Targeted depletion of activated fibroblasts via [177Lu]Lu-FAPI radionuclide therapy ameliorates bleomycin-induced lung fibrosis.

INTRODUCTION: Fibroblast activation protein (FAP)-targeted radiopharmaceuticals have been widely applied in oncologic imaging and therapy, while their application in pulmonary fibrosis remains underexplored. This study investigated the biodistribution and therapeutic potential of [177Lu]Lu-labeled FAP inhibitor (FAPI) in pulmonary fibrosis using two administered activity regimens.

METHODS: The therapeutic potential of an albumin-binder-conjugated FAPI radiopharmaceutical, [177Lu]Lu-TEFAPI-06 was evaluated in a murine model of bleomycin-induced pulmonary fibrosis. Targeting efficiency and pharmacokinetics were evaluated by small-animal PET/CT, SPECT/CT, and ex vivo biodistribution analyses. Therapeutic efficacy and tissue responses were then compared between two administered activity regimens.

RESULTS: [177Lu]Lu-TEFAPI-06 preferentially accumulated and was retained in fibrotic lungs with high uptake in FAP-positive lesions. The 11.1 MBq regimen significantly attenuated pulmonary fibrosis, reducing collagen deposition by approximately 50%, whereas the 18.5 MBq regimen failed to improve fibrosis and was accompanied by increased pulmonary macrophage infiltration and enrichment of Arg1-positive macrophages. Both regimens were well tolerated, with no detectable short-term toxicity.

DISCUSSION: This study provides proof-of-concept for FAP-targeted radionuclide therapy in experimental pulmonary fibrosis. Our findings suggest that distinct therapeutic outcomes are accompanied by different local tissue responses following treatment and support further evaluation of stromal-targeted radionuclide therapy for pulmonary fibrosis.