{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:20:19Z","timestamp":1793089219044,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T00:00:00Z","timestamp":1709769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The antigen-presenting cell function of insulin-reactive B cells promotes type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by stimulating pathogenic T cells leading to destruction of insulin-producing \u03b2-cells of pancreatic islets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods\/Results<\/jats:title><jats:p>To target insulin-reactive B cells, AKS-107, a human IgG1 Fc molecule fused with human insulin A and B chains, was engineered to retain conformational insulin epitopes that bound mouse and human B cell receptors but prevented binding to the insulin metabolic receptor.  AKS-107 Fc-mediated deletion of insulin-reactive B cells was demonstrated <jats:italic>via ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> experiments with insulin-reactive B cell receptor transgenic mouse strains, VH125Tg\/NOD and Tg125(H+L)\/NOD. As an additional immune tolerance feature, the Y16A mutation of the insulin B<jats:sub>(9-23)<\/jats:sub> dominant T cell epitope was engineered into AKS-107 to suppress activation of insulin-specific T cells.  In mice and non-human primates, AKS-107 was well-tolerated, non-immunogenic, did not cause hypoglycemia even at high doses, and showed an expectedly protracted pharmacokinetic profile. AKS-107 reproducibly prevented spontaneous diabetes from developing in NOD and VH125Tg\/NOD mice that persisted for months after cessation of treatment, demonstrating durable immune tolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These preclinical outcomes position AKS-107 for clinical development in T1D prevention settings.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1367514","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T04:28:15Z","timestamp":1709785695000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["An antigen-specific immunotherapeutic, AKS-107, deletes insulin-specific B cells and prevents murine autoimmune diabetes"],"prefix":"10.3389","volume":"15","author":[{"given":"David G.","family":"Alleva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea 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