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Synthesis and Biologic Evaluation of a Novel 18 F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression

2017; Society of Nuclear Medicine and Molecular Imaging; Volume: 59; Issue: 3 Linguagem: Inglês

10.2967/jnumed.117.199596

1535-5667

David J. Donnelly, R. Adam Smith, Paul E. Morin, Daša Lipovšek, Jochem Gokemeijer, Daniel N. Cohen, Virginie Lafont, Tritin Tran, Erin L. Cole, Martin C. Wright, Joon‐Young Kim, Adrienne Pena, Daniel Kukral, Douglas D. Dischino, Patrick L Chow, Jinping Gan, Olufemi Adelakun, Xitao Wang, Kai Cao, David Leung, Samuel J. Bonacorsi, Wendy Hayes,

CAR-T cell therapy research

The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti–PD-L1 adnectin after 18 F-fluorine labeling. Methods: An anti–PD-L1 adnectin was labeled with 18 F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate 18 F-BMS-986192. 18 F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1–negative (PD-L1(–)) and PD-L1–positive (PD-L1(+)) subcutaneous tumors. 18 F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results: 18 F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18 F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18 F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, P < 0.0001) was observed in L2987 than in control HT-29 (PD-L1(–)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti–PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1–specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1–rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E–01 mSv/MBq. Conclusion: 18 F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies with 18 F-BMS-986192 are under way to measure PD-L1 expression in human tumors.