DSP502 Combines Dual Inhibition of PD-L1 and PVR to Trigger Anticancer Immune Responses.
Publication/Presentation Date
8-4-2026
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.
Volume
25
Issue
8
First Page
1246
Last Page
1263
ISSN
1538-8514
Published In/Presented At
Melo Gallegos, V. A., Greenwald, S., Tamir, A., Jacob, L. J., González Corrales, M., Tsveyer, L., Aronin, A., Pecker, I., Tabakman, R., Ghantous, L., Tamir, L., Kahn, R., Zorde Khvalevsky, E., Peled, A., Wald, O., Tykocinski, M., Pereg, Y., Chajut, A., & Bremer, E. (2026). DSP502 Combines Dual Inhibition of PD-L1 and PVR to Trigger Anticancer Immune Responses. Molecular cancer therapeutics, 25(8), 1246–1263. https://doi.org/10.1158/1535-7163.MCT-25-0102
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
41578832
Department(s)
Administration and Leadership
Document Type
Article