A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo

A human antibody inhibits BACE1 activity and Aβ peptide production in cultured neurons and in the central nervous system of mouse and monkey. A Trojan Horse Antibody Scales a Mighty Fortress As impenetrable as the walls of ancient Troy, the tight endothelial cell layer of the blood-brain barrier (BBB) allows only a few select molecules to enter the brain. Unfortunately, this highly effective fortress blocks passage of therapeutic antibodies, limiting their usefulness for treating diseases of the brain and central nervous system. Enter Ryan Watts and his team at Genentech with their ambitious dual goal of making a therapeutic antibody against a popular Alzheimer’s disease drug target, the enzyme β-secretase (BACE1), and developing a strategy to boost the amount of this antibody that enters the brain (Atwal et al. and Yu et al.). BACE1 processes the amyloid precursor protein into amyloid-β (Aβ) peptides including those molecular species that aggregate to form the amyloid plaques found in the brains of Alzheimer’s disease patients. By blocking the activity of BACE1, BACE1 inhibitors should reduce production of the aggregation-prone Aβ peptides, thus decreasing amyloid plaque formation and slowing Alzheimer’s disease progression. Although small-molecule inhibitors of BACE1 have been developed and can readily cross the BBB because of their small size, they do not show sufficient specificity and hence may have toxic side effects. Watts envisaged that a better approach to blocking BACE1 activity might be passive immunization with a highly specific anti-BACE1 antibody. So his team engineered an anti-BACE1 antibody that bound to BACE1 with exquisite specificity and blocked its activity (Atwal et al.). The investigators then showed that this antibody could reduce production of aggregation-prone Aβ peptides in cultured primary neurons. Next, Watts and his colleagues injected the antibody into mice and monkeys and demonstrated a sustained decrease in the concentrations of Aβ peptide in the circulation of these animals and to a lesser extent in the brain. The researchers knew that they must find a way to increase the amount of antibody getting into the brain to reduce Aβ peptide concentrations in the brain sufficiently to obtain a therapeutic effect. So Watts teamed up with fellow Genentechie, Mark Dennis, and they devised an ingenious solution (Yu et al.). The Genentech researchers knew that high-affinity antibodies against the transferrin receptor might be able to cross the BBB using a natural process called receptor-mediated transcytosis. However, when they tested their antibody, they found that although it readily bound to the BBB, it could not detach from the transferrin receptor and hence was not released into the brain. So, they made a series of lower-affinity mouse anti-transferrin receptor antibodies and found variants that could cross the BBB by receptor-mediated transcytosis and were released into the mouse brain once they got across the endothelial cell layer. Next, they designed a bispecific mouse antibody with one arm comprising a low-affinity anti-transferrin receptor antibody and the other arm comprising the high-affinity anti-BACE1 antibody that had shown therapeutic promise in their earlier studies. They demonstrated that their bispecific antibody was able to cross the BBB and reach therapeutic concentrations in the mouse brain. They then showed that this bispecific antibody was substantially more effective at reducing Aβ peptide concentrations in the mouse brain compared to the monospecific anti-BACE1 antibody. This elegant pair of papers not only demonstrates the therapeutic potential of an anti-BACE1 antibody for treating Alzheimer’s disease but also provides a strategy worthy of the ancient Greeks that could be applied to other therapeutic antibodies that require safe passage into the human brain. Reducing production of amyloid-β (Aβ) peptide by direct inhibition of the enzymes that process amyloid precursor protein (APP) is a central therapeutic strategy for treating Alzheimer’s disease. However, small-molecule inhibitors of the β-secretase (BACE1) and γ-secretase APP processing enzymes have shown a lack of target selectivity and poor penetrance of the blood-brain barrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and is anti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Aβ production in human cell lines expressing APP and in cultured primary neurons. Anti-BACE1 is highly selective and does not inhibit the related enzymes BACE2 or cathepsin D. Competitive binding assays and x-ray crystallography indicate that anti-BACE1 binds noncompetitively to an exosite on BACE1 and not to the catalytic site. Systemic dosing of mice and nonhuman primates with anti-BACE1 resulted in sustained reductions in peripheral Aβ peptide concentrations. Anti-BACE1 also reduces central nervous system Aβ concentrations in mouse and monkey, consistent with a measurable uptake of antibody across the BBB. Thus, BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer’s disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain.