ArticleResearch square2025
Longitudinal pharmacokinetic and safety studies for dose optimization of a brain- penetrating erythropoietin for Alzheimer's disease.
Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Erythropoietin (EPO) is a potential therapeutic for Alzheimer's disease (AD), but has limited brain penetration, requiring high systemic doses that lead to hematopoietic side effects. To overcome this, EPO was conjugated with a transferrin receptor monoclonal antibody (TfRMAb) to enhance blood-brain barrier transport. This study assessed the pharmacokinetics (PK), safety, and efficacy of this modified EPO after repeated dosing in mice. Methods: For the PK and safety study, a multidose design was employed with 10-week-old C57 male mice (n=4-5/dose) receiving low (1 mg/kg), mid (3 and 6 mg/kg), or high (20 mg/kg) doses SQ for 4 weeks, aimed to evaluate the dose-dependent plasma concentrations and biodistribution, and metabolic and hematologic safety of the modified EPO. The dose that resulted in the highest safety and sustained plasma exposure was then dosed SQ to 5.5-month-old male APP Results: The 1 mg/kg dose showed no adverse effects and sustained brain and plasma exposure following repeated dosing, making it suitable for longitudinal treatment. Mid and high doses reduced plasma and brain exposure, and altered hematocrit, TfR expression, and spleen weight; changes that were largely reversible upon treatment cessation. Reduced plasma exposure at mid and high doses was not completely explained by increased TfR expression, anti-drug antibodies, tissue sequestration, or EPO receptor expression. Subsequently, 5.5-month-old APP Conclusions: With the advancement of TfRMAb-based therapeutics into clinical trials for AD, these findings are particularly significant. They offer essential preclinical data to guide dose optimization in longitudinal studies using TfRMAb-based therapeutics, specifically modified-EPO, and show the robust therapeutic potential of low-dose brain-penetrating EPO in the APP
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