A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AsO). Therapeutic antibodies targeting As monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AsO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational As epitope predicted by computational modeling to be presented on toxic AsO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AsO-selective binding profile. In vitro, PMN310 inhibited AsO propagation and toxicity. In vivo, PMN310 prevented AsO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other As-directed antibodies showing a lack of adverse event-associated binding to As deposits in AD brains, and greater selective binding to AsO-enriched AD brain fractions that contain synaptotoxic As species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AsO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.