Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria
Foss, Stian; Sakya, Siri A; Aguinagalde, Leire; Lustig, Marta; Shaughnessy, Jutamas; Cruz, Ana Rita; Scheepmaker, Lisette; Mathiesen, Line; Ruso-Julve, Fulgencio; Anthi, Aina Karen; Gjølberg, Torleif Tollefsrud; Mester, Simone; Bern, Malin; Evers, Mitchell; Bratlie, Diane B; Michaelsen, Terje E; Schlothauer, Tilman; Sok, Devin; Bhattacharya, Jayanta; Leusen, Jeanette; Valerius, Thomas; Ram, Sanjay; Rooijakkers, Suzan H M; Sandlie, Inger; Andersen, Jan Terje
(2024) Nature Communications, volume 15, issue 1
(Article)
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
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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.
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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, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Publisher Copyright: © The Author(s) 2024.
(Peer reviewed)