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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

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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.

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Acknowledgements

The authors would like to thank Michael Miller, Louis Lombardo, Percy Carter, Virginie Lafont, Yawu Jing and Wendy Hayes for their efforts in support of the work generated in this manuscript.

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Author notes

  1. David J. Donnelly and Joonyoung Kim contributed equally to this work.

Authors and Affiliations

  1. Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA

    David J. Donnelly, Tritin Tran, Erin L. Cole, Daniel Batalla & Samuel J. Bonacorsi Jr

  2. Imaging, Bristol Myers Squibb, Princeton, USA

    Joonyoung Kim, Adrienne Pena, Thomas Petrone, Patrick L. Chow, Andrea Olga Shorts & Shuyan Du

  3. Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, USA

    Paul M. Scola, Yunhui Zhang & Kenneth M. Boy

  4. Biology, Bristol Myers Squibb, Princeton, USA

    Daniel Tenney

  5. Small Molecule Drug Discovery, Bristol Myers Squibb, Princeton, USA

    Michael A. Poss & Nicholas A. Meanwell

  6. Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, USA

    Matthew G. Soars & Benjamin M. Johnson

  7. Biologics and Platforms, Bristol Myers Squibb, Princeton, USA

    Daniel Cohen

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Correspondence to David J. Donnelly.

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Conflict of Interest

Authors: David J. Donnelly, Joonyoung Kim, Tritin Tran, Paul M. Scola, Daniel Tenney, Adrienne Pena, Thomas Petrone, Yunhui Zhang, Kenneth M. Boy, Michael A. Poss, Erin L. Cole, Matthew G. Soars, Benjamin M. Johnson, Daniel Cohen, Daniel Batalla, Patrick L. Chow, Andrea Olga Shorts, Shuyan Du, Nicholas A. Meanwell and Samuel J. Bonacorsi, Jr. were employees and stockholders of Bristol Myers Squibb Co. at the time of manuscript preparation. Ethical approval: All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures involving animal studies were reviewed and approved by the Bristol Myers Squibb animal care/use committee and in adherence to 3Rs principles of animal research (AALAC) https://www.bms.com/about-us/sustainability/environment/product-stewardship.html. This article does not contain any studies with human participants performed by any of the authors. [18F]BMS-986229, [18F]BMS-986192, BMS-986189, BMS-936559 and [18F]BMT-187144 are the subject of granted patents and pending patent applications US7943743, US8383796, WO2017201111A1 and W02017210302A1. No other conflict of interest relevant to this article was reported.

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Sadly, Tritin Tran passed away during the preparation of this manuscript, his contributions to the field of PET ligand discovery are sorely missed.

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Donnelly, D.J., Kim, J., Tran, T. et al. 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 51, 978–990 (2024). https://doi.org/10.1007/s00259-023-06527-3

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