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
References
- Siegel R L, Miller K D, Jemal A. Cancer statistics 2020. CA Cancer J Clin. 2020;70:7–30.
- He H, Chen N, Hou Y et al.Trends in the incidence and survival of patients with esophageal cancer: A SEER database analysis. Thorac Cancer. 2020;11:1121–1128.
- Prasad G A, Bansal A, Sharma P et al.Predictors of progression in Barrett's esophagus: current knowledge and future directions. Am J Gastroenterol. 2010;105:1490–1502.
- Sharma P, Savides T J, Canto M I et al.The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on imaging in Barrett's Esophagus. Gastrointest Endosc. 2012;76:252–254.
- American Gastroenterological Association . Spechler S J, Sharma P et al.American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology. 2011;140:1084–1091.
- Sturm M B, Wang T D. Endoscopic imaging techniques: beyond narrow band. Am J Gastroenterol. 2018;113:1103–1107.
- Cronin J, McAdam E, Danikas A et al.Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett's esophagus (BE) Am J Gastroenterol. 2011;106:46–56.
- Plum P S, Gebauer F, Krämer M et al.HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer. 2019;19:38.
- Zhou J, Joshi B P, Duan X et al.EGFR overexpressed in colonic neoplasia can be detected on wide-field endoscopic imaging. Clin Transl Gastroenterol. 2015;6:e101.
- Joshi B P, Zhou J, Pant A et al.Design and synthesis of near-infrared peptide for in vivo molecular imaging of HER2. Bioconjug Chem. 2016;27:481–494.
- Chen J, Zhou J, Gao Z et al.Multiplexed targeting of Barrett’s neoplasia with a heterobivalent ligand: Imaging study on mouse xenograft in vivo and human specimens ex vivo. J Med Chem. 2018;61:5323–5331.
- Chen J, Gao Z, Li G et al.Dual-modal in vivo fluorescence and photoacoustic imaging using a heterodimeric peptide. Chem Comm. 2018;54:13196–13199.
- Chen J, Jiang Y, Chang T S et al.Multiplexed endoscopic imaging of Barrett's neoplasia using targeted fluorescent heptapeptides in a phase 1 proof-of-concept study. Gut. 2021;70:1010–1013.
- Bird-Lieberman E L, Neves A A, Lao-Sirieix P et al.Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett’s esophagus. Nat Med. 2012;18:315–321.
- Nagengast W B, Hartmans E, Garcia-Allende P B et al.Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A. Gut. 2019;68:7–10.
- Labrijn A F, Janmaat M L, Reichert J M et al.Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.
- Ding L, Tian C, Feng S et al.Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy. Theranostics. 2015;5:378.
- Yan Y, Chen X. Peptide heterodimers for molecular imaging. Amino Acids. 2011;41:1081–1092.
- Zhang J, Niu G, Lang L et al. Clinical translation of a dual integrin α v β 3 –and gastrin-releasing peptide receptor-targeting PET radiotracer, 68 Ga-BBN-RGD . J Nucl Med. 2017;58:228–234.
- Razumienko E J, Chen J C, Cai Z et al. Dual-receptor-targeted radioimmunotherapy of human breast cancer xenografts in athymic mice coexpressing HER2 and EGFR using 177 Lu-or 111 In-labeled bispecific radioimmunoconjugates . J Nucl Med. 2016;57:444–452.
Source: PubMed