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Structure-based design of nanobodies that inhibit seeding of Alzheimer’s patient–extracted tau

Structure-based design of nanobodies that inhibit seeding of Alzheimer’s patient–extracted tau fibrils


PNAS October 6, 2023 120 (41) e2300258120


Significance

Alzheimer’s disease (AD) is associated with aggregation of the protein tau in the brain. Antibodies that bind tau and halt its aggregation are one approach to slowing the progression of AD; however, traditional animal-produced antibodies are often limited by weak target binding, low production, and low brain delivery. We propose a method for designing antibodies in which we graft tau-specific sequences into a camelid antibody fragment or “nanobody”. Our engineered nanobodies are easily produced and block the propagation of tau aggregation in test tube experiments. Next, by linking our best tau-targeting nanobody behind a brain-targeting nanobody, we created a double nanobody designed to enter the brain. Our results demonstrate an alternative approach to engineering antibodies to target tau aggregation.

Abstract

Despite much effort, antibody therapies for Alzheimer’s disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood–brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

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