Abstract 6738: Towards developing a novel therapy for pain: A monoclonal antibody that specifically inhibits voltage-gated sodium channels Nav1.7

Abstract Background: Pain is caused by the transmission of action potentials through nerve fibers to the dorsal root ganglia, ultimately reaching the higher nervous system. Voltage-gated sodium channels (VGSCs) member Nav1.7, encoded by SCN9A and primarily localized to the dorsal root ganglion neurons, has been explored as a prominent target for pain management. The Nav1.7 protein is structurally complex. Composed of about 2000 amino acids, this protein possesses four homologous domains, each containing six transmembrane alpha helices. In addition, the Nav family has nine members that share high sequence homology. This structural complexity makes it particularly challenging to develop antibodies that bind to epitopes that cause inhibitory effects on the target. And it’s high sequence homologymakes it particularly challenging to develop antibodies with high specificity. Leveraging on our NovoiSMART® technology, we successfully developed NP067, a highly specific and functional monoclonal antibody against Nav1.7. Methods: It was previously shown that IL-1β upregulates the expression of ADAMTS1, and this upregulation is disrupted by the inhibition of Nav1.7. Therefore we measured the expression of ADAMTS1 under IL-1β induced upregulation, with or without our new antibody NP067. We also compared several known Nav1.7 antagonists and NP067 for their effects to influence the expression of ADAMTS1. The specificity of NP067 against Nav1.7 was confirmed by flow cytometry experiments on two cell lines. MCF-7 cells were used for negative confirmation as this cell line expresses SCN5A/SCN7A/SCN8A antigens but not SCN9A. And A549 cells were used for positive confirmation and this cell line expresses SCN5A/SCN7A/SCN8A as well as SCN9A. Results: NP067 inhibited IL-1β-induced ADAMTS1 gene expression, and the effects were stronger than other reference molecules. Flow cytometry data showed that NP067 was highly specific to Nav1.7, and the affinity were higher than other reference molecules. Conclusions: NP067 is a functional and specific Nav1.7 antibody that have great potential in pain treatment. NP067 also shows great potential both as a monotherapy or coupling with other drugs. Citation Format: Debin Li, Na Lu, Rui Song, Meimei Liu, Gavin Zhang, Huihui Xu, Yuting Xue, Liyan Su, Huaxing Zhu. Towards developing a novel therapy for pain: A monoclonal antibody that specifically inhibits voltage-gated sodium channels Nav1.7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6738.