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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a high prevalence, and an estimated 24 million people worldwide and 5.8 million people in America suffer from AD [1]
One approach to non-invasively deliver biologics into the brain across the blood-brain barrier (BBB) is to target endogenous BBB receptor-mediated transcytosis (RMT) systems, which exist for ligands, such as transferrin, leptin, insulin, and insulin-like growth factors [4]
This study aims to fill this gap by characterizing the effect of a high-affinity bivalent TfRMAb, with a murine constant region, on hematologic, iron- and behavior-indices following SQ acute- and chronic-dosing at low therapeutic doses, in mice
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a high prevalence, and an estimated 24 million people worldwide and 5.8 million people in America suffer from AD [1]. The largest class of disease-modifying therapies being developed for AD target amyloid-beta or tau, and the majority (>50%) of these drug candidates are biologics including anti-tau and anti-amyloid beta antibodies [2]. One of the major hurdles while trying to develop a biologic, including anti-amyloid and anti-tau therapies for AD, is low brain bioavailability of the biologic due to the blood-brain barrier (BBB) [3]. One approach to non-invasively deliver biologics into the brain across the BBB is to target endogenous BBB receptor-mediated transcytosis (RMT) systems, which exist for ligands, such as transferrin, leptin, insulin, and insulin-like growth factors [4]. Among the RMT systems, the transferrin receptor-1 (TfR) is the most extensively studied for its ability to deliver biologics into the brain [5]. Antibodies against the TfR (TfRMAbs) that target epitopes spatially removed from the Tf binding site on the TfR are under pre-clinical and clinical development for brain drug delivery [5,6,7,8,9,10,11]
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