2016年EASL ARC-520摘要3

StephenW

FRI-144
PREDICTING HBSAG CLEARANCE RESPONSES DURING ARC-520
RNA INTERFERENCE (RNAI) THERAPY BASED ON HBSAG EPITOPE
PROFILE ANALYSIS
R. Walsh1, R. Hammond1, L. Yuen1, J. Deerain1, B. Given2, T. Schluep2,
M.-F. Yuen3, H.L.-Y. Chan4, C.-L. Lai3, J. Hamilton2, J.Y. Lau5, C. Ferrari6,
R.G. Gish7, S.A. Locarnini1. 1Victorian Infectious Diseases Reference
Laboratory, Melbourne, Australia; 2Arrowhead Research Corporation,
Pasadena, California, United States; 3The University of Hong Kong; 4The
Chinese University of Hong Kong; 5Hong Kong Polytechnic University,
Hong Kong SAR, China; 6University of Parma, Parma, Italy; 7Hepatitis B
Foundation, Doylestown, United States
E-mail: [email protected]
Background and Aims: Functional cure in chronic hepatitis B
requires HBV DNA negativity, HBsAg loss and anti-HBs
seroconversion. ARC-520 RNAi drug therapy targets cccDNA derived
mRNA, including the full-length HBsAg transcript. Using a 19plex
anti-HBs panel to map HBsAg epitopes, we have developed a
predictive algorithm of an HBsAg clearance profile in patients
undergoing HBsAg loss during tenofovir therapy, defined as
reduced recognition at loop 1 and loop 2 HBsAg “a” determinant
epitopes. Complimentary to this, we have developed assays to detect
co-existing complexed anti-HBs (with HBsAg), and analysed the ARC-
520 cohorts with the aim of evaluating the impact of RNAi therapy on
HBsAg loss, the identification of an HBsAg clearance profile and the
development of co-existing anti-HBs.
Methods: Analysis of HBsAg clearance profiles and concomitant anti-
HBs was performed for 40 ARC-520 study HBeAg-negative (n = 32)
and HBeAg-positive (n = 8) patients (under code: 30 ARC-520; 10
placebo), from pre-treatment to day 85, and then compared to the
quantitative HBsAg responses. All were entecavir suppressed prior to
(mean 5 years) and during ARC-520 therapy.
Results: ARC-520 therapy resulted in a dose response maximum
decline in HBsAg of 0.3 log IU/mL observed at 1 mg/kg vs 0.5 log at
4 mg/kg in the HBeAg-negative patients (n = 24), and 0.7 log at 4 mg/
kg in HBeAg-positive (n = 6) patients. Analysis of the treated group
identified that an HBsAg clearance profile preceded and/or coincided
with HBsAg decline. A significant association between HBsAg
clearance profile development and ARC-520 treatment emerged at
week1 (11/30, p = 0.038), and strengthened at week2 (12/30, p-value
0.019) and week3 (16/30, p = 0.003). A late HBsAg response at week6
was associated with development of an HBsAg clearance profile (14/
30, p = 0.007). Clearance profiles were not observed in the placebo
group. Complexed anti-HBs development coincided with HBsAg
decline and HBsAg clearance profile detection.
Conclusions: Development of the HBsAg clearance profile was
predictive of HBsAg decline due to ARC-520 therapy, with an
increasing significant association from week1-3 coinciding with or
preceding the HBsAg decline, and the detection of complexed anti-HBs,
reflective of recovery of the anti-HBs response. Further longitudinal and
multiple dose studies will assess the magnitude and persistence of
HBsAg loss on ARC-520 therapy, in the context of the predictive potential of HBsAg clearance profile and anti-HBs response.

StephenW

FRI-144
预测HBsAg清除响应ARC-520期间
RNA干扰（RNAi）疗法BASED对HBsAg表位
PROFILE分析
R. Walsh1，R. Hammond1，L. Yuen1，J. Deerain1，B. Given2，T. Schluep2，
M.-F. Yuen3，H.L.-Y. Chan4，C.-L. Lai3，J. Hamilton2，J.Y. Lau5，C Ferrari6，
R.G. Gish7，S.A Locarnini 1.1维多利亚传染病参考
实验室，墨尔本，澳大利亚; 2Arrowhead研究公司，
加利福尼亚州帕萨迪纳，美国;香港3The大学; 4The
香港中国大学; 5Hong香港理工大学，
香港特区，中国;帕尔马，帕尔马，意大利6University; 7乙肝
基金会Doylestown的，美国
电子信箱：[email protected]
背景和目的：慢性乙型肝炎功能治愈
需要HBV DNA阴性，HBsAg消失和抗-HBs
血清学转换。 ARC-520的RNAi药物治疗的目标派生的cccDNA
基因，其中包括全长HBsAg的成绩单。使用19plex
抗HBs面板地图的HBsAg抗原决定簇，我们已经开发出一种
患者的HBsAg清除轮廓的预测算法
替诺福韦治疗期间经历HBsAg消失，其定义为
减少在环1和环2的HBsAg“a”决定识别
表位。免费此，我们已经开发测定以检测
共存络合抗HBs（用HBsAg）和分析ARC-
520同伙与评估RNA干扰治疗的影响的目的
HBsAg消失，一个HBsAg清除轮廓和鉴定
共存抗-HBs发展。
方法：HBsAg清除型材和随之而来的反分析
HBs抗体进行40 ARC-520的研究HBeAg阴性表现（N = 32）
和HBeAg阳性（8例）的患者（下码：30 ARC-520 10
安慰剂），从治疗前85天，然后相对于
乙肝表面抗原定量的反应。所有的人都恩替卡韦之前抑制
（平均5年）和ARC-520治疗期间。
结果：ARC-520治疗导致剂量响应最大
0.3 HBsAg的下降登录IU / mL的1毫克观察/千克VS 0.5在日志
4毫克/公斤，HBeAg阴性患者（n = 24），和0.7日志在4毫克/
公斤HBeAg阳性（6例）的患者。治疗组的分析
确定了一个HBsAg清除轮廓前面和/或正值
用HBsAg下降。乙肝表面抗原之间的关联显著
间隙轮廓开发和ARC-520处理出现在
week1（11/30，p值= 0.038），并且在week2（12/30，p值加强
0.019）和译员更加（16/30，P = 0.003）。在week6逾期乙肝表面抗原反应
在与HBsAg清除轮廓的发展（14相关的/
30，p值= 0.007）。间隙轮廓均未安慰剂观察到的
组。复合抗-HBs发展正好与乙肝表面抗原
下降，HBsAg清除轮廓检测。
结论：HBsAg清除轮廓的发展是
HBsAg的下降，由于ARC-520治疗，与预测
从week1-3重合增加与显著协会或
乙肝表面抗原的下降，复合抗-HBs的检测前，
反射的抗-HBs应答的恢复。进一步的纵向和
多剂量研究将评估的幅度和持续性
HBsAg消失上的ARC-520治疗，在HBsAg的间隙轮廓和抗-HBs应答的预测潜在的上下文。

