Development, Characterization, and Radiation Dosimetry Studies of 18 F-BMS-986229, a 18 F-Labeled PD-L1 Macrocyclic Peptide PET Tracer

• Published in: Molecular imaging and biology
• Main Authors: Kim, Joonyoung, Donnelly, David J, Tran, Tritin, Pena, Adrienne, Shorts, Andrea Olga, Petrone, Thomas V, Zhang, Yunhui, Boy, Kenneth M, Scola, Paul M, Tenney, Daniel J, Poss, Michael A, Soars, Matthew G, Bonacorsi, Jr, Samuel J, Cole, Erin L, Grootendorst, Diederik J, Chow, Patrick L, Meanwell, Nicholas A, Du, Shuyan
• Format: Journal Article
• Language: English
• Published: United States 20.12.2023
• Subjects: Preclinical PET imaging; 18F-labeled macrocyclic peptide; PD-1:PD-L1 checkpoint inhibitor
• ISSN: 1860-2002

In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients. F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of F-BMS-986229 in healthy non-human primates (NHPs) was performed. In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1 +) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90-100 min after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq. F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.