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Article(id=1240710433791865154, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.10.02, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1701100800000, receivedDateStr=2023-11-28, revisedDate=null, revisedDateStr=null, acceptedDate=1723392000000, acceptedDateStr=2024-08-12, onlineDate=1773738018701, onlineDateStr=2026-03-17, pubDate=1729785600000, pubDateStr=2024-10-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773738018701, onlineIssueDateStr=2026-03-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773738018701, creator=13701087609, updateTime=1773738018701, updator=13701087609, issue=Issue{id=1240710432898478399, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='10', pageStart='721', pageEnd='800', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773738018488, creator=13701087609, updateTime=1773738214158, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240711253669237259, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240711253669237260, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=728, endPage=735, ext={EN=ArticleExt(id=1240710434014163271, articleId=1240710433791865154, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Progress in novel drugs development of chronic hepatitis B, columnId=1207314219599499390, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Despite the existence of preventive vaccines, hepatitis B virus infection remains a global health issue.In the past several years, significant progress has been made in the research and development of drugs for the treatment of chronic hepatitis B (CHB) , with the development of new targets and the adoption of new drug forms. On the basis of introducing the concept of functional cure of CHB, the paper elucidated the therapeutic targets of CHB and reviewed the important progress in developing antiviral drugs and immunotherapy drugs. The synergistic combination of these drugs with different mechanisms of action might be the key strategy and direction to achieve clinical cure of CHB.

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尽管存在预防性疫苗，但乙型肝炎病毒感染仍然是一个全球性健康问题。过去几年，慢性乙型肝炎（CHB）治疗药物研发取得了重大进展，发展了新的靶点，采用了新的药物形式。本文在介绍CHB功能性治愈概念的基础上，阐明了CHB的治疗靶点，综述在抗病毒药物和免疫治疗药物两个领域新药研发取得的重要进展，不同作用机制药物的协同联合可能是实现CHB临床治愈的关键策略和研究方向。

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张记
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朱校宇，男，本科在读，主要从事多肽疫苗的研究，E-mail:

张记，男，副研究员，博士，主要从事治疗性疫苗与多肽药物的研究，E-mail:

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张记，男，副研究员，博士，主要从事治疗性疫苗与多肽药物的研究，E-mail:

