Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody

• Published in: Alzheimer's research & therapy 2018-05, Vol.10 (1), p.49-49, Article 49
• Main Authors: Syvänen, Stina, Hultqvist, Greta, Gustavsson, Tobias, Gumucio, Astrid, Laudon, Hanna, Söderberg, Linda, Ingelsson, Martin, Lannfelt, Lars, Sehlin, Dag
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Alzheimer’s disease (AD); Amyloid beta-protein; Amyloid-β (Aβ); Antibodies; Care and treatment; Health aspects; Immunization; Immunoglobulins; Immunotherapy; Monoclonal antibodies; Monoclonal antibody; Oligomers; Pathology; Protofibrils; Rodents; Testing; Transgenic animals; Viral antibodies
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-018-0377-8

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.