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 Leusen, Thomas Valerius, Sanjay Ram, Suzan H. M. Rooijakkers, Inger Sandlie and Jan Terje Andersen ()
Additional contact information
Stian Foss: Oslo University Hospital
Siri A. Sakya: Oslo University Hospital
Leire Aguinagalde: University Medical Center Utrecht, Utrecht University
Marta Lustig: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Jutamas Shaughnessy: University of Massachusetts Chan Medical School
Ana Rita Cruz: University Medical Center Utrecht, Utrecht University
Lisette Scheepmaker: University Medical Center Utrecht, Utrecht University
Line Mathiesen: University of Copenhagen
Fulgencio Ruso-Julve: Oslo University Hospital
Aina Karen Anthi: Oslo University Hospital
Torleif Tollefsrud Gjølberg: Oslo University Hospital
Simone Mester: Oslo University Hospital
Malin Bern: Oslo University Hospital
Mitchell Evers: University Medical Center Utrecht
Diane B. Bratlie: Norwegian Institute of Public Health
Terje E. Michaelsen: Norwegian Institute of Public Health
Tilman Schlothauer: Roche Innovation Center Munich
Devin Sok: International AIDS Vaccine Initiative (IAVI)
Jayanta Bhattacharya: NCR Biotech Science Cluster
Jeanette Leusen: University Medical Center Utrecht
Thomas Valerius: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Sanjay Ram: University of Massachusetts Chan Medical School
Suzan H. M. Rooijakkers: University Medical Center Utrecht, Utrecht University
Inger Sandlie: University of Oslo
Jan Terje Andersen: Oslo University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46321-9

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