{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:36:09Z","timestamp":1792816569893,"version":"4.5.0"},"reference-count":55,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T00:00:00Z","timestamp":1681862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Dysregulated APRIL\/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and lupus nephritis. We undertook this study to develop and evaluate a high\u2010affinity APRIL\/BAFF antagonist to overcome the clinical limitations of existing B cell inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A variant of TACI\u2010Fc generated by directed evolution showed enhanced binding for both APRIL and BAFF and was designated povetacicept (ALPN\u2010303). Povetacicept was compared to wild\u2010type (WT) TACI\u2010Fc and related molecules in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Povetacicept inhibited APRIL and BAFF more effectively than all evaluated forms of WT TACI\u2010Fc and selective APRIL and BAFF inhibitors in cell\u2010based reporter assays and primary human B cell assays, mediating potent suppression of B cell proliferation, differentiation, and immunoglobulin (Ig) secretion. In mouse immunization models, povetacicept significantly reduced serum immunoglobulin titers and antibody\u2010secreting cells more effectively than anti\u2010CD20 monoclonal antibodies, WT TACI\u2010Fc, or APRIL and BAFF inhibitors. In the NZB\u2009\u00d7\u2009NZW mouse lupus nephritis model, povetacicept significantly enhanced survival and suppressed proteinuria, anti\u2013double\u2010stranded DNA antibody titers, blood urea nitrogen, glomerulonephritis, and renal immunoglobulin deposition. In the bm12 mouse lupus model, povetacicept significantly reduced splenic plasmablasts, follicular helper T cells, and germinal center B cells. In non\u2010human primates, povetacicept was well tolerated, exhibited high serum exposure, and significantly decreased serum IgM, IgA, and IgG levels after a single dose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Enhanced APRIL and BAFF inhibition by povetacicept led to greater inhibition of B cell populations critical for autoantibody production compared to WT TACI\u2010Fc and CD20\u2010, APRIL\u2010, or BAFF\u2010selective inhibitors. Potent, dual inhibition by povetacicept has the potential to significantly improve clinical outcomes in autoantibody\u2010related autoimmune diseases.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42462-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42462","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T09:39:52Z","timestamp":1674812392000},"page":"1187-1202","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Povetacicept, an Enhanced Dual\n                    <scp>APRIL<\/scp>\n                    \/\n                    <scp>BAFF<\/scp>\n                    Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell\u2013Related Autoimmune Diseases"],"prefix":"10.1002","volume":"75","author":[{"given":"Lawrence S.","family":"Evans","sequence":"first","affiliation":[{"name":"Alpine Immune Sciences, Inc.  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