Abstract
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 18F-fluorine labeling. Methods: An anti-PD-L1 Adnectin was labeled with 18F in two steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified Adnectin to generate 18F-BMS-986192. 18F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET using mice bearing bilateral PD-L1(-) and PD-L1(+) subcutaneous tumors. 18F-BMS-986192 was evaluated for distribution, binding and radiation dosimetry in healthy cynomolgus monkey. Results: 18F-BMS-986192 bound to human and cynomolgus PD-L1 with a KD of <35 pM, as measured by surface plasmon resonance (SPR). This Adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18F-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 a PD-L1(+), L2987 xenograft tumors. Two hrs after dosing, a 3.5-fold higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 %ID/g, P < 0.0001) was observed in L2987 compared to control HT-29 (PD-L1(-)) tumors. Co-administration of 3 mg/kg ADX_5322_A02 anti-PD-L1 Adnectin reduced tumor uptake at 2 hrs post-injection by approximately 70%, while HT-29 uptake remained unchanged, demonstrating PD-L1 specific binding. Biodistribution in non-human 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 co-administration 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: 18F-BMS-986192 demonstrated the feasibility of non-invasively imaging the PD-L1 status of tumors by micro-PET studies. Clinical studies with 18F-BMS-986192 are underway to measure PD-L1 expression in human tumors.
- PET
- Radiochemistry
- Radioimmunoimaging
- 18F-labeled Adnectin
- PD-1/PD-L1 checkpoint inhibitor
- PD-L1
- PET
- [18F]BMS-986192
- Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.