Abstract 1339: Claudin 18.2-targeted 68Ga-labeled NODAGA-SNA014 for gastric cancer imaging by PET

Abstract Introduction: Claudin 18.2 is a tight-junction protein with primary expression in nonmalignant gastric epithelium and limited expression in normal tissues. Its upregulation has been identified as the result of the malignant transformation of gastric epithelial tissue. CLDN18.2 therefore becomes a highly selective theranostic target for the development of gastric cancer radiopharmaceuticals. We preclinically evaluated 68Ga-NODAGA-SNA014 as a novel PET imaging agent for gastric cancer. Methods: SNA014 is a single domain antibody (SdAb) derived from alpaca immunization and screened out by phage display. SNA014 was then conjugated with NODAGA to enable efficient 68Ga labelling. The binding property of 68Ga-NODAGA-SNA014 was characterized by saturation binding assay on claudin 18.2-expressing AGS cells. Screening of renal uptake inhibitors was conducted by in vivo biodistribution studies on NDG mice bearing claudin 18.2-expressing tumors. Biodistribution properties, pharmacokinetic profile and competitive blocking effects were determined by ex vivo biodistribution studies on AGS 18.2-bearing NDG mice. Organ-adsorbed doses were estimated using OLINDA software to extrapolate to the adult female phantom the ex vivo biodistribution data of 68Ga-NODAGA-SNA014. Results: Radiolabeling was quantitative (>99%) after 15 min of incubation at room temperature. The saturable specific binding of 68Ga-NODAGA-SNA014 indicated a dissociation constant of 2.18 nM. Gleofusine showed effective reduce in the kidney uptake of 68Ga-NODAGA-SNA014 without lowering tumor uptake when compared to other inhibitors. The ex vivo biodistribution studies showed the tumor, kidney and stomach uptake of 68Ga-NODAGA-SNA014 were at 15.57 ± 6.06, 6.15 ± 0.90 and 75.27 ± 7.93 %ID/g at 1 h postinjection, respectively. Competitive blocking assay suggested NODAGA-SNA014 was able to block uptake of 68Ga-NODAGA-SNA014 at stomach in a dose-dependent fashion, ranging from 10 to 60 μg, without dramatically altering the tumor and kidney uptake. Pharmacokinetic profile revealed 68Ga-NODAGA-SNA014 had a plasma half-life of 45.23 ± 3.87 min. In addition, the effective dose was estimated at 0.0608 mSv/MBq. Conclusions: We developed a novel claudin 18.2-targeted PET agent 68Ga-NODAGA-SNA014 for gastric cancer imaging. The 68Ga-NODAGA-SNA014 showed specific in vitro binding to claudin 18.2, favorable ex vivo biodistribution properties in terms of tumor, kidney and stomach uptake, and safety profile based on dosimetry studies, which prompt us to further develop NODAGA-SNA014-based radiopharmaceuticals for radiotherapy. Citation Format: Yanling Yang, Hao Qi, Zheng Qiao, Fusen Sun, Fangfang Li, Jiachang Xu, Tao Xu. Claudin 18.2-targeted Ga-labeled NODAGA-SNA014 for gastric cancer imaging by PET. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1339.