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Publication Abstract from PubMed

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.

Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.,Abskharon R, Pan H, Sawaya MR, Seidler PM, Olivares EJ, Chen Y, Murray KA, Zhang J, Lantz C, Bentzel M, Boyer DR, Cascio D, Nguyen BA, Hou K, Cheng X, Pardon E, Williams CK, Nana AL, Vinters HV, Spina S, Grinberg LT, Seeley WW, Steyaert J, Glabe CG, Ogorzalek Loo RR, Loo JA, Eisenberg DS Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2300258120. doi: , 10.1073/pnas.2300258120. Epub 2023 Oct 6. PMID:37801475^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.