Acute and Chronic Dosing of a High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody in Mice

Authors

Demi M. Castellanos, Keck Graduate InstituteFollow
Jiahong Sun, Keck Graduate InstituteFollow
Joshua Yang, Keck Graduate InstituteFollow
Weijun Ou, Keck Graduate InstituteFollow
Alexander C. Zambon, Keck Graduate InstituteFollow
William M. Pardridge, University of California, Los AngelesFollow
Rachita K. Sumbria, Chapman UniversityFollow

Document Type

Article

Publication Date

9-8-2020

Abstract

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent TfRMAb with a murine constant region following acute and chronic subcutaneous dosing in adult C57BL/6J male mice. Mice received a single (acute dosing) 3 mg/kg dose, or were treated for four weeks (chronic dosing). TfRMAb and control IgG1 significantly altered reticulocyte counts following acute and chronic dosing, while other hematologic parameters showed minimal change. Chronic TfRMAb dosing did not alter plasma- and brain-iron measurements, nor brain TfR levels, however, it significantly increased splenic-TfR and -iron. Plasma concentrations of TfRMAb were significantly lower in mice chronically treated with IgG1 or TfRMAb. Overall, no injection related reactions were observed in mice

Comments

This article was originally published in Pharmaceutics, volume 12, in 2020. https://doi.org/10.3390/pharmaceutics12090852

Recommended Citation

Castellanos DM, Sun J, Yang J, et al. Acute and chronic dosing of a high-affinity rat/mouse chimeric transferrin receptor antibody in mice. Pharmaceutics 2020;12:852. https://doi.org/10.3390/pharmaceutics12090852

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The authors

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This work is licensed under a Creative Commons Attribution 4.0 License.