Geometry-enforced TYK2 dependence enables myeloid-selective IL-10 receptor agonist [T cell RNA-Seq]

Efforts to engineer selective IL-10 variants have been constrained by short half-life, immunogenicity, and incomplete decoupling of beneficial and harmful activities. Here we show that a tetravalent myeloid-selective IL-10 receptor agonist (msIL-10R agonist) fully recapitulates IL-10’s potent suppression of cytokine production, dendritic cell maturation, and T-cell priming in myeloid cells while avoiding T-cell stimulation.

Cryo-EM reveals a distinct receptor crosslinking geometry from natural IL-10 family cytokine. Tetravalent msIL-10R agonist crosslinking renders signaling strictly TYK2-dependent and reliant on high IL-10Ra/IL-10Rb density unique to myeloid cells. This enables myeloid selectivity in vitro and in humanized mouse models of LPS challenge, delayed-type hypersensitivity, and colitis, achieving efficacy comparable to native IL-10.