Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism
Year: 2026
Type: article
Abstract: Interleukin-10 (IL-10) is a central anti-inflammatory cytokine that suppresses immune responses in myeloid cells but can also activate T cells, limiting its therapeutic use in chronic inflammatory diseases owing to narrow efficacy windows and dose-limiting toxicities 1–5 . Here we show that myeloid and T cells differ in their dependence on JAK-family kinase pairing for IL-10 signalling and function. We took advantage of this differential kinase dependence to engineer a tetravalent nanobody-based myeloid-selective IL-10 receptor agonist (msIL-10R agonist) that fully recapitulates IL-10’s potent suppression of monocytes, macrophages and dendritic cells while avoiding stimulation of T cells. Cryo-electron microscopy structural analysis reveals a distinct receptor cross-linking geometry of the msIL-10R agonist compared with native IL-10 family cytokines. This tetravalent architecture renders signalling strictly TYK2-dependent and highly sensitive to IL-10Rα and IL-10Rβ receptor abundance, thereby conferring selective activity in myeloid cells. This msIL-10R agonist reduces inflammation in humanized mouse models of lipopolysaccharide challenge, delayed-type hypersensitivity and colitis. A humanized version exhibits IgG-like pharmacokinetics, sustained receptor occupancy and durable myeloid suppression up to 30 days without T cell activation or haematological toxicities in non-human primates. These findings establish a geometry-based strategy for achieving cell-type-selective cytokine signalling and identify the msIL-10R agonist as a therapeutic candidate for myeloid-driven inflammatory diseases, including inflammatory bowel diseases.
Source: Nature
Authors: D. Alejandro Canaria, Trang T. T. Nguyen, Huang Huang, Hui Xu, Lili Yue, Yongyao Fu, Hoa Truong, Kerul Patel, Weimei Xing, Jayamary Divya Ravichandar, Cong Xing, Aron L. Martin, George Delidakis, Sylvia Wong, Andrew Pae, Yu Yu, Ramsay Macdonald, Zhiyu Huang, Meagan C. Main, Amanali Rodriguez, Xiaoli Lin, Maria L. Mouchess, Magdeleine Hung, Ellen M. McGlinchey, Lei Chen, Nicole Schirle Oakdale, Brian Carr, Megan L. Koleske, Chingwei V. Lee, Chen Chen, Tangsheng Yi
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7222116604