Development and comparison of 68Ga/18F/64Cu-labeled nanobody tracers probing Claudin18.2

Weijun Wei; Di Zhang; You Zhang; Lianghua Li; Yuchen Jin; Shuxian An; Chun Lv; Haitao Zhao; Cheng Wang; Yanshan Huang; Jiali Dong; Gang Huang; Jianjun Liu

doi:10.1016/j.omto.2022.11.003

Development and comparison of ⁶⁸Ga/¹⁸F/⁶⁴Cu-labeled nanobody tracers probing Claudin18.2

Mol Ther Oncolytics. 2022 Nov 14:27:305-314. doi: 10.1016/j.omto.2022.11.003. eCollection 2022 Dec 15.

Authors

Weijun Wei¹, Di Zhang¹, You Zhang¹, Lianghua Li¹, Yuchen Jin¹, Shuxian An¹, Chun Lv¹, Haitao Zhao¹, Cheng Wang¹, Yanshan Huang², Jiali Dong², Gang Huang^{1

3}, Jianjun Liu¹

Affiliations

¹ Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, China.
² Zhejiang Doer Biologics Corporation, Hangzhou, China.
³ Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.

Abstract

Claudin 18.2 (CLDN18.2) is an emerging target for the treatment of gastric cancers. We aim to develop tracers to image the expression of CLDN18.2. A humanized nanobody targeting CLDN18.2 (clone hu19V3) was produced and labeled with ⁶⁸Ga, ⁶⁴Cu, and ¹⁸F. The tracers were investigated in subcutaneous and metastatic models established using two different mouse types (nude and Balb/c mice) and two different cell lines (CHO-CLDN18.2 and CT26-CLDN18.2). Gastric cancer patient-derived xenograft (PDX) models were further established for validation experiments. Three novel CLDN18.2-targeted tracers (i.e., [⁶⁸Ga]Ga-NOTA-hu19V3, [⁶⁴Cu]Cu-NOTA-hu19V3, and [¹⁸F]F-hu19V3) were developed with good radiochemical yields and excellent radiochemical purities. [⁶⁸Ga]Ga-NOTA-hu19V3 immuno-positron emission tomography (immunoPET) rapidly delineated subcutaneous CHO-CLDN18.2 lesions and CT26-CLDN18.2 tumors, as well as showing excellent diagnostic value in PDX models naturally expressing CLDN18.2. While [⁶⁸Ga]Ga-NOTA-hu19V3 had high kidney accumulation, [⁶⁴Cu]Cu-NOTA-hu19V3 showed reduced kidney accumulation and improved image contrast at late time points. Moreover, [¹⁸F]F-hu19V3 was developed via click chemistry reaction under mild conditions and precisely disseminated CHO-CLDN18.2 lesions in the lungs. Furthermore, region of interest analysis, biodistribution study, and histopathological staining results correlated well with the in vivo imaging results. Taken together, immunoPET imaging with the three tracers can reliably visualize CLDN18.2 expression.

Keywords: Claudin 18.2; companion diagnostics; immunoPET; nanobody; radiopharmaceuticals.