Chen Weiqiang, Lou Li, Qiang Xiaoling, Zhu Cassie Shu, Li Jianhua, Chen Shujin, Xiong Brian, Yang Huan, Wang Ping, Tracey Kevin J, Wang Haichao
The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
Departments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549, USA.
Res Sq. 2025 Sep 19:rs.3.rs-7633404. doi: 10.21203/rs.3.rs-7633404/v1.
Sepsis and rheumatoid arthritis (RA) are distinct yet mechanistically related conditions commonly driven by dysregulated inflammatory responses. Here, we explored the counterintuitive hypothesis that an epitope from a deleterious anti-tetranectin (TN) antibody (mAb9) could hold unforeseen therapeutic potential. By mapping mAb9's epitope to P2 (residue 55-70), a region crucial for TN's protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in a RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to high mobility group box 1 (HMGB1) and selectively suppressed HMGB1-induced mRNA upregulation and procathepsin L (pCTS-L) secretion from human immune cells, crucially without perturbing other HMGB1-induced cytokines and chemokines. We further validated pCTS-L as a therapeutic target by demonstrating that a neutralizing antibody conferred potent anti-arthritic effects, reducing joint inflammation, pain, and structural damage. Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from paradoxical antibody action into targeted therapeutics for the HMGB1-pCTS-L axis, not only delivering P2-1 as a potent therapy but also establishing pCTS-L as crucial mediator of inflammatory diseases like sepsis and RA.
脓毒症和类风湿性关节炎（RA）是截然不同但在机制上相关的病症，通常由失调的炎症反应驱动。在此，我们探讨了一个与直觉相悖的假说，即一种有害的抗腱生蛋白（TN）抗体（mAb9）的表位可能具有意想不到的治疗潜力。通过将mAb9的表位定位到P2（第55 - 70位氨基酸残基），这是TN发挥保护功能的关键区域，我们开发了P2 - 1，一种作为靶向治疗的水溶性衍生物。在脓毒症模型中，P2 - 1显著提高了生存率并减轻了全身炎症，在RA模型中，即使在疾病发作后进行治疗给药，也减轻了关节炎严重程度和疼痛敏感性。从机制上讲，P2 - 1与高迁移率族蛋白B1（HMGB1）表现出高亲和力结合，并选择性抑制HMGB1诱导的人免疫细胞mRNA上调和组织蛋白酶L前体（pCTS - L）分泌，关键在于不会干扰其他HMGB1诱导的细胞因子和趋化因子。我们通过证明一种中和抗体具有强大的抗关节炎作用，减少关节炎症、疼痛和结构损伤，进一步验证了pCTS - L作为治疗靶点。我们的研究结果引入了一种范式转变的药物发现策略，将自相矛盾的抗体作用的见解转化为针对HMGB1 - pCTS - L轴的靶向治疗，不仅将P2 - 1作为一种有效的治疗方法，还将pCTS - L确立为脓毒症和RA等炎症性疾病的关键介质。
