Extracellular domain shedding influences specific tumor uptake and organ distribution of the EGFR PET tracer 89Zr-imgatuzumab

// Martin Pool 1 , Arjan Kol 1 , Marjolijn N. Lub-de Hooge 2, 3 , Christian A. Gerdes 4 , Steven de Jong 1 , Elisabeth G.E. de Vries 1 , Anton G.T. Terwisscha van Scheltinga 2 1 Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 2 Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 3 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4 Department of Roche Pharma Research and Early Development, Roche Innovation Center Zürich, Schlieren, Switzerland Correspondence to: Anton G.T. Terwisscha van Scheltinga, email: a.g.t.terwisscha.van.scheltinga@umcg.nl Keywords: imgatuzumab, EGFR, 89 Zr, immunoPET, shedding Received: January 06, 2016      Accepted: August 27, 2016      Published: September 02, 2016 ABSTRACT Preclinical positron emission tomography (PET) imaging revealed a mismatch between in vivo epidermal growth factor receptor (EGFR) expression and EGFR antibody tracer tumor uptake. Shed EGFR ectodomain (sEGFR), which is present in cancer patient sera, can potentially bind tracer and therefore influence tracer kinetics. To optimize EGFR-PET, we examined the influence of sEGFR levels on tracer kinetics and tumor uptake of EGFR monoclonal antibody 89 Zr-imgatuzumab in varying xenograft models. Human cancer cell lines A431 (EGFR overexpressing, epidermoid), A549 and H441 (both EGFR medium expressing, non-small cell lung cancer) were xenografted in mice. Xenografted mice received 10, 25 or 160 μg 89 Zr-imgatuzumab, co-injected with equal doses 111 In-IgG control. MicroPET scans were made 24, 72 and 144 h post injection, followed by biodistribution analysis. sEGFR levels in liver and plasma samples were determined by ELISA. 89 Zr-imgatuzumab uptake in A431 tumors was highest (29.8 ± 5.4 %ID/g) in the 160 μg dose group. Contrary, highest uptake in A549 and H441 tumors was found at the lowest (10 μg) 89 Zr-imgatuzumab dose. High 89 Zr-imgatuzumab liver accumulation was found in A431 xenografted mice, which decreased with antibody dose increments. 89 Zr-imgatuzumab liver uptake in A549 and H441 xenografted mice was low at all doses. sEGFR levels in liver and plasma of A431 bearing mice were up to 1000-fold higher than levels found in A549, H441 and non-tumor xenografted mice. 89 Zr-imgatuzumab effectively visualizes EGFR-expressing tumors. High sEGFR levels can redirect 89 Zr-imgatuzumab to the liver, in which case tumor visualization can be improved by increasing tracer antibody dose.