Evaluation of (89)Zr-pertuzumab in Breast cancer xenografts

Mol Pharm. 2014 Nov 3;11(11):3988-95. doi: 10.1021/mp500323d. Epub 2014 Aug 5.


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 (89)Zr to increase the sensitivity of HER2 detection in vivo. Here, we investigate the biodistribution of (89)Zr-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 (89)Zr-pertuzumab was conducted in severely combined immunodeficient mice, subcutaneously inoculated with BT-474 and MDA-MB-231 cells. (89)Zr-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 (89)Zr-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 (89)Zr-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.

Keywords: 89Zr; HER2; NOG; PET; breast cancer xenograft; pertuzumab; trastuzumab.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized* / chemistry
  • Antibodies, Monoclonal, Humanized* / pharmacokinetics
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carrier Proteins / physiology
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, SCID
  • Molecular Imaging
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals* / pharmacokinetics
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / immunology*
  • Spectrometry, Mass, Electrospray Ionization
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Zirconium* / pharmacokinetics


  • Antibodies, Monoclonal, Humanized
  • Carrier Proteins
  • Radiopharmaceuticals
  • noggin protein
  • Zirconium
  • Receptor, ErbB-2
  • pertuzumab