Optimization of a VHH targeting Tau nucleation core and inhibiting Tau seeding

Authors

Justine Mortelecque¹ , Orgeta Zejneli² , Séverine Bégard³ , Marine NGuyen⁴ , François-Xavier Cantrelle⁴ , Xavier Hanoulle¹ , Jean-Christophe Rain⁵ , Morvane Colin² , Luc Buée⁶ , Isabelle Landrieu¹ , Clément Danis⁷ , Elian Dupré⁴

1. CNRS-EMR 9002, U1167 RID-AGE
2. UnivLille-U1172
3. Inserm-U1172
4. UnivLille-EMR 9002, U1167 RID-AGE
5. Hybrigenics Services SA
6. CNRS-U1172
7. Inserm-EMR 9002, Inserm U1167, Inserm-U1172

Conference / event

Eurotau 2023, April 2023 (Lille, France)

Poster summary

Tau is a neuronal protein linked to pathologies called tauopathies, including Alzheimer’s disease (AD). In AD, tau aggregates into filaments leading to the observation of intraneuronal fibrillary tangles. We recently described VHH Z70 (Variable domain of the heavy-chain only antibody Z70), a single domain antibody fragment binding tau. VHH Z70 is able to reduce tau in vitro aggregation, tau seeding in a cellular model and tau pathology in a transgenic murine model. VHH Z70 optimization of its binding affinity was carried out by random mutagenesis followed by yeast two hybrid screening. We confirmed that all optimized VHHs kept the same epitope and had improved binding affinities. However, in vitro aggregation and cellular seeding experiments revealed that the inhibition ability of the VHH Z70 variants was not solely dependent on this property and proved difficult to predict. Indeed, our results demonstrate that VHH stability is another key to their efficacy.

Keywords

Single‐domain antibody (sdAb,nanobody), Antibody engineering, Protein-protein interactions, Tau protein, Protein aggregation, Structural biology

Research areas

Bioengineering, Biochemistry

References

1. Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment. Danis C, Dupré E, Zejneli O, Caillierez R, Arrial A, Bégard S, Mortelecque J, Eddarkaoui S, Loyens A, Cantrelle FX, Hanoulle X, Rain JC, Colin M, Buée L, Landrieu I. Mol Ther. 2022 Apr 6;30(4):1484-1499. doi: 10.1016/j.ymthe.2022.01.009.
2. Strategy of selection and optimization of single domain antibodies targeting the PHF6 linear peptide within the Tau intrinsically disordered protein Justine Mortelecque, Orgeta Zejneli, Séverine Bégard, Nguyen Marine, François-Xavier Cantrelle, Xavier Hanoulle, Jean-Christophe Rain, Morvane Colin, Luc Buée, Isabelle Landrieu, Clément Danis, Elian Dupré bioRxiv 2023.07.18.549252; doi: https://doi.org/10.1101/2023.07.18.549252

Funding

1. Agence Nationale de la Recherche (France) (No. ANR-11-LABX-01)
2. Agence Nationale de la Recherche (France) (No. ANR-18-CE44-0016)

Supplemental files

No data provided

Additional information

Competing interests

JC Rain is CEO of Hybrigenics services Part of the work is included in patent WO2020120644 NEW ANTI TAU SINGLE DOMAIN ANTIBODY Landrieu I, Buée L, Dupré E., Danis C, Rain J.-C., Arial A.

Data availability statement

The datasets generated during and / or analyzed during the current study are available elsewhere (e.g., repository).
10.5281/zenodo.8083246

Creative Commons license

Copyright © 2023 Mortelecque et al. This is an open access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.