Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria
Stian Foss, Siri Aastedatter Sakya, Leire Aguinagalde, Marta Lustig, Jutamas Shaughnessy, Ana Rita Cruz, Lisette M. Scheepmaker, Line Mathiesen, Fulgencio Ruso‐Julve, Aina Karen Anthi, Torleif Tollefsrud Gjølberg, Simone Mester, Malin Bern, Mitchell Evers, D. B. Bratlie, Terje E. Michaelsen, Tilman Schlothauer, Devin Sok, Jayanta Bhattacharya, Jeanette H.W. Leusen, Thomas Valerius, Sanjay Ram, Suzan H. M. Rooijakkers, Inger Sandlie, Jan Terje Andersen
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.