Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis

Wei-Qiang Chen; Li Lou; Xiao-Ling Qiang; Cassie Shu Zhu; Jian-Hua Li; Shu-Jin Chen; Brian Xiong; Huan Yang; Ping Wang; Kevin J. Tracey; Hai-Chao Wang

doi:10.1186/s40779-026-00686-8

Your Location：

Home >

Browse articles >

Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis

RESEARCH | Updated：2026-08-20

- Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis
- Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis
- Military Medical Research 2026年13卷第7期页码：1061-1080
- Affiliations：
  
  The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
  Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA
- Author bio：
  
  * Hai-Chao Wang hwang@northwell.edu
- Funds：
  
  NIGMS(R35GM145331);NICCH(R01AT005076)
- DOI：10.1186/s40779-026-00686-8
  中图分类号：
- 收稿：2025-10-03，
  
  录用：2026-01-30，
  
  网络首发：2026-02-17，
  
  纸质出版：2026-07
- Accepted：
Scan QR Code
Wei-Qiang Chen, Li Lou, Xiao-Ling Qiang, 等. Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis[J]. Military Medical Research, 2026,13(7):1061-1080.

Wei-Qiang Chen, Li Lou, Xiao-Ling Qiang, et al. Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis[J]. Military Medical Research, 2026, 13(7): 1061-1080.
Wei-Qiang Chen, Li Lou, Xiao-Ling Qiang, 等. Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis[J]. Military Medical Research, 2026,13(7):1061-1080. DOI： 10.1186/s40779-026-00686-8.

Wei-Qiang Chen, Li Lou, Xiao-Ling Qiang, et al. Repurposing a detrimental antibody epitope as targeted therapeutics for sepsis and rheumatoid arthritis[J]. Military Medical Research, 2026, 13(7): 1061-1080. DOI： 10.1186/s40779-026-00686-8.

摘要

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 sensi-tivity

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. Mecha-nistically

P2-1 exhibited high-affinity binding to HMGB1 and selectively suppressed HMGB1-induced cathepsin L (

Ctsl

) mRNA upregulation and 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 neu-tralizing antibody conferred potent antiarthritic effects

reducing joint inflammation

pain

and structural damage.

Conclusions

Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from harm-ful 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.

关键词

Keywords

references

Rudd KE , Johnson SC , Agesa KM , Shackelford KA , Tsoi D , Kievlan DR , et al . Global, regional, and national sepsis incidence and mortality,1990-2017: analysis for the global burden of disease study . Lancet . 2020 ; 395 ( 10219 ): 200 – 11 .

Tracey KJ , Fong Y , Hesse DG , Manogue KR , Lee AT , Kuo GC , et al . Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia . Nature . 1987 ; 330 ( 6149 ): 662 – 4 .

Wang H , Bloom O , Zhang M , Vishnubhakat JM , Ombrellino M , Che J , et al . HMG-1 as a late mediator of endotoxin lethality in mice . Science . 1999 ; 285 ( 5425 ): 248 – 51 .

Yang H , Ochani M , Li J , Qiang X , Tanovic M , Harris HE , et al . Reversing established sepsis with antagonists of endogenous high-mobility group box 1 . Proc Natl Acad Sci U S A . 2004 ; 101 ( 1 ): 296 – 301 .

Zhu CS , Qiang X , Chen W , Li J , Lan X , Yang H , et al . Identification of procathepsin L (pCTS-L)-neutralizing monoclonal antibodies to treat potentially lethal sepsis . Sci Adv . 2023 ; 9 ( 5 ): eadf4313 .

Li J , Zhu CS , He L , Qiang X , Chen W , Wang H . A two-decade journey in identifying high mobility group box 1 (HMGB1) and procathepsin L(pCTS-L) as potential therapeutic targets for sepsis . Expert Opin Ther Targets . 2023 ; 27 ( 7 ): 575 – 91 .

