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Multivalent antigen arrays exhibit high avidity binding and modulation of B cell receptor-mediated signaling to drive efficacy against experimental autoimmune encephalomyelitis
dc.contributor.author | Hartwell, Brittany L. | |
dc.contributor.author | Pickens, Chad J. | |
dc.contributor.author | Leon, Martin | |
dc.contributor.author | Berkland, Cory | |
dc.date.accessioned | 2020-10-21T14:59:58Z | |
dc.date.available | 2020-10-21T14:59:58Z | |
dc.date.issued | 2017-05-05 | |
dc.identifier.citation | Hartwell, 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.7b00335 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30797 | |
dc.description | This 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.abstract | A 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.sponsorship | NIH T32 GM008545 | en_US |
dc.description.sponsorship | Madison and Lila Self Graduate Fellowship at the University of Kansas | en_US |
dc.description.sponsorship | Howard Rytting pre-doctoral fellowship from the Department of Pharmaceutical Chemistry at the University of Kansas | en_US |
dc.publisher | American Chemical Society | en_US |
dc.rights | Copyright © 2017 American Chemical Society | en_US |
dc.subject | Molecular properties | en_US |
dc.subject | Cell signaling | en_US |
dc.subject | Peptides and proteins | en_US |
dc.subject | Antigens | en_US |
dc.subject | Receptors | en_US |
dc.title | Multivalent antigen arrays exhibit high avidity binding and modulation of B cell receptor-mediated signaling to drive efficacy against experimental autoimmune encephalomyelitis | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Hartwell, Brittany L. | |
kusw.kuauthor | Pickens, Chad J. | |
kusw.kuauthor | Leon, Martin | |
kusw.kuauthor | Berkland, Cory | |
kusw.kudepartment | Bioengineering Graduate Program | en_US |
kusw.kudepartment | Pharmaceutical Chemistry | en_US |
kusw.kudepartment | Chemistry | en_US |
kusw.kudepartment | Chemical and Petroleum Engineering | en_US |
dc.identifier.doi | 10.1021/acs.biomac.7b00335 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-5438-9010 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-9346-938X | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7388272 | en_US |
dc.rights.accessrights | openAccess | en_US |