{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:30:01Z","timestamp":1787725801596,"version":"build-2784847793"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004755","name":"EMD Serono","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004755","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Chronically activated T-effector (Teff) cells can play a pivotal role in T-cell-mediated diseases including systemic lupus erythematosus subsets, lupus nephritis and graft-vs-host disease (GvHD). Since T cells require diverse costimulation signals to fully activate, proliferate, and differentiate into Teffs, we hypothesized that modulating two costimulatory pathways (CD28 and OX40) with a single bifunctional molecule would provide better control of pathogenic Teffs in autoimmune diseases than currently available T-cell costimulation modulators. We assessed the effects of dual-pathway blockade by M5542, a novel CD80, CD86, and OX40L antagonist and bifunctional fusion molecule. We determined the advantages of M5542 blocking both CD28 and OX40 pathways over single-pathway blockade in\n                      <jats:italic>in vitro<\/jats:italic>\n                      potency and\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies, to more effectively curb T-cell-mediated inflammation in autoimmune diseases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>M5542, single-agent comparators CTLA-4Ig (abatacept), anti-OX40L, and both single agents in combination were tested for their ability to inhibit proinflammatory cytokine production in a mixed lymphocyte reaction of activated monocyte-derived dendritic cells and T cells from healthy donors or peripheral blood mononuclear cells from individuals with SLE. The target occupancy of CD80 and OX40L on dendritic cells was assessed by flow cytometry. The effects of M5542 and comparators on T-cell-mediated inflammation were assessed using a keyhole limpet hemocyanin (KLH) peptide-induced delayed-type hypersensitivity (DTH) humanized hOX40\/hOX40L mouse model. All molecules were also tested for their efficacy to reduce disease in a humanized xenogenic GvHD (xGvHD) mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      M5542 potently reduced proinflammatory cytokine production and dampened T-cell proliferation compared with CTLA-4Ig or anti-OX40L\n                      <jats:italic>in vitro<\/jats:italic>\n                      . M5542 also neutralized OX40L-mediated T-regulatory cell (Treg) dysfunction\n                      <jats:italic>in vitro<\/jats:italic>\n                      and suppressed Teff proliferation in conjunction with Tregs\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Moreover, M5542 dose-dependently reduced T-cell-mediated ear swelling and anti-KLH antibody production in the KLH-DTH mouse model. In the xGvHD model, M5542 demonstrated improved efficacy over CTLA-4Ig or anti-OX40L alone in suppressing human IFN\u03b3 and preventing disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this preclinical study, the bifunctional M5542 blocked CD28 and OX40-mediated T-cell inflammation with greater immunomodulatory activity than monofunctional agents and in some assays comparable to or better than the combination of the monofunctional agents. These findings support further evaluation of M5542 in T-cell-driven autoimmune disease settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1809074","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:57:31Z","timestamp":1787723851000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["M5542, a bifunctional fusion protein targeting CD80, CD86, and OX40L that modulates excessive T-cell activity: a preclinical proof-of-concept study"],"prefix":"10.3389","volume":"17","author":[{"given":"Michelle","family":"Downing","sequence":"first","affiliation":[{"name":"Research Unit \u2013 Neuroscience and Immunology, EMD Serono Research and Development Institute, Inc., an affiliate of Merck KGaA","place":["Billerica, MA, United 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