The discovery and evaluation of [18F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement

• Published in: European journal of nuclear medicine and molecular imaging 2024-03, Vol.51 (4), p.978-990
• Main 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, Samuel J.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Autoradiography; B7-H1 Antigen - metabolism; Background noise; Binding; Carcinoma, Non-Small-Cell Lung; Cardiology; Chemical synthesis; Evaluation; Fibronectin Type III Domain; Fluorine; Fluorine isotopes; Fluorine Radioisotopes; Humans; Imaging; Ligands; Lung Neoplasms; Macaca fascicularis - metabolism; Medical imaging; Medicine; Medicine & Public Health; Mice; Non-small cell lung carcinoma; Nuclear Medicine; Oncology; Original Article; Orthopedics; PD-1 protein; PD-L1 protein; Peptides; Peptides - chemistry; Positron emission; Positron-Emission Tomography - methods; Primates; Radiology; Recombinant Proteins; Small cell lung carcinoma; Tumors
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-023-06527-3

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 [ 18 F]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 18 F-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 [ 18 F]BMS-986229 to measure PD-L1 expression in tumors.