89 Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I
2018
// Rufael Chekol 1, 2 , Viswas Raja Solomon 1, 2 , Elahe Alizadeh 1, 2 , Wendy Bernhard 3 , Darrell Fisher 4 , Wayne Hill 3 , Kris Barreto 3 , John Francis DeCoteau 3 , Angel Casaco Parada 5 , Clarence R. Geyer 3 and Humphrey Fonge 1, 2, 6 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 Correspondence to: Humphrey Fonge, email: humphrey.fonge@usask.ca Clarence R. Geyer, email: ron.geyer@usask.ca Keywords: epidermal growth factor receptor I; zirconium-89; nimotuzumab; immunoPET/CT; radiochemistry Received: January 08, 2018 Accepted: February 26, 2018 Published: March 30, 2018 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 89 Zr-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 89 Zr-desferoxamine-nimotuzumab ( 89 Zr-DFO-nimotuzumab) of a product prepared under GMP conditions. Nimotuzumab was conjugated to DFO and radiolabeled with 89 Zr. 89 Zr-DFO-nimotuzumab was characterized by in vitro gel-electrophoresis, biolayer interferometry (BLI) and flow cytometry. 89 Zr-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: 89 Zr-DFO-nimotuzumab had low organ absorbed dose and effective dose that makes it suitable for potential human use.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
22
References
17
Citations
NaN
KQI