Noninvasive Imaging of Claudin 18.2 Expression in Gastric Adenocarcinoma: Synthesis, Preclinical Evaluation, and Preliminary Clinical Study of a Novel [Zr]Zr-DFO-NY005 Immuno-Positron Emission Tomography Tracer.

[PURPOSE] Claudin 18.2 (CLDN18.2) is predominantly expressed in the gastric mucosa and becomes exposed and accessible during malignant transformation. Its highly restricted expression pattern and function in gastric cancer (GC) make CLDN18.2 a promising target for the treatment of GC. Accordingly, the accurate assessment of CLDN18.2 expression is imperative for CLDN18.2-targeted cancer therapeutics. In this study, we aimed to develop a CLDN18.2-targeting positron emission tomography (PET) probe for the in vivo assessment of CLDN18.2 expression.

[METHODS AND MATERIALS] Anti-CLDN18.2 recombinant single-chain antibody fused with IgG1-fragment crystallizable (VHH-Fc) fusion protein NY005 was radiolabeled using p-isothiocyanatobenzyl-desferrioxamine B chelator and Zr to obtain the [Zr]Zr-DFO-NY005 PET probe. The specific activity, radiochemical purity, and the stability of the probe were then assayed. We evaluated the CLDN18.2-targeting capability of [Zr]Zr-DFO-NY005 in the A549 xenograft tumor model and investigated its biodistribution, pharmacokinetics, and biosafety in Institute of Cancer Research mice. Furthermore, we performed the PET/computed tomography imaging of [Zr]Zr-DFO-NY005 in patients with GC to assess the clinical application potential.

[RESULTS] The successfully synthesized [Zr]Zr-DFO-NY005 exhibited promising specific activity, radiochemical purity, and stability and demonstrated excellent targeting capability against CLDN18.2 in the A549 xenograft tumor model. After administration, [Zr]Zr-DFO-NY005 was mainly distributed in the liver, spleen, and kidneys of Institute of Cancer Research mice. In vivo assessment showed that [Zr]Zr-DFO-NY005 had a T1/2α of 2.6 hour and a T1/2β of 98.84 hour, with no apparent toxicity detected. PET/computed tomography imaging performed in patients with GC demonstrated the capability of [Zr]Zr-DFO-NY005 for the noninvasive assessment of CLDN18.2 expression.

[CONCLUSIONS] We successfully developed a CLDN18.2-targeting PET probe, [Zr]Zr-DFO-NY005, and demonstrated promising capability for the evaluation of CLDN18.2 expression in GC.