{"id":68346,"date":"2026-06-25T00:52:41","date_gmt":"2026-06-24T22:52:41","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/06\/25\/a-tnfr2-biparatopic-antagonist-reverses-immune-suppression-through-a-crosslinking-resistant-and-adcc-independent-mechanismshusu-liu-on-24-de-june-de-2026-at-1000\/"},"modified":"2026-06-25T00:52:41","modified_gmt":"2026-06-24T22:52:41","slug":"a-tnfr2-biparatopic-antagonist-reverses-immune-suppression-through-a-crosslinking-resistant-and-adcc-independent-mechanismshusu-liu-on-24-de-june-de-2026-at-1000","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/06\/25\/a-tnfr2-biparatopic-antagonist-reverses-immune-suppression-through-a-crosslinking-resistant-and-adcc-independent-mechanismshusu-liu-on-24-de-june-de-2026-at-1000\/","title":{"rendered":"A TNFR2 biparatopic antagonist reverses immune suppression through a crosslinking-resistant and ADCC- independent mechanism\u200bShusu Liu on 24 de June de 2026 at 10:00"},"content":{"rendered":"
\n

J Leukoc Biol<\/b>. 2026 Jun 24:qiag086. doi: 10.1093\/jleuko\/qiag086. Online ahead of print.<\/p>\n

ABSTRACT<\/b><\/p>\n

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 ‘agonistic conversion’ upon crosslinking within the tumor microenvironment. To overcome these liabilities, we engineered Duo1, a novel biparatopic antagonist that enables simultaneous, monovalent engagement of two distinct TNFR2 epitopes. Biophysical analysis confirmed Duo1 forms stable 1:1 complexes with TNFR2 with high-affinity (KD = 0.165 nM), structurally locking the target to prevent the receptor oligomerization required for agonistic signaling. Crucially, while conventional bivalent frameworks convert into potent agonists upon cross-linking, 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 anti-tumor 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. By uncoupling anti-tumor activity from both the risks of cross-linking 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.<\/p>\n

PMID:42341157<\/a> | DOI:10.1093\/jleuko\/qiag086<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"

J Leukoc Biol. 2026 Jun 24:qiag086. doi: 10.1093\/jleuko\/qiag086. Online ahead of print. ABSTRACT 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 … Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[86,42],"tags":[],"class_list":["post-68346","post","type-post","status-publish","format-standard","hentry","category-journal-of-leukocyte-biology","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/68346","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=68346"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/68346\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=68346"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=68346"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=68346"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}