DSP502 Combines Dual Inhibition of PD-L1 and PVR to Trigger Anticancer Immune Responses
Vinicio A Melo Gallegos1,2,3, Shirley Greenwald2, Ami Tamir2
1Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Abstract:
PD-1 immune checkpoint inhibition (ICI) is ineffective in most patients with cancer. However, combination therapy can improve response rates, with the checkpoint TIGIT being a particularly interesting candidate as it is expressed on tumor-infiltrating exhausted T and NK cells. TIGIT's primary ligand, PVR, is overexpressed in many cancers, and both TIGIT and PVR correlate with poor prognosis. To therapeutically exploit this, we developed a novel therapeutic termed dual signaling protein 502 (DSP502). DSP502 is composed of the extracellular domains of TIGIT and PD-1, each fused to human IgG1 Fc containing knob-in-hole mutations. DSP502 was designed to simultaneously block PVR/TIGIT and PD-L1/PD-1 by binding to cancer cell-expressed PVR and PD-L1. Moreover, the human IgG1 domain can recruit FcR-positive effector cells to further reactivate anticancer immunity. Treatment with DSP502 potentiated NK cell activation and boosted the anticancer cytotoxicity of peripheral blood mononuclear cells and tumor-infiltrating lymphocytes from patients with non-small cell lung cancer (NSCLC) and metastatic colorectal cancer toward cancer cells expressing both PD-L1 and PVR. Transcriptomic analysis confirmed NSCLC as a potential target, showing co-expression of TIGIT and PD-1 (PDCD1) on a high percentage of exhausted CD8+ T cells. Notably, treatment with DSP502 not only blocked checkpoint signaling but also preserved surface expression of the co-stimulatory PVR ligand, DNAM-1, on T and NK cells. Finally, DSP502 inhibited tumor growth by potentiating antitumor immunity in xenograft ovarian and lung cancer models. Collectively, these findings demonstrate that DSP502, by blocking PVR and PD-L1 pathways, has dual ICI activity and holds potential therapeutic benefits for cancers such as NSCLC.
Insights
A novel dual immune checkpoint inhibitor, DSP502, blocks TIGIT and PD-1 pathways simultaneously. This approach enhances anti-cancer immunity and shows promise for treating cancers like non-small cell lung cancer (NSCLC).
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Immune checkpoint inhibition (ICI) using PD-1 blockade is often ineffective for many cancer patients.
- TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a promising checkpoint target, expressed on exhausted T and NK cells, with its ligand PVR overexpressed in various cancers.
- Both TIGIT and PVR are correlated with poor patient prognosis, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To develop and evaluate a novel dual-acting immune checkpoint inhibitor, DSP502, targeting both TIGIT and PD-1 pathways.
- To assess DSP502's ability to block PVR/TIGIT and PD-L1/PD-1 interactions and reactivate anti-cancer immunity.
- To investigate DSP502's therapeutic potential in preclinical cancer models, including non-small cell lung cancer (NSCLC).
Main Methods:
- DSP502 was engineered by fusing the extracellular domains of TIGIT and PD-1 to a human IgG1 Fc domain with knob-in-hole mutations.
- The efficacy of DSP502 was tested in vitro using peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) from NSCLC and colorectal cancer patients.
- In vivo studies involved xenograft models of ovarian and lung cancer to evaluate DSP502's anti-tumor effects.
Main Results:
- DSP502 treatment potentiated NK cell activation and enhanced the cytotoxic activity of PBMCs and TILs against cancer cells expressing both PD-L1 and PVR.
- Transcriptomic analysis revealed co-expression of TIGIT and PD-1 on exhausted CD8+ T cells in NSCLC.
- DSP502 inhibited tumor growth in vivo by enhancing anti-tumor immunity and preserved the co-stimulatory ligand DNAM-1.
Conclusions:
- DSP502 demonstrates dual immune checkpoint inhibitory activity by simultaneously blocking PVR/TIGIT and PD-L1/PD-1 pathways.
- The engineered protein can recruit FcR-positive effector cells, further boosting anti-cancer immunity.
- DSP502 holds significant therapeutic potential for various cancers, particularly NSCLC, and warrants further clinical investigation.
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