biostudies-literatureUnknown15(1)Foss SWellcome TrustMonoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.Nature communications2007https://www.ebi.ac.uk/biostudies/studies/S-EPMC10920689biostudies-literatureHuman IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria.PMC10920689Ram SAndersen JTEvers MMichaelsen TERooijakkers SHMShaughnessy JLeusen JSok DRuso-Julve FMathiesen LSakya SAMester SBern MScheepmaker LCruz ARSchlothauer TLustig MAguinagalde LAnthi AKBratlie DBValerius TFoss SSandlie IGjolberg TTBhattacharya JfalseHuman IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria.Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.2024-01-01T00:00:00Z2024 Mar2026-07-15T12:08:02.488Z2026-07-04T03:12:44.028ZS-EPMC109206893845392210.1038/s41467-024-46321-9