Immuno-PET Imaging to Assess Target Engagement: Experience from <sup>89</sup>Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors.
Where this comes from
- Record sourced from PubMed, PMID 30733323.
- Also identified by DOI 10.2967/jnumed.118.214726 and PMC identifier 6604691.
- Licence recorded as CC BY.
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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 <sup>89</sup>Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. <b>Methods:</b><sup>89</sup>Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of <sup>89</sup>Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of <sup>89</sup>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<sub>50</sub> and ID<sub>90</sub>) of target-mediated antibody uptake were calculated using a Patlak transformation. <b>Results:</b> 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 <sup>89</sup>Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID<sub>50</sub> of 2 mg/kg and ID<sub>90</sub> of 18 mg/kg have been determined. <b>Conclusion:</b> In this immuno-PET study, dose-dependent inhibition of tumor uptake of <sup>89</sup>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.
Medical subject headings
- Antibodies, Monoclonal, Humanized
- Neoplasms
- Positron-Emission Tomography
- Radioisotopes
- Receptor, ErbB-3
- Zirconium