mp500323d_si_001.pdf (223.29 kB)
Evaluation of 89Zr-pertuzumab in Breast Cancer Xenografts
journal contribution
posted on 2015-12-17, 05:31 authored by Bernadette
V. Marquez, Oluwatayo F. Ikotun, Alexander Zheleznyak, Brian Wright, Amrita Hari-Raj, Richard A. Pierce, Suzanne E. LapiPertuzumab is a monoclonal antibody that binds to HER2 and is used
in combination with another HER2–specific monoclonal antibody,
trastuzumab, for the treatment of HER2+ metastatic breast cancer.
Pertuzumab binds to an HER2 binding site distinct from that of trastuzumab,
and its affinity is enhanced when trastuzumab is present. We aim to
exploit this enhanced affinity of pertuzumab for its HER2 binding
epitope and adapt this antibody as a PET imaging agent by radiolabeling
with 89Zr to increase the sensitivity of HER2 detection
in vivo. Here, we investigate the biodistribution of 89Zr-pertuzumab in HER2–expressing BT-474 and HER2–nonexpressing
MDA-MB-231 xenografts to quantitatively assess HER2 expression in
vivo. In vitro cell binding studies were performed resulting in retained
immunoreactivity and specificity for HER2–expressing cells.
In vivo evaluation of 89Zr-pertuzumab was conducted in
severely combined immunodeficient mice, subcutaneously inoculated
with BT-474 and MDA-MB-231 cells. 89Zr-pertuzumab was systemically
administered and imaged at 7 days postinjection (p.i.) followed by
terminal biodistribution studies. Higher tumor uptake was observed
in BT-474 compared to MDA-MB-231 xenografts with 47.5 ± 32.9
and 9.5 ± 1.7% ID/g, respectively at 7 days p.i (P = 0.0009) and blocking studies with excess unlabeled pertuzumab
showed a 5-fold decrease in BT-474 tumor uptake (P = 0.0006), confirming the in vivo specificity of this radiotracer.
Importantly, we observed that the tumor accumulation of 89Zr-pertuzumab was increased in the presence of unlabeled trastuzumab,
at 173 ± 74.5% ID/g (P = 0.01). Biodistribution
studies correlate with PET imaging quantification using max SUV (r = 0.98, P = 0.01). Collectively, these
results illustrate that 89Zr-pertuzumab as a PET imaging
agent may be beneficial for the quantitative and noninvasive assessment
of HER2 expression in vivo especially for patients undergoing trastuzumab
therapy.
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BTnoninvasive assessmentHER 2 expressionvivo evaluationBreast Cancer XenograftsPertuzumabtumor uptaketumor accumulationmax SUVtrastuzumab therapyHER 2 detectionterminal biodistribution studiessubcutaneously inoculatedvivo specificity7 days postinjectionHER 2 binding sitecell binding studiesPET imaging agentHER 2PET imaging quantification89 Zr7 days p.iIDHER 2 binding epitopeimmunodeficient mice
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