P4‐704: BAN2401 SHOWS STRONGER BINDING TO SOLUBLE AGGREGATED AMYLOID‐BETA SPECIES THAN ADUCANUMAB

Development of several monoclonal antibodies targeting amyloid-β (Aβ) has been discontinued due to lack of efficacy and/or adverse effects. There has been an increasing interest in soluble aggregated Aβ species, i.e. oligomers (<75 kDa) and protofibrils (>75 kDa), as key pathogenic species. We examined differences in binding characteristics of BAN2401, an antibody continuing in development in phase 3 and aducanumab, an antibody which met futility in phase 3, to better understand the apparent differences in mechanism of action. BAN2401 was designed based on the Arctic mutation (Aβ E22G) which causes AD due to an enhanced propensity to form protofibrils. Aducanumab was developed from healthy old individuals and was in this study produced by us from the published sequence. Inhibition ELISA was used to investigate the antibodies binding to oligomers and protofibrils in solution. Binding properties was also investigated by Surface Plasmon Resonance (SPR, Biacore). The binding strength (IC50 value) of BAN2401 and aducanumab to Aβ protofibrils, as measured by inhibition ELISA, was 35 nM for aducanumab and 1.1 nM for BAN2401. Thus, BAN2401 binds more than 30 times stronger to Aβ protofibrils as compared with aducanumab. Interaction analysis of BAN2401 and aducanumab to protofibrils by SPR demonstrated similar data, with fast on-rates for both antibodies but with a much slower off-rate for BAN2401. BAN2401 binds Aβ protofibrils with a KD of 0.3 nM and aducanumab with a KD of 15 nM. Thus, BAN2401 binds 50 times stronger to protofibrils than aducanumab in this experimental setting. Preliminary results indicate that the binding differences between the antibodies are even greater when analyzing smaller Aβ aggregates (<75 kDa), i.e. oligomers. Several clinical trials in AD with monoclonal antibodies against Aβ have recently failed. One explanation for these failures might be that these antibodies have been targeting the wrong forms of Aβ. Aβ protofibrils and oligomers are attractive species for therapy, as these Aβ forms are toxic. BAN2401 has a 30–50 fold higher binding to Aβ protofibrils in vitro than aducanumab. These differences in binding to toxic Aβ species may mediate differences in clinical responses observed between the two antibodies.