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.
Highlights
ErbB3/HER3 is a member of the epidermal growth factor receptor family of receptor tyrosine kinases comprising HER1 (EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) which play an important role in the development and progression of cancer[1]
It has species cross reactivity to human, mouse, rat, and cynomolgus nonhuman primate HER3. It has been engineered with 3 distinct mechanisms of action: a) disruption of ligand-dependent signaling leading to inhibition of HER3 signaling and function; b) enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by enhanced FcɣR3a binding of effector cells (e.g., NK cells, macrophages) leading to lysis or phagocytosis of HER3 expressing target cells; c) enhanced complement-dependent cytotoxicity (CDC) by enhanced C1q binding and complement activation[7]
We showed that Immuno-PET monitoring of a 89Zr-tagged monoclonal antibody directed against HER3 (89Zr-GSK2849330) can be used for non-invasive kinetic assessment of the mAb biodistribution in tumors and other organs
Summary
ErbB3/HER3 is a member of the epidermal growth factor receptor family of receptor tyrosine kinases comprising HER1 (EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) which play an important role in the development and progression of cancer[1]. It has species cross reactivity to human, mouse, rat, and cynomolgus nonhuman primate HER3 It has been engineered with 3 distinct mechanisms of action: a) disruption of ligand-dependent signaling leading to inhibition of HER3 signaling and function; b) enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by enhanced FcɣR3a binding of effector cells (e.g., NK cells, macrophages) leading to lysis or phagocytosis of HER3 expressing target cells; c) enhanced complement-dependent cytotoxicity (CDC) by enhanced C1q binding and complement activation[7]. The latter two mechanisms provide an opportunity for differentiation from current HER3-directed mAbs in the clinic based on direct killing of both dividing and non-dividing cells, independent of inhibition of downstream signaling
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