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

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

  • J Nucl Med. 2026 Feb 2;67(2):269-275. doi: 10.2967/jnumed.125.270782.
Anja C L Mortensen 1 2,  Tabassom Mohajershojai 3,  Amanda Gustafsson 2,  Hanna Berglund 2,  Ram Kumar Selvaraju 4,  Camilla Hofström 5,  Helena Persson 5,  Mats Ohlin 6,  Thuy A Tran 7,  Anton Forsberg Morén 8,  Piotr Ochniewicz 8,  Jan Zedenius 9 10,  Peter Bernhardt 11 12,  Fredrik Y Frejd 2,  Marika Nestor 2
Affiliations

Affiliations

  • 1 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; [email protected].
  • 2 Department of Immunology, Genetics, and Pathology, Science for Life Laboratories, Uppsala University, Uppsala, Sweden.
  • 3 Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 4 Preclinical PET-MRI Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
  • 5 Drug Discovery and Development, Science for Life Laboratories and Royal Institute of Technology, Stockholm, Sweden.
  • 6 Drug Discovery and Development, Science for Life Laboratories and Department of Immunotechnology, Lund University, Lund, Sweden.
  • 7 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
  • 8 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • 9 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • 10 Department of Breast, Endocrine Tumors, and Sarcoma, Karolinska University Hospital, Stockholm, Sweden.
  • 11 Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; and.
  • 12 Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden.
PMID: 41198237 DOI: 10.2967/jnumed.125.270782
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 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.

Keywords

CD44v6; RPT; rADCs; radioantibody–drug conjugates; translational oncology.

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