Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism.

A tetravalent nanobody-based IL-10 receptor agonist achieves myeloid cell selectivity by relying on TYK2 dependence, avoiding T cell activation in inflammatory models.

• Why it matters: Selective targeting of IL-10's anti-inflammatory effects in myeloid cells is crucial to prevent the toxicities and limited efficacy caused by its activation of T cells, addressing a key challenge in treating chronic inflammatory diseases.
• What they did: The authors engineered a tetravalent nanobody-based msIL-10R agonist that mimics IL-10's suppression of myeloid cells, using cryo-electron microscopy to reveal a distinct receptor cross-linking geometry, and tested its effects in humanized mouse models and non-human primates.
• The result: The msIL-10R agonist reduces inflammation and sustains myeloid suppression for up to 30 days without T cell activation or hematological toxicities, suggesting its potential as a targeted therapy for myeloid-driven inflammatory diseases.