Development and Preclinical Evaluation of [68Ga]BMSH as a New Potent Positron Emission Tomography Tracer for Imaging Programmed Death-Ligand 1 Expression

Author:

Huang Yong1,Li Chengze1,Li Zhongjing1,Wang Qiong1,Huang Size1,Liu Qi23ORCID,Liang Ying1

Affiliation:

1. Department of Nuclear Medicine, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China

2. International Cancer Center, Shenzhen University School of Medicine, Shenzhen University, Shenzhen 518057, China

3. Institute of Biomedical Engineering, Shenzhen Graduate School, Peking University, Shenzhen 518055, China

Abstract

Immunotherapy targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) pathway has shown remarkable efficacy against various cancers, but the overall response rate (ORR) is still low. PD-L1 expression in tumors may predict treatment response to immunotherapy. Indeed, ongoing clinical studies utilize a few PD-L1 radiotracers to assess PD-L1 expression as a predictive biomarker for immunotherapy. Here, we present a novel positron emission tomography (PET) radiotracer called [68Ga]BMSH, which is derived from a small molecule inhibitor specifically targeting the binding site of PD-L1. The inhibitor was modified to optimize its in vivo pharmacokinetic properties and enable chelation of 68Ga. In vitro evaluation revealed [68Ga]BMSH possessed a strong binding affinity, high specificity, and rapid internalization in PD-L1 overexpressing cells. Biodistribution studies showed that PD-L1 overexpressing tumors had an uptake of [68Ga]BMSH at 4.22 ± 0.65%ID/g in mice, while the number was 2.23 ± 0.41%ID/g in PD-L1 low-expressing tumors. Micro-PET/CT imaging of tumor-bearing mice further confirmed that, compared to [18F]FDG, [68Ga]BMSH can specifically identify tumors with varying levels of PD-L1 expression. Our findings suggest that the [68Ga]BMSH is a PD-L1 radioligand with ideal imaging properties, and its further application in the clinical screening of PD-L1 overexpressing tumors may improve ORR for immunotherapy.

Funder

National Natural Science Foundation of China

National Cancer Center

Shenzhen High-level Hospital Construction Fund

Shenzhen Science and Technology Program of China

Shenzhen Clinical Research Center for Cancer

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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