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- Title
The discovery and evaluation of [<sup>18</sup>F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.
- Authors
Donnelly, David J.; Kim, Joonyoung; Tran, Tritin; Scola, Paul M.; Tenney, Daniel; Pena, Adrienne; Petrone, Thomas; Zhang, Yunhui; Boy, Kenneth M.; Poss, Michael A.; Cole, Erin L.; Soars, Matthew G.; Johnson, Benjamin M.; Cohen, Daniel; Batalla, Daniel; Chow, Patrick L.; Shorts, Andrea Olga; Du, Shuyan; Meanwell, Nicholas A.; Bonacorsi Jr, Samuel J.
- Abstract
Purpose: A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1. Methods: [18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression. Results: Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%. Conclusion: A novel 18F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [18F]BMS-986229 to measure PD-L1 expression in tumors.
- Subjects
PEPTIDES; PROGRAMMED death-ligand 1; NON-small-cell lung carcinoma; POSITRON emission tomography; KRA
- Publication
European Journal of Nuclear Medicine & Molecular Imaging, 2024, Vol 51, Issue 4, p978
- ISSN
1619-7070
- Publication type
Article
- DOI
10.1007/s00259-023-06527-3