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

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 ?g 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 ?g dose group. Contrary, highest uptake in A549 and H441 tumors was found at the lowest (10 ?g) 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.

SUBMITTER: Pool M

PROVIDER: S-EPMC5356542 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Pool Martin M Kol Arjan A Lub-de Hooge Marjolijn N MN Gerdes Christian A CA de Jong Steven S de Vries Elisabeth G E EG Terwisscha van Scheltinga Anton G T AG

Oncotarget 20161001 42

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 ...[more]

PMID: 27602494

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Project description:The variances and biases inherent in quantifying PET tracer uptake from instrumentation factors are needed to ascertain the significance of any measured differences such as in quantifying response to therapy. The authors studied the repeatability and reproducibility of serial PET measures of activity as a function of object size, acquisition, reconstruction, and analysis method on one scanner and at three PET centers using a single protocol with long half-life phantoms.The authors assessed standard deviations (SDs) and mean biases of consecutive measures of PET activity concentrations in a uniform phantom and a NEMA NU-2 image quality (IQ) phantom filled with 9 months half-life 68Ge in an epoxy matrix. Activity measurements were normalized by dividing by a common decay corrected true value and reported as recovery coefficients (RCs). Each experimental set consisted of 20 consecutive PET scans of either a stationary phantom to evaluate repeatability or a repositioned phantom to assess reproducibility. One site conducted a comprehensive series of repeatability and reproducibility experiments, while two other sites repeated the reproducibility experiments using the same IQ phantom. An equation was derived to estimate the SD of a new PET measure from a known SD based on the ratios of available coincident counts between the two PET measures.For stationary uniform phantom scans, the SDs of maximum RCs were three to five times less than predicted for uncorrelated pixels within circular regions of interest (ROIs) with diameters ranging from 1 to 15 cm. For stationary IQ phantom scans from 1 cm diameter ROIs, the average SDs of mean and maximum RCs ranged from 1.4% to 8.0%, depending on the methods of acquisition and reconstruction (coefficients of variation range 2.5% to 9.8%). Similar SDs were observed for both analytic and iterative reconstruction methods (p > or = 0.08). SDs of RCs for 2D acquisitions were significantly higher than for 3D acquisitions (p < or =s 0.008) for same acquisition and processing parameters. SDs of maximum RCs were larger than corresponding mean values for stationary IQ phantom scans ( < or = 0.02), although the magnitude of difference is reduced due to noise correlations in the image. Increased smoothing decreased SDs ( < or =s 0.045) and decreased maximum and mean RCs (p < or = 0.02). Reproducibility of GE DSTE, Philips Gemini TF, and Siemens Biograph Hi-REZ PET/CT scans of the same IQ phantom, with similar acquisition, reconstruction, and repositioning among 20 scans, were, in general, similar (mean and maximum RC SD range 2.5% to 4.8%).Short-term scanner variability is low compared to other sources of error. There are tradeoffs in noise and bias depending on acquisition, processing, and analysis methods. The SD of a new PET measure can be estimated from a known SD if the ratios of available coincident counts between the two PET scanner acquisitions are known and both employ the same ROI definition. Results suggest it is feasible to use PET/CTs from different vendors and sites in clinical trials if they are properly cross-calibrated.

Dataset Information

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

Publications

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

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