패혈증 및 류마티스 관절염을 위한 표적 치료제로서 해로운 항체 에피톱의 재활용

  • role: Contribute equally, First author同等贡献者, 第一作者
  • Affiliation:

    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

Wei-Qiang Chen12,  
  • role: Contribute equally同等贡献者
  • Affiliation:

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Li Lou1,  
  • role: Contribute equally同等贡献者
  • Affiliation:

    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

Xiao-Ling Qiang12,  
  • role: Contribute equally同等贡献者
  • Affiliation:

    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

Cassie Shu Zhu12,  
  • Affiliation:

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Jian-Hua Li1,  
  • Affiliation:

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Shu-Jin Chen1,  
  • Affiliation:

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Brian Xiong1,  
  • Affiliation:

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Huan Yang1,  
  • Affiliation:

    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

Ping Wang12,  
  • Affiliation:

    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

Kevin J. Tracey12,  
  • role: Corresponding author通信作者
  • Affiliation:

    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

  • Email:hwang@northwell.edu
  • Introduction:* Hai-Chao Wang hwang@northwell.edu
Hai-Chao Wang12*

추상적인

배경: 패혈증과 류마티스 관절염(RA)은 별개의 상태이지만 기전적으로 관련된 질환으로, 주로 조절되지 않은 염증 반응에 의해 유발됩니다. 본 연구에서는 해로운 항-테트라넥틴(TN) 항체(mAb9)의 에피톱이 예상치 못한 치료 잠재력을 가질 수 있다는 직관에 반하는 가설을 탐구했습니다. 방법: mAb9의 에피톱을 TN의 보호 기능에 중요한 영역인 P2(잔기 55–70)로 매핑함으로써 표적 치료제로서 수용성 유도체인 P2-1을 개발했습니다. 이후 패혈증(맹장 결찰 및 천공) 및 관절염(콜라겐 항체 유도 관절염) 동물 모델을 사용하여 P2, P2-1 및 프로카텝신 L(pCTS-L) 중화 항체의 치료 효과를 패혈증 생존율, 관절염 중증도, 통증 민감도, 관절 조직 조직학 평가를 통해 살펴보았습니다. 동시에 표면 플라스몬 공명(SPR) 분석 및 계산 모델링을 활용하여 P2-1과 고이동성 그룹 박스 1(HMGB1) 간의 상호작용을 조사했습니다. 마지막으로 P2-1이 HMGB1에 의해 유도된 pCTS-L 및 기타 사이토카인, 케모카인의 분비에 미치는 영향을 1차 인간 말초 혈액 단핵 세포(PBMC)를 이용해 규명했습니다. 결과: P2-1은 패혈증 모델에서 생존율을 유의하게 향상시키고 전신 염증을 감소시켰으며, RA 모델에서는 질병 발병 후 치료 투여에도 불구하고 관절염 중증도 및 통증 민감도를 완화시켰습니다. 기전적으로 P2-1은 HMGB1에 높은 친화력을 보였으며, HMGB1에 의해 유도된 카텝신 L(Ctsl) mRNA 상향 조절 및 pCTS-L 분비를 인간 면역 세포에서 선택적으로 억제했으며, 다른 HMGB1 유도 사이토카인 및 케모카인에는 영향을 주지 않았습니다. 우리는 또한 중화 항체가 강력한 항관절염 효과를 나타내며 관절 염증, 통증 및 구조적 손상을 감소시킨다는 것을 입증함으로써 pCTS-L을 치료 표적으로서 검증했습니다. 결론: 우리의 연구 결과는 해로운 항체 작용의 통찰을 HMGB1-pCTS-L 축을 위한 표적 치료제로 전환하는 패러다임을 전환하는 약물 발견 전략을 제시합니다. 이 접근법은 강력한 치료제로서 P2-1을 제공할 뿐만 아니라 pCTS-L을 패혈증 및 RA와 같은 염증성 질환에서 중요한 매개체로 확립합니다.

키워드

고이동성 그룹 박스 1(HMGB1);프로카텝신 L;테트라넥틴;패혈증;류마티스 관절염(RA);항체;모방 펩타이드;에피톱;선천 면역 세포

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