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 89Zr-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 89Zr-imgatuzumab, co-injected with equal doses 111In-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. 89Zr-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) 89Zr-imgatuzumab dose. High 89Zr-imgatuzumab liver accumulation was found in A431 xenografted mice, which decreased with antibody dose increments. 89Zr-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. 89Zr-imgatuzumab effectively visualizes EGFR-expressing tumors. High sEGFR levels can redirect 89Zr-imgatuzumab to the liver, in which case tumor visualization can be improved by increasing tracer antibody dose.
Highlights
Overexpression and mutations of epidermal growth factor receptor (EGFR) are associated with tumor cell growth, differentiation, proliferation, apoptosis and cellular invasiveness [1]
The immunoreactive fraction of Dfimgatuzumab conjugate was assessed by competition assay at 68.9 ± 6.3% compared to unmodified imgatuzumab (Supplementary Figure S1B). 89Zr-imgatuzumab was stable in vitro, the maximum observed decrease in radiochemical purity (RCP) was from 99.4 ± 0.1% to 93.4 ± 0.8% in 0.5 M HEPES buffer pH 7.2 after 14 days at 37°C (Supplementary Figure S1C)
Blood levels of 89Zr-imgatuzumab were highest for the 160 μg tracer dose at day 1 pi for all tested models and decreased gradually over time (Figure 1B). 89Zr-imgatuzumab blood levels were significantly lower in A431 tumor bearing mice compared to both A549 and H441 at 10 μg and 25 μg (P < 0.001) and at 160 μg (A549: P < 0.01, H441: P < 0.05)
Summary
Overexpression and mutations of epidermal growth factor receptor (EGFR) are associated with tumor cell growth, differentiation, proliferation, apoptosis and cellular invasiveness [1]. Clinical treatment options for KRAS wildtype EGFR in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer (mCRC), encompass monoclonal antibodies (mAbs) cetuximab and panitumumab. Imgatuzumab (GA201) is a novel humanized anti-EGFR IgG1 isotype mAb, glycoengineered for enhanced ADCC, as well as inhibiting liganddependent signaling of EGFR. Imgatuzumab recognizes human EGFR and is not cross-reactive with murine EGFR [5]. It showed superior in vivo efficacy compared to www.impactjournals.com/oncotarget cetuximab and non-glycoengineered imgatuzumab in both KRAS-mutant and KRAS-wild type tumor models. In phase 1 studies imgatuzumab demonstrated promising efficacy in heavily pretreated patients with advanced EGFR-positive solid tumors and KRAS-mutant EGFR-positive advanced colorectal cancer [6, 7]
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