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TitleDual agonism and selective T-cell depletion activity of a PD-1-directed antibody for treating autoimmune diseases.
Journal, issue, pagesMAbs, Vol. 18, Issue 1, Page 2624881, Year 2026
Publish dateFeb 4, 2026
AuthorsWenbo Jiang / Lingyun Li / Weili Xue / Xuzhi He / Xuebin Chu / Lei Song / Xue Li / Ranran Zhao / Xinghang Yuan / Xiaoliang Jin / Lishi Fan / Tian Sun / Aisi Zhu / Ling Zhou / Fei Gu / Qian Xu / Guangli Ma / Siqin Wang / Lei Jin / John L Xu /
PubMed AbstractPrecise inhibition of autoreactivity without concomitant induction of general immunosuppression is an overarching goal that remains elusive for the treatment of autoimmune diseases. PD-1 is ...Precise inhibition of autoreactivity without concomitant induction of general immunosuppression is an overarching goal that remains elusive for the treatment of autoimmune diseases. PD-1 is preferentially expressed on activated T cells that drive autoimmunity. These PD-1 T cells could serve as a target for therapeutic intervention. Here, we report the discovery of a unique PD-1 agonist antibody, GenSci120, that exhibited potent and selective T-cell inhibition in vitro and T-cell depletion activity both in vitro and in vivo. Target engagement by GenSci120 directly promoted SHP2 recruitment into the PD-1 signaling pathway but also enhanced the binding of PD-1 to its natural ligands and augmented PD-L1-induced PD-1 signaling. Moreover, GenSci120 exhibited robust efficacy in several animal models of human autoimmune disease. Thus, GenSci120, by selectively depleting PD-1 T cells and by directly (via PD-1 binding and SHP2 recruitment) or indirectly (via enhancing PD-1 and ligand interaction) stimulating PD-1 signaling, has the capability to restore immune balance in autoimmunity. In a first-in-human study in healthy adults (NCT06827457), GenSci120 demonstrated favorable safety/tolerability and pharmacokinetic profiles as well as robust pharmacodynamic effect. Together, these findings suggest the potential of GenSci120 as an innovative precision medicine for treating autoimmune diseases and support further evaluation of this investigational new drug in future clinical trials.
External linksMAbs / PubMed:41640111 / PubMed Central
MethodsEM (single particle)
Resolution2.96 Å
Structure data

EMDB-65617, PDB-9w43:
Structure of the complex of human PD-1 and a PD-1-directed antibody
Method: EM (single particle) / Resolution: 2.96 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / PD-1 / PD-1-directed antibody / antigen-antibody complex

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