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Vaccines （Basel）,2022, 10（12）: 2087., articleTitle=Action mechanisms and scientific rationale of using nasal vaccine （HeberNasvac） for the treatment of chronic hepatitis B, refAbstract=null), Reference(id=1240719597582734046, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=null, pmid=null, pmcid=null, year=2021, volume=3, issue=6, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[36], rfOrder=37, authorNames=MA H, LIM TH, LEERAPUN A, journalName=JHEP Rep, refType=null, unstructuredReference=MA H, LIM TH, LEERAPUN A, et al. Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study[J]. JHEP Rep, 2021, 3（6）:100361., articleTitle=Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study, refAbstract=null), Reference(id=1240719597675008737, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=null, pmid=null, pmcid=null, year=2019, volume=71, issue=5, pageStart=900, pageEnd=907, url=null, language=null, rfNumber=[37], rfOrder=38, authorNames=GANE E, VERDON DJ, BROOKS AE, journalName=J Hepatol, refType=null, unstructuredReference=GANE E, VERDON DJ, BROOKS AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study[J]. J Hepatol, 2019,71（5）: 900-907., articleTitle=Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study, refAbstract=null), Reference(id=1240719597788254948, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=10.1097/HEP.0000000000001006, pmid=null, pmcid=null, year=2024, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[38], rfOrder=39, authorNames=WANG GQ, QIAN JD, CUI YM, journalName=Hepatology, refType=null, unstructuredReference=WANG GQ, QIAN JD, CUI YM, et al. A randomized phase IIb study of subcutaneous PD-L1 antibody ASC22 in virally-suppressed, HBeAg negative chronic hepatitis B patients[J].Hepatology, 2024., articleTitle=A randomized phase IIb study of subcutaneous PD-L1 antibody ASC22 in virally-suppressed, HBeAg negative chronic hepatitis B patients, refAbstract=null), Reference(id=1240719597872141033, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=null, pmid=null, pmcid=null, year=2023, volume=102, issue=16, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[39], rfOrder=40, authorNames=OMER I, ABUTHIYAB N, AL-OMARI B, journalName=Medicine （Baltimore）, refType=null, unstructuredReference=OMER I, ABUTHIYAB N, AL-OMARI B, et al. Efficacy and safety of vesatolimod in chronic hepatitis B: a systematic review and meta-analysis[J]. Medicine （Baltimore）, 2023, 102（16）: e33609., articleTitle=Efficacy and safety of vesatolimod in chronic hepatitis B: a systematic review and meta-analysis, refAbstract=null), Reference(id=1240719597943444202, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=null, pmid=null, pmcid=null, year=2023, volume=23, issue=4, pageStart=496, pageEnd=507, url=null, language=null, rfNumber=[40], rfOrder=41, authorNames=YUEN MF, BALABANSKA R, COTTREEL E, journalName=Lancet Infect Dis, refType=null, unstructuredReference=YUEN MF, BALABANSKA R, COTTREEL E, et al. TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind,placebo-controlled, phase 1 trial[J]. Lancet Infect Dis, 2023, 23（4）: 496-507., articleTitle=TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind,placebo-controlled, phase 1 trial, refAbstract=null), Reference(id=1240719598065079023, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=null, pmid=null, pmcid=null, year=2021, volume=74, issue=4, pageStart=1737, pageEnd=1749, url=null, language=null, rfNumber=[41], rfOrder=42, authorNames=GANE EJ, KIM HJ, VISVANATHAN K, journalName=Hepatology, refType=null, unstructuredReference=GANE EJ, KIM HJ, VISVANATHAN K, et al. Safety,Pharmacokinetics, and pharmacodynamics of the oral TLR8 agonist selgantolimod in chronic hepatitis B[J]. Hepatology, 2021, 74（4）:1737-1749., articleTitle=Safety,Pharmacokinetics, and pharmacodynamics of the oral TLR8 agonist selgantolimod in chronic hepatitis B, refAbstract=null), Reference(id=1240719598169936627, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, doi=null, pmid=null, pmcid=null, year=2022, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[42], rfOrder=43, authorNames=BOURGEOIS S, LIM Y, GANE EJ, journalName=null, refType=null, unstructuredReference=BOURGEOIS S, LIM Y, GANE EJ, et al. IMC-I109V, a novel T cell receptor （TCR） bispecific （ENVxCD3） designed to eliminate HBV-infected hepatocytes in chronic HBV patients: initial data from a first-in-human study: proceedings of the International Liver Congress 2022, June 22-26, 2022[C]. 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PD-1：程序性死亡受体1，HBsAg：乙型肝炎病毒表面抗原，pDC细胞：浆细胞样树突状细胞，NKT细胞：自然杀伤性T细胞，NK细胞：自然杀伤细胞，IL：白细胞介素

, figureFileSmall=aFhjnHC2w4ULMnmOTqn0yw==, figureFileBig=Z7ZDEIB8U3ka0AqaQuAuzA==, tableContent=null), ArticleFig(id=1240719593044496903, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
药物分类及其靶点作用机制药物名称临床试验阶段研发单位
入胞抑制剂（靶点1）阻断HBV进入肝细胞中的受体NTCPbulevirtide（Hepcludex®）Ⅱ期完成美国Gilead
贺普拉肽（L47）Ⅱ期在研上海贺普药业
VIR-3434Ⅱ期在研美国Vir
GC1102Ⅱ期在研韩国Green Cross
siRNA药物（靶点2）干预cccDNA转录环节RG6346（RO7445482）Ⅱ期在研瑞士Roche
ARC-520Ⅱ期在研美国Arrowhead
JNJ-3989（JNJ-73763989）Ⅱb期在研美国Janssen
AB7-29-001Ⅱ期在研加拿大Arbutus
VIR-2218Ⅱ期在研美国Vir
ALG-125755Ⅰ期在研美国Aligos
反义寡核苷酸（靶点2）干预cccDNA转录环节bepirovirsen（GSK3228836）Ⅲ期在研英国GSK
RO7062931研发终止瑞士Roche
ALG-020572-401研发终止美国Aligos
衣壳装配调节剂（靶点3）干扰乙肝病毒衣壳装配GLS4Ⅲa期在研广东东阳光药业
bersacapavir（JNJ-56136379，JNJ-6379）Ⅱa期终止美国Janssen
vebicorvir（ABI-H0731）Ⅱ期终止美国Assembly
canocapavir（ZM-H1505R）Ⅱ期在研上海挚盟医药
EDP-514Ⅱ期在研美国Enanta
ABI-H3733Ⅰ期在研美国Assembly
QL-007Ⅱ期在研山东齐鲁制药
RG7907Ⅱ期在研瑞士Roche
AB-836Ⅱ期在研加拿大Arbutus
ALG-000184Ⅰ期在研美国Aligos
RO7049389Ⅰ期在研瑞士Roche
核苷酸类似物（靶点4）竞争性结合HBV聚合酶ATI-2173Ⅱa期完成美国Antios
艾米替诺福韦（HS-10234）Ⅲ期在研江苏豪森药业
核酸聚合物（靶点5）抑制HBV表面抗原分泌REP2139/REP2165Ⅰ期在研加拿大Replicor
), ArticleFig(id=1240719593115800079, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, language=CN, label=表1, caption=

