PreclinicalEvaluation of 177Lu-LabeledAnti-CLDN18.2 VHH-Fc for Radioimmunotherapy in Gastric Cancer

作者：X G Wang, P Chen, Jun Li, Rui Zhang, Haoyi Yan, Zhan Li, Zixuan Huang, Chuanmian Xu, J Zhang, Wenjing Zhu, Qiyu Peng, Siwei Xie, Dawei Jiang, 董孟杰 · 发表于：Molecular Pharmaceutics · 年份：2026 · DOI：10.1021/acs.molpharmaceut.6c00113 · 研究领域：Barrier Structure and Function Studies、Radiopharmaceutical Chemistry and Applications、Drug Transport and Resistance Mechanisms

PURPOSE: Claudin18.2 (CLDN18.2) has emerged as a significant therapeutic target for advanced gastric cancer. In this study, we aimed to develop a 177Lu-radiolabeled anti-CLDN18.2 VHH-Fc (SN-1A01) for radioimmunotherapy in gastric cancer (GC) tumor-bearing models. METHODS: Immunohistochemistry (IHC) for CLDN18.2 was performed on gastric lesions induced by tumors from 37 patients with GC, as well as in a GC patient-derived xenograft (GC-PDX) tumor and GC xenograft tumors (N87-18.2 and NUCG4). The SN-1A01 was conjugated with DOTA and radiolabeled using 177Lu, resulting in the formation of the radioimmunoconjugate [177Lu]Lu-DOTA-SN-1A01. We established a safe dosage for the application of [177Lu]Lu-DOTA-SN-1A01 and evaluated the therapeutic efficacy of a single dose in GC models. Ki67 expression levels in tumors were detected via IHC following treatment with [177Lu]Lu-DOTA-SN-1A01. RESULTS: IHC analysis demonstrated moderate-to-high CLDN18.2 expression in 45.9% of GC patient tumor tissues. Additionally, elevated levels of CLDN18.2 were detected in GC-PDX and N87-18.2 tumors, whereas lower expression was shown in NUGC4. A single dose of [177Lu]Lu-DOTA-SN-1A01 below 300 μCi (11.1 MBq) was well tolerated. [177Lu]Lu-DOTA-SN-1A01 significantly inhibited tumor growth and increased survival time in both GC-PDX and N87-18.2 models across a dose of 100 and 300 μCi. However, the tumor-suppressive effect was comparatively weaker in the NUGC4 model. Reduced Ki67 expression was evident in all...