Safety, Biodistribution, and Dosimetry of FAP and Integrin α_vβ₃ Dual-Targeting Radioligand ¹⁷⁷Lu-DOTA-FAPI-RGD: Preclinical Validation and First-in-Human Study in Patients with Advanced Adenocarcinomas.

Authors

Jialin Xiang, Xuejun Wen, Rongxi Wang, Jiarou Wang, Xingtong Peng, Yanwei Wang, Naixin Liang, Dongyan Cao, Xiaoyuan Chen, Zhaohui Zhu, Jingjing Zhang

Published in

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Aug 20, 2026. Epub Aug 20, 2026.

Abstract

Fibroblast activation protein (FAP) and integrin α_vβ₃ are attractive theranostic targets. We developed a dual-targeting radiotheranostic agent, ¹⁷⁷Lu-DOTA-FAPI-RGD (¹⁷⁷Lu-LNC1009), and conducted a first-in-human study to evaluate its safety, biodistribution, dosimetry, and preliminary efficacy in patients with advanced adenocarcinomas. Methods: LNC1009 was synthesized by conjugating an FAP inhibitor, an RGDfK peptide, and DOTA. Preclinical biodistribution was assessed in HT1080-FAP and U87MG xenografts. Nine patients with advanced solid tumors and positive ⁶⁸Ga-FAPI-RGD PET/CT received 2.0 ± 0.3 GBq (range, 1.6-2.4 GBq) of ¹⁷⁷Lu-LNC1009. Primary endpoints included biodistribution, dosimetry, and safety; efficacy was the secondary endpoint. Results: ¹⁷⁷Lu-LNC1009 showed high radiochemical purity and stability, strong dual-target binding, and sustained tumor uptake with favorable tumor-to-background ratios. In patients, treatment was well-tolerated, with no grade 4 adverse events. The whole-body effective dose was 0.08 ± 0.02 mSv/MBq. Mean absorbed doses were 0.04 ± 0.01 Gy/GBq (red marrow), 0.50 ± 0.31 Gy/GBq (liver), and 0.31 ± 0.11 Gy/GBq (kidneys). Tumor-absorbed doses reached 6.10 ± 1.42 Gy/GBq (lung metastases) and 4.20 ± 0.84 Gy/GBq (lymph nodes). Grade 3 adverse events included thrombocytopenia (n = 3), leukopenia (n = 2), and anemia (n = 1). Partial responses occurred in 2 patients (22.2%), stable disease in 6 (66.7%), and progressive disease in 1 (11.1%), yielding an objective response rate of 22.2% and disease control rate of 88.9%. Conclusion: This first-in-human, dual-targeting radiopharmaceutical therapy agent ¹⁷⁷Lu-LNC1009 demonstrated favorable dosimetry, high tumor radiation delivery, and encouraging preliminary efficacy across a variety of advanced solid tumors. Future ligand structural optimization and refined screening protocols are warranted to improve safety and further efficacy in multicycle, tumor-specific dose-escalation trials.

PMID:
42624650
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.

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