Preclinical and exploratory human studies of novel 68Ga-labeled D-peptide antagonist for PET imaging of TIGIT expression in cancers

Xiaobo Wang; Ming Zhou; Bei Chen; Huanhuan Liu; Jianyang Fang; Shijun Xiang; Shuo Hu; Xianzhong Zhang

doi:10.1007/s00259-021-05672-x

Preclinical and exploratory human studies of novel ⁶⁸Ga-labeled D-peptide antagonist for PET imaging of TIGIT expression in cancers

Eur J Nucl Med Mol Imaging. 2022 Jul;49(8):2584-2594. doi: 10.1007/s00259-021-05672-x. Epub 2022 Jan 17.

Authors

Xiaobo Wang^#¹, Ming Zhou^#², Bei Chen², Huanhuan Liu¹, Jianyang Fang¹, Shijun Xiang², Shuo Hu³, Xianzhong Zhang⁴

Affiliations

¹ Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, 4221-116 Xiang'an South Rd, Xiamen, 361102, China.
² Department of PET Center, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, 410008, China.
³ Department of PET Center, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, 410008, China. hushuo2018@163.com.
⁴ Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, 4221-116 Xiang'an South Rd, Xiamen, 361102, China. zhangxzh@xmu.edu.cn.

^# Contributed equally.

Abstract

Purpose: While TIGIT has been propelled as a next-generation target in cancer immunotherapy, anti-TIGIT therapy seems to be promising for a fraction of patients in clinical trials. Therefore, patient stratification is critical for this therapy, which could benefit from a whole-body, non-invasive, and quantitative evaluation of TIGIT expression in cancers. In this study, a ⁶⁸Ga-labeled D-peptide antagonist, ⁶⁸Ga-GP12, was developed and validated for PET imaging of TIGIT expression in vitro, in vivo, and in an exploratory human study.

Methods: The D-enantiomer peptide antagonists were modified and radiolabeled with ⁶⁸Ga. In vitro binding assays were performed in human peripheral blood mononuclear cells (PBMCs) to assess their affinity and specificity. The imaging capacity, biodistribution, pharmacokinetics, and radiation dosimetry were investigated. Flow cytometry, autoradiography, and immunohistochemical staining were used to confirm the expression of TIGIT. The safety and potential of ⁶⁸Ga-GP12 for PET/CT imaging of TIGIT expression were evaluated in NSCLC patients.

Results: ⁶⁸Ga-labeled D-peptides were conveniently produced with high radiochemical yields, radiochemical purities and molar activities. In vitro binding assays demonstrated ⁶⁸Ga-GP12 has high affinity and specificity for TIGIT with a K_D of 37.28 nM. In vivo and ex vivo studies demonstrated the capacity of ⁶⁸Ga-GP12 for PET imaging of TIGIT expression with high tumor uptake of 4.22 ± 0.68 %ID/g and the tumor-to-muscle ratio of 12.94 ± 2.64 at 60 min post-injection. In NSCLC patients, primary and metastatic lesions found in ⁶⁸Ga-GP12 PET images were comparable to that in ¹⁸F-FDG PET images. Moreover, tracer uptake in primary and metastatic lesions and intra-tumoral distribution in the large tumor were inhomogenous, indicating the heterogeneity of TIGIT expression.

Conclusion: ⁶⁸Ga-GP12 is a promising radiotracer for PET imaging of TIGIT expression in cancers, indicating its potential as a potential companion diagnostic for anti-TIGIT therapies.

Keywords: D-Peptide antagonist; Immune checkpoints; PET imaging; TIGIT.

MeSH terms

Carcinoma, Non-Small-Cell Lung*
Cell Line, Tumor
Gallium Radioisotopes / pharmacokinetics
Humans
Leukocytes, Mononuclear
Lung Neoplasms*
Peptides
Positron Emission Tomography Computed Tomography / methods
Positron-Emission Tomography / methods
Receptors, Immunologic
Tissue Distribution

Substances

Gallium Radioisotopes
Peptides
Receptors, Immunologic
TIGIT protein, human