Immuno-PET Imaging to Assess Target Engagement: Experience from Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors.

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 Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of Zr-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 (ID and ID) of target-mediated antibody uptake were calculated using a Patlak transformation. 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 Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID of 2 mg/kg and ID of 18 mg/kg have been determined. In this immuno-PET study, dose-dependent inhibition of tumor uptake of Zr-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.