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

Mortensen, Anja C L ; Mohajershojai, Tabassom ; Gustafsson, Amanda ; Berglund, Hanna ; Selvaraju, Ram Kumar ; Hofström, Camilla ; Persson, Helena ; Ohlin, Mats LU orcid ; Tran, Thuy A LU and Morén, Anton Forsberg , et al. (2025) In Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Abstract

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... (More)

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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publishing date
type
Contribution to journal
publication status
epub
subject
in
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
publisher
Society of Nuclear Medicine Inc.
external identifiers
  • pmid:41198237
ISSN
0161-5505
DOI
10.2967/jnumed.125.270782
language
English
LU publication?
yes
additional info
© 2025 by the Society of Nuclear Medicine and Molecular Imaging.
id
2ff23ad5-cd9e-4162-9aa9-def477b898c9
date added to LUP
2025-11-21 13:17:04
date last changed
2025-11-25 12:26:50
@article{2ff23ad5-cd9e-4162-9aa9-def477b898c9,
  abstract     = {{<p>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.</p>}},
  author       = {{Mortensen, Anja C L and Mohajershojai, Tabassom and Gustafsson, Amanda and Berglund, Hanna and Selvaraju, Ram Kumar and Hofström, Camilla and Persson, Helena and Ohlin, Mats and Tran, Thuy A and Morén, Anton Forsberg and Ochniewicz, Piotr and Zedenius, Jan and Bernhardt, Peter and Frejd, Fredrik Y and Nestor, Marika}},
  issn         = {{0161-5505}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{Society of Nuclear Medicine Inc.}},
  series       = {{Journal of nuclear medicine : official publication, Society of Nuclear Medicine}},
  title        = {{Preclinical Validation of [177Lu]Lu-AKIR001, a CD44v6-Targeted Radiotherapeutic Entering First-in-Human Trials}},
  url          = {{http://dx.doi.org/10.2967/jnumed.125.270782}},
  doi          = {{10.2967/jnumed.125.270782}},
  year         = {{2025}},
}