{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T17:14:16Z","timestamp":1783703656590,"version":"3.55.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"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>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cytokine Release Syndrome (CRS) is a life-threatening complication of T-cell-engaging immunotherapies, causing vascular leakage and multi-organ dysfunction. Standard Interleukin-6 (IL-6) blockade often fails in severe cases by leaving the upstream initiator, Tumor Necrosis Factor-\u03b1 (TNF-\u03b1), unchecked. TNF-\u03b1 drives early macrophage activation and endothelial injury, whereas IL-6 amplifies systemic inflammation. To decisively interrupt this inflammatory feedback loop, we developed IDC007, a novel bispecific antibody simultaneously neutralizing TNF-\u03b1 and IL-6 receptor (IL-6R).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the neutralizing effects of IDC007 in an in vitro CRS model utilizing OKT3\/R848-stimulated human peripheral blood mononuclear cells and human umbilical vein endothelial cells. Furthermore, we utilized an OKT3-induced humanized CRS mouse model to assess in vivo target engagement and therapeutic efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In vitro, IDC007 effectively suppressed pro-inflammatory cytokine secretion (e.g., TNF-\u03b1, IFN-\u03b3) and prevented endothelial barrier dysfunction. In vivo, IDC007 successfully engaged both targets. Administration mitigated physiological deterioration, including hypothermia and weight loss, leading to improved survival. Dual inhibition effectively prevented immune hyperactivation, evidenced by the significant attenuation of splenomegaly and lung-specific organ damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings serve as a preclinical proof-of-concept demonstrating that dual targeting of TNF-\u03b1 and IL-6R offers a potent mechanistic approach to attenuate severe CRS by preserving vascular endothelial integrity and overcoming the therapeutic limitations of conventional monotherapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1848290","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:28:31Z","timestamp":1783700911000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Inhibition of TNF-\u03b1 and IL-6R mitigates cytokine release syndrome via protection of endothelial integrity and reduction of organ damage in mouse models"],"prefix":"10.3389","volume":"17","author":[{"given":"Hyeyun","family":"Won","sequence":"first","affiliation":[{"name":"Prestige BioPharma IDC","place":["Busan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Prestige BioPharma IDC","place":["Busan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Gil","family":"Roh","sequence":"additional","affiliation":[{"name":"Prestige BioPharma IDC","place":["Busan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mincheol","family":"Kang","sequence":"additional","affiliation":[{"name":"Prestige BioPharma IDC","place":["Busan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nari","family":"Kim","sequence":"additional","affiliation":[{"name":"Prestige BioPharma IDC","place":["Busan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","article-title":"Chimeric antigen receptor T-cell therapy - assessment and management of toxicities","volume":"15","author":"Neelapu","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41577-021-00547-6","article-title":"Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy","volume":"22","author":"Morris","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-793141","article-title":"Kinetics and biomarkers of severe cytokine release syndrome in CD19 chimeric antigen receptor T-cell therapy","volume":"130","author":"Hay","year":"2017","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2019.1629904","article-title":"Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome","volume":"15","author":"Kotch","year":"2019","journal-title":"Expert Rev Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0036-4","article-title":"Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity in CAR T-cell therapy","volume":"24","author":"Norelli","year":"2018","journal-title":"Nat Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0041-7","article-title":"CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade","volume":"24","author":"Giavridis","year":"2018","journal-title":"Nat Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-08-802413","article-title":"Cytokine release syndrome associated with chimeric-antigen receptor T-cell therapy: clinicopathological implications","volume":"130","author":"Obstfeld","year":"2017","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-485623","article-title":"Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated by cytokine-directed therapy","volume":"121","author":"Teachey","year":"2013","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.47","article-title":"Pathogenesis of macrophage activation syndrome and potential for precision medicine","volume":"11","author":"Schulert","year":"2015","journal-title":"Nat Rev Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202149181","article-title":"Immunological analysis of the murine anti-CD3-induced cytokine release syndrome model and therapeutic efficacy of anti-cytokine antibodies","volume":"51","author":"Nouveau","year":"2021","journal-title":"Eur J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001203R","article-title":"A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome","volume":"34","author":"Ye","year":"2020","journal-title":"FASEB J"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.3.1259","article-title":"Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8","volume":"174","author":"Gorden","year":"2005","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0040","article-title":"Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia","volume":"6","author":"Teachey","year":"2016","journal-title":"Cancer Discov"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-155846","article-title":"Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease","volume":"112","author":"Nishimoto","year":"2008","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40425-018-0343-9","article-title":"Cytokine release syndrome","volume":"6","author":"Shimabukuro-Vornhagen","year":"2018","journal-title":"J Immunother Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nri2156","article-title":"Getting to the site of inflammation: the leukocyte adhesion cascade","volume":"7","author":"Ley","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1357","article-title":"Endothelial cell-cell junctions: happy together","volume":"5","author":"Dejana","year":"2004","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.697405","article-title":"Myeloid-derived suppressor cells as a potential biomarker and therapeutic target in COVID-19","volume":"12","author":"Rowlands","year":"2021","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0572-6","article-title":"Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)","volume":"27","author":"Agrati","year":"2020","journal-title":"Cell Death Differ"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb8925","article-title":"Cytokine release syndrome in severe COVID-19","volume":"368","author":"Moore","year":"2020","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-703751","article-title":"Toxicities of chimeric antigen receptor T cells: recognition and management","volume":"127","author":"Brudno","year":"2016","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/s41419-018-0918-x","article-title":"The biological basis and clinical symptoms of CAR-T therapy-associated toxicites","volume":"9","author":"Titov","year":"2018","journal-title":"Cell Death Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1128\/mmbr.05015-11","article-title":"Into the eye of the cytokine storm","volume":"76","author":"Tisoncik","year":"2012","journal-title":"Microbiol Mol Biol Rev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s00253-025-13596-x","article-title":"A novel bispecific antibody targeting TNF-\u03b1 and IL-6 receptor as a potent immunotherapeutic agent for inflammation","volume":"109","author":"Heravi","year":"2025","journal-title":"Appl Microbiol Biotechnol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.molimm.2015.01.003","article-title":"Alternative molecular formats and therapeutic applications for bispecific antibodies","volume":"67","author":"Spiess","year":"2015","journal-title":"Mol Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev-pharmtox-010611-134715","article-title":"Therapeutic targeting of the interleukin-6 receptor","volume":"52","author":"Tanaka","year":"2012","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.4989","article-title":"IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6","volume":"8","author":"Rose-John","year":"2012","journal-title":"Int J Biol Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.19.7099","article-title":"Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells","volume":"85","author":"Chiu","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2005.05.010","article-title":"Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family","volume":"5","author":"Mihara","year":"2005","journal-title":"Int Immunopharmacol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/s41467-019-13880-1","article-title":"Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy","volume":"11","author":"Sheih","year":"2020","journal-title":"Nat Commun"},{"key":"B33","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41392-021-00764-4","article-title":"Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2009.11.005","article-title":"Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer","volume":"21","author":"Grivennikov","year":"2010","journal-title":"Cytokine Growth Factor Rev"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.027","article-title":"Pleiotropy and specificity: insights from the interleukin 6 family of cytokines","volume":"50","author":"Murakami","year":"2019","journal-title":"Immunity"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1848290\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:28:32Z","timestamp":1783700912000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1848290\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2026.1848290"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1848290","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]},"article-number":"1848290"}}