Strategy of selection and optimization of single domain antibodies targeting the PHF6 linear peptide within the Tau intrinsically disordered protein

Abstract

VHHs (Variable Heavy-chain of the Heavy-chain-only antibodies), also named single domain antibodies or nanobodies (1), are the smallest domains of natural Camelidae single chain antibodies that are still capable to recognize an antigen. Their many interesting properties and potential for engineering make VHHs ideal candidates for the design of innovative treatments (2) and new investigation tools (3, 4), including for in-cell imaging (5). Their clinical use has indeed been established in recent years, first with caplacizumab that targets von Willebrand factor to treat thrombotic thrombocytopenic purpura (6) and ozoralizumab that targets TNF-alpha (and human serum albumin) to treat the chronic, autoimmune inflammatory disease rheumatoid arthritis (7). In this later case, the advantages stemming from the biochemical properties of VHHs were put forward, observed as a fast onset of action and the absence of secondary reaction, even in a model of prolonged treatment where no anti-VHH antibodies were formed (8). VHH development covers many additional applications and is gaining ground in neurodegenerative disorders (9, 10) although their medical use in this field has not yet been demonstrated. However, given their better potential than immunoglobulins to be delivered to the central nervous system (11), they are considered as biomolecules of high interest to be developed as disease-modifying next-generation treatments for related pathologies