Positron Emission Tomography Imaging with F-Labeled ZHER2:2891 Affibody for Detection of HER2 Expression and Pharmacodynamic Response to HER2-Modulating Therapies

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, [F]GE-226, for positron emission tomography (PET) imaging. Experimental design: Intrinsic cellular [F]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: [F]GE-226 uptake was 11 to 67-fold higher in ten HER2 positive versus 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/cm /min) 0.0069 ± 0.0014) from HER2 positive tumors (NUV60 and Ki: MCF7-HER2, 10.9 ± 1.5 and 0.015 ± 0.0035; MDA-MB-361, 18.2 ± 3.4 and 0.025 ± 0.0052; SKOV-3, 18.7 ± 2.4 and 0.036 ± 0.0065) within 1h. Tumor uptake correlated with HER2 expression determined by ELISA (r = 0.78), and a fluorophore-labled tracer analogue co-localized with HER2 expression. Tracer uptake was not influenced by shortterm 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 versus 9.0 ± 0.9 %ID/mL for vehicle or drug, respectively). Conclusions: [F]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. on May 1, 2017. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 3, 2014; DOI: 10.1158/1078-0432.CCR-13-2421