Document Type
Article
Publication Date
12-2-2025
Abstract
Erythropoietin (EPO) shows promise for Alzheimer's disease (AD) but has poor brain penetration, necessitating high doses that cause hematopoietic side effects. To improve brain delivery, EPO was fused to a transferrin receptor monoclonal antibody (TfRMAb), and this study evaluated the pharmacokinetics (PK), safety, and efficacy of repeated TfRMAb-EPO dosing in mice to further its preclinical development. C57BL/6J male mice (10 weeks old, n = 4–5/dose) received subcutaneous (SQ) low (1 mg/kg), mid (3 and 6 mg/kg), or high (20 mg/kg) TfRMAb-EPO doses for 4 weeks. The 1 mg/kg dose showed no adverse effects and resulted in sustained brain and plasma exposure, making it suitable for longitudinal dosing. Paradoxically, higher doses reduced plasma and brain exposure, and altered hematocrit, TfR expression, and spleen weight; these changes were largely reversible. Anti-drug antibodies and TfR expression changes likely contributed to reduced plasma exposure at higher doses. Subsequently, 5.5-month-old APPSAA knock-in (KI) mice (n = 6) received 1 mg/kg TfRMAb-EPO SQ for 14 weeks. Controls included vehicle-treated APPSAA KI and APP wild-type mice (n = 4–5/group). Despite the low dose, TfRMAb-EPO showed profound brain Aβ-lowering effects measured by immunostaining (70–80 % reduction, p < 0.001) and improved spatial memory in the Y maze (p < 0.05). These findings offer important preclinical data to guide dose optimization in longitudinal studies using TfRMAb-based therapeutics, specifically TfRMAb-EPO, given the movement of TfRMAb-based therapeutics into clinical trials for AD, and show the robust therapeutic potential of low-dose TfRMAb-EPO in APPSAA KI AD mice.
Recommended Citation
Chang, R., Chandrashekar, D.V., Chuli Roules, G., Jagadeesan, N., Iwasaki, E., Oyegbesan, A., et al., 2025. Longitudinal pharmacokinetic and safety studies for dose optimization of a brain- penetrating erythropoietin for Alzheimer’s disease. Int. J. Pharmaceutics: X 10, 100459. https://doi.org/10.1016/j.ijpx.2025.100459
Supplementary material provides supporting data on the anti-drug antibody responses (Supplemental Fig. 1), kidney weights (Supplemental Fig. 1), full blot images of the Western blot experiments (Supplemental Fig. 2), EPOR levels in different tissues (Supplemental Fig. 3), blood chemistry analysis (Supplemental Fig. 4), and immunostaining data (Supplemental Fig. 5) following TfRMAb-EPO dosing.
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The authors
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This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
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Comments
This article was originally published in International Journal of Pharmaceutics: X, volume 10, in 2025. https://doi.org/10.1016/j.ijpx.2025.100459