Optimizing the pharmacokinetic properties of polymeric IgA in mice

Abstract IgA antibodies have broad potential as a novel therapeutic platform based on their superior receptor-mediated cytotoxic activity, potent neutralization of pathogens, and ability to transcytose across mucosal barriers via polymeric immunoglobulin receptor (pIgR)-mediated transport, compared to traditional IgG-based drugs. However, the transition of IgA into clinical development has been challenged by complex expression and characterization, as well as rapid serum clearance. Here, we present the biochemical, biophysical, and structural characterization of recombinantly produced monomeric, dimeric and polymeric human IgA. We further explore two strategies to overcome the rapid serum clearance of polymeric IgA, which may enable the IgA platform the potential to specifically target pIgR expressing tissues, while maintaining low systemic exposure. This strategy may thus allow for targeting antigens previously untenable with conventional IgG1, while allowing for lower drug exposure in non-targeted regions.