TY - JOUR
T1 - Preclinical Evaluation of 89Zr-Desferrioxamine-Bexmarilimab, a Humanized Antibody Against Common Lymphatic Endothelial and Vascular Endothelial Receptor-1, in a Rabbit Model of Renal Fibrosis
AU - Moisio, Olli
AU - Virta, Jenni
AU - Yatkin, Emrah
AU - Liljenbäck, Heidi
AU - Palani, Senthil
AU - Viitanen, Riikka
AU - Miner, Maxwell W. G.
AU - Oikonen, Vesa
AU - Tolvanen, Tuula
AU - Vugts, Danielle J.
AU - Taimen, Pekka
AU - Li, Xiang-Guo
AU - Hollmén, Maija
AU - Jalkanen, Sirpa
AU - Roivainen, Anne
N1 - Funding Information:
Timothy Johnson and Toby Holmes (Sheffield University, U.K.) are thanked for their advice and help regarding the UUO rabbit model. Professional assistance from Aake Honkaniemi (Turku PET Centre), Sari Mäki (MediCity Research Laboratory), and Marja-Riitta Kajaala and Erika Nyman (the University of Turku Histocore Facility) is greatly appreciated. The personnel of the University of Turku Central Animal Laboratory are thanked for expert animal care. We thank Timo Kattelus for preparing the figures.
Funding Information:
Maija Hollmén and Sirpa Jalkanen own stock in Faron Pharmaceuticals. The study was financially supported by grants from Business Finland, the Jane and Aatos Erkko Foundation, the Academy of Finland (#350117), and the Finnish Cultural Foundation. Olli Moisio is a PhD student partially supported by the Drug Research Doctoral Program of the University of Turku Graduate School and the doctoral module of the InFLAMES Flagship. No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
COPYRIGHT © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Bexmarilimab is a new humanized monoclonal antibody against common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) and is in clinical trials for macrophage-guided cancer immunotherapy. In addition being associated with cancer, CLEVER-1 is also associated with fibrosis. To facilitate prospective human PET studies, we preclinically evaluated 89Zr-labeled bexmarilimab in rabbits. Methods: Bexmarilimab was conjugated with desferrioxamine (DFO) and radiolabeled with 89Zr. Retained immunoreactivity was confirmed by flow cytometry. The distribution kinetics of intravenously administered 89Zr-DFO-bexmarilimab (0.1 mg/kg) were determined for up to 7 d in a rabbit model of renal fibrosis mediated by unilateral ureteric obstruction. The in vivo stability of 89Zr-DFO-bexmarilimab was evaluated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis in combination with autoradiography. Additionally, we estimated the human radiation dose from data obtained in healthy rabbits. Results: 89Zr-DFO-bexmarilimab cleared rapidly from the blood circulation and distributed to the liver and spleen. At 24 h after injection, PET/CT, ex vivo g-counting, and autoradiography demonstrated that there was significantly higher 89Zr-DFO-bexmarilimab uptake in unilateral ureteric obstruction–operated fibrotic renal cortex, characterized by abundant CLEVER-1–positive cells, than in contralateral or healthy kidneys. The estimated effective dose for a 70-kg human was 0.70 mSv/MBq. Conclusion: The characteristics of 89Zr-DFO-bexmarili-mab support future human PET studies to, for example, stratify patients for bexmarilimab treatment, evaluate the efficacy of treatment, or monitor disease progression.
AB - Bexmarilimab is a new humanized monoclonal antibody against common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) and is in clinical trials for macrophage-guided cancer immunotherapy. In addition being associated with cancer, CLEVER-1 is also associated with fibrosis. To facilitate prospective human PET studies, we preclinically evaluated 89Zr-labeled bexmarilimab in rabbits. Methods: Bexmarilimab was conjugated with desferrioxamine (DFO) and radiolabeled with 89Zr. Retained immunoreactivity was confirmed by flow cytometry. The distribution kinetics of intravenously administered 89Zr-DFO-bexmarilimab (0.1 mg/kg) were determined for up to 7 d in a rabbit model of renal fibrosis mediated by unilateral ureteric obstruction. The in vivo stability of 89Zr-DFO-bexmarilimab was evaluated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis in combination with autoradiography. Additionally, we estimated the human radiation dose from data obtained in healthy rabbits. Results: 89Zr-DFO-bexmarilimab cleared rapidly from the blood circulation and distributed to the liver and spleen. At 24 h after injection, PET/CT, ex vivo g-counting, and autoradiography demonstrated that there was significantly higher 89Zr-DFO-bexmarilimab uptake in unilateral ureteric obstruction–operated fibrotic renal cortex, characterized by abundant CLEVER-1–positive cells, than in contralateral or healthy kidneys. The estimated effective dose for a 70-kg human was 0.70 mSv/MBq. Conclusion: The characteristics of 89Zr-DFO-bexmarili-mab support future human PET studies to, for example, stratify patients for bexmarilimab treatment, evaluate the efficacy of treatment, or monitor disease progression.
KW - CLEVER-1
KW - PET/CT
KW - Zr
KW - bexmarilimab
KW - renal fibrosis
KW - whole-body distribution
UR - http://www.scopus.com/inward/record.url?scp=85148108049&partnerID=8YFLogxK
U2 - 10.2967/jnumed.122.264725
DO - 10.2967/jnumed.122.264725
M3 - Article
C2 - 36302655
SN - 0161-5505
VL - 64
SP - 555
EP - 560
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 4
ER -