{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T09:14:25Z","timestamp":1778318065831,"version":"3.51.4"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":70,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Interdisciplinary Cultivation Program at Shandong University, Weihai, China"},{"name":"Project of the Natural Science Foundation of Shandong Province, China"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Rheumatoid arthritis is driven by T cell dysregulation and TNF\u03b1-mediated inflammation. Dual targeting of OX40 ligand (OX40L) and tumor necrosis factor alpha (TNF\u03b1) may offer synergistic therapeutic effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A murine monoclonal antibody against OX40L (KD-0025) was generated and humanized via complementarity-determining region grafting. A bispecific construct incorporating single-chain variable fragments for OX40L and TNF\u03b1 was expressed in CHO-K1 cells. High-expressing clones were selected, and antibodies were purified using Protein A\/G chromatography. Binding to 293\u00a0T-OX40L cells, A172 cells, and TNF\u03b1 was assessed by flow cytometry and ELISA. Functional blockade of OX40L\u2013OX40 and TNF\u03b1\u2013TNFR pathways was evaluated using a luciferase reporter assay. Binding kinetics were measured using the ForteBio Octet system. In vivo efficacy was tested in a collagen antibody-induced arthritis (CAIA) mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The parental KD-0025 antibody showed EC50 values of 0.4024\u00a0\u03bcg\/ml (human OX40L) and 0.1126\u00a0\u03bcg\/ml (monkey OX40L), with an IC50 of 0.07893\u00a0\u03bcg\/ml. Humanized KA-3966 improved EC50 (0.1374\u00a0\u03bcg\/ml) and had an IC50 of 0.5997\u00a0\u03bcg\/ml. The bispecific antibody KA-5484 demonstrated superior affinity (KD\u00a0=\u00a01.90\u00a0\u00d7\u00a010\u221210\u00a0M) and dual-target binding (EC50: 0.1062 and 0.06240\u00a0\u03bcg\/ml for human and monkey OX40L, respectively). It blocked OX40L\u2013OX40 (IC50\u00a0=\u00a00.1318\u00a0\u03bcg\/ml) and showed 15\u201320% greater TNF\u03b1 pathway suppression than the control antibody KB-1580. KA-5484 significantly reduced inflammation in the CAIA mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>A humanized bispecific antibody targeting OX40L and TNF\u03b1 was successfully developed, exhibiting potent dual-target engagement and blockade. The antibody demonstrated synergistic modulation of immune and inflammatory pathways, providing a promising foundation for future preclinical development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1093\/abt\/tbag003","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T12:05:43Z","timestamp":1768478743000},"page":"76-85","source":"Crossref","is-referenced-by-count":0,"title":["A novel bispecific antibody targeting OX40L and TNF\u03b1 for the targeted treatment of rheumatoid arthritis"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4707-5344","authenticated-orcid":false,"given":"Qun","family":"Zhang","sequence":"first","affiliation":[{"name":"Marine College, Shandong University , Weihai, Shandong, 264209 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuliang","family":"Song","sequence":"additional","affiliation":[{"name":"Marine College, Shandong University , Weihai, Shandong, 264209 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"2026050904364424700_ref1","doi-asserted-by":"publisher","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"2026050904364424700_ref2","first-page":"836","article-title":"Chinese registry of rheumatoid arthritis (CREDIT): I. 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