Immunoglobulin GM (γ marker) allotypes as potential genetic markers of efficacy of lecanemab therapy in Alzheimer's disease.

Abstract

Lecanemab is a humanized IgG1 monoclonal antibody that targets amyloid-β (Aβ) aggregates, a pathological hallmark of Alzheimer's disease (AD). In the largest clinical trial of its kind to date, lecanemab slowed cognitive decline by 27% in patients with early-stage AD. Lecanemab has also been shown to reduce cerebral Aβ deposition. Lecanemab expresses the immunoglobulin GM 3 allotype, which is defined by an arginine residue in the CH1 region of the γ1 chain and is potentially immunogenic in individuals who lack this allotype. I hypothesize that anti-GM 3 antibodies, generated either following lecanemab administration or acquired previously through maternal-fetal incompatibility or transfusion of allotype-incompatible blood products, may form immune complexes with the therapeutic antibody. These immune complexes could be cleared by phagocytic cells, including microglia, thereby reducing the availability and efficacy of lecanemab and contributing to therapeutic nonresponsiveness. If validated, GM allotypes could serve as genetic markers for predicting response to lecanemab therapy and may help guide personalized treatment strategies in AD.