1. Immuno-PET Imaging to Assess Target Engagement: Experience from 89 Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors.
- Author
-
Menke-van der Houven van Oordt CW, McGeoch A, Bergstrom M, McSherry I, Smith DA, Cleveland M, Al-Azzam W, Chen L, Verheul H, Hoekstra OS, Vugts DJ, Freedman I, Huisman M, Matheny C, van Dongen G, and Zhang S
- Subjects
- Adult, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Dose-Response Relationship, Immunologic, Female, Humans, Male, Middle Aged, Neoplasms immunology, Neoplasms pathology, Safety, Tissue Distribution, Antibodies, Monoclonal, Humanized immunology, Neoplasms diagnostic imaging, Positron-Emission Tomography, Radioisotopes, Receptor, ErbB-3 immunology, Zirconium
- Abstract
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
89 Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. Methods:89 Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of89 Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of89 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 (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 of89 Zr-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 of89 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., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2019
- Full Text
- View/download PDF