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Gastric cancer (GC) is one of the most common types of cancer worldwide, with limited therapeutic options available for patients with advanced‑stage disease. Claudin 18.2 (CLDN18.2) has emerged as a popular target for the diagnosis and treatment of GC. Although antibody‑drug conjugates (ADCs) and radionuclide‑drug conjugates (RDCs) targeting CLDN18.2 have been assessed, to the best of our knowledge, no comparative studies have evaluated the efficacy and toxicity profiles of these two treatment modalities. The present study aimed to compare the antitumor efficacy and toxicity of ADCs and RDCs derived from the same anti‑CLDN18.2 monoclonal antibody (mAb) targeting CLDN18.2‑positive tumors. Modified DFO/DOTA‑SYSA1801mAb, labeled with ⁸⁹Zr and ¹⁷⁷Lu, was used in cell‑based assays, positron emission tomography and biodistribution studies to evaluate its targeting specificity. In an NUGC‑4‑CLDN18.2 xenograft tumor model, the antitumor efficacy and toxicity of the mAb (SYSA1801mAb), as well as the ADC (SYSA1801) and RDC ([¹⁷⁷Lu]Lu‑DOTA‑SYSA1801mAb), and their combinations in different sequences (ADC→RDC and RDC→ADC), were systematically assessed. [⁸⁹Zr]Zr‑DFO‑SYSA1801mAb demonstrated notable in vitro stability and effectively imaged tumors with high CLDN18.2 expression. [¹⁷⁷Lu]Lu‑DOTA‑SYSA1801mAb exhibited strong tumor‑targeting ability, with significantly higher tumor uptake than other tissues. By day 145, the complete remission (CR) rate in the ADC group was 60%, with an overall survival (OS) rate of 60%. In the ADC→RDC group, the CR and OS rates were both 40%. The OS rates in the RDC, RDC→ADC, mAb and control groups were all 0%. The ADC group exhibited minimal changes in hematological parameters and hepatic/renal function, whereas the RDC and RDC→ADC groups showed more significant changes. These preclinical findings suggested that ADC monotherapy may demonstrate superior efficacy and safety profiles when compared with RDC monotherapy. Furthermore, sequential combination therapy that starts with ADC appears to be more favorable than approaches that start with RDC. Although ADC→RDC sequential therapy did not significantly outperform ADC monotherapy in this model, it may serve as an effective subsequent treatment strategy.