YTE-engineered antibodies: From neonatal Fc receptor binding mechanisms to next-generation therapeutics

Engineering antibody Fc domains has become a strong method to improve the pharmacokinetics and therapeutic effects of monoclonal antibodies. Among these Fc changes, the triple substitution M252Y/S254T/T256E (YTE) is one of the most studied. By boosting the immunoglobulin G’s affinity for the neonatal Fc receptor (FcRn) at acidic pH and keeping dissociation at neutral pH, YTE mutations support effective FcRn-mediated recycling and significantly increase serum half-life. Structural studies show localized changes at the CH2-CH3 interface that improve receptor binding. Furthermore, preclinical tests in primates showed up to a four-fold increase in antibody persistence. The first trial in humans with motavizumab-YTE confirmed an extended half-life of up to 100 days, ongoing RSV neutralizing activity, and a good safety profile. With this proof-of-concept, YTE substitutions have been applied to antibodies targeting viral pathogens such as human immunodeficiency virus-1 and severe acute respiratory syndrome coronavirus 2, as well as to cytokine inhibitors for inflammatory diseases. This approach allows for long-lasting treatments with fewer doses. However, challenges still exist regarding the potential effects on Fc-mediated functions, the risk of immunogenicity, and differences in FcRn binding across species. This review brings together current knowledge of the YTE mutation, compares its performance with other Fc engineering methods like LS and QL substitutions, and looks at future possibilities for using YTE in bispecific antibodies, Fc-fusion proteins, and next-generation biologics. Overall, YTE engineering shows the practical potential of Fc modifications in developing long-lasting antibody therapies.