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Preclinical Evaluation of a Humanized Antibody Against Common Lymphatic Endothelial and Vascular Endothelial Receptor-1, 89Zr-Desferrioxamine-Bexmarilimab, in a Rabbit Model of Renal Fibrosis

Tolvanen Tuula; Liljenbäck Heidi; Miner Maxwell WG; Taimen Pekka; Yatkin Emrah; Oikonen Vesa; Jalkanen Sirpa; Roivainen Anne; Viitanen Riikka; Virta Jenni; Moisio Olli; Hollmén Maija; Li Xiang-Guo; Vugts Danielle J; Palani Senthil

Preclinical Evaluation of a Humanized Antibody Against Common Lymphatic Endothelial and Vascular Endothelial Receptor-1, 89Zr-Desferrioxamine-Bexmarilimab, in a Rabbit Model of Renal Fibrosis

Tolvanen Tuula
Liljenbäck Heidi
Miner Maxwell WG
Taimen Pekka
Yatkin Emrah
Oikonen Vesa
Jalkanen Sirpa
Roivainen Anne
Viitanen Riikka
Virta Jenni
Moisio Olli
Hollmén Maija
Li Xiang-Guo
Vugts Danielle J
Palani Senthil
Katso/Avaa
jnumed.122.264725.full-1.pdf (2.552Mb)
Lataukset: 

Society of Nuclear Medicine
doi:10.2967/jnumed.122.264725
URI
https://doi.org/10.2967/jnumed.122.264725
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe202301173192
Tiivistelmä

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 to 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. Distribution kinetics of intravenously administered 89Zr-DFO-bexmarilimab (0.1 mg/kg) for up to 7 days in a rabbit model of renal fibrosis mediated by unilateral ureteric obstruction (UUO). 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 hours post-injection, PET/CT, ex-vivo gamma counting and autoradiography demonstrated that there was significantly higher 89Zr-DFO-bexmarilimab uptake in UUO-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-bexmarilimab support future human PET studies to, for example, stratify patients for bexmarilimab treatment, evaluate the efficacy of treatment, or monitor disease progression.

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