A novel Fc-optimized anti-Ebola neutralizing antibody with extended in vivo half-life

Zaire Ebola virus (EBOV) is one of the main pathogens causing Ebola hemorrhagic fever. The whole human monoclonal antibody Mab114, which can specifically recognize EBOV, has good functions of neutralizing the virus and improving the survival rate of infected animals. The longer in vivo half-life of antibody drugs is mainly achieved through pH dependent binding of the receptor FcRn. This study used computer simulation methods to construct the spatial conformation of human Fc and human FcRn complexes based on molecular docking and mechanical optimization. The key structural domains and important amino acid sites for the binding of human Fc and human FcRn were determined. Based on this, two Fc mutants were designed, and two Fc mutant antibodies Mab114-M5 and Mab114-M6 were constructed using whole human monoclonal antibody Mab114 as the model antibody. The affinity, in vivo and in vitro neutralization function, in vivo serum metabolism of human FcRn transgenic mice, and in vivo antiviral activity were verified through experiments. The results showed that the mutant antibody had a significantly longer retention time in mice compared to Mab114, and also exhibited similar activity in neutralizing EBOV as the maternal antibody Mab114. Fc mutants have the potential to have a long half-life in vivo, thereby reducing medication frequency and providing new ideas for the development of long-acting antibody therapy drugs.