Bioscience seminar series

  • Datum: –09.30
  • Plats: Biomedicinskt centrum C4:2 Seminar room
  • Föreläsare: Lars Lannfelt, MD, PhD, Senior Professor, Dept of Public Health/Geriatrics, Uppsala University and BioArctic AB
  • Kontaktperson: Anna Nilsson
  • Seminarium

Targeting Aß protofibrils with BAN2401 - from mutation to potential therapy for Alzheimer’s disease

Currently available therapie for Alzheimer’s disease (AD) is symptomatic. Ongoing research is actively examining potential pathways and therapies with the goal of developing a disease modifying therapy for AD. Recent studies have suggested that soluble, aggregated forms of amyloid β-protein (Aβ) plays an important role in the pathogenesis of AD. Soluble Aβ aggregates are toxic, reducing synapse formation, and neuronal survival. Aβ monomers aggregate to form dimers, trimers, low molecular weight oligomers, eventually forming soluble protofibrils, and finally fibrils. Protofibrils are intermediates in the Aβ aggregation process. Hypothesised as a major culprit in the pathogenesis of AD, protofibrils represent a promising target for immunotherapy. To develop an effective immunotherapy several challenges must be solved - the antibody must be able to reach its target, be efficacious by delivering clinical benefits and be well tolerated. In addition, it is important to identify biomarkers that can be used to both diagnose AD in its early stages as well as assess the clinical efficacy of any treatment. The humanized monoclonal antibody BAN2401, and its murine counterpart mAB158, are monoclonal antibodies specifically designed to target the conformational structure of soluble, aggregated amyloid-β (Aβ) such as protofibrils. They do not target linear epitopes. Development of several monoclonal antibodies targeting Aβ has failed due to lack of efficacy and/or adverse effects. There has been an increasing interest in in soluble aggregated Aβ species, i.e. oligomers and protofibrils, as the key pathogenic species. We examined differences in binding characteristics of BAN2401, an antibody continuing in development in phase 3 and compared it with Biogen’s antibody aducanumab, which met futility in phase 3 in March 2019 , 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. The antibodies binding profile to small and large protofibrils and oligomers was investigated by inhibition ELISA, surface plasmon resonance (SPR) and immunoprecipitation of soluble Aβ from AD brain extracts. With inhibition ELISA, BAN2401 showed approximately 100 times stronger binding to small protofibrils and approximately 15 times stronger binding to large protofibrils as compared to aducanumab. SPR analysis using protofibrils demonstrated similar data, with fast on-rates for both antibodies but with a much slower off-rate for BAN2401. BAN2401 had a KD of 1.32 nM to small protofibrils and aducanumab a KD of 138 nM. Thus, BAN2401 had approximately 100 times stronger binding to these Aβ species, and, in addition, showed stronger binding to large protofibrils and small oligomers (<75 kDa). BAN2401 was also more efficient than aducanumab to immunoprecipitate Aβ protofibrils/oligomers from AD brain extracts. BAN2401 had a much stronger in vitro binding to Aβ protofibrils and oligomers compared to aducanumab and was more effective in depleting Aβ protofibrils/oligomers from AD brain extracts. These differences in binding to Aβ may mediate the differences in clinical efficacy and safety observed for the two antibodies in phase 2/3 clinical trials.