ArticleMilitary Medical Research2025
Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis.
Article in Military Medical Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed.
- A comparative analysis of HMGB1 and pCTS-L immunomodulatory properties in human peripheral blood mononuclear cells.Frontiers in immunology · 2026Article
- Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases.Frontiers in immunology · 2026Review
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Authors and funding
11 authors.
Funding
Abstract
Background: 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. Methods: By mapping mAb9's epitope to P2 (residues 55-70), a region crucial for TN's protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. We then employed animal models of sepsis (cecal ligation and puncture) and arthritis (collagen antibody-induced arthritis) to evaluate the therapeutic effects of P2, P2-1, and a procathepsin L (pCTS-L)-neutralizing antibody by assessing septic survival, arthritis severity, pain sensitivity, and joint tissue histology. In parallel, we utilized a surface plasmon resonance (SPR) assay and computational modeling to examine the P2-1/high mobility group box 1 (HMGB1) interaction. Finally, we elucidate the effect of P2-1 on the HMGB1-induced release of pCTS-L and other cytokines and chemokines using primary human peripheral blood mononuclear cells (PBMCs). Results: P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in an RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to HMGB1 and selectively suppressed HMGB1-induced cathepsin L ( Conclusions: Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from harmful antibody action into targeted therapeutics for the HMGB1-pCTS-L axis. This approach not only delivers P2-1 as a potent therapy but also establishes pCTS-L as a crucial mediator in inflammatory diseases such as sepsis and RA. Supplementary Information: The online version contains supplementary material available at 10.1186/s40779-026-00686-8.
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