进入临床试验阶段的慢性乙型肝炎抗病毒药物

, figureFileSmall=null, figureFileBig=null, tableContent=
药物分类及其靶点作用机制药物名称临床试验阶段研发单位
入胞抑制剂（靶点1）阻断HBV进入肝细胞中的受体NTCPbulevirtide（Hepcludex®）Ⅱ期完成美国Gilead
贺普拉肽（L47）Ⅱ期在研上海贺普药业
VIR-3434Ⅱ期在研美国Vir
GC1102Ⅱ期在研韩国Green Cross
siRNA药物（靶点2）干预cccDNA转录环节RG6346（RO7445482）Ⅱ期在研瑞士Roche
ARC-520Ⅱ期在研美国Arrowhead
JNJ-3989（JNJ-73763989）Ⅱb期在研美国Janssen
AB7-29-001Ⅱ期在研加拿大Arbutus
VIR-2218Ⅱ期在研美国Vir
ALG-125755Ⅰ期在研美国Aligos
反义寡核苷酸（靶点2）干预cccDNA转录环节bepirovirsen（GSK3228836）Ⅲ期在研英国GSK
RO7062931研发终止瑞士Roche
ALG-020572-401研发终止美国Aligos
衣壳装配调节剂（靶点3）干扰乙肝病毒衣壳装配GLS4Ⅲa期在研广东东阳光药业
bersacapavir（JNJ-56136379，JNJ-6379）Ⅱa期终止美国Janssen
vebicorvir（ABI-H0731）Ⅱ期终止美国Assembly
canocapavir（ZM-H1505R）Ⅱ期在研上海挚盟医药
EDP-514Ⅱ期在研美国Enanta
ABI-H3733Ⅰ期在研美国Assembly
QL-007Ⅱ期在研山东齐鲁制药
RG7907Ⅱ期在研瑞士Roche
AB-836Ⅱ期在研加拿大Arbutus
ALG-000184Ⅰ期在研美国Aligos
RO7049389Ⅰ期在研瑞士Roche
核苷酸类似物（靶点4）竞争性结合HBV聚合酶ATI-2173Ⅱa期完成美国Antios
艾米替诺福韦（HS-10234）Ⅲ期在研江苏豪森药业
核酸聚合物（靶点5）抑制HBV表面抗原分泌REP2139/REP2165Ⅰ期在研加拿大Replicor
), ArticleFig(id=1240719593195491863, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
药物分类作用机制药物名称临床试验阶段研发单位
治疗性疫苗重建或者激活机体抗HBV适应性免疫应答εPA-44Ⅲ期在研中国陆军军医大学
ABX203（HeberNasvac）Ⅲ期完成古巴基因工程和生物技术中心
GS-4774Ⅱ期完成美国Gilead
HepTcellⅡ期在研美国Altimmune
VTP-300（ChAdOx–HBV）Ⅱ期在研英国Vaccitech
BRII-179（VBI-2601）Ⅱ期在研中国腾盛博药
TG-1050（T101）Ⅱ期在研法国Transgene
VVX001Ⅱ期在研奥地利Viravax
GSK3528869AⅡ期在研英国GSK
免疫检查点抑制剂PD-1单抗纳武利尤单抗Ⅱ期在研美国BMS
PD-L1单抗恩沃利单抗（ASC22）Ⅱ期在研中国歌礼制药
固有免疫激动剂TLR7激动剂vesatolimod（GS-9620）Ⅱ期在研美国Gilead
RG7854（RO7020531）Ⅱ期在研瑞士Roche
TLR8激动剂selgantolimod（GS-9688）Ⅱ期在研美国Gilead
TCR双特异性抗体重定向特性T细胞IMC-I109VⅡ期在研英国Immunocore
), ArticleFig(id=1240719593312932385, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433791865154, language=CN, label=表2, caption=

