Molecular pharmaceutics · 2026
Preclinical Evaluation of 177Lu-Labeled Anti-CLDN18.2 VHH-Fc for Radioimmunotherapy in Gastric Cancer.
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Wang Xiaoyan, Chen Ping, Li Jun, Zhang Rui, Yan Haoyi, Li Zhan, Huang Zixuan, Xu Chuanmian, Zhang JinYuan, Zhu Wenjing, Peng Qiyu, Xie Siwei, Jiang Dawei, Dong Mengjie
Аннотация
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 [177Lu]Lu-DOTA-SN-1A01-treated tumors.
CONCLUSION: In preclinical studies, [177Lu]Lu-DOTA-SN-1A01 demonstrated significant antitumor efficacy with acceptable toxicity, which indicated a strong potential for clinical translation in GC therapy.
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 [177Lu]Lu-DOTA-SN-1A01-treated tumors.
CONCLUSION: In preclinical studies, [177Lu]Lu-DOTA-SN-1A01 demonstrated significant antitumor efficacy with acceptable toxicity, which indicated a strong potential for clinical translation in GC therapy.