Abstract
Gastric cancer remains a major global health challenge with few durable treatments, and claudin-18.2 (CLDN18.2) has emerged as an attractive therapeutic target, highlighted by the modest activity of zolbetuximab in clinical trials. To further leverage CLDN18.2 as a therapeutic target, we developed a radiotheranostic strategy using [(89)Zr]Zr-zolbetuximab and [(177)Lu]Lu-zolbetuximab for molecular imaging and targeted radiotherapy, respectively. Methods: We performed [(89)Zr]Zr-zolbetuximab immuno-PET imaging to quantify and localized CLDN18.2 expression in vivo, comparing uptake with [(89)Zr]Zr-trastuzumab in matched human epidermal growth factor receptor 2-positive patient-derived xenograft models. We then evaluated the therapeutic efficacy and safety of [(177)Lu]Lu-zolbetuximab versus [(177)Lu]Lu-trastuzumab, assessing tumor inhibition, tolerability, hematologic profiles, and histopathology. Results: PET imaging confirmed selective accumulation in tumor tissue, which correlated with immunohistochemistry results, validating a biomarker-driven approach for patient stratification. Therapeutic dosing resulted in sustained tumor control with an acceptable safety profile characterized by transient weight loss and hematologic suppression that largely recovered over time. Unlike prior studies using engineered cell line-derived xenografts that overexpress CLDN18.2 and display high hepatic uptake with limited tumor localization, we used patient-derived xenograft models that preserved endogenous antigen levels, stromal complexity, and vascular heterogeneity, achieving superior tumor targeting and lower nonspecific liver uptake. Conclusion: These findings outline a clinically relevant roadmap for CLDN18.2 radiotheranostics in which imaging enables patient selection and dosimetry, therapy delivers targeted tumor control, and rational combinations with chemotherapy or immunotherapy may further extend efficacy. Ultimately, this approach could make antibody-based radiopharmaceuticals a transformative modality in gastric cancer.