进入临床试验阶段的慢性乙型肝炎免疫治疗药物

, figureFileSmall=null, figureFileBig=null, tableContent=
药物分类作用机制药物名称临床试验阶段研发单位
治疗性疫苗重建或者激活机体抗HBV适应性免疫应答εPA-44Ⅲ期在研中国陆军军医大学
ABX203（HeberNasvac）Ⅲ期完成古巴基因工程和生物技术中心
GS-4774Ⅱ期完成美国Gilead
HepTcellⅡ期在研美国Altimmune
VTP-300（ChAdOx–HBV）Ⅱ期在研英国Vaccitech
BRII-179（VBI-2601）Ⅱ期在研中国腾盛博药
TG-1050（T101）Ⅱ期在研法国Transgene
VVX001Ⅱ期在研奥地利Viravax
GSK3528869AⅡ期在研英国GSK
免疫检查点抑制剂PD-1单抗纳武利尤单抗Ⅱ期在研美国BMS
PD-L1单抗恩沃利单抗（ASC22）Ⅱ期在研中国歌礼制药
固有免疫激动剂TLR7激动剂vesatolimod（GS-9620）Ⅱ期在研美国Gilead
RG7854（RO7020531）Ⅱ期在研瑞士Roche
TLR8激动剂selgantolimod（GS-9688）Ⅱ期在研美国Gilead
TCR双特异性抗体重定向特性T细胞IMC-I109VⅡ期在研英国Immunocore
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慢性乙型肝炎治疗新药研发进展
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朱校宇 , 吴桂娟 , 蓝竹 , 吴玉章 , 张记
中国新药与临床杂志 | 综述 2024,43(10): 728-735
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中国新药与临床杂志 | 综述 2024, 43(10): 728-735
慢性乙型肝炎治疗新药研发进展
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朱校宇 , 吴桂娟, 蓝竹, 吴玉章, 张记
作者信息
  • 中国人民解放军陆军军医大学 全军免疫学研究所，重庆　400038

    • 朱校宇，男，本科在读，主要从事多肽疫苗的研究，E-mail:

    张记，男，副研究员，博士，主要从事治疗性疫苗与多肽药物的研究，E-mail:

通讯作者:

张记
Progress in novel drugs development of chronic hepatitis B
Xiao-yu ZHU , Gui-juan WU, Zhu LAN, Yu-zhang WU, Ji ZHANG
Affiliations
  • Institute of Immunology, PLA, Army Medical University, CHONGQING 400038, China
出版时间: 2024-10-25 doi: 10.14109/j.cnki.xyylc.2024.10.02
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摘要
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尽管存在预防性疫苗，但乙型肝炎病毒感染仍然是一个全球性健康问题。过去几年，慢性乙型肝炎（CHB）治疗药物研发取得了重大进展，发展了新的靶点，采用了新的药物形式。本文在介绍CHB功能性治愈概念的基础上，阐明了CHB的治疗靶点，综述在抗病毒药物和免疫治疗药物两个领域新药研发取得的重要进展，不同作用机制药物的协同联合可能是实现CHB临床治愈的关键策略和研究方向。

乙型肝炎病毒  /  慢性乙型肝炎  /  抗病毒药  /  免疫治疗

Despite the existence of preventive vaccines, hepatitis B virus infection remains a global health issue.In the past several years, significant progress has been made in the research and development of drugs for the treatment of chronic hepatitis B (CHB) , with the development of new targets and the adoption of new drug forms. On the basis of introducing the concept of functional cure of CHB, the paper elucidated the therapeutic targets of CHB and reviewed the important progress in developing antiviral drugs and immunotherapy drugs. The synergistic combination of these drugs with different mechanisms of action might be the key strategy and direction to achieve clinical cure of CHB.

