Antigen-Specific Binding of Multivalent Soluble Antigen Arrays Induces Receptor Clustering and Impedes B Cell Receptor Mediated Signaling

Biomacromolecules
Brittany HartwellCory Berkland

Abstract

A pressing need exists for autoimmune disease therapies that act in an antigen-specific manner while avoiding global immunosuppression. Multivalent soluble antigen arrays (SAgAPLP:LABL), designed to induce tolerance to a specific multiple sclerosis autoantigen, consist of a flexible hyaluronic acid (HA) polymer backbone cografted with multiple copies of autoantigen peptide (PLP) and cell adhesion inhibitor peptide (LABL). Previous in vivo studies revealed copresentation of both signals on HA was necessary for therapeutic efficacy. To elucidate therapeutic cellular mechanisms, in vitro studies were performed in a model B cell system to evaluate binding and specificity. Compared to HA and HA arrays containing only grafted PLP or LABL, SAgAPLP:LABL displaying both PLP and LABL exhibited greatly enhanced B cell binding. Furthermore, the binding avidity of SAgAPLP:LABL was primarily driven by the PLP antigen, determined via flow cytometry competitive dissociation studies. Fluorescence microscopy showed SAgAPLP:LABL induced mature receptor clustering that was faster than other HA arrays with only one type of grafted peptide. SAgAPLP:LABL molecules also reduced and inhibited IgM-stimulated signaling as discerned by a calcium flux assa...Continue Reading

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Citations

Sep 27, 2019·Nucleic Acids Research·Matthew I J RaybouldCharlotte M Deane
Feb 11, 2020·Chemical Society Reviews·Jingying LiHuanghao Yang
Oct 31, 2019·Bioinformatics·Yoochan MyungDouglas E V Pires
Apr 24, 2020·Advanced Drug Delivery Reviews·J Daniel GriffinCory J Berkland
Jan 21, 2021·Biomedicines·Zachary C StenslandMia J Smith
Jan 27, 2019·Molecular Pharmaceutics·Martin A LeonCory Berkland
Sep 10, 2020·Molecular Pharmaceutics·Matthew A ChristopherCory J Berkland
Jul 2, 2019·ACS Chemical Biology·Martin A LeonCory Berkland
Sep 9, 2021·Biomaterials Science·Qunye HeZhenbao Liu

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