Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria

Nat Commun. 2024 Mar 7;15(1):2007. doi: 10.1038/s41467-024-46321-9.


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.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Antibodies, Monoclonal
  • Gram-Negative Bacteria / metabolism
  • Gram-Positive Bacteria / metabolism
  • Half-Life
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunoglobulin G
  • Mice
  • Mice, Transgenic
  • Neoplasms* / drug therapy
  • Neoplasms* / therapy
  • Receptors, Fc*


  • Receptors, Fc
  • Immunoglobulin G
  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • Histocompatibility Antigens Class I