AASLD2018[438]结合TG1050的研究性治疗， 一种HBV特异性免疫治疗

StephenW

438
Investigational Treatment Combining TG1050,
an HBV-Specific Immunotherapeutic, with
Direct Acting Antivirals or Immunomodulators,
Improves Sustained Antiviral Effects and
Immune Responses in HBV-Persistent Mice
Roland Kratzer1, Karine Lélu1, Alexei Evlachev1, Marie
Baldazza1, Doris Schmitt2, Nathalie Silvestre2, Benoit
Sansas3, Antoine F Carpentier4,5,6, Claire Banissi4,6, Abigail
Liebow Liebow7, Stuart Milstein7, Laura Sepp-Lorenzino7,
Yunfu Chen8, Qingyun Ren8, Li Jing8, Genevieve Inchauspe1
and Perrine Martin1, (1)Dept. of Infectious Diseases,
Lyon, France, Transgene SA, (2)Smart Virus Lab, Illkirch
Graffenstaden, France, Transgene SA, (3)Smart Data Lab,
Illkirch Graffenstaden, France, Transgene SA, (4)Laboratoire
De Recherches Biochirurgicales, Université Paris Descartes,
Hôpital Européen Georges Pompidou, Paris, France, (5)
Université Paris Diderot, Sorbonne Paris Cité, Paris, France,
(6)Hôpital Saint-Louis, Assistance Publique-Hôpitaux De
Paris (AP-HP), Paris, France, (7)Alnylam Pharmaceuticals,
Cambridge, MA 02142, USA, (8)The State Key Laboratory of
Anti-Infection Drug Development, HEC Pharma Group, Dong
Guan 523871, China
Background: Therapies for chronic hepatitis B virus (HBV)
infection rarely achieve functional cure. Novel direct-acting
antivirals (DAA), immunomodulators (IM) and therapeutic
vaccines are under development. Combination therapies
appear to be required to achieve functional cure. We explored
4 combination therapies to potentiate or complete the activity
of TG1050, a therapeutic vaccine based on an adenovirus
encoding a polyprotein comprising HBV Pol, Core and
domains of HBsAg, in phase 1 clinical trial (NCT02428400).
We associated TG1050 with an IM (TLR9 agonist CpG-
28, Oligovax or myeloid derived suppressor cell inhibitor
sildenafil) to boost or restore host immunity or with a DAA
(siRNA-HBV or capsid inhibitor HEC73045, HEC Pharma)
to lower HBsAg burdens, hence lower host tolerance, or
inhibit capsid formation. Methods: Combinations associating
TG1050 and DAA or IM were assessed in AAV-HBV infected
mice. Viral parameters in blood (HBV-DNA by qPCR and
HBsAg by ELISA), anti-HBc and anti-HBs antibodies (ELISA)
were monitored. HBV-RNA (by RT-qPCR) and liver function
(ALT) were studied in selected experiments. T cell immunity
was analyzed at the end of experiments (IFNγ-ELISpot
assays or IFNγ/IL-2/TNFa ICS). Results: TG1050+CpG-28
combination led to a sustained 1.6 log decrease in viremia
and 1.3 log decrease in circulating HBsAg levels 84 days post
1st treatment (means). Polymerase-specific T cell responses
in mice treated by TG1050+CpG-28 were correlated with
viral parameter decreases and moderate ALT elevation.
TG1050+sildenafil combination led to strong and sustained
off-treatment antiviral effects (73 days post 1st treatment): 0.8
log decrease in viremia, 1.1 log decrease in circulating HBsAg
levels and 0.7 log decrease in HBV-RNA. No beneficial effect
was seen, neither on maximum HBV DNA decrease (mean 2.7
log) nor on maximum HBsAg decrease (mean 2.9 log) when
TG1050 was combined with siRNA-HBV but the rebound of
circulating HBsAg and HBV DNA levels after therapy arrest
was significantly delayed. TG1050+HEC73045 combination
had no additive effect on viral parameters but increased
significantly anti-HBc antibodies induced by TG1050.
No combination effect was observed when TG1050 was
associated with NUC. Conclusion: Under our experimental
conditions we obtained proof-of-concept data in favor of
beneficial antiviral effects when TG1050 is combined with
three compounds: siRNA, MDSC inhibitor or TLR9 agonist,
paving the way to clinical investigation.

