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

التفاصيل البيبلوغرافية
العنوان:	The discovery and evaluation of [ ¹⁸ F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.
المؤلفون:	Donnelly DJ; Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA. david.donnelly@bms.com., Kim J; Imaging, Bristol Myers Squibb, Princeton, USA., Tran T; Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA., Scola PM; Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, USA., Tenney D; Biology, Bristol Myers Squibb, Princeton, USA., Pena A; Imaging, Bristol Myers Squibb, Princeton, USA., Petrone T; Imaging, Bristol Myers Squibb, Princeton, USA., Zhang Y; Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, USA., Boy KM; Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, USA., Poss MA; Small Molecule Drug Discovery, Bristol Myers Squibb, Princeton, USA., Cole EL; Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA., Soars MG; Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, USA., Johnson BM; Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, USA., Cohen D; Biologics and Platforms, Bristol Myers Squibb, Princeton, USA., Batalla D; Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA., Chow PL; Imaging, Bristol Myers Squibb, Princeton, USA., Shorts AO; Imaging, Bristol Myers Squibb, Princeton, USA., Du S; Imaging, Bristol Myers Squibb, Princeton, USA., Meanwell NA; Small Molecule Drug Discovery, Bristol Myers Squibb, Princeton, USA., Bonacorsi SJ Jr; Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA.
المصدر:	European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2024 Mar; Vol. 51 (4), pp. 978-990. Date of Electronic Publication: 2023 Dec 05.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Springer-Verlag Berlin Country of Publication: Germany NLM ID: 101140988 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1619-7089 (Electronic) Linking ISSN: 16197070 NLM ISO Abbreviation: Eur J Nucl Med Mol Imaging Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: Berlin : Springer-Verlag Berlin, 2002-
مواضيع طبية MeSH:	Carcinoma, Non-Small-Cell Lung* , Lung Neoplasms* , Fibronectin Type III Domain* , Fluorine Radioisotopes* , Recombinant Proteins*, Humans ; Mice ; Animals ; B7-H1 Antigen/metabolism ; Ligands ; Macaca fascicularis/metabolism ; Positron-Emission Tomography/methods ; Peptides/chemistry
مستخلص:	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. (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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فهرسة مساهمة:	Keywords: PD-L1; PD-L1 expression; PD-L1 macrocyclic peptide PET ligand; [18F]BMS-986229
المشرفين على المادة:	0 (B7-H1 Antigen) 0 (Ligands) 0 (adnectin) GZ5I74KB8G (Fluorine-18) 0 (Peptides) 0 (Fluorine Radioisotopes) 0 (Recombinant Proteins)
تواريخ الأحداث:	Date Created: 20231204 Date Completed: 20240222 Latest Revision: 20240222
رمز التحديث:	20240222
DOI:	10.1007/s00259-023-06527-3
PMID:	38049658
قاعدة البيانات:	MEDLINE

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تدمد:	1619-7089
DOI:	10.1007/s00259-023-06527-3