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bioRxiv · 10.1101/2025.06.30.662446

Single-Domain Antibody-Based Autophagosome-Targeting Chimera for Tau Clearance and Motor Function Restoration in Tauopathies

Sigurdsson, E.·Jiang, Y.·Tetlow, A. M.·Lin, Y.·Ji, C.·Laborc, K. F.·Mar, A. C.·Pan, R.·Kong, X.-P.·Congdon, E. E.
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Abstract

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge. Here, we present 1D9-LIR{Delta}TP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance via the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIR{Delta}TP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In frontotemporal dementia (FTD) patient-derived neurons and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIR{Delta}TP53INP2 significantly reduced tau levels and improved motor function in mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

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Sigurdsson, E., Jiang, Y., Tetlow, A. M., Lin, Y., Ji, C., Laborc, K. F., Mar, A. C., Pan, R., Kong, X.-P., Congdon, E. E.. 2025-07-04. Single-Domain Antibody-Based Autophagosome-Targeting Chimera for Tau Clearance and Motor Function Restoration in Tauopathies. https://doi.org/10.1101/2025.06.30.662446

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