Clinical translation of a novel CLDN18.2-targeting nanobody PET tracer 68Ga-PMD22 in gastric cancer patients

Introduction: This study aimed to evaluate the feasibility for a novel CLDN18.2-targeting nanobody, PMD22, labeled with ⁶⁸Ga, for non-invasive evaluating CLND18.2 expression in gastric cancer patients using PET/CT imaging.

Methods: based on the CLDN18.2-targeting nanobody PMD22, ⁶⁸Ga-PMD22 was synthesized and its cell binding properties were assayed. Preclinical pharmacokinetics were determined in CLDN18.2-positive xenografts using small animal PET/CT and biodistribution experiments. With institutional review board approval and informed consent, all 17 enrolled participants with gastrointestinal cancer (GC) met the Eastern Oncology Cooperative Group eligibility criteria (score ≤ 2). Within 1 week before surgery, patients underwent PET/CT scans following intravenous injection of 5.2 ± 1.0 mCi of ⁶⁸Ga-PMD22. The effective dosimetry of ⁶⁸Ga-PMD22 was evaluated using OLINDA software from dynamic PET data in 5 GC patients, and PET/CT imaging of ⁶⁸Ga-PMD22 and ¹⁸F-FDG was performed head-to-head in 17 GC patients. SUVs were measured from tumor lesions and normal gastric wall as background for comparison. Pathological sections were obtained for CLND18.2 immunohistochemical (IHC) staining for further analysis.

Results: Cell binding assay showed that [⁶⁸Ga]Ga-PMD22 had higher binding ability to AGS^CLDN18.2 and BGC823^CLDN18.2 than to AGS and BGC823 cells (p < 0.001). Micro PET/CT images showed that [⁶⁸Ga]Ga-PMD22 rapidly accumulated in AGS^CLDN18.2 tumor, and high contrast tumor to background imaging was clearly observed. A total of 17 patients (10 males, 7 females, median age, 62 ± 12 years) with gastrointestinal cancer were prospectively enrolled between May 2023 to Oct 2023 and no remarkable adverse events related to the study were reported. In the pilot study, the effective dose of ⁶⁸Ga-PMD22 was 1.68E-02 ± 1.45E-02 mSv/MBq. When pathological staining of 1+ and above is defined as positive for CLDN18.2 expression, the accuracy of [⁶⁸Ga]Ga-PMD22 PET in diagnosing CLDN18.2-positive gastric cancer is 93.3% (14/15), and there is a high correlation between uptake of ¹⁸F-FDG and ⁶⁸Ga-PMD22 in both SUVmax and SUVmean, with a correlation coefficient of 0.60 and 0.622 (P < 0.05), respectively. The IHC staining result was highly correlated with the SUV_max/BKG_stomach of ⁶⁸Ga-PMD22 (r_s = 0.848, P < 0.01).

Conclusions: A novel ⁶⁸Ga-labelled nanobody probe targeting CLDN18.2, ⁶⁸Ga-PMD22, was developed and preliminarily proved to be safe and effective in detecting CLDN18.2-positive gastric cancer, providing a basis for the clinical translation of the imaging agent.

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