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Updated: Aug 17, 2026
Tracking Bispecific Antibody-Induced T Cell Trafficking Using Luciferase-Transduced Human T Cells
Published on: May 12, 2023
Simultaneous targeting of IL-10 and PD-(L)1 pathways with a bispecific anti-PD-L1/IL-10-trap antibody enhances T cell
Latika Singh1, Natalia Zabavnik2, Sambasivan Venkatasubramanian1
1Research Unit Oncology, EMD Serono Research and Development Institute, Inc., Billerica, MA 01821, USA.
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.
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.
