赖氨酰氧化酶样2（LOXL2）的选择性靶向抑制肝纤维化进展并

StephenW

Gut doi:10.1136/gutjnl-2016-312473

    Hepatology

    Original article

Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal
Open Access

    Naoki Ikenaga1, Zhen-Wei Peng1,2, Kahini A Vaid1, Susan B Liu1, Shuhei Yoshida1, Deanna Y Sverdlov1, Amanda Mikels-Vigdal3, Victoria Smith3, Detlef Schuppan1,4, Yury V Popov1

    1Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
    2Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    3Gilead Sciences, Foster City, California, USA
    4Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Mainz, Germany

    Correspondence to Dr Yury V Popov, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02115, USA; ypopov{at}bidmc.harvard.edu

    Received 21 June 2016
    Revised 7 December 2016
    Accepted 18 December 2016
    Published Online First 10 January 2017

Abstract

Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice.

Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2−/− and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro.

Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2−/− and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment.

Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

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StephenW

Gut doi：10.1136 / gutjnl-2016-312473

    肝脏病学

    原文

赖氨酰氧化酶样2（LOXL2）的选择性靶向抑制肝纤维化进展并加速其逆转
开放获取

    Naoki Ikenaga1，Zhen-Wei Peng1,2，Kahini A Vaid1，Susan B Liu1，Shuhei Yoshida1，Deanna Y Sverdlov1，Amanda Mikels-Vigdal3，Victoria Smith3，Detlef Schuppan1,4，Yury V Popov1

    消化内科和肝脏病学，Beth以色列女执事医疗中心，哈佛医学院，波士顿，马萨诸塞，美国
    中山大学第一附属医院肿瘤科，广州，中国
    3Gilead Sciences，Foster City，California，USA
    4德国美因茨大学医学中心免疫治疗的免疫学和免疫研究中心

    通讯作者：Yury V Popov博士，消化内科和肝病学部，Beth Israel Deaconess Medical Center，Harvard Medical School，330 Brookline Avenue，Boston，MA 02115，USA; ypopov {at} bidmc.harvard.edu

    收到2016年6月21日
    修订于2016年12月7日
    接受2016年12月18日
    在线发布首先10月2017年1月10日

抽象

背景/目的我们研究了赖氨酰氧化酶样2（LOXL2）在胶原交联和肝祖细胞（HPC）分化中的作用，以及LOXL2阻断性单克隆抗体对小鼠肝纤维化进展/逆转的治疗功效。

方法在硫代乙酰胺（TAA）诱导的纤维化进展期间或在恢复期间施用抗LOXL2抗体，对照抗甲酰基氧化酶抗体或安慰剂。在BALB / c.Mdr2 - / - 和3,5-二乙氧基羰基-1,4-二氢喹啉（DDC）给药小鼠中测试了在胆汁纤维化中的治疗功效。在组织学和生物化学方面评估胶原交联，纤维化进展和逆转。体外在原发性EpCAM（+）肝细胞中研究HPC分化。

结果LOXL2实际上没有健康，但在纤维化肝中强烈诱导，主要定位在纤维化隔膜内。延迟的抗LOXL2治疗活性TAA纤维化显着减少胶原交联和桥接纤维化的组织学迹象，形态测定胶原沉积减少53％。在已确立的TAA纤维化中，LOXL2抑制促进纤维化逆转，具有增强的纤维化隔膜的分裂和变薄，以及在4周恢复时胶原面积减少45％。在Mdr2 - / - 和DDC诱导的胆管纤维化模型中，抗LOXL2抗体类似地实现显着的抗纤维化功效并抑制了管状反应，而肝细胞复制增加。阻断LOXL2在体外对原发性EpCAM（+）HPC行为具有深远的直接作用，促进它们向肝细胞分化，同时抑制导管细胞谱系定型。

结论LOXL2介导胶原交联和肝纤维化过程中的纤维化基质稳定，并独立促进纤维化的HPC分化。通过阻断这两个收敛的纤维化途径，治疗性LOXL2抑制减弱实质性和胆管纤维化并促进纤维化逆转。

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MP4

Simtuzumab (GS-6624)


吉利德寄予厚望的单抗药simtuzumab近日在胰腺癌II期研究中失败，对其刚组建的肿瘤学部门而言是一个不小的打击。

simtuzumab是一种单克隆抗体，靶向阻断赖氨酰氧化酶样蛋白-2 (LOXL2) 。LOXL2是一种蛋白酶，可通过促进胶原纤维的交联修饰胞外基质，被认为在肿瘤恶化和纤维化中发挥重要作用。在胰腺癌II期研究中，与安慰剂相比，simtuzumab未能改善晚期胰腺癌患者的无进展生存期（PFS），未能达到研究的主要终点。

不过，该项研究失败，并不意味着宣判simtuzumab死刑，因为吉利德目前正在开展5个II期研究，胰腺癌研究仅是其中一项，另4个研究分别调查simtuzumab治疗结直肠癌、骨髓纤维化、严重肺脏和肝脏纤维化疾病的潜力。分析师认为，后2个适应症（肺纤维化和肝纤维化）可能是simtuzumab的最佳赌注。

肺部疾病方面，吉利德正在调查simtuzumab治疗特发性肺间质纤维化（IPF），该病在美国尚无获批的药物。