Di Matteo A , Bathon JM , Emery P . Rheumatoid arthritis . Lancet . 2023 ; 402 ( 10416 ): 2019 – 33 .

McInnes IB , Schett G . Pathogenetic insights from the treatment of rheu-matoid arthritis . Lancet . 2017 ; 389 ( 10086 ): 2328 – 37 .

Kokkola R , Li J , Sundberg E , Aveberger AC , Palmblad K , Yang H , et al . Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity . Arthritis Rheum . 2003 ; 48 ( 7 ): 2052 – 8 .

Yang H , Zeng Q , Silverman HA , Gunasekaran M , George SJ , Devarajan A , et al . HMGB1 released from nociceptors mediates inflammation . Proc Natl Acad Sci U S A . 2021 . https://doi.org/10.1073/pnas.2102034118 .

Burmester GR , Pope JE . Novel treatment strategies in rheumatoid arthritis . Lancet . 2017 ; 389 ( 10086 ): 2338 – 48 .

Elliott MJ , Maini RN , Feldmann M , Kalden JR , Antoni C , Smolen JS , et al . Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis . Lancet . 1994 ; 344 ( 8930 ): 1105 – 10 .

Wang H , Ayala A , Aziz M , Billiar TR , Deutschman CS , Jeyaseelan S , et al . Value of animal sepsis research in navigating the translational labyrinth . Front Immunol . 2025 ; 16 : 1593342 .

Yang H , Wang H , Ju Z , Ragab AA , Lundback P , Long W , et al . MD-2 is required for disulfide HMGB1-dependent TLR4 signaling . J Exp Med . 2015 ; 212 ( 1 ): 5 – 14 .

Yu M , Wang H , Ding A , Golenbock DT , Latz E , Czura CJ , et al . HMGB1 sig-nals through toll-like receptor (TLR) 4 and TLR2 . Shock . 2006 ; 26 ( 2 ): 174 – 9 .

Tian J , Avalos AM , Mao SY , Chen B , Senthil K , Wu H , et al . Toll-like receptor 9-dependent activation by DNA-containing immune complexes is medi-ated by HMGB1 and RAGE . Nat Immunol . 2007 ; 8 ( 5 ): 487 – 96 .

Xu J , Jiang Y , Wang J , Shi X , Liu Q , Liu Z , et al . Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis . Cell Death Differ . 2014 ; 21 ( 8 ): 1229 – 39 .

Deng M , Tang Y , Li W , Wang X , Zhang R , Zhang X , et al . The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis . Immunity . 2018 ; 49 ( 4 ): 740 – 53 .

Yang H , Wang H , Levine YA , Gunasekaran MK , Wang Y , Addorisio M , et al . Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes . JCI Insight . 2016 ; 1 ( 7 ): e85375 .

Son M , Porat A , He M , Suurmond J , Santiago-Schwarz F , Andersson U , et al . C1q and HMGB1 reciprocally regulate human macrophage polariza-tion . Blood . 2016 ; 128 ( 18 ): 2218 – 28 .

Chen W , Qiang X , Wang Y , Zhu S , Li J , Babaev A , et al . Identification of tetranectin-targeting monoclonal antibodies to treat potentially lethal sepsis . Sci Transl Med . 2020 ; 12 ( 539 ): 12/539 .

Lemaire R , Huet G , Zerimech F , Grard G , Fontaine C , Duquesnoy B , et al . Selective induction of the secretion of cathepsins B and L by cytokines in synovial fibroblast-like cells . Br J Rheumatol . 1997 ; 36 ( 7 ): 735 – 43 .

Gerber A , Wille A , Welte T , Ansorge S , Buhling F . Interleukin-6 and trans-forming growth factor-beta 1 control expression of cathepsins B and L in human lung epithelial cells . J Interferon Cytokine Res . 2001 ; 21 ( 1 ): 11 – 9 .

Chen W , Zhu CS , Qiang X , Chen S , Li J , Wang P , et al . Development of pro-cathepsin L (pCTS-L)-inhibiting lanosterol-carrying liposome nanoparti-cles to treat lethal sepsis . Int J Mol Sci . 2023 ; 24 ( 10 ): 8649 .

Qiang X , Chen W , Zhu CS , Li J , Qi T , Lou L , et al . Therapeutic potential of procathepsin L-inhibiting and progesterone-entrapping dimethyl-β-cyclodextrin nanoparticles in treating experimental sepsis . Front Immunol . 2024 ; 15 : 1368448 .

Yang S , Chen K , Yu J , Jin Z , Zhang M , Li Z , et al . Inhibition of cathepsin L ameliorates inflammation through the A20/NF-κB pathway in endotoxin-induced acute lung injury . iScience . 2024 ; 27 ( 11 ): 111024 .

Ikeda Y , Ikata T , Mishiro T , Nakano S , Ikebe M , Yasuoka S . Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase . J Med Invest . 2000 ; 47 ( 1–2 ): 61 – 75 .

Ruge T , Södergren A , Wållberg-Jonsson S , Larsson A , Arnlöv J . Circulat-ing plasma levels of cathepsin S and L are not associated with disease severity in patients with rheumatoid arthritis . Scand J Rheumatol . 2014 ; 43 ( 5 ): 371 – 3 .

Weitoft T , Larsson A , Manivel VA , Lysholm J , Knight A , Rönnelid J . Cathepsin S and cathepsin L in serum and synovial fluid in rheumatoid arthritis with and without autoantibodies . Rheumatology (Oxford) . 2015 ; 54 ( 10 ): 1923 – 8 .

Keyszer GM , Heer AH , Kriegsmann J , Geiler T , Trabandt A , Keysser M , et al . Comparative analysis of cathepsin L, cathepsin D, and collagenase mes-senger RNA expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis, by in situ hybridization . Arthritis Rheum . 1995 ; 38 ( 7 ): 976 – 84 .

Iwata Y , Mort JS , Tateishi H , Lee ER . Macrophage cathepsin L, a factor in the erosion of subchondral bone in rheumatoid arthritis . Arthritis Rheum . 1997 ; 40 ( 3 ): 499 – 509 .

Schurigt U , Eilenstein R , Gajda M , Leipner C , Sevenich L , Reinheckel T , et al . Decreased arthritis severity in cathepsin L-deficient mice is attributed to an impaired T helper cell compartment . Inflamm Res . 2012 ; 61 ( 9 ): 1021 – 9 .

Schedel J , Seemayer CA , Pap T , Neidhart M , Kuchen S , Michel BA , et al . Targeting cathepsin L (CL) by specific ribozymes decreases CL protein synthesis and cartilage destruction in rheumatoid arthritis . Gene Ther . 2004 ; 11 ( 13 ): 1040 – 7 .

Jensen BA , McNair P , Hyldstrup L , Clemmensen I . Plasma tetranectin in healthy male and female individuals, measured by enzyme-linked immu-nosorbent assay . J Lab Clin Med . 1987 ; 110 ( 5 ): 612 – 7 .

McDonald K , Glezeva N , Collier P , O’Reilly J , O’Connell E , Tea I , et al . Tetranectin, a potential novel diagnostic biomarker of heart failure, is expressed within the myocardium and associates with cardiac fibrosis . Sci Rep . 2020 ; 10 ( 1 ): 7507 .

Kopeva KV , Grakova EV , Shilov SN , Berezikova EN , Bobyleva ET , Teplyakov AT . Tetranectin as a potential novel prognostic biomarker in anthracy-cline-related cardiac dysfunction . Heart Vessels . 2023 ; 38 ( 10 ): 1256 – 66 .

Kamper EF , Kopeikina LT , Trontzas P , Kyriazis NC , Vaiopoulos G , Stavridis J . Comparative study of tetranectin levels in serum and synovial fluid of patients with rheumatoid arthritis, seronegative spondylarthritis and osteoarthritis . Clin Rheumatol . 1998 ; 17 ( 4 ): 318 – 24 .

