Detection of Barrett's neoplasia with a near-infrared fluorescent heterodimeric peptide

Jing Chen, Yang Jiang, Tse-Shao Chang, Joel H Rubenstein, Richard S Kwon, Erik J Wamsteker, Anoop Prabhu, Lili Zhao, Henry D Appelman, Scott R Owens, David G Beer, D Kim Turgeon, Eric J Seibel, Thomas D Wang, Jing Chen, Yang Jiang, Tse-Shao Chang, Joel H Rubenstein, Richard S Kwon, Erik J Wamsteker, Anoop Prabhu, Lili Zhao, Henry D Appelman, Scott R Owens, David G Beer, D Kim Turgeon, Eric J Seibel, Thomas D Wang

Abstract

Background: Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease with poor prognosis that is rising rapidly in incidence. We aimed to demonstrate specific binding by a peptide heterodimer to Barrett's neoplasia in human subjects.

Methods: Peptide monomers specific for EGFR and ErbB2 were arranged in a heterodimer configuration and labeled with IRDye800. This near-infrared (NIR) contrast agent was topically administered to patients with Barrett's esophagus (BE) undergoing either endoscopic therapy or surveillance. Fluorescence images were collected using a flexible fiber accessory passed through the instrument channel of an upper gastrointestinal endoscope. Fluorescence images were collected from 31 BE patients. A deep learning model was used to segment the target (T) and background (B) regions.

Results: The mean target-to-background (T/B) ratio was significantly greater for high grade dysplasia (HGD) and EAC versus BE, low grade dysplasia (LGD), and squamous epithelium. At a T/B ratio of 1.5, sensitivity and specificity of 94.1 % and 92.6 %, respectively, were achieved for the detection of Barrett's neoplasia with an area under the curve of 0.95. No adverse events attributed to the heterodimer were found. EGFR and ErbB2 expression were validated in the resected specimens.

Conclusions: This "first-in-human" clinical study demonstrates the feasibility of detection of early Barrett's neoplasia using a NIR-labeled peptide heterodimer.

Trial registration: ClinicalTrials.gov NCT03852576.

Conflict of interest statement

J. Chen and T.D. Wang are inventors on patents filed by the University of Michigan on the peptide heterodimer used in the study. E.J. Seibel is an inventor on patents filed by the University of Washington on the multimodal scanning fiber endoscope. The remaining authors declare that they have no conflict of interest.

The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Figures

Fig. 1
Fig. 1
Representative in vivo images using white light (WL), fluorescence (FL), and reflectance (R) collected endoscopically following topical administration of QRH*-KSP*-IRDye800 onto:asquamous epithelium (SQ);bnon-dysplastic Barrett’s esophagus (BE);clow grade dysplasia (LGD);dhigh grade dysplasia (HGD);eesophageal adenocarcinoma (EAC). In the white-light images, the salmon-red areas (arrows) identify regions of BE. Co-registered reflectance images provide anatomical correlation. The merged images show areas of high contrast in pseudocolor that indicate regions of increased target expression (arrows).
Fig
Fig
.2 The imaging performance shown graphically.aA scatter plot of the T/B ratios measured from the near-infrared fluorescence images illustrate the mean (SD) values for squamous epithelium (SQ; n = 13), Barret’s esophagus (BE; n = 11), low grade dysplasia (LGD; n = 3), high grade dysplasia (HGD; n = 4), and esophageal adenocarcinoma (EAC; n = 13), which were found to be 1.24 (0.06), 1.40 (0.10), 1.49 (0.19), 1.69 (0.15), and 1.72 (0.24), respectively (the results were confirmed by histology using H&E staining andPvalues were determined using a Tukey–Kramer test).bLog-transformed data were classified as either positive (HGD, EAC) or negative (SQ, BE, LGD) for Barrett’s neoplasia; mean (SD) T/B ratios of 1.71 (0.22) and 1.33 (0.13), respectively, were measured (P < 0.001).cThe tradeoffs in imaging performance.dReceiver operating characteristic (ROC) curves showing the optimal values of 94.1 % sensitivity and 92.6 % specificity (arrow). AUC, area under the curve.
Fig
Fig
.3A set of white light (WL), near-infrared fluorescence (FL), and reflectance (R) images from a patient with high grade dysplasia:abefore treatment; andb14 weeks after endoscopic mucosal resection. Prior to resection, the WL images show a Barret’s esophagus segment with a region of high grade dysplasia (arrow), which shows greater intensity on the FL images.cLog T/B ratios before and after therapy show mean (SD) results of 1.72 (0.13) vs. 1.39 (0.05) respectively;P < 0.001 by paired, one-tailedttest.

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