A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice.
A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice.
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DOI：
10.1002/hep.28736
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发表时间：
2016-11
期刊：
影响因子：
13.5
通讯作者：
Harris, Helena Erlandsson
中科院分区：
文献类型：
--
作者：
Lundback, Peter;Lea, Jonathan D.;Sowinska, Agnieszka;Ottosson, Lars;Furst, Camilla Melin;Steen, Johanna;Aulin, Cecilia;Clarke, Joanna I.;Kipar, Anja;Klevenvall, Lena;Yang, Huan;Palmblad, Karin;Park, B. Kevin;Tracey, Kevin J.;Blom, Anna M.;Andersson, Ulf;Antoine, Daniel J.;Harris, Helena Erlandsson
对乙酰氨基酚（APAP）过量服用是临床上的主要问题。越来越多的证据强调了无菌性损伤后炎症在APAP诱导的急性肝损伤（APAP-ALI）中的致病作用，并证明了开发抗炎治疗的合理性，其疗效超出了目前唯一治疗选择N-乙酰半胱氨酸（NAC）的治疗窗。炎症介质高迁移率族蛋白1（HMGB 1）是一系列肝损伤疾病的关键调节因子，在临床和临床前APAP-ALI中升高。抗HMGB 1抗体（m2 G7）在多种炎症性疾病中具有治疗益处，抗HMGB 1多克隆抗体治疗可改善APAP-ALI模型的存活率。在此，我们开发并研究了部分人源化抗HMGB 1单克隆抗体（mAb; h2 G7）的治疗效果，并确定了其在临床前APAP-ALI中的作用机制。通过将m2 G7的可变结构域与人抗体-Fc骨架合并，将小鼠抗HMGB 1 mAb（m2 G7）部分人源化（h2 G7）。与h2 G7相比，在体外和临床前APAPAP-ALI中评估了h2 G7的效应子功能缺陷变体。h2 G7保留了与m2 G7相同的抗原特异性和相当的亲和力。与NAC相比，2G 7治疗显著减弱了APAP诱导的丙氨酸氨基转移酶和microRNA-122的血清升高，并完全消除了APAP诱导的炎症标志物（肿瘤坏死因子、单核细胞趋化蛋白1和趋化因子[C-X-C基序]配体1），具有延长的治疗功效。补体和/或Fc受体结合的去除不影响h2 G7功效。结论：这是第一份描述部分人源化HMGB 1中和抗体的生成的报告，与NAC相比，该抗体在APAP-ALI中具有经验证的治疗效果和延长的治疗窗。HMGB 1的中和作用和减轻损伤后炎症是其治疗作用的重要机制。这些结果代表了HMGB 1特异性治疗作为治疗APAP-ALI和其他炎症性疾病的临床实施的重要进展。（Hepatology 2016;64：1699 - 1710）。
Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP‐induced acute liver injury (APAP‐ALI) and justifies development of anti‐inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N‐acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP‐ALI. The anti‐HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti‐HMGB1 polyclonal antibody treatment improves survival in a model of APAP‐ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti‐HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP‐ALI. The mouse anti‐HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody‐Fc backbones. Effector function‐deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP‐ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP‐induced serum elevations of alanine aminotransferase and microRNA‐122 and completely abrogated markers of APAP‐induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C‐X‐C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1‐neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP‐ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1‐specific therapy as a means to treat APAP‐ALI and other inflammatory conditions. (Hepatology 2016;64:1699‐1710).
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影响因子：
13.5
作者：
Antoine, Daniel J.;Dear, James W.;Lewis, Philip Starkey;Platt, Vivien;Coyle, Judy;Masson, Moyra;Thanacoody, Ruben H.;Gray, Alasdair J.;Webb, David J.;Moggs, Jonathan G.;Bateman, D. Nicholas;Goldring, Christopher E.;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
25.7
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
10.6
作者：
Kang, Rui;Chen, Ruochan;Zhang, Qiuhong;Hou, Wen;Wu, Sha;Cao, Lizhi;Huang, Jin;Yu, Yan;Fan, Xue-gong;Yan, Zhengwen;Sun, Xiaofang;Wang, Haichao;Wang, Qingde;Tsung, Allan;Billiar, Timothy R.;Zeh, Herbert J., III;Lotze, Michael T.;Tang, Daolin
通讯作者：
Tang, Daolin
影响因子：
64.8
作者：
Scaffidi, P;Misteli, T;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
5.7
作者：
Antoine, Daniel James;Williams, Dominic P.;Park, B. Kevin
通讯作者：
Park, B. Kevin