StephenW

38
结合TG1050的研究性治疗，
一种HBV特异性免疫治疗药物
直接作用抗病毒药或免疫调节剂，
改善持续的抗病毒效果和
HBV持续性小鼠的免疫应答
Roland Kratzer1，KarineLélu1，Alexei Evlachev1，Marie
Baldazza1，Doris Schmitt2，Nathalie Silvestre2，Benoit
Sansas3，Antoine F Carpentier4,5,6，Claire Banissi4,6，Abigail
Liebow Liebow7，Stuart Milstein7，Laura Sepp-Lorenzino7，
陈云富8，任庆云8，李静8，Genevieve Inchauspe1
和Perrine Martin1，（1）部门。传染病，
法国里昂，Transgene SA，（2）智能病毒实验室，Illkirch
Graffenstaden，法国，Transgene SA，（3）智能数据实验室，
Illkirch Graffenstaden，法国，Transgene SA，（4）Laboratoire
De Recherches Biochirurgicales，UniversitéParisDescartes，
HôpitalEuropéenGeorgesPompidou，法国巴黎，（5）
UniversitéParisDiderot，SorbonneParisCité，巴黎，法国，
（6）HôpitalSaint-Louis，Assistance Publique-HôpitauxDe
巴黎（AP-HP），法国巴黎，（7）Alnylam Pharmaceuticals，
剑桥，MA 02142，美国，（8）国家重点实验室
抗癌药物开发，HEC Pharma Group，Dong
Guan 523871，中国
背景：慢性乙型肝炎病毒（HBV）治疗
感染很少实现功能性治愈。新颖的直接行动
抗病毒药物（DAA），免疫调节剂（IM）和治疗药物
疫苗正在开发中。联合疗法
似乎需要实现功能性治愈。我们探索过
4种组合疗法可以增强或完成活动
TG1050，一种基于腺病毒的治疗性疫苗
编码包含HBV Pol，Core和的多蛋白
HBsAg的结构域，在1期临床试验中（NCT02428400）。
我们将TG1050与IM（TLR9激动剂CpG-）联系起来
28，Oligovax或髓源抑制细胞抑制剂
西地那非）用于增强或恢复宿主免疫力或使用DAA
（siRNA-HBV或衣壳抑制剂HEC73045，HEC Pharma）
降低HBsAg负担，从而降低宿主耐受性，或
抑制衣壳形成。方法：组合关联
在AAV-HBV感染中评估TG1050和DAA或IM
老鼠。血液中的病毒参数（qPCR和HBV-DNA）
通过ELISA检测HBsAg），抗HBc和抗HBs抗体（ELISA）
受到监控。 HBV-RNA（通过RT-qPCR）和肝功能
（ALT）在选定的实验中进行了研究。 T细胞免疫
在实验结束时分析（IFNγ-ELISpot
测定或IFNγ/ IL-2 /TNFαICS）。结果：TG1050 + CpG-28
组合导致病毒血症持续减少1.6个百分点
并且84天后循环HBsAg水平下降1.3个百分点
第一次治疗（手段）。聚合酶特异性T细胞反应
用TG1050 + CpG-28处理的小鼠与其相关
病毒参数减少和中度ALT升高。
TG1050 +西地那非的组合导致强劲和持久
治疗后抗病毒作用（第1次治疗后73天）：0.8
病毒血症日志减少，循环HBsAg减少1.1 log
HBV-RNA水平和0.7 log降低。没有好处
可见，最大HBV DNA下降（平均值为2.7）
log）也没有最大HBsAg减少（平均2.9 log）时
TG1050与siRNA-HBV结合但反弹
治疗停止后循环HBsAg和HBV DNA水平
被大大推迟了。 TG1050 + HEC73045组合
对病毒参数没有累加效应但增加
由TG1050诱导的显着抗-HBc抗体。
当TG1050为时没有观察到组合效应
与NUC相关联。结论：在我们的实验中
条件我们获得了有利于概念的概念证明数据
TG1050联合使用时有益的抗病毒作用
三种化合物：siRNA，MDSC抑制剂或TLR9激动剂，
为临床研究铺平了道路。

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Conclusion: Under our experimental
conditions we obtained proof-of-concept data in favor of
beneficial antiviral effects when TG1050 is combined with
three compounds: siRNA, MDSC inhibitor or TLR9 agonist,
paving the way to clinical investigation.

newchinabok

这个药还是蛮期待的

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