Production, characterization, and in vivo half-life extension of polymeric IgA molecules in mice. Issue 6 (18th August 2019)

• Record Type: Journal Article
• Authors: Lombana, T. Noelle; Rajan, Sharmila; Zorn, Julie A.; Mandikian, Danielle; Chen, Eugene C.; Estevez, Alberto; Yip, Victor; Bravo, Daniel D.; Phung, Wilson; Farahi, Farzam; Viajar, Sharon; Lee, Sophia; Gill, Avinash; Sandoval, Wendy; Wang, Jianyong; Ciferri, Claudio; Boswell, C. Andrew; Matsumoto, Marissa L.; Spiess, Christoph
• Is Part Of: MAbs. Volume 11:Issue 6(2019)
• Page Start: 1122
• Page End: 1138
• Publication Date: 2019-08-18
• Subjects: Asialoglycoprotein receptor (ASGPR) -- N-linked glycan -- polymeric IgG receptor (pIgR) -- serum half-life -- transcytosis; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2019.1622940
• Languages: English
• ISSNs: 1942-0862

Abstract

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 that is thought to be mediated by glycan receptor scavenging of recombinantly produced IgA monomer bearing incompletely sialylated N-linked glycans. Here, we present a comprehensive 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: removal of all N-linked glycosylation sites creating an aglycosylated polymeric IgA and engineering in FcRn binding with the generation of a polymeric IgG-IgA Fc fusion. While previous reports and the results presented in this study indicate that glycan-mediated clearance plays a major role for monomeric IgA, systemic clearance of polymeric IgA in mice is predominantly controlled by mechanisms other than glycan receptor clearance, such as pIgR-mediated transcytosis. The developed IgA platform now provides the potential to specifically target pIgR expressing tissues, while maintaining low systemic exposure.