Radiosynthesis and Preclinical PET Evaluation of 89Zr-Nivolumab (BMS-936558) in Healthy Non-Human Primates

Publication date: Available online 4 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Erin L. Cole, Joonyoung Kim, David J. Donnelly, R. Adam Smith, Daniel Cohen, Virginie Lafont, Paul E. Morin, Richard Y.-C. Huang, Patrick L. Chow, Wendy Hayes, Samuel Bonacorsi
Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types. This study reports the preparation and in vivo evaluation of ⁸⁹Zr labeled nivolumab in healthy non-human primates (NHP) as a preliminary study of biodistribution and clearance. The radiochemical and in vivo stabilities of the ⁸⁹Zr complex were shown to be acceptable for imaging. Three naïve NHPs were intravenously injected with tracer only or tracer co-injected with nivolumab followed by co-registered by positron emission tomography (PET) and magnetic resonance imaging (MRI), acquired for eight days following injection. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis. Radioactivity in the spleen was significantly reduced by addition of excess nivolumab compared to the tracer only study at all imaging time points. Liver uptake of the radiotracer was consistent as a clearance organ with minimal signal from other tissues: lung, muscle, brain, heart, and kidney. The results indicate specific biodistribution to the spleen, which can be blocked by co-administration of excess nivolumab. Distribution to other organs is consistent with elimination pathways of antibodies, with primary clearance through the liver.

Graphical abstract

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