Molecular imaging of a fluorescent antibody against epidermal growth factor receptor detects high-grade glioma

Carmel T Chan,Christy Wilson,Sanjiv S Gambhir,Guolan Lu,Frank Schonig,Muna Aryal,Michael E Moseley,Hannes Vogel,Gerald A Grant,Quan Zhou,Michelle Rai Santoso,Michael J Mandella,Romain Cayrol,Nynke S Van Den Berg,Eben L Rosenthal,Johana C M Vega Leonel

doi:10.1038/s41598-021-84831-4

Carmel T Chan, Christy Wilson + Show 14 more

Open Access

https://doi.org/10.1038/s41598-021-84831-4

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Abstract

The prognosis for high-grade glioma (HGG) remains dismal and the extent of resection correlates with overall survival and progression free disease. Epidermal growth factor receptor (EGFR) is a biomarker heterogeneously expressed in HGG. We assessed the feasibility of detecting HGG using near-infrared fluorescent antibody targeting EGFR. Mice bearing orthotopic HGG xenografts with modest EGFR expression were imaged in vivo after systemic panitumumab-IRDye800 injection to assess its tumor-specific uptake macroscopically over 14 days, and microscopically ex vivo. EGFR immunohistochemical staining of 59 tumor specimens from 35 HGG patients was scored by pathologists and expression levels were compared to that of mouse xenografts. Intratumoral distribution of panitumumab-IRDye800 correlated with near-infrared fluorescence and EGFR expression. Fluorescence distinguished tumor cells with 90% specificity and 82.5% sensitivity. Target-to-background ratios peaked at 14 h post panitumumab-IRDye800 infusion, reaching 19.5 in vivo and 7.6 ex vivo, respectively. Equivalent or higher EGFR protein expression compared to the mouse xenografts was present in 77.1% HGG patients. Age, combined with IDH-wildtype cerebral tumor, was predictive of greater EGFR protein expression in human tumors. Tumor specific uptake of panitumumab-IRDye800 provided remarkable contrast and a flexible imaging window for fluorescence-guided identification of HGGs despite modest EGFR expression.

Highlights

The prognosis for high-grade glioma (HGG) remains dismal and the extent of resection correlates with overall survival and progression free disease
A major barrier to the clinical translation of Epidermal growth factor receptor (EGFR) targeting imaging probes is the heterogeneity of EGFR protein expression which can vary by orders of magnitude in human HGGs11,12
As an imaging probe for fluorescence-guided surgery, panitumumab-IRDye[800] could potentially outperform 5-ALA which suffers from limited imaging contrast and low negative predicting value (16.7% for HGG)[16]

Summary

Introduction

The prognosis for high-grade glioma (HGG) remains dismal and the extent of resection correlates with overall survival and progression free disease. In a fluorescence imaging study, the IRDye800CW (Ex/Em: 774/789 nm) labeled therapeutic antibody, panitumumab-IRDye[800], bound to EGFR positive rat glioma cells with higher affinity than the fluorescent EGFR ligand, E GF8008. This fully humanized EGFR antibody has an improved safety profile compared to its chimeric counterpart, cetuximab[9,10]. This study examined the feasibility of detecting human HGGs via fluorescence imaging using panitumumab-IRDye[800] in a preclinical orthotopic tumor model with only modest level of EGFR expression which was benchmarked against similar expression levels in patient HGG tissues. Since biopsies are not usually taken before resection surgeries, HGG specimens were characterized to stratify a patient population with positive EGFR protein expression that would benefit most from intraoperative targeted imaging to assist in resection

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