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Novel multivalent design of a monoclonal antibody improves binding strength to soluble aggregates of amyloid beta

Translational Neurodegeneration 2021年第3期10卷 502-517页

作者： Fadi Rofo Jos Buijs Ronny Falk Ken Honek Lars Lannfelt Anna M.Lilja Nicole G.Metzendorf Tobias Gustavsson Dag Sehlin Linda Söderberg Greta Hultqvist Protein Drug Design Faculty of PharmacyUppsala University75124 UppsalaSweden Department of Immunology Genetics and PathologyUppsala University75185 UppsalaSweden Ridgeview Instruments 75237 UppsalaSweden BioArctic AB 11251 StockholmSweden Department of Public Health and Caring Sciences Uppsala University75185 UppsalaSweden

Background:Amyloid-β(Aβ)immunotherapy is a promising therapeutic strategy in the fght against Alzheimer’s disease(AD).A number of monoclonal antibodies have entered clinical trials for *** of them have failed due to the lack of efcacy or side-efects,two antibodies are currently in phase 3,and one has been approved by *** soluble intermediate aggregated species of Aβ,termed oligomers and protofbrils,are believed to be key pathogenic forms,responsible for synaptic and neuronal degeneration in ***,antibodies that can strongly and selectively bind to these soluble intermediate aggregates are of great diagnostic and therapeutic ***:We designed and recombinantly produced a hexavalent antibody based on mAb158,an Aβprotofbrilselective *** humanized version of mAb158,lecanemab(BAN2401),is currently in phase 3 clinical trials for the treatment of *** new designs involved recombinantly fusing single-chain fragment variables to the N-terminal ends of mAb158 ***-time interaction analysis with LigandTracer and surface plasmon resonance were used to evaluate the kinetic binding properties of the generated antibodies to Aβ*** ELISA setups were applied to demonstrate the binding strength of the hexavalent antibody to Aβaggregates of diferent ***,the ability of the antibodies to protect cells from Aβ-induced efects was evaluated by MTT ***:Using real-time interaction analysis with LigandTracer,the hexavalent design promoted a 40-times enhanced binding with avidity to protofbrils,and most of the added binding strength was attributed to the reduced rate of ***,ELISA experiments demonstrated that the hexavalent design also had strong binding to small oligomers,while retaining weak and intermediate binding to monomers and insoluble *** hexavalent antibody also reduced cell death induced by a mixture of soluble Aβ***:We provide a new antibody design with i

关键词： multivalent antibodies Alzheimer’s disease Aβ Avidity Oligomers Protofbrils

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