DSP502 Combines Dual Inhibition of PD-L1 and PVR to Trigger Anticancer Immune Responses

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.