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Title: Evaluation of 89 Zr-pertuzumab in Breast Cancer Xenografts

Abstract

Here, pertuzumab 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 tumormore » 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.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [1]
+ Show Author Affiliations
  1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States
  2. Department of Medicine, Pulmonary and Critical Care Division, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
Publication Date:
Research Org.:
Washington Univ., St. Louis, MO (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1158715
Alternate Identifier(s):
OSTI ID: 1452814
Grant/Contract Number:  
SC0002032; SC0008432
Resource Type:
Published Article
Journal Name:
Molecular Pharmaceutics
Additional Journal Information:
Journal Name: Molecular Pharmaceutics Journal Volume: 11 Journal Issue: 11; Journal ID: ISSN 1543-8384
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 89Zr; breast cancer xenograft; HER2; NOG; pertuzumab; PET; trastuzumab

Citation Formats

Marquez, Bernadette V., Ikotun, Oluwatayo F., Zheleznyak, Alexander, Wright, Brian, Hari-Raj, Amrita, Pierce, Richard A., and Lapi, Suzanne E. Evaluation of 89 Zr-pertuzumab in Breast Cancer Xenografts. United States: N. p., 2014. Web. doi:10.1021/mp500323d.
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Marquez, Bernadette V., Ikotun, Oluwatayo F., Zheleznyak, Alexander, Wright, Brian, Hari-Raj, Amrita, Pierce, Richard A., & Lapi, Suzanne E. Evaluation of 89 Zr-pertuzumab in Breast Cancer Xenografts. United States. https://doi.org/10.1021/mp500323d
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Marquez, Bernadette V., Ikotun, Oluwatayo F., Zheleznyak, Alexander, Wright, Brian, Hari-Raj, Amrita, Pierce, Richard A., and Lapi, Suzanne E. Fri . "Evaluation of 89 Zr-pertuzumab in Breast Cancer Xenografts". United States. https://doi.org/10.1021/mp500323d.
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@article{osti_1158715,
title = {Evaluation of 89 Zr-pertuzumab in Breast Cancer Xenografts},
author = {Marquez, Bernadette V. and Ikotun, Oluwatayo F. and Zheleznyak, Alexander and Wright, Brian and Hari-Raj, Amrita and Pierce, Richard A. and Lapi, Suzanne E.},
abstractNote = {Here, pertuzumab 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.},
doi = {10.1021/mp500323d},
journal = {Molecular Pharmaceutics},
number = 11,
volume = 11,
place = {United States},
year = {Fri Apr 25 00:00:00 EDT 2014},
month = {Fri Apr 25 00:00:00 EDT 2014}
}
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https://doi.org/10.1021/mp500323d
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