Positron emission tomography imaging with 18f- labeled Zher2:2891 affibody for detection of HER2 expression and pharmacodynamic response to HER2-modulating therapies

Abstract

Purpose: Expression of HER2 has profound implications on treatment strategies in various types of cancer. We investigated the specificity of radiolabeled HER2-targeting ZHER2:2891 Affibody, [18F]GE-226, for positron emission tomography (PET) imaging. Experimental Design: Intrinsic cellular [18F]GE-226 uptake and tumor-specific tracer binding were assessed in cells and xenografts with and without drug treatment. Specificity was further determined by comparing tumor localization of a fluorescently labeled analogue with DAKO HercepTest. Results: [18F]GE-226 uptake was 11- to 67-fold higher in 10 HER2-positive versus HER2-negative cell lines in vitro independent of lineage. Uptake in HER2-positive xenografts was rapid with net irreversible binding kinetics making possible the distinction of HER2-negative [MCF7 and MCF7-p95HER2: NUV60 (%ID/mL) 6.1 0.7; Ki (mL/cm3/min) 0.0069 0.0014] from HER2-positive tumors (NUV60 and Ki: MCF7-HER2, 10.91.5 and 0.015 0.0035; MDA-MB-361, 18.23.4 and 0.0250.0052; SKOV-3, 18.7 2.4 and 0.036 0.0065) within 1 hour. Tumor uptake correlated with HER2 expression determined by ELISA (r2 1/4 0.78), and a fluorophore-labeled tracer analogue colocalized with HER2 expression. Tracer uptake was not influenced by short-term or continuous treatment with trastuzumab in keeping with differential epitope binding, but reflected HER2 degradation by short-term NVP-AUY922 treatment in SKOV-3 xenografts (NUV60: 13.5 2.1 %ID/mL vs. 9.0 0.9 %ID/mL for vehicle or drug, respectively). Conclusions: [18F]GE-226 binds with high specificity to HER2 independent of cell lineage. The tracer has potential utility for HER2 detection, irrespective of prior trastuzumab treatment, and to discern HSP90 inhibitor-mediated HER2 degradation. © 2014 American Association for Cancer Research.