89Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I

Rufael Chekol; Viswas Raja Solomon; Elahe Alizadeh; Wendy Bernhard; Darrell Fisher; Wayne Hill; Kris Barreto; John Francis DeCoteau; Angel Casaco Parada; Clarence Ronald Geyer; Humphrey Fonge

doi:10.18632/oncotarget.24965

⁸⁹Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I

Oncotarget. 2018 Mar 30;9(24):17117-17132. doi: 10.18632/oncotarget.24965.

Authors

Rufael Chekol^{1

2}, Viswas Raja Solomon^{1

2}, Elahe Alizadeh^{1

2}, Wendy Bernhard³, Darrell Fisher⁴, Wayne Hill³, Kris Barreto³, John Francis DeCoteau³, Angel Casaco Parada⁵, Clarence Ronald Geyer³, Humphrey Fonge^{1

2

6}

Affiliations

¹ Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada.
² Saskatchewan Centre for Cyclotron Sciences (SCCS), The Fedoruk Centre, Saskatoon, SK, Canada.
³ Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada.
⁴ Versant Medical Physics and Radiation Safety, Boston, MA, USA.
⁵ Centre for Molecular Immunology, Havana, Cuba.
⁶ Department of Medical Imaging, Royal University Hospital Saskatoon, Saskatoon, SK, Canada.

Abstract

Rationale: Epidermal growth factor receptor (EGFR) upregulation is associated with enhanced proliferation and drug resistance in a number of cancers. Nimotuzumab is a humanized monoclonal antibody with high affinity for EGFR. The objective of this study was to determine if ⁸⁹Zr-DFO-nimotuzumab could be suitable for human use as a PET probe for quantifying EGFR in vivo.

Methods: To evaluate the pharmacokinetics, biodistribution, microPET imaging, radiation dosimetry, and normal tissue toxicity in tumor and non-tumor bearing mice of ⁸⁹Zr-desferoxamine-nimotuzumab (⁸⁹Zr-DFO-nimotuzumab) of a product prepared under GMP conditions. Nimotuzumab was conjugated to DFO and radiolabeled with ⁸⁹Zr. ⁸⁹Zr-DFO-nimotuzumab was characterized by in vitro gel-electrophoresis, biolayer interferometry (BLI) and flow cytometry. ⁸⁹Zr-DFO-nimotuzumab was evaluated in vivo by microPET and ex vivo by biodistribution in healthy and EGFR-positive tumor bearing mice.

Results: Flow cytometry with A431 cells showed no significant difference in the dissociation constant of nimotuzumab (13 ± 2 nM) compared with DFO-nimotuzumab (17 ± 4 nM). PET imaging in mice xenografts showed persistently high tumor uptake with the highest uptake obtained in DLD-1 xenograft (18.3 %IA/cc) at 168 hp.i. The projected human effective dose was low and was 0.184 mSv/MBq (0.679 rem/mCi) in females and 0.205 mSv/MBq (0.757 rem/mCi) in males. There was no apparent normal tissue toxicity as shown by cell blood counts and blood biochemistry analyses at 168-fold and 25-fold excess of the projected human radioactive and mass dose of the agent.

Conclusion: ⁸⁹Zr-DFO-nimotuzumab had low organ absorbed dose and effective dose that makes it suitable for potential human use.

Keywords: epidermal growth factor receptor I; immunoPET/CT; nimotuzumab; radiochemistry; zirconium-89.