SECN-15: A novel treatment option for patients with checkpoint inhibitor–resistant tumors by targeting Neuropilin-1 with antisense oligonucleotides.

2580 Background: SECN-15 is a high-affinity antisense oligonucleotide (ASO) targeting Neuropilin-1 (NRP1), a transmembrane protein that exerts a variety of protumorigenic functions by interacting with various receptors and ligands. NRP1 contributes to an immunosuppressive microenvironment, tumor growth, metastasis, and neoangiogenesis. The recent success of bispecific antibodies targeting PD-1/PD-L1 and VEGF such as ivonescimab has highlighted the potential of combining checkpoint inhibitors with anti-angiogenic approaches. Consequently, NRP1 represents a highly attractive target for treating patients with tumors that are resistant to or insufficiently responsive to checkpoint inhibitor therapies, such as gastric (GC) and breast cancer, where high NRP1 expression correlates with poor prognosis. Methods: NRP1-specific locked nucleic acid (LNA)-modified ASOs were identified using our OligoCreator platform. We assessed in vivo anti-tumor efficacy after systemic administration in various mouse tumor models as monotherapy and in combination with checkpoint inhibitors. Target downregulation was analyzed in tissues and in plasma by measuring soluble NRP1. Cell composition and transcriptome changes in tumors were analyzed using flow cytometry and RNA sequencing. Exaggerated pharmacology was investigated in a 28 non-GLP tolerability study in mice. In silico analyses of patient transcriptomics data were performed to prioritize indications for the upcoming Phase I/II clinical trial. Results: Systemic administration of NRP1-specific ASOs resulted in robust knockdown in tumors across various cell types, including macrophages and T cells. Soluble NRP1 levels were reduced in treated animals, serving as a target engagement biomarker. Tumor growth was delayed in the monotherapy setting, with several animals showing complete responses. Combining NRP1-specific ASOs with checkpoint inhibitors enhanced efficacy in models where checkpoint inhibitors alone had limited activity. Transcriptomic analysis showed upregulation of inflammatory genes and downregulation of extracellular matrix organization genes. No adverse effects were observed from persistent NRP1 downregulation in non-tumor-bearing mice. In silico analyses revealed that NRP1 expression is negatively associated with survival and increases in advanced GC stages. GC was selected as one of the priority indications for the upcoming Phase I/II clinical trial to investigate SECN-15's safety and efficacy as monotherapy and in combination with PD-1 blocking antibodies. Conclusions: Targeting NRP1 with ASOs is a promising therapeutic strategy for solid cancers. Combining NRP1 ASOs with ICIs significantly enhances anti-tumor efficacy, potentially overcoming current ICI therapy limitations. IND-enabling studies are underway to advance SECN-15 into clinical development.