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

  • Eur J Nucl Med Mol Imaging. 2024 Mar;51(4):978-990. doi: 10.1007/s00259-023-06527-3.
David J Donnelly  #  1 ,  Joonyoung Kim  #  2 ,  Tritin Tran  3 ,  Paul M Scola  4 ,  Daniel Tenney  5 ,  Adrienne Pena  2 ,  Thomas Petrone  2 ,  Yunhui Zhang  4 ,  Kenneth M Boy  4 ,  Michael A Poss  6 ,  Erin L Cole  3 ,  Matthew G Soars  7 ,  Benjamin M Johnson  7 ,  Daniel Cohen  8 ,  Daniel Batalla  3 ,  Patrick L Chow  2 ,  Andrea Olga Shorts  2 ,  Shuyan Du  2 ,  Nicholas A Meanwell  6 ,  Samuel J Bonacorsi Jr  3
Affiliations
  • 1. Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA. [email protected].
  • 2. Imaging, Bristol Myers Squibb, Princeton, USA.
  • 3. Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA.
  • 4. Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, USA.
  • 5. Biology, Bristol Myers Squibb, Princeton, USA.
  • 6. Small Molecule Drug Discovery, Bristol Myers Squibb, Princeton, USA.
  • 7. Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, USA.
  • 8. Biologics and Platforms, Bristol Myers Squibb, Princeton, USA.
  • # Contributed equally.
PMID: 38049658 DOI: 10.1007/s00259-023-06527-3
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.

Keywords
PD-L1; PD-L1 expression; PD-L1 macrocyclic peptide PET ligand; [18F]BMS-986229.
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