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#双抗/多抗

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Oct 15Thu
  1. nature.com83

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

    IL-10's therapeutic use is limited because its myeloid-suppressive and T-cell-activating effects cannot be separated. Using the JAK1 inhibitor VVD-118313 in bone-marrow-derived macrophages, the authors show that JAK1-JAK1 transphosphorylation only partially reduces IL-10-induced STAT3 phosphorylation, with TYK2-mediated transphosphorylation compensating; in TYK2-deficient BMDMs, VVD-118313 fully abrogated STAT3 phosphorylation and IL-10 function. In human monocytes, the TYK2 inhibitor zasocitinib similarly partially reduced IL-10-driven STAT3 phosphorylation, revealing differential TYK2 dependence that may enable myeloid-selective IL-10 receptor agonism.

    Why it matters: It maps a signalling route that could separate IL-10's anti-inflammatory benefit from its toxic T-cell activation.

Oct 2Fri
  1. Nature70

    GPCR antagonism via rewiring of receptor trafficking and degradation.

    Bispecific antibody chimeras termed GTACs drive GPCRs into TfR1-mediated endocytosis and lysosomal degradation, achieving potent and selective downregulation of BILF1, RXFP1 and CCR6, targets that have been difficult to drug. GTACs completely inhibit receptor signalling, including constitutive signalling, with one to two orders of magnitude greater potency than conventional antibody antagonists. The work establishes induced endocytosis and rewired protein trafficking as a route to therapeutic GPCR modulation.

    Why it matters: It turns GPCR antagonism into receptor degradation, boosting potency over conventional antibodies by one to two orders of magnitude.

Sep 30Wed
  1. medrxiv.org72

    CD3-engaging bispecific antibodies convert human regulatory T cells into cytotoxic effectors

    CD3-engaging bispecific T cell engagers convert human FOXP3+ regulatory T cells into an AP-1-imprinted hybrid cytotoxic state that contributes to tumor clearance. In newly diagnosed multiple myeloma patients treated with BTCE-based induction in the phase 2 GMMG-HD10/DSMM-XX/MajesTEC-5 trial, single-cell sequencing showed Tregs expressing GZMA, GNLY and NKG7, and in vitro BTCE-exposed Tregs killed tumor cells in a target- and dose-dependent manner. IMiDs amplified and reshaped this cytotoxic program, supporting BTCE-IMiD combination regimens.

    Why it matters: Reframes Tregs as active cytotoxic effectors of bispecific antibody therapy and gives a mechanistic basis for BTCE-IMiD combinations.

Sep 10Thu
  1. nature.com51

    A bispecific CD3×CD19 antibody for systemic lupus erythematosus: a phase 1 trial

    A next-generation CD3×CD19 bispecific T cell engager given intravenously was well tolerated in patients with active systemic lupus erythematosus in a phase 1 trial, and most patients showed improvements in disease activity scores. The findings support further testing of B cell-directed T cell engagers in systemic lupus erythematosus.

    Why it matters: First-in-class tolerability and disease activity signal for a CD3×CD19 bispecific antibody in active SLE.

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