89Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I
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Rufael Chekol1,2, Viswas Raja Solomon1,2, Elahe Alizadeh1,2, Wendy Bernhard3, Darrell Fisher4, Wayne Hill3, Kris Barreto3, John Francis DeCoteau3, Angel Casaco Parada5, Clarence Ronald Geyer3 and Humphrey Fonge1,2,6
1Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada
2Saskatchewan Centre for Cyclotron Sciences (SCCS), The Fedoruk Centre, Saskatoon, SK, Canada
3Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada
4Versant Medical Physics and Radiation Safety, Boston, MA, USA
5Centre for Molecular Immunology, Havana, Cuba
6Department of Medical Imaging, Royal University Hospital Saskatoon, Saskatoon, SK, Canada
Humphrey Fonge, email: [email protected]
Clarence Ronald Geyer, email: [email protected]
Keywords: epidermal growth factor receptor I; zirconium-89; nimotuzumab; immunoPET/CT; radiochemistry
Received: January 08, 2018 Accepted: February 26, 2018 Published: March 30, 2018
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.
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