An IgA mimicry of IgG that binds polymeric immunoglobulin receptor for mucosa transcytosis

Abstract

Most pathogens establish infection through mucosa, where secretory immunoglobulin A (sIgA) plays an 'immune exclusion' role in humoral defense. Extravasation of intravenously (i.v.) administrated therapeutic immunoglobulin G (IgG) mainly relies on convection and/or neonatal Fc receptor-mediated transcytosis from circulation into interstitial space. Active transport of interstitial IgG further across epithelium into mucosa, like sIgA, is a much desired feature for the next generation of therapeutic antibodies, especially for antiinfection purposes. For the first time, we report the engineering of an IgA mimicry of IgG, with its Fc portion in fusion with the 18-aa tail piece (tp) of sIgA and the J chain, possessing sIgA's full binding activity towards polymeric immunoglobulin receptor that mediates mucosa transcytosis. In a diphtheria toxin receptor (DTR) knockin mouse model, i.v. injected anti-diphtheria toxin (DT) IgG(tp)J protected DTR+ cells from deletion upon DT injection. The compact design of IgG(tp)J opens new revenues for more effective therapeutic IgG mimicking some of the important biological functions of IgA. Statement of Significance: Unlike secretory immunoglobulin A (sIgA), translocation of intravenously (i.v.) administrated therapeutic immunoglobulin G (IgG) ontomucosal surface is limited and, if any, ismediated by neonatal Fc receptor (FcRn). Among all the IgG-IgA hybrids, the IgG(tp)J form contains sufficient structural requirements for full binding to polymeric immunoglobulin receptor (pIgR), mimicking sIgA function in mucosa transcytosis against infectious agents and their products.