1. Academic Radiation Oncology, The University of Manchester, The Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester, UK;
2. GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, Du Cane Road, London, UK;
3. Wolfson Molecular Imaging Centre, Manchester Academic Health Sciences Centre (MAHSC), The University of Manchester, Manchester, UK;
4. School of Cancer and Enabling Sciences, The Christie Hospital NHS Foundation Trust, MAHSC; The University of Manchester, Manchester, UK;
5. Eli Lilly and Company Ltd, Earl Wood Research Centre, Windlesham, UK;
6. Eli Lilly and Company, Early Oncology Clinical Investigation, Indianapolis, USA;
7. The University of Oxford Department of Medical Oncology, Oxford Radcliffe Hospitals Trust, UK;
8. Department of Surgery and Cancer, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du Cane Road, London, UK.
Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([11C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [11C]methylated-LY2181308 was observed in tumors (mean=32.5ng/mL per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [11C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, 18F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.
Keywords: Positron emission tomography (PET) imaging, antisense oligonucleotide (ASO), cancer patients, biodistribution, pharmacokinetic (PK) modeling.