UMMS Affiliation

MassBiologics

Publication Date

2020-11-03

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Digestive System | Immunoprophylaxis and Therapy | Immunotherapy

Abstract

Mucosal surfaces of the gastrointestinal tract play an important role in immune homeostasis and defense and may be compromised by enteric disorders or infection. Therapeutic intervention using monoclonal antibody (mAb) offers the potential for treatment with minimal off-target effects as well as the possibility of limited systemic exposure when administered orally. Critically, to achieve efficacy at luminal surfaces, mAb must remain stable and functionally active in the gastrointestinal environment. To better understand the impact of isotype, class, and molecular structure on the intestinal stability of recombinant antibodies, we used an in vitro simulated intestinal fluid (SIF) assay to evaluate a panel of antibody candidates for enteric mAb-based therapeutics. Recombinant IgG1 was the least stable following SIF incubation, while the stability of IgA generally increased upon polymerization, with subtle differences between subclasses. Notably, patterns of variability within and between mAbs suggest that variable regions contribute to mAb stability and potentially mediate mAb susceptibility to proteases. Despite relatively rapid degradation in SIF, mAbs targeting Enterotoxigenic Escherichia coli (ETEC) displayed functional activity following SIF treatment, with SIgA1 showing improved function compared to SIgA2. The results of this study have implications for the design of enteric therapeutics and subsequent selection of lead candidates based upon in vitro intestinal stability assessments.

Keywords

immunoglobulin A, dIgA, sIgA, intestinal stability

Rights and Permissions

Copyright The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

DOI of Published Version

10.1016/j.vaccine.2020.09.070

Source

Wallace AL, Schneider MI, Toomey JR, Schneider RM, Klempner MS, Wang Y, Cavacini LA. IgA as a potential candidate for enteric monoclonal antibody therapeutics with improved gastrointestinal stability. Vaccine. 2020 Nov 3;38(47):7490-7497. doi: 10.1016/j.vaccine.2020.09.070. Epub 2020 Oct 8. PMID: 33041102; PMCID: PMC7604562. Link to article on publisher's site

Journal/Book/Conference Title

Vaccine

Related Resources

Link to Article in PubMed

PubMed ID

33041102

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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