Positron emission tomography imaging with 18F-labeled ZHER2:2891 affibody for detection of HER2 expression and pharmacodynamic response to HER2-modulating therapies.
OBJECTIVE
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, [(18)F]GE-226, for positron emission tomography (PET) imaging.


METHODS
Intrinsic cellular [(18)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
[(18)F]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/cm(3)/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 1 hour. Tumor uptake correlated with HER2 expression determined by ELISA (r(2) = 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
[(18)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.
Authors' Affiliations: Comprehensive Cancer Imaging Centre at Imperial College, Faculty of Medicine, Imperial College London, London; and GE Healthcare, Medical Diagnostics, The Grove Centre, White Lion Road, Amersham, Buckinghamshire, United Kingdom.
Sebastian
S
Trousil
Susan
S
Hoppmann
Quang-Dé
QD
Nguyen
Maciej
M
Kaliszczak
Giampaolo
G
Tomasi
Peter
P
Iveson
Duncan
D
Hiscock
Eric O
EO
Aboagye
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics*
D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins