biostudies-literatureUnknownChen WNCCIH NIH HHSNIGMS NIH HHSSepsis 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 selectivResearch squarers.3.rs-7633404https://www.ebi.ac.uk/biostudies/studies/S-EPMC12458545biostudies-literatureRepurposing a Detrimental Antibody Epitope as Targeted Therapeutics for Sepsis and Rheumatoid Arthritis.PMC12458545R01 AT005076R35 GM145331Yang HLi JWang PTracey KJChen WXiong BQiang XZhu CSWang HChen SLou LfalseRepurposing a Detrimental Antibody Epitope as Targeted Therapeutics for Sepsis and Rheumatoid Arthritis.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 selectiv2025-01-01T00:00:00Z2025 Sep2026-06-04T03:16:52.795Z2026-06-04T03:06:36.734ZS-EPMC124585454100154610.21203/rs.3.rs-7633404/v1