StephenW

Disan
先前发布
上述摘要.

上述摘要难以理解。我请求Medhelp的Studyforhelp发表评论。以下是他的解释。谢谢Studyforhelp.

StephenW

Studyforhope:

The key to understand what they mean by "hbsag clearance profile" comes from the 19 monoclonal antibody assay that locarnini has been eble to develop.

The protruding loops of the hbsag outside of  the surface antigen particle membrane contain apprantly several different bcell epitopes . The monoclonals are specific for these separate epitopes and bind selectively to them.

These binding sites have various strength and dissociation constants. Some bind very forcefully,  others rather weak.

When probing a sample of a patient with no hidden hbsag antibody, a certain binding profile to each of the monoclonal will be obtained and can be expressed quantitatively.

Once the natural spontaneous polyclonal antibodies Start developing in a patient, they will tend to complex and remove and block the hbsag epitopes  to an increasing extent.

But the binding will lead preferentially to complexing of the strong sticky epitopes since antibody clones develop best against stronger binding epitopes.

Thus the reactivity profile of locarninis monoclonal panel will change, since the best binders are reduced first, showing diminished reactivity.

Quantification of this phenomenon will lead to an "altered hbsag profile", and indicate the  formation of endogenous antibody even in the absence of measurable surface antibody.

Simultaneously you expect the appearance of hbsag specific immuncomplexes, which they seem to have a method for measuring.

One reason that the antibodies, even the invisible ones, seem to appear only after lowering of the hbsag level is likely that the critical cd4 tcell helper response to drive bcell development can only start below that level. Above that level the massive amount of antigen leads to tcell tolerance also on the cd4 level,  abrogating bcell stimulation and antibody development. That's probably what Carlo ferrari was contributing in this context.

For arrowhead this study is meant to encourage the view that something in the direction of antibody development is starting under IRNA treatment, proven both by suspect monoclonal profile change as well as by the appearance of specific immune complexes. This is good for the stock. ..a step in the right direction, so to speak, with the hope of further intensification after multiple rounds. ..

StephenW

Studyforhope:

关键要理解他们所说的“HBsAg清除个人资料”来自19单克隆抗体测定的locarnini已经eble发展。
的HBsAg的表面抗原颗粒膜的外侧的突出环包含apprantly几种不同的B细胞表位。的单克隆抗体是特异于这些单独的表位和选择性地结合到它们。
这些结合位点具有各种强度和离解常数。结合一些非常有力的，其他比较薄弱。
当探测，没有隐藏-HBsAg抗体的患者的样品，对各单克隆的一定结合个人资料将被获得，并且可以定量地表示。
一旦自然自发多克隆抗体开始在患者中发展，它们将趋向于复杂，并删除与阻断的HBsAg抗原决定簇的增加的程度。
但结合将优先导致粘性强表位的配合，因为抗体克隆发展最好的对抗更强的结合表位。
从而locarninis单克隆面板的反应轮廓会发生变化，因为最好粘合剂首先减少，显示出减少的反应性。
这种现象量化将导致“改变的HBsAg信息”，并指示内源性抗体的甚至在没有可测量的表面抗体的形成。
同时你期望的HBsAg具体immuncomplexes，他们似乎对测量方法的外观。
原因之一是，抗体，即使是不可见的那些，似乎只有在HBsAg的水平的下降后出现是可能的临界CD4 T细胞辅助细胞应答来驱动B细胞发展只能启动低于这一水平。在该水平之上抗原的巨量导致同样T细胞对CD4水平宽容，废除B细胞刺激和抗体的发展。这可能是什么卡罗法拉利在这一背景下作出贡献。
为箭头本研究的目的是鼓励认为东西抗体发展的方向是根据IRNA治疗开始，两者均由疑单克隆轮廓变化以及由特异性免疫复合物的外观证实。这是良好的股票。 ..A步在正确的方向，可以这么说，有进一步激化的多轮后的希望。 ..

齐欢畅2

什么时候的消息，没看懂。

齐欢畅2

一、会议名称：2016年欧洲肝脏研究协会(EASL)：国际肝脏大会
二、活动地点：西班牙-巴塞罗那
三、会议时间：2016年4月13日 -2016年4月17日
四、参会报名：
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                         包含国会材料：（2016年2月3日前）838.50欧元/人；（2016年2月4日-3月9日）911.10欧元/人；（2016年3月10日后）938.70欧元/人。
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11666169

谁给解读下

齐欢畅2

主要就是可以降低表抗，但具体没有说多少。