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

Stian Foss, Siri A Sakya, Leire Aguinagalde, Marta Lustig, Jutamas Shaughnessy, Ana Rita Cruz, Lisette Scheepmaker, Line Mathiesen, Fulgencio Ruso-Julve, Aina Karen Anthi, Torleif Tollefsrud Gjølberg, Simone Mester, Malin Bern, Mitchell Evers, Diane B Bratlie, Terje E Michaelsen, Tilman Schlothauer, Devin Sok, Jayanta Bhattacharya, Jeanette LeusenThomas Valerius, Sanjay Ram, Suzan H M Rooijakkers, Inger Sandlie, Jan Terje Andersen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number2007
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2024

Keywords

  • 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/therapy
  • Receptors, Fc

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