Central amyloid-β-specific single chain variable fragment ameliorates Aβ aggregation and neurotoxicity

• Published in: Protein engineering, design and selection design and selection, 2013-10, Vol.26 (10), p.571-580
• Main Authors: Nisbet, R.M., Nigro, J., Breheney, K., Caine, J., Hattarki, M.K., Nuttall, S.D.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - immunology; Animals; Antibody Specificity; Cell Differentiation - drug effects; Female; Mice; Molecular Sequence Data; Neurons - cytology; Neurons - drug effects; PC12 Cells; Peptide Fragments - chemistry; Peptide Fragments - immunology; Pregnancy; Protein Engineering; Protein Multimerization - immunology; Protein Structure, Secondary; Rats; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Single-Chain Antibodies - chemistry; Single-Chain Antibodies - genetics; Single-Chain Antibodies - immunology
• ISSN: 1741-0126; 1741-0134
• DOI: 10.1093/protein/gzt025

Anti-amyloid-β immunotherapies are a promising therapeutic approach for the treatment and prevention of Alzheimer's disease (AD). Single chain antibody fragments (scFv) are an attractive alternative to whole antibodies due to their small size, single polypeptide format and inability to stimulate potentially undesirable Fc-mediated immune effector functions. We have generated the scFv derivative of anti-Aβ monoclonal antibody, 1E8, known to target residues 17–22 of Aβ. Here we show that the soluble 1E8 scFv binds to the central region of Aβ with an affinity of ∼55 nM and significantly reduces fibril formation of Aβ1–42. Furthermore, 1E8 scFv ameliorates Aβ1–42-mediated toxicity in the PC12 cell line and murine primary neuronal cultures. This ability to both target the central region of Aβ and prevent Aβ1–42 neurotoxicity in vitro makes it a promising therapeutic antibody building block for further functionalization, toward the treatment of AD.