Abstract
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 Ctsl 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.