Enhanced Alzheimer's Treatment through Modified Antibody

In the ongoing quest to combat Alzheimer's disease, a new antibody transport vesicle is making waves in the scientific community. This innovative construct, developed by Michelle Pizzo and her colleagues, may hold the key to overcoming challenges faced by current anti-amyloid drugs and FDA-approved Alzheimer's immunotherapies.

Current treatments, such as aducanumab, lecanemab, and donanemab, target Aβ plaques in the brain, but they are not a cure and have limited ability to halt or reverse disease symptoms. One of the major issues with these treatments is the risk of serious side effects, including brain swelling and microbleeds in the brain, collectively referred to as amyloid-related imaging abnormalities (ARIA).

The new antibody transport vesicle, known as ATV:Aβ, addresses these challenges by showing promise as a potential solution. In a study published in the prestigious journal Science, it was found that the ATV:Aβ construct primarily crossed capillaries, reducing inflammatory responses. This means that it can effectively penetrate brain tissue, providing better target engagement with parenchymal plaques.

The work also suggests that it may be possible to preserve both brain penetration and immune effector function in a single therapeutic design. Mice treated with the engineered therapy showed near-complete elimination of ARIA-like lesions and vascular inflammation.

The authors concluded that ATV has the potential to improve the next generation of Aβ immunotherapy, through enhanced biodistribution mediated by transport across the blood-brain barrier (BBB). This could be critical for next-generation anti-Aβ therapies, as the combination of efficacy and safety could be key to overcoming the limitations of current treatments.

The team engineered the ATV with asymmetrical Fc mutations that reduce interactions with immune cells and immature red blood cells, further enhancing its safety profile. The antibody transport capsule developed by Denali Therapeutics together with Biogen is planned to be tested in clinical trials starting in 2023.

In a related Perspective, Mengen Xing, PhD, and Weihong Song, PhD, agreed that the findings provide more than preclinical proof of concept and establish a framework for therapeutic design. They noted that the researchers explored receptor-mediated transport across the BBB to address both efficacy and safety limitations, making this a significant step forward in the development of effective Alzheimer's treatments.

A functional hallmark of Alzheimer's disease is the buildup of amyloid-β (Aβ) protein plaques in the brain. By addressing this issue with a more effective and safer treatment, researchers hope to make a significant impact on the lives of those affected by this devastating disease.