IgA as a potential candidate for enteric monoclonal antibody therapeutics with improved gastrointestinal stability
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Authors
Wallace, Aaron L.Schneider, Matthew I.
Toomey, Jacqueline R.
Schneider, Ryan M.
Klempner, Mark S.
Wang, Yang
Cavacini, Lisa A.
UMass Chan Affiliations
MassBiologicsDocument Type
Journal ArticlePublication Date
2020-11-03Keywords
immunoglobulin AdIgA
sIgA
intestinal stability
Amino Acids, Peptides, and Proteins
Digestive System
Immunoprophylaxis and Therapy
Immunotherapy
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Show full item recordAbstract
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.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
DOI
10.1016/j.vaccine.2020.09.070Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41654PubMed ID
33041102Related Resources
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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/)Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.vaccine.2020.09.070
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Except where otherwise noted, this item's license is described as 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/)