44v6-Targeted Radiotherapeutic Entering First-in-Human Trials
Autori: Mortensen, Anja C L, Mohajershojai, Tabassom, Gustafsson, Amanda, Berglund, Hanna, Selvaraju, Ram Kumar, Hofström, Camilla, Persson, Helena, Ohlin, Mats, Tran, Thuy A, Morén, Anton Forsberg, Ochniewicz, Piotr, Zedenius, Jan, Bernhardt, Peter, Frejd, Fredrik Y, Nestor, Marika
Prispievatelia: Lund University, Faculty of Engineering, LTH, Departments at LTH, Department of Immunotechnology, Lunds universitet, Lunds Tekniska Högskola, Institutioner vid LTH, Institutionen för immunteknologi, Originator
Zdroj: Journal of nuclear medicine : official publication, Society of Nuclear Medicine.
Predmety: Medical and Health Sciences, Medical Biotechnology, Biomedical Laboratory Science/Technology, Medicin och hälsovetenskap, Medicinsk bioteknologi, Biomedicinsk laboratorievetenskap/teknologi
Popis: 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.
Prístupová URL adresa: https://doi.org/10.2967/jnumed.125.270782
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  Data: Preclinical Validation of [177Lu]Lu-AKIR001, a CD44v6-Targeted Radiotherapeutic Entering First-in-Human Trials
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  Data: 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.
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