Date Published: May 24, 2018
Publisher: BioMed Central
Author(s): Stina Syvänen, Greta Hultqvist, Tobias Gustavsson, Astrid Gumucio, Hanna Laudon, Linda Söderberg, Martin Ingelsson, Lars Lannfelt, Dag Sehlin.
Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD). Despite recent progress targeting aggregated forms of Aβ, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aβ protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aβ protofibrils.
Aβ protein precursor (AβPP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFv8D3), in comparison with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158). Soluble Aβ protofibrils and total Aβ in the brain were measured by enzyme-linked immunosorbent assay (ELISA). Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoradiography.
ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble Aβ protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no Aβ protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed different brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect Aβ levels by different mechanisms.
With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aβ immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.
Alzheimer’s disease (AD) is a devastating neurodegenerative disease that, despite years of effort, cannot yet be treated effectively. Immunotherapy directed against amyloid-β (Aβ), which is generally considered to drive AD pathology, appears to be the most promising strategy to modify the causal mechanisms of the progressive synapse loss and neurodegeneration . A pioneering study in the late 1990s demonstrated that active vaccination cleared Aβ pathology in Aβ protein precursor (AβPP)-transgenic mice . However, when tested in humans, active Aβ vaccination caused severe side effects, and the study was subsequently halted . Instead, the field shifted toward passive immunization, which allows antibody properties and doses to be determined with better accuracy, potentially resulting in improved treatment efficacy and safety.
We have previously shown that mAb158 can efficiently and selectively reduce brain levels of Aβ protofibrils in the tg-ArcSwe mouse model and, if given at an early stage of Aβ pathology, can prevent accumulation of Aβ plaques . A humanized version of this antibody, BAN2401 , is currently being evaluated in a phase IIb clinical trial . Similar to aducanumab, which recently showed promising results in a small trial, mAb158 binds with high selectivity to aggregated Aβ and has a very low affinity for monomeric Aβ. This selectivity could be key to successfully eliminating the pathogenic species of Aβ while leaving the abundant, and possibly physiologically relevant, Aβ monomers intact. Further, mAb158 binds with moderate affinity to Aβ fibrils, which could decrease the risk of side effects related to antibody interactions with fibrillar Aβ deposits in vessel walls. Such interactions may cause microbleeding and amyloid-related imaging abnormalities, which are frequently observed side effects in AD immunotherapy trials. In this respect, mAb158/BAN2401 may differ from aducanumab, which is reported to bind fibrillar Aβ with high affinity .
By combining Aβ immunotherapy and in vivo PET imaging, this study demonstrates that TfR-mediated transcytosis can markedly improve brain uptake and distribution of the Aβ protofibril-selective antibody mAb158, leading to an increased target engagement in the brain of transgenic mice (tg-ArcSwe) with AD-like Aβ pathology, probably through a mechanism that is different from traditional Aβ immunotherapy. This strategy increases therapeutic efficacy and may allow for decreased antibody doses to be administered, thereby reducing side effects and treatment costs.