{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:57:52Z","timestamp":1781287072877,"version":"3.54.1"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011570","name":"Stichting Diabetes Onderzoek Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011570","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019180","name":"HORIZON EUROPE European Research Council","doi-asserted-by":"publisher","award":["ERC-AdG 101200304"],"award-info":[{"award-number":["ERC-AdG 101200304"]}],"id":[{"id":"10.13039\/100019180","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Iscalimab is a nondepleting anti-CD40 monoclonal antibody, expected to suppress immune responses by blocking the costimulation by antigen-presenting cells through CD40-CD40L ligation. This therapeutic antibody indeed inhibited proliferation of B lymphocytes and TNF production by dendritic cells and is being tested in clinical trials to treat B cell mediated autoimmune diseases. Since iscalimab showed limited clinical benefit and did not improve kidney and liver transplantation outcomes compared to standard tacrolimus treatment, we studied whether a biosimilar of iscalimab affects T cell responses in vitro. For this, we stimulated autoreactive effector and alloreactive na\u00efve CD4 T cells in the presence of anti-CD40 antibody and measured the impact on cell proliferation. While we confirmed the capacity of iscalimab biosimilar antibody to bind to B cells and dendritic cells and to completely inhibit proliferating B cells, it showed limited to no efficacy to inhibit proliferation of diabetogenic beta-cell specific effector CD4 T cell clones. The CD40 blockade also did not affect the induction of proliferation of na\u00efve alloreactive CD4 T cells, by dendritic cells. Based on our in vitro data pointing to minimal inhibition of T cells by CD40 blockade, we propose that iscalimab may not suffice to accomplish durable benefit as intervention strategy to treat type 1 diabetes or other T cell mediated diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0351131","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:22:55Z","timestamp":1781284975000},"page":"e0351131","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Limited efficacy of a therapeutic anti-CD40 monoclonal antibody to inhibit activated CD4 T cell autoimmunity in vitro"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6811-2290","authenticated-orcid":true,"given":"Chelsea","family":"Gootjes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaap Jan","family":"Zwaginga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Nikolic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3110-7391","authenticated-orcid":true,"given":"Bart O.","family":"Roep","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"issue":"4","key":"pone.0351131.ref001","first-page":"233","article-title":"The global landscape of approved antibody therapies","volume":"5","author":"X Lyu","year":"2022","journal-title":"Antib Ther"},{"issue":"4","key":"pone.0351131.ref002","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrd3003","article-title":"The safety and side effects of monoclonal antibodies","volume":"9","author":"TT Hansel","year":"2010","journal-title":"Nat Rev Drug Discov"},{"issue":"7","key":"pone.0351131.ref003","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.4049\/jimmunol.165.7.3860","article-title":"Phosphatidylinositol 3-kinase and NF-kappa B\/Rel are at the divergence of CD40-mediated proliferation and survival pathways","volume":"165","author":"S Andjelic","year":"2000","journal-title":"J Immunol"},{"issue":"2","key":"pone.0351131.ref004","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.4049\/jimmunol.174.2.1081","article-title":"TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages","volume":"174","author":"L Mukundan","year":"2005","journal-title":"J Immunol"},{"key":"pone.0351131.ref005","doi-asserted-by":"crossref","first-page":"107709","DOI":"10.1016\/j.pharmthera.2020.107709","article-title":"Molecular basis and therapeutic implications of CD40\/CD40L immune checkpoint","volume":"219","author":"T Tang","year":"2021","journal-title":"Pharmacol Ther"},{"key":"pone.0351131.ref006","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3389\/fimmu.2013.00376","article-title":"CD40-Mediated Activation of the NF-\u03baB2 Pathway","volume":"4","author":"BS Hostager","year":"2013","journal-title":"Front Immunol"},{"issue":"5","key":"pone.0351131.ref007","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.4049\/jimmunol.161.5.2094","article-title":"Dendritic cells require maturation via CD40 to generate protective antitumor immunity","volume":"161","author":"MF Mackey","year":"1998","journal-title":"J Immunol"},{"key":"pone.0351131.ref008","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1615\/CritRevImmunol.v23.i12.50","article-title":"CD40 and dendritic cell function","volume":"23","author":"B O\u2019Sullivan","year":"2003","journal-title":"Crit Rev Immunol"},{"issue":"4","key":"pone.0351131.ref009","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1084\/jem.191.4.651","article-title":"CD40 ligand (CD154) triggers a short-term CD4(+) T cell activation response that results in secretion of immunomodulatory cytokines and apoptosis","volume":"191","author":"PJ Blair","year":"2000","journal-title":"J Exp Med"},{"issue":"9","key":"pone.0351131.ref010","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.4049\/jimmunol.156.9.3133","article-title":"Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis","volume":"156","author":"MH Blotta","year":"1996","journal-title":"J Immunol"},{"issue":"2","key":"pone.0351131.ref011","doi-asserted-by":"crossref","first-page":"598","DOI":"10.4049\/jimmunol.152.2.598","article-title":"CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule\/CD40-L. 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