Bispecifiek anti-PD-L1/IL-10-trap-antistof versterkt T-celactivatie door gelijktijdige blokkade van immuunremmende paden

Immune checkpoint inhibitors (ICIs) demonstrate clinical benefits with durable responses but only in a subset of patients with cancer. Understanding the mechanisms that limit T cell-mediated cytotoxicity of tumor cells and developing new therapies are both needed to overcome such limitations. Interleukin-10 (IL-10) is a cytokine with known pro- and anti-tumor roles. Here, we demonstrate that the nature of IL-10 activity depends on its concentration: very high exogenous IL-10 concentrations induce IFNγ production by T cells, while concentrations similar to those found in the serum of patients with cancer suppress T cell activity. To test if simultaneously trapping IL-10 while blocking PD-L1 could overcome these suppressive effects, which are hypothesized to limit the activity of anti-PD-L1 or drive adaptive resistance, we developed an anti-PD-L1/IL-10-trap antibody comprising a Fab paratope directed against programmed death ligand 1 (PD-L1) fused to a VHH domain targeting IL-10, which acts as an IL-10 "trap." We found that treatment with anti-PD-L1/IL-10-trap protects T cells from suppressive IL-10 and drives superior activation compared to anti-PD-L1 or IL-10-trap alone. Furthermore, anti-PD-L1/IL-10-trap shifted macrophage polarization toward a more mature and activated phenotype and enhanced CD8+ T cell activation compared with anti-PD-(L)1, IL-10-trap, or their combination. Our data support the immunosuppressive role of IL-10 in tumors and demonstrate that simultaneous targeting of PD-L1 and IL-10 may provide superior T cell responses compared to anti-PD-(L)1 therapies alone or in combination with anti-IL-10 antibodies.