Effects of SECN-15, a neuropilin-1–targeting antisense oligonucleotide, on resistance to immune checkpoint inhibitors in preclinical tumor models.

Abstract

2613 Background: Neuropilin-1 (NRP1) is a transmembrane co-receptor implicated in tumor growth, metastasis, angiogenesis, and immune suppression. High NRP1 expression is associated with poor prognosis in multiple solid tumors, including gastric cancer (GC) and breast cancer. SECN-15 is a high-affinity antisense oligonucleotide (ASO) designed to selectively downregulate NRP1. In light of recent clinical success of combined PD-1/PD-L1 and anti-angiogenic strategies and given its dual role in angiogenesis and immune suppression, NRP1 represents an attractive target to overcome resistance to immune checkpoint inhibition. Methods: NRP1-specific ASOs were identified using the OligoCreator platform. Anti-tumor efficacy was assessed following systemic administration in multiple syngeneic mouse tumor models, both as monotherapy and in combination with immune checkpoint inhibitors. Target engagement was evaluated at the RNA level in tissues and at the protein level in plasma via soluble NRP1 quantification. In silico analyses of patient transcriptomic datasets were conducted to prioritize indications for clinical development. PK/PD characterization and dose optimization studies are currently underway to support dose selection for GLP toxicology studies and first-in-human evaluation. Results: Systemic administration of SECN-15 achieved robust target knockdown in tumors across multiple cell populations and modulated the tumor microenvironment, including downregulation of extracellular matrix and EMT genes. A single dose resulted in near-complete and sustained suppression of plasma soluble NRP1 levels for up to 28 days, consistent with durable target engagement. SECN-15 delayed tumor growth as monotherapy, with complete regressions observed in a subset of animals, and significantly enhanced anti-tumor activity in combination with immune checkpoint inhibitors in models with limited responsiveness to checkpoint blockade alone. Single-cell RNA-seq analyses from gastric cancer patients identified endothelial cells and macrophages as major NRP1-expressing populations, with NRP1high subsets exhibiting TGF-β, hypoxia, and EMT pathway activation and suppression of allograft rejection signatures, consistent with an immunosuppressive, pro-angiogenic tumor microenvironment. In silico analyses showed that high NRP1 expression correlates with poor survival and advanced disease stage in gastric cancer, supporting its prioritization for clinical development. Conclusions: Targeting Neuropilin-1 with the ASO SECN-15 remodels the tumor microenvironment and enhances responsiveness to immune checkpoint blockade, supporting NRP1 inhibition as a strategy to overcome resistance to ICI therapy in solid tumors. The program is approaching IND-enabling development to support the clinical translation of SECN-15.