{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:14:24Z","timestamp":1783433664632,"version":"3.54.6"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tumor necrosis factor receptor 2 (TNFR2) is a promising immunotherapeutic target due to its high upregulation on immunosuppressive populations, like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The clinical efficacy of conventional bivalent TNFR2 antagonists, such as BI1808, is fundamentally constrained by a heavy reliance on Fc-mediated effector functions and a significant risk of \u201cagonistic conversion\u201d upon crosslinking within the tumor microenvironment. To overcome these liabilities, we engineered \u201cDuo1,\u201d a novel biparatopic antagonist that enables simultaneous, monovalent engagement of 2 distinct TNFR2 epitopes.<\/jats:p>\n                  <jats:p>Biophysical analysis confirmed Duo1 forms stable 1:1 complexes with TNFR2 with high-affinity (KD = 0.165\u2005nM), structurally locking the target to prevent the receptor oligomerization required for agonistic signaling. Crucially, while conventional bivalent frameworks convert into potent agonists upon crosslinking, Duo1 maintains absolute, durable antagonism regardless of Fc\u03b3R engagement. Functionally, Duo1 potently suppressed Treg differentiation and reversed Treg-mediated immunosuppression in vitro without impairing CD8 + effector T cell or CD4 + conventional T cell function. In a TNFR2-humanized MC38 syngeneic model, Duo1 mediated significant, dose-dependent tumor growth inhibition comparable to benchmark BI1808. Notably, this antitumor efficacy was fully preserved in an effector-silent (PGLALA) variant, confirming that its therapeutic mechanism operates through pure antagonistic signaling blockade, independent of Fc-mediated effector functions. Furthermore, treatment with Duo1 significantly remodeled the tumor microenvironment, markedly reducing immunosuppressive populations and increasing the intratumoral CD8+\/Treg ratio.<\/jats:p>\n                  <jats:p>By uncoupling antitumor activity from both the risks of crosslinking induced agonistic conversion and a dependence on immune cell mediated effector function, Duo1 represents a highly superior next-generation immunotherapeutic paradigm for TNFR2-rich, immunosuppressive malignancies.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag086","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:43:50Z","timestamp":1782215030000},"source":"Crossref","is-referenced-by-count":0,"title":["A TNFR2 biparatopic antagonist reverses immune suppression through a crosslinking-resistant and ADCC-independent mechanism"],"prefix":"10.1093","volume":"118","author":[{"given":"Shusu","family":"Liu","sequence":"first","affiliation":[{"name":"Biologics Discovery & Development, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7968-1352","authenticated-orcid":false,"given":"Zhichao (Eric)","family":"Ai","sequence":"additional","affiliation":[{"name":"Oncology Discovery, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinli","family":"Xie","sequence":"additional","affiliation":[{"name":"Biologics Discovery & Development, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yu","sequence":"additional","affiliation":[{"name":"Biologics Discovery & Development, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Chen","sequence":"additional","affiliation":[{"name":"Oncology Discovery, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongzhou","family":"Zheng","sequence":"additional","affiliation":[{"name":"External Alliance, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Gao","sequence":"additional","affiliation":[{"name":"Biologics Discovery & Development, China Innovation Center of Roche , 371 Lishizhen Road, Shanghai 201203 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