Immunotherapy with B28, an antibody to Aβ oligomers, potently decreases amyloid plaques, microgliosis, and memory decline in APP knock-in mice.

Immunotherapy against amyloid β-protein (Aβ) for Alzheimer's disease (AD) has been widely approved. Breakthrough disease-modifying treatments such as lecanemab and donanemab are often followed by drugs with improved efficacy. By immunizing Trianni mice with aggregated synthetic Aβ, we obtained B28, a fully human antibody specifically selected for its neutralization of tau neuritic dystrophy induced by AD brain-derived oligomers. In a blinded trial in mutant human APPNL-G-F knock-in mice, weekly infusions of B28 for four months markedly reduced both amyloid plaques and Aβ oligomers, attenuated plaque-associated astrocytosis and microgliosis, preserved neurons, and lessened memory decline. Biochemical and histological analyses showed that B28 engaged both plaque-bound and diffusible Aβ, forming immune complexes and depleting free Aβ. In in vitro immunoassays, B28 had significantly higher affinity and captured more Aβ from AD brain extracts than did lecanemab. B28 is a potent, aggregate-preferring Aβ antibody that clears plaques and decreases gliosis, supporting its clinical development.