Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China; Department of Anesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Biomed Pharmacother. 2023 Dec;168:115666. doi: 10.1016/j.biopha.2023.115666. Epub 2023 Oct 11.
Rheumatoid arthritis (RA) is the most common chronic autoimmune disease worldwide. Although progress has been made in RA treatment in recent decades, remission cannot be effectively achieved for a considerable proportion of RA patients. Thus, novel potential targets for therapeutic strategies are needed. Semaphorin 5A (SEMA5A) plays a pivotal role in RA progression by facilitating pannus formation, and it is a promising therapeutic target. In this study, we sought to develop an antibody treatment strategy targeting SEMA5A and evaluate its therapeutic effect using a collagen-induced arthritis (CIA) model. We generated SYD12-12, a fully human SEMA5A blocking antibody, through phage display technology. SYD12-12 intervention effectively inhibited angiogenesis and aggressive phenotypes of RA synoviocytes in vitro and dose-dependently inhibited synovial hyperplasia, pannus formation, bone destruction in CIA mice. Notably, SYD12-12 also improved the Treg/Th17 imbalance in CIA mice. We confirmed through immunofluorescence and molecular docking that SYD12-12 integrated with the unique TSP-1 domain of SEMA5A. In conclusion, we developed and characterized a fully human SEMA5A-blocking antibody for the first time. SYD12-12 effectively alleviated disease progression in CIA mice by inhibiting pannus formation and improving the Treg/Th17 imbalance, demonstrating its potential for the RA treatment.
类风湿关节炎（RA）是全球最常见的慢性自身免疫性疾病。尽管近年来 RA 的治疗取得了进展，但相当一部分 RA 患者仍无法有效实现缓解。因此，需要寻找新的潜在治疗策略靶点。信号素 5A（SEMA5A）通过促进血管翳形成在 RA 进展中发挥关键作用，是有前途的治疗靶点。在这项研究中，我们试图开发一种针对 SEMA5A 的抗体治疗策略，并使用胶原诱导性关节炎（CIA）模型评估其治疗效果。我们通过噬菌体展示技术生成了全人源 SEMA5A 阻断抗体 SYD12-12。SYD12-12 干预可有效抑制 RA 滑膜细胞的血管生成和侵袭表型，并呈剂量依赖性抑制 CIA 小鼠滑膜增生、血管翳形成和骨破坏。值得注意的是，SYD12-12 还改善了 CIA 小鼠中的 Treg/Th17 失衡。我们通过免疫荧光和分子对接证实，SYD12-12 与 SEMA5A 的独特 TSP-1 结构域结合。总之，我们首次开发并表征了一种全人源 SEMA5A 阻断抗体。SYD12-12 通过抑制血管翳形成和改善 Treg/Th17 失衡，有效缓解 CIA 小鼠的疾病进展，显示出其在 RA 治疗中的潜力。
