RT Journal Article SR Electronic T1 Immuno-PET Imaging to Assess Target Engagement: Experience from 89Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 902 OP 909 DO 10.2967/jnumed.118.214726 VO 60 IS 7 A1 C. Willemien Menke-van der Houven van Oordt A1 Adam McGeoch A1 Mats Bergstrom A1 Iain McSherry A1 Deborah A. Smith A1 Matthew Cleveland A1 Wasfi Al-Azzam A1 Liangfu Chen A1 Henk Verheul A1 Otto S. Hoekstra A1 Danielle J. Vugts A1 Immanuel Freedman A1 Marc Huisman A1 Chris Matheny A1 Guus van Dongen A1 Sean Zhang YR 2019 UL http://jnm.snmjournals.org/content/60/7/902.abstract AB PET imaging with radiolabeled drugs provides information on tumor uptake and dose-dependent target interaction to support selection of an optimal dose for future efficacy testing. In this immuno-PET study of the anti–human epidermal growth factor receptor (HER3) mAb GSK2849330, we investigated the biodistribution and tumor uptake of 89Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. Methods: 89Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of 89Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of 89Zr-GSK2849330 uptake in tumor tissues was evaluated 2 wk later using increasing doses of unlabeled GSK2849330 in combination with the tracer. Up to 3 PET scans (2 hours post infusion [p.i.] and days 2 and 5 p.i.) were performed after tracer administration. Biodistribution and tumor targeting were assessed visually and quantitatively using SUV. The 50% and 90% inhibitory mass doses (ID50 and ID90) of target-mediated antibody uptake were calculated using a Patlak transformation. Results: At baseline, imaging with tracer showed good tumor uptake in all evaluable patients. Predosing with unlabeled mAb reduced the tumor uptake rate in a dose-dependent manner. Saturation of 89Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID50 of 2 mg/kg and ID90 of 18 mg/kg have been determined. Conclusion: In this immuno-PET study, dose-dependent inhibition of tumor uptake of 89Zr-GSK2849330 by unlabeled mAb confirmed target engagement of mAb to the HER3 receptor. This study further validates the use of immuno-PET to directly visualize tissue drug disposition in patients with a noninvasive approach and to measure target engagement at the site of action, offering the potential for dose selection.