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dc.contributor.authorHartwell, Brittany L.
dc.contributor.authorPickens, Chad J.
dc.contributor.authorLeon, Martin
dc.contributor.authorBerkland, Cory
dc.date.accessioned2020-10-21T14:59:58Z
dc.date.available2020-10-21T14:59:58Z
dc.date.issued2017-05-05
dc.identifier.citationHartwell, B. L., Pickens, C. J., Leon, M., & Berkland, C. (2017). Multivalent Soluble Antigen Arrays Exhibit High Avidity Binding and Modulation of B Cell Receptor-Mediated Signaling to Drive Efficacy against Experimental Autoimmune Encephalomyelitis. Biomacromolecules, 18(6), 1893–1907. https://doi.org/10.1021/acs.biomac.7b00335en_US
dc.identifier.urihttp://hdl.handle.net/1808/30797
dc.descriptionThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Biomacromolecules, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biomac.7b00335.en_US
dc.description.abstractA pressing need exists for antigen-specific immunotherapies (ASIT) that induce selective tolerance in autoimmune disease while avoiding deleterious global immunosuppression. Multivalent soluble antigen arrays (SAgAPLP:LABL), consisting of a hyaluronic acid (HA) linear polymer backbone co-grafted with multiple copies of autoantigen (PLP) and cell adhesion inhibitor (LABL) peptides, are designed to induce tolerance to a specific multiple sclerosis (MS) autoantigen. Previous studies established that hydrolyzable SAgAPLP:LABL, employing a degradable linker to codeliver PLP and LABL, was therapeutic in experimental autoimmune encephalomyelitis (EAE) in vivo and exhibited antigen-specific binding with B cells, targeted the B cell receptor (BCR), and dampened BCR-mediated signaling in vitro. Our results pointed to sustained BCR engagement as the SAgAPLP:LABL therapeutic mechanism, so we developed a new version of the SAgA molecule using non-hydrolyzable conjugation chemistry, hypothesizing it would enhance and maintain the molecule’s action at the cell surface to improve efficacy. ‘Click SAgA’ (cSAgAPLP:LABL) uses hydrolytically stable covalent conjugation chemistry (Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC)) rather than a hydrolyzable oxime bond to attach PLP and LABL to HA. We explored cSAgAPLP:LABL B cell engagement and modulation of BCR-mediated signaling in vitro through flow cytometry binding and calcium flux signaling assays. Indeed, cSAgAPLP:LABL exhibited higher avidity B cell binding and greater dampening of BCR-mediated signaling than hydrolyzable SAgAPLP:LABL. Furthermore, c SAgAPLP:LABL exhibited significantly enhanced in vivo efficacy compared to hydrolyzable SAgAPLP:LABL, achieving equivalent efficacy at one quarter of the dose. These results indicate that non-hydrolyzable conjugation increased the avidity of cSAgAPLP:LABL to drive in vivo efficacy through modulated BCR-mediated signaling.en_US
dc.description.sponsorshipNIH T32 GM008545en_US
dc.description.sponsorshipMadison and Lila Self Graduate Fellowship at the University of Kansasen_US
dc.description.sponsorshipHoward Rytting pre-doctoral fellowship from the Department of Pharmaceutical Chemistry at the University of Kansasen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsCopyright © 2017 American Chemical Societyen_US
dc.subjectMolecular propertiesen_US
dc.subjectCell signalingen_US
dc.subjectPeptides and proteinsen_US
dc.subjectAntigensen_US
dc.subjectReceptorsen_US
dc.titleMultivalent antigen arrays exhibit high avidity binding and modulation of B cell receptor-mediated signaling to drive efficacy against experimental autoimmune encephalomyelitisen_US
dc.typeArticleen_US
kusw.kuauthorHartwell, Brittany L.
kusw.kuauthorPickens, Chad J.
kusw.kuauthorLeon, Martin
kusw.kuauthorBerkland, Cory
kusw.kudepartmentBioengineering Graduate Programen_US
kusw.kudepartmentPharmaceutical Chemistryen_US
kusw.kudepartmentChemistryen_US
kusw.kudepartmentChemical and Petroleum Engineeringen_US
dc.identifier.doi10.1021/acs.biomac.7b00335en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-5438-9010en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-9346-938Xen_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7388272en_US
dc.rights.accessrightsopenAccessen_US


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