Innovative Antibody Delivery Method Enhances Brain Penetration

The blood-brain barrier (BBB) presents a significant challenge for therapeutic antibodies, often limiting their effectiveness in treating neurological conditions. Recent advancements have introduced a sophisticated delivery vehicle that significantly improves the ability of these antibodies to penetrate the BBB while simultaneously reducing the risk of adverse effects associated with existing treatments.

Therapeutic antibodies, such as Donanemab and Lecanemab, are designed to target and eliminate ?-amyloid plaques in the brain, a hallmark of Alzheimer's disease. However, their efficacy is often hampered by the BBB, necessitating high doses that frequently result in low tissue concentration within the brain and potential side effects, including amyloid-related imaging abnormalities (ARIA), which can cause serious complications such as swelling and bleeding in the brain.

A new study published in the journal Science outlines a versatile platform technology that enhances the delivery of antibodies across the BBB. This innovative method leverages transferrin receptors (TfR) expressed on brain endothelial cells to facilitate the transport of antibodies. Researchers from Denali Therapeutics have ingeniously used these receptors as a 'Trojan horse' to shuttle antibodies into the brain.

To create an effective antibody transport vehicle (ATV), the team modified the Fc region of human immunoglobulin G1 (IgG1) to bind to TfR. This modification was combined with an anti-?-amyloid antibody, resulting in a complete transport construct capable of effectively crossing the BBB.

Another critical challenge addressed by the researchers was the potential for off-target effects, particularly in peripheral tissues where transferrin receptors are also present. To mitigate this issue, they intentionally altered the effector functions of the transport vehicle using LALA mutations (L234A and L235A) in the Fc region. These mutations significantly reduce the binding affinity of IgG1 to Fc-gamma receptors (Fc?R), thereby minimizing unwanted immune activation.

In animal studies, the researchers demonstrated that using an asymmetric LALA mutation--applied only to the side of the Fc domain responsible for TfR binding--successfully eliminated hematological risks. Furthermore, in vitro experiments with amyloid-treated mouse brain cells and transgenic Alzheimer's model mice confirmed that the ATV effectively recruited microglia and facilitated the clearance of amyloid deposits.

This groundbreaking advancement in antibody delivery not only enhances therapeutic potential for Alzheimer's treatment but also paves the way for more effective strategies addressing other neurological disorders. Through improved brain penetration and reduced side effects, this innovative technology holds promise for revolutionizing the landscape of treatments targeting central nervous system diseases.