Lorentsen RH , Graversen JH , Caterer NR , Thogersen HC , Etzerodt M . The heparin-binding site in tetranectin is located in the N-terminal region and binding does not involve the carbohydrate recognition domain . Biochem J . 2000 ; 347 ( Pt 1 ): 83 – 7 .

Graversen JH , Lorentsen RH , Jacobsen C , Moestrup SK , Sigurskjold BW , Thogersen HC , et al . The plasminogen binding site of the C-type lectin tetranectin is located in the carbohydrate recognition domain,and binding is sensitive to both calcium and lysine . J Biol Chem . 1998 ; 273 ( 44 ): 29241 – 6 .

Westergaard UB , Andersen MH , Heegaard CW , Fedosov SN , Petersen TE . Tetranectin binds hepatocyte growth factor and tissue-type plasminogen activator . Eur J Biochem . 2003 ; 270 ( 8 ): 1850 – 4 .

Paterson CW , Ford ML , Coopersmith CM . Breaking the bond between tetranectin and HMGB1 in sepsis . Sci Transl Med . 2020 ; 12 ( 539 ): 12/539 .

Lewis MJ . Predicting best treatment in rheumatoid arthritis . Semin Arthritis Rheum . 2024 ; 64s : 152329 .

Atzeni F , Nucera V , Gerratana E , Cirillo M , Marino F , Miceli G , et al . Concerns about the safety of anti-TNF agents when treating rheumatic diseases . Expert Opin Drug Saf . 2020 ; 19 ( 6 ): 695 – 705 .

Rubbert-Roth A , Szabó MZ , Kedves M , Nagy G , Atzeni F , Sarzi-Puttini P . Failure of anti-TNF treatment in patients with rheumatoid arthritis: the pros and cons of the early use of alternative biological agents . Autoimmun Rev . 2019 ; 18 ( 12 ): 102398 .

Prado MS , Bendtzen K , Andrade LEC . Biological anti-TNF drugs: immuno-genicity underlying treatment failure and adverse events . Expert Opin Drug Metab Toxicol . 2017 ; 13 ( 9 ): 985 – 95 .

Osuchowski MF , Ayala A , Bahrami S , Bauer M , Boros M , Cavaillon JM , et al . Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal mod-eling in sepsis . Shock . 2018 ; 50 ( 4 ): 377 – 80 .

Zingarelli B , Coopersmith CM , Drechsler S , Efron P , Marshall JC , Moldawer L , et al . Part I: Minimum quality threshold in preclinical sepsis studies(MQTiPSS) for study design and humane modeling endpoints . Shock . 2019 ; 51 ( 1 ): 10 – 22 .

Chen W , Brenner M , Aziz M , Chavan SS , Deutschman CS , Diamond B , et al . Buprenorphine markedly elevates a panel of surrogate markers in a murine model of sepsis . Shock . 2019 ; 52 ( 5 ): 550 – 3 .

Cotroneo TM , Hugunin KM , Shuster KA , Hwang HJ , Kakaraparthi BN , Nemzek-Hamlin JA . Effects of buprenorphine on a cecal liga-tion and puncture model in C57BL/6 mice . J Am Assoc Lab Anim Sci . 2012 ; 51 ( 3 ): 357 – 65 .

Hayer S , Vervoordeldonk MJ , Denis MC , Armaka M , Hoffmann M , Bäcklund J , et al . Smash recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal mod-els . Ann Rheum Dis . 2021 ; 80 ( 6 ): 714 – 26 .

Zhu S , Ashok M , Li J , Li W , Yang H , Wang P , et al . Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory mark-ers . Mol Med . 2009 ; 15 ( 7–8 ): 275 – 82 .

Zhu SC , Li J , Wang H . Use of open surface plasma resonance (OpenSPR) to characterize teh binding affinity of protein-protein interactions . Bio-Protoc . 2023 ; 13 ( 17 ): e4795 .

