The prospect of orally administered monoclonal secretory IgA (SIgA) antibodies to prevent enteric bacterial infections

Abstract

Eliminating diarrheal diseases as a leading cause of childhood morbidity and mortality in low-and middleincome countries (LMICs) will require multiple intervention strategies. In this review, we spotlight a series of preclinical studies investigating the potential of orally administered monoclonal secretory IgA (SIgA) antibodies (MAbs) to reduce disease associated with three enteric bacterial pathogens: Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC), and invasive Salmonella enterica serovar Typhimurium. IgA MAbs targeting bacterial surface antigens (flagella, adhesins, and lipopolysaccharide) were generated from mice, humanized mice, and human tonsillar B cells. Recombinant SIgA1 and/or SIgA2 derivates of those MAbs were purified from supernatants following transient transfection of 293 cells with plasmids encoding antibody heavy and light chains, J-chain, and secretory component (SC). When administered to mice by gavage immediately prior to (or admixed with) the bacterial challenge, SIgA MAbs reduced infection C. jejuni, ETEC, and S. Typhimurium infections. Fv-matched IgG1 MAbs by comparison were largely ineffective against C. jejuni and S. Typhimurium under the same conditions, although they were partially effective against ETEC. While these findings highlight future applications of orally administered SIgA, the studies also underscored the fundamental challenges associated with using MAbs as prophylactic tools against enteric bacterial diseases.

Immunoglobulin A antibody composition is sculpted to bind the self gut microbiome

“…S9). The above results demonstrate that our hybridoma-produced IgA antibodies, at least for the tested clones, are dimeric in structure, are resistant to digestive and bacterial enzyme degradation, and retain binding capability after passing through the gastrointestinal tract, which may be used potentially for therapeutic purposes ( 5 , 7 , 40 ).…”

“…Our results also demonstrate that the hybridoma-derived IgAs can transit through the harsh environment of the gastrointestinal tract and retain binding capability against bacterial antigens. This observation implies the potential usage of in vitro engineered IgA antibodies as therapeutics (40,(50)(51)(52). Compared with naturally secreted IgA antibodies, those hybridoma-derived IgAs lack the bound secretory component, which may ultimately compromise their stability to bacterial proteases in the gut lumen (53,54).…”

Rabbit IgA Hinges That Resist IgA1 Protease Action Provide Options for Improved IgA-Based Therapeutic Agents

“…The data suggests that the rabbit Ca15 hinge can be an interesting alternative for a long hinge that remains resistant to IgA protease cleavage, raising new possibilities for therapeutic IgA antibodies engineered with improved functions, an area of increasing biotechnological interest (7). This hinge allows binding with equal efficiency to small antigens, and does not affect the Fc-mediated effector function, while remaining resistant to some IgA proteases.…”

“…The characteristics of IgA antibodies and their functions have been attracting significant attention in recent years for use as therapeutic antibodies. These can be administered via the oral or nasal pathways, delivering to mucosal organs including the lungs and gastrointestinal tract, with clear benefits over intravenous and subcutaneous routes of delivery, and have been shown to be more effective than IgG in neutralizing several viruses such as HIV, rotavirus, influenza virus and SARS-CoV2, as well as bacterial pathogens most frequently associated with diarrheal diseases (1,(3)(4)(5)(6)(7). Design considerations for IgA mAb development have included the limitation of a relatively short serum half-life, and methodologies to aid retention in the protective mucus barrier and gut, and optimization for protease resistance (1,6).…”

Special focus issue: passive immunization

“…Nicholas Mantis discusses the use of transgenic mice to test passive immune protection against GI tract pathogens, and methods for efficient delivery of sIgA to the gut. 29 As has long been known to mucosal immunologists, most bacteria in the gut are restricted to the luminal surface of the mucus coat by the apparent viscidity (stickiness) of mucus and now as revealed by the trapping actions of secreted antibodies. The predominant antibody in GI tract secretions, sIgA, is especially well designed for trapping in mucus gel since the pair of Fc moieties as well as the SC moiety increase the dwell-time of the antibody with the mucus gel.…”