Human and porcine IgG subclasses differentially engage porcine Fc receptors.

Antibody fragment crystallizable (Fc)-mediated effector functions and pharmacokinetics are governed by interactions between immunoglobulin G (IgG) subclasses and Fc gamma receptors (FcγRs) and Fc neonatal receptor (FcRn). Although pigs are increasingly used as translational models for therapeutic antibody evaluation, the interactions between porcine Fc receptors (pFcγRs) and porcine (pIgG) or human IgG (hIgG) subclasses remain poorly defined. Here, we characterized the interactions of pIgG and hIgG subclasses with pFcγRs and pFcRn and assessed their ability to mediate Fc-dependent effector functions in porcine immune cells. Using biolayer interferometry, we demonstrated subclass-dependent differences in receptor binding, driven primarily by dissociation kinetics. Porcine IgG2 and pIgG5c exhibited stable FcγR interactions, whereas pIgG3 and pIgG5b showed weak binding to several low-affinity receptors (FcγRIIa, FcγRIIb, and FcγRIIIa). Human IgG subclasses displayed distinct binding profiles to pFcγRs, with hIgG3 showing the strongest and hIgG2 the weakest binding affinity. Furthermore, hIgG1 and hIgG4 did not bind to pFcγRIIIa. Functional studies demonstrated that hIgGs mediate Fc-dependent phagocytosis and natural killer cell degranulation, although receptor-binding affinity did not always correlate with functional activity. Comparative phylogenetic and functional analyses further revealed that FcγR-binding phenotypes are only partially predicted by Fc domain sequence similarity. All pIgG and hIgG subclasses interacted with pFcRn in a comparable pH-dependent manner. These findings demonstrate substantial, but incomplete, conservation of Fc biology between humans and pigs. While supporting the use of pigs as a translational model for antibody pharmacokinetic studies, they also indicate the need for integrated biophysical, structural, and functional analyses before extrapolating Fc-mediated therapeutic activity between species.