ABDEG mutations in engineered IgG1 Fc fragments balance FcRn engagement and molecular stability to maximize IgG degradation

Immunoglobulin G (IgG) antibodies play a central role in autoimmune and inflammatory diseases. Therapeutic strategies targeting IgG recycling via the neonatal Fc receptor (FcRn) have shown promise. Here, we show how modulating FcRn engagement affects IgG clearance, through evaluation of five engineered Fc IgG1 fragments (YPY, ABDEG, YY, HN, HN/ABDEG). Fc IgG1 -ABDEG demonstrated superior pharmacological potential, exhibiting enhanced FcRn affinity at both physiological and endosomal pH while maintaining near-native stability, unlike YPY, which destabilized the Fc region despite maximal FcRn engagement. In vivo, ABDEG achieved favorable serum persistence and significant IgG reduction compared with YPY, confirming that increased FcRn binding improves outcomes only to a threshold. Subclass analyses identified IgG1 as the optimal backbone for ABDEG incorporation. Furthermore, the importance of FcRn:IgG binding stoichiometry was highlighted using an asymmetrically engineered Fc variant. These findings underscore Fc engineering as a viable approach for modulating IgG homeostasis and inform future optimization of FcRn-targeted therapies.