Engineering an IgG3 Antibody for Enhanced Dual Targeting of Amyloid-Beta and Tau in Alzheimer's Disease

This research proposal outlines a novel immunotherapeutic approach for Alzheimer’s disease (AD) by bioengineering an IgG3-based monoclonal antibody with enhanced properties. Unlike current IgG1-based therapies, which primarily target amyloid-beta (Aβ) and have limited success with tau pathology and significant safety concerns, this proposed antibody features dual specificity for both Aβ and phosphorylated tau. The design incorporates advanced molecular engineering strategies—such as hinge region stabilization, Fc glycoengineering, LS mutations for extended half-life, and bispecific Fab arms—to optimize effector functions, reduce inflammatory side effects, and enhance brain penetration via receptor-mediated transcytosis. The proposal includes a structured preclinical testing plan involving in vitro affinity and effector assays, in vivo validation in 3xTg-AD mouse models, and pharmacokinetic profiling. If successful, this antibody construct could significantly improve pathological clearance and neuroinflammatory modulation in AD, potentially serving as a foundation for future clinical development.