Developing Topics

Background: Therapeutic monoclonal antibodies targeting amyloid beta-protein (Ab), such as lecanemab, represent a promising approach for disease-modification in Alzheimer's disease (AD). Due to its relatively short half-life, lecanemab is given as a bi-monthly infusion (typically 10mg/kg). Binding to high abundance plasma proteins (PPB) can influence the pharmacokinetics of drugs in the blood, including their half-life.

Method: In this study, we investigated the potential of PPB for lecanemab using a biosimilar synthetized from publicly available lecanemab sequence (Lec-bs). Lec-bs biosimilar immunoreactivity was assessed in human plasma fractions obtained by size exclusion chromatography using both ELISA and Western blotting. The binding of lec-bs to candidate PPB was validated through Western blotting, ELISA, and surface plasmon resonance analysis.

Result: Using a combination of equilibrium dialysis, ELISA, and Western blotting of human plasma, we first describe the presence of likely PPB for Lec-bs, and then identify fibrinogen as a probable major plasma protein binding partner for Lec-bs. Utilizing surface plasmon resonance, we confirmed that Lec-bs binds to fibrinogen, albeit with lower affinity (318 µM) than to monomeric Ab (324 nM).

Conclusion: In the context of lecanemab therapy, these results suggest that fibrinogen levels may influence free antibody levels in blood and that fibrinogen may act as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration for the clinical use of therapeutic antibodies in neurodegenerative disease.