Immuno-PET Imaging to Assess Target Engagement: Experience from ⁸⁹Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors

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 of 89 Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of 89 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 50 and ID 90 ) 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 89 Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID 50 of 2 mg/kg and ID 90 of 18 mg/kg have been determined. Conclusion: In this immuno-PET study, dose-dependent inhibition of tumor uptake of 89 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.

Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody

“…Target engagement assessment is an important parameter for optimizing the BED of antibodies and antibody conjugates, and it can be used to construct pharmacokinetic/pharmacodynamic (PK/PD) models bridging animal and human testing. [1][2][3][4][5] Flow cytometry, [5][6][7][8] enzyme-linked immunosorbent assays (ELISAs), 9 and mass spectrometry 10 are commonly employed to measure the target saturation of monoclonal antibody (mAb) binding to the receptors of circulating blood cells, and immunohistochemistry (IHC) is usually used to assess the selective localization of target proteins in tissue specimens. 8,11 Studies have shown that molecular imaging can be used to assess target engagement.…”

“…8,15 Second, it can provide real-time and accurate systemic antibody IHC imaging of the whole body simultaneously, not only for all tumor lesions and their metastases but also for normal tissues, such as the spleen, which is an immune organ that is expected to predict the safety of antibody immunotherapy. 17 In addition to its use in PK investigations of mAbs, 18 including BsAbs 19,20 and antibody-drug conjugates (ADCs), 21 recent studies 1,4,13 have shown that the target engagement for mAbs can be assessed by PET. The assessment of BsAbs, however, is more urgent and difficult than that for canonical (i.e., monospecific) mAbs.…”

Immuno-PET to Optimize the Dose of Monoclonal Antibodies for Cancer Therapy: How Much Is Enough?

“…In this issue of The Journal of Nuclear Medicine, Menke-van der Houven van Oordt et al report an immuno-PET study with 89 Zr-labeled GSK2849330 antihuman epidermal growth factor receptor-3 (HER3) mAbs in 6 patients with HER3-positive tumors (8). Tumor and normal-tissue uptake were evaluated, and the effect of therapeutic doses of GSK2849330 mAbs (GlaxoSmithKline) on tumor uptake was assessed as an indicator of receptor occupancy.…”

“…In the current clinical study (8), it was determined that an 8-mg mass dose (37 MBq) was sufficient to avoid rapid elimination of 89 Zr-GSK2849330 from the blood. This dose provided liver uptake equivalent to a larger mass dose (24 mg) and permitted tumor visualization (8). PET scans were acquired at 48 and 120 h after injection of 89 Zr-GSK2849330.…”

“…There have been only a few reports of immuno-PET to assess expression of HER3 on tumors preclinically (9,16) or clinically (14,17). The immuno-PET studies reported by Menke-van der Houven van Oordt et al (8) and by others (14,17) demonstrate the feasibility of imaging HER3 in patients with cancer. Such imaging studies may yield information on resistance pathways or aid in selecting patients for treatment with HER3-targeted mAbs.…”