Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice

Abstract

The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced ‘AccretaMab’ monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.

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

“…PET imaging with a 89 Zr-labeled mAb may be used to gain better insight into the in vivo behavior of antibodies. 1,12,13 For any immunotherapeutic antibody evaluation, the first and foremost issue is to assess target saturation, which is helpful for effective therapy dose selection. In this study, dose escalation PET imaging was performed, and the dosedependent target engagement was first evaluated for a BsAb.…”

“…8,11 Studies have shown that molecular imaging can be used to assess target engagement. [12][13][14] In 2017, Alsaid et al investigated GSK2849330 HER3 receptor occupancy in HER3-positive xenograft tumors (BxPC3, and CHL-1) by near-infrared fluorescence optical imaging. 12 Another report by Burvenich et al showed that gamma camera imaging of the 111 In-labeled anti-DR 5 antibody CS-1008 can be used to measure DR5 target saturation in vivo.…”

“…[12][13][14] In 2017, Alsaid et al investigated GSK2849330 HER3 receptor occupancy in HER3-positive xenograft tumors (BxPC3, and CHL-1) by near-infrared fluorescence optical imaging. 12 Another report by Burvenich et al showed that gamma camera imaging of the 111 In-labeled anti-DR 5 antibody CS-1008 can be used to measure DR5 target saturation in vivo. 13 In addition, due to its high sensitivity, high resolution, excellent quantitative performance and ability to bridge preclinical and clinical research, positron emission tomography (PET) imaging has become a powerful imaging modality for antibody drug development.…”

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

“…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. This report follows an earlier preclinical PET study in which 89 Zr-GSK2849330 mAbs (0.5 mg/kg; 5 MBq) were administered to mice with HER3-positive CHL-1 human melanoma xenografts or HER3-negative MIA-PaCa-2 human pancreatic tumors (9). In this earlier study, PET showed lower uptake of 89 Zr-GSK2849330 in MIA-PaCa-2 than in CHL-1 tumors, and tumor uptake of 89 Zr-GSK2849330 was blocked by preadministering a 100-fold excess of unlabeled GSK2849330 (50 mg/kg), revealing that tumor uptake was HER3-specific.…”

“…HER3 overexpression has been implicated in resistance to cancer treatment. 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.…”