PET and SPECT Imaging of the EGFR Family (RTK Class I) in Oncology

Abstract

The human epidermal growth factor receptor family (EGFR-family, other designations: HER family, RTK Class I) is strongly linked to oncogenic transformation. Its members are frequently overexpressed in cancer and have become attractive targets for cancer therapy. To ensure effective patient care, potential responders to HER-targeted therapy need to be identified. Radionuclide molecular imaging can be a key asset for the detection of overexpression of EGFR-family members. It meets the need for repeatable whole-body assessment of the molecular disease profile, solving problems of heterogeneity and expression alterations over time. Tracer development is a multifactorial process. The optimal tracer design depends on the application and the particular challenges of the molecular target (target expression in tumors, endogenous expression in healthy tissue, accessibility). We have herein summarized the recent preclinical and clinical data on agents for Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) imaging of EGFR-family receptors in oncology. Antibody-based tracers are still extensively investigated. However, their dominance starts to be challenged by a number of tracers based on different classes of targeting proteins. Among these, engineered scaffold proteins (ESP) and single domain antibodies (sdAb) show highly encouraging results in clinical studies marking a noticeable trend towards the use of smaller sized agents for HER imaging.

HER3 PET Imaging: 68Ga-Labeled Affibody Molecules Provide Superior HER3 Contrast to 89Zr-Labeled Antibody and Antibody-Fragment-Based Tracers

“…It is important that the imaging agent binds the target with high affinity and clears efficiently from the blood and other non-targeted tissues. Several different types of targeting molecules have been explored for radionuclide imaging of HER3 expression [ 8 ]. The limited success of antibody-based tracers for PET imaging of HER3 expression suggests that the modification of preexisting therapeutic antibodies might not be sufficient for imaging of a challenging targets such as HER3.…”

“…Many factors need to be considered when developing potential molecular imaging agents. The choice of the targeting molecule (e.g., its size, polarity, and local charge) could appreciably influence the pharmacokinetics and biodistribution of the tracer and thereby the image contrast and sensitivity of the scan [ 6 , 7 , 8 ]. The ideal radiotracer should bind to the target receptor with high affinity, clear efficiently from the blood, and have minimal accumulation in non-targeted tissue [ 6 , 8 ].…”

“…The choice of the targeting molecule (e.g., its size, polarity, and local charge) could appreciably influence the pharmacokinetics and biodistribution of the tracer and thereby the image contrast and sensitivity of the scan [ 6 , 7 , 8 ]. The ideal radiotracer should bind to the target receptor with high affinity, clear efficiently from the blood, and have minimal accumulation in non-targeted tissue [ 6 , 8 ]. Radiolabeled monoclonal antibodies were among the first tracers to be evaluated for molecular imaging of the HER-receptor family [ 8 , 9 ].…”

“…The ideal radiotracer should bind to the target receptor with high affinity, clear efficiently from the blood, and have minimal accumulation in non-targeted tissue [ 6 , 8 ]. Radiolabeled monoclonal antibodies were among the first tracers to be evaluated for molecular imaging of the HER-receptor family [ 8 , 9 ]. However, the slow extravasation and long residence time in blood are potential disadvantages for antibody-based imaging agents, because they result in an elevated background signal from blood-borne activity and increase the unspecific accumulation in non-targeted tissue [ 10 ].…”

“…In recent years, a variety of smaller tracers based on different classes of targeting molecules have emerged as alternatives to antibody-based tracers and shown potential value and advantages as radionuclide-based agents for imaging of HER family members. These include peptides, antibody-fragments (e.g., Fab- and F(ab’) 2 -fragments and scFvs), single-domain antibodies (sdAbs, e.g., nanobodies), and engineered scaffold proteins (ESPs) [ 6 , 8 , 10 ].…”