Roy A , Kucukural A , Zhang Y . I-TASSER: a unified platform for automated protein structure and function prediction . Nat Protoc . 2010 ; 5 ( 4 ): 725 – 38 .

Li W , Bao G , Chen W , Qiang X , Zhu S , Wang S , et al . Connexin 43 hemichannel as a novel mediator of sterile and infectious inflammatory diseases . Sci Rep . 2018 ; 8 ( 1 ): 166 – 18452 .

Chen W , Zhu S , Wang Y , Li J , Qiang X , Zhao X , et al . Enhanced macrophage pannexin 1 expression and hemichannel activation exacerbates lethal experimental sepsis . Sci Rep . 2019 ; 9 ( 1 ): 160 – 37232 .

Costanza B , Turtoi A , Bellahcène A , Hirano T , Peulen O , Blomme A , et al . Innovative methodology for the identification of soluble biomarkers in fresh tissues . Oncotarget . 2018 ; 9 ( 12 ): 10665 – 80 .

Heuer JG , Sharma GR , Gerlitz B , Zhang T , Bailey DL , Ding C , et al . Evalu-ation of protein C and other biomarkers as predictors of mortality in a rat cecal ligation and puncture model of sepsis . Crit Care Med . 2004 ; 32 ( 7 ): 1570 – 8 .

Li W , Ashok M , Li J , Yang H , Sama AE , Wang H . A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1 . PLoS One . 2007 ; 2 ( 11 ): e1153 .

Sakkas LI , Bogdanos DP . Infections as a cause of autoimmune rheumatic diseases . Autoimmun Highlights . 2016 ; 7 ( 1 ): 13 .

Yang H , Hreggvidsdottir HS , Palmblad K , Wang H , Ochani M , Li J , et al . A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release . Proc Natl Acad Sci U S A . 2010 ; 107 ( 26 ): 11942 – 7 .

Tang D , Kang R , Zeh HJ , Lotze MT . The multifunctional protein HMGB1: 50 years of discovery . Nat Rev Immunol . 2023 ; 23 ( 12 ): 824 – 41 .

Andersson U , Wang H , Palmblad K , Aveberger AC , Bloom O , Erlandsson-Harris H , et al . High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes . J Exp Med . 2000 ; 192 ( 4 ): 565 – 70 .

Etherington DJ , Taylor MA , Henderson B . Elevation of cathepsin L levels in the synovial lining of rabbits with antigen-induced arthritis . Br J Exp Pathol . 1988 ; 69 ( 2 ): 281 – 9 .

Jr Stone CA ., Spiller BW , Smith SA . Engineering therapeutic monoclonal antibodies . J Allergy Clin Immunol . 2024 ; 153 ( 3 ): 539 – 48 .

Al Shoyaib A , Archie SR , Karamyan VT . Intraperitoneal route of drug administration: should it be used in experimental animal studies? . Pharm Res . 2019 ; 37 ( 1 ): 12 .

Qin S , Wang H , Yuan R , Li H , Ochani M , Ochani K , et al . Role of HMGB1 in apoptosis-mediated sepsis lethality . J Exp Med . 2006 ; 203 ( 7 ): 1637 – 42 .

Wang H , Liao H , Ochani M , Justiniani M , Lin X , Yang L , et al . Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis . Nat Med . 2004 ; 10 ( 11 ): 1216 – 21 .

浏览量

Downloads

CSCD

文章被引用时，请邮件提醒。

Submit

工具集

关联资源

An ongoing search for potential targets and therapies for lethal sepsis

Therapeutic effects of anti-endotoxin antibodies and antibiotics on endotoxemia in patients with severe burns

Sepsis in burns: lessons learned, challenges remain

Cell-free DNA in sepsis: from molecular insights to clinical management

National and subnational burden and causes of anemia in China from 1990 to 2023: findings from the Global Burden of Disease Study 2023