New antibody targeting approach, tested in mice, improves distribution and safety of Alzheimer’s immunotherapies

A newly engineered antibody transport vehicle targeting the transferrin receptor enables enhanced delivery of anti-amyloid antibodies to the brains of mouse models of Alzheimer’s disease, researchers report. According to the study, the approach preserves key immune functions, such as microglial clearance of plaques, while offering a safer and more effective delivery strategy for anti–amyloid immunotherapies. Alzheimer’s disease (AD) is marked by the buildup of amyloid-β (Aβ) protein plaques in the brain. FDA-approved anti-amyloid drugs, like aducanumab, lecanemab, and donanemab, have shown limited success in reducing Aβ plaque buildup and slightly slowing cognitive decline in AD. Still, they do not stop the disease from progressing. Their clinical benefits might be further constrained by suboptimal penetration into the brain and by common side effects, including brain swelling and small brain bleeds, collectively known as amyloid-related imaging abnormalities (ARIA). To overcome these limitations, Michelle Pizzo and colleagues engineered a novel antibody transport vehicle (ATV) that targets the transferrin receptor – a natural gateway on blood vessels that allows certain molecules to cross the BBB. The design, called ATV^cisLALA, incorporates a mutation to reduce harmful interactions with immune receptors on immature red blood cells, thereby preventing cytotoxic side effects. In a mouse model of AD, Pizzo et al. show that, when fused with an anti–amyloid-β antibody (creating ATV^cisLALA:Aβ), the modified therapy successfully entered brain tissue more efficiently than conventional antibodies. Notably, ATV^cisLALA:Aβ distributed broadly throughout the brain parenchyma, increasing brain concentrations by five- to eightfold. The researchers’ approach also showed enhanced targeting of plaque-associated Aβ in brain tissue rather than in blood vessels, which reduced vascular inflammation and significantly lowered the incidence of ARIA-like side effects. “Taken together, the findings of Pizzo et al. provide more than preclinical proof of concept; they also establish a framework for therapeutic design,“ write Mengen Xing and Weihong Song in a related Perspective. “By precisely controlling the route of antibody entry and modulating its function, ATV^cisLALA:Aβ overcomes long-standing limitations of AD immunotherapy.