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

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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 KD 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. Graphical abstract
Funding Information
  • Key Programme (U1967222)
  • National Natural Science Foundation of China (81801762, 91859207)
  • Natural Science Foundation of Hunan Province (2020JJ5956)
  • Major Research Plan (91959122)

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