hepatitis B virus  /  chronic hepatitis B  /  antiviral agents  /  immunotherapy
朱校宇, 吴桂娟, 蓝竹, 吴玉章, 张记. 慢性乙型肝炎治疗新药研发进展. 中国新药与临床杂志, 2024 , 43 (10) : 728 -735 . DOI: 10.14109/j.cnki.xyylc.2024.10.02
Xiao-yu ZHU, Gui-juan WU, Zhu LAN, Yu-zhang WU, Ji ZHANG. Progress in novel drugs development of chronic hepatitis B[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (10) : 728 -735 . DOI: 10.14109/j.cnki.xyylc.2024.10.02
正文
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世界卫生组织于2016年制定了2030年消除乙型肝炎病毒（hepatitis B virus，HBV）和丙型肝炎病毒（hepatitis C virus，HCV）的目标。丙型肝炎治疗药物已经取得了巨大成功，基本实现了临床治愈，但乙型肝炎的情况不容乐观。据估计，全球有2.96亿HBV慢性感染者，每年新增150万感染者[1]。慢性乙型肝炎（chronic hepatitis B, CHB）会逐步进展并恶化为肝硬化、肝衰竭及肝癌。全世界约30%肝硬化和53%肝癌归因于乙型肝炎[1]。目前，CHB临床治疗药物是干扰素（interferon）和核苷酸类似物（nucleoside analogue, NA），这两种药物可以抑制HBV DNA复制，减少肝脏炎症和纤维化，降低肝硬化、肝癌和肝脏相关死亡的风险，但其临床治疗效果距离CHB的临床治愈尚有很大距离。因此，CHB需要临床效果更好的治疗药物[2]。在此大背景下，CHB治疗药物研发相当迅速，过去几年治疗药物研发取得了重大进展，发现了新的靶点，采用了新的药物形式，涉及直接抗病毒和激发内源性免疫两个领域。目前，有几十种候选药物进入到临床试验阶段，部分药物进入Ⅲ期临床并呈现出极好的上市前景。
CHB的治疗终点和药物治疗现状
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HBV是一种嗜肝DNA病毒。成人感染HBV，通常在机体适应性免疫作用下自限自愈；而围产期感染HBV后，90%以上的宿主不能清除病毒，发展成CHB[1]。血清HBV表面抗原 （HBsAg）、HBVe抗原 （HBeAg）、HBV核心抗体（HBcAb）和HBV DNA是CHB的标志。目前，国际上追求的CHB治疗终点是功能性治愈（functional cure），即HBsAg消失，HBV DNA检测不到，丙氨酸转氨酶（ALT）水平恢复正常，伴随或不伴随HBsAg血清转化。
NA和干扰素是目前针对CHB的临床一线药物。NA药物主要包括恩替卡韦（entecavir，ETV，2005年FDA批准）、富马酸替诺福韦二吡呋酯（tenofovir disoproxil fumarate，TDF，2008年FDA批准）和富马酸丙酚替诺福韦 （tenofovir alafenamide fumarate，TAF，2016年FDA批准）等。NA药物安全有效[3]，其治疗目标是将HBV DNA降低至不可测水平，使血清转氨酶水平恢复正常，并减轻炎症和纤维化[4]。NA药物的不足之处在于其血清学转化率低和HBV DNA反弹。目前用于CHB临床治疗的干扰素包括普通干扰素（包括2a、2b和1b类型）和聚乙二醇化的长效干扰素（包括2a和2b类型）；较之NA,干扰素治疗CHB具有更高的HBeAg血清转化率和HBsAg消失发生率[5]。NA与干扰素在临床上联用是进一步提高治疗效果的重要策略，一项TDF联用干扰素试验表明，9%的患者实现HBsAg消失，显著高于单药治疗[6]。
CHB的治疗靶点
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CHB治疗新药开发有两个方向（见图1），一个方向是新型抗病毒药物，其靶向于HBV病原体结构本身；另一个方向是免疫治疗药物，其靶向于人体内源性抗病毒免疫应答。学界对于HBV生命周期（life cycle）细节和CHB发病机制的深度解析，为CHB治疗新药开发提供了新靶点。HBV生命周期研究是新型抗病毒药物开发的基础，而疾病免疫病理研究则为免疫治疗药物研发提供了理论依据。
1　抗HBV药物的靶点
HBV基因组是一个长约3.2 kb的双链松弛环状DNA（rcDNA） [1]。病毒感染肝细胞后，rcDNA易位并释放到宿主细胞核内，rcDNA转化为共价闭合环状DNA（cccDNA），cccDNA是所有病毒基因产物的转录模板。cccDNA转录的前基因组RNA（pgRNA）选择性包装成核衣壳，然后逆转录成 rcDNA；衣壳可以回收到细胞核进行cccDNA扩增和维持，或被包裹和释放（见图1）。上述HBV生命周期为抗病毒治疗提供了多个靶点[1]。HBV生命周期第一步是病毒进入细胞，这个步骤对病毒传播和维持起重要作用。感染性HBV颗粒通过其肝细胞受体钠离子-牛磺胆酸共转运蛋白（sodium taurocholate cotransporting polypeptide，NTCP）进入肝细胞，这个步骤是HBV病毒入胞抑制剂药物的靶点（抗病毒靶点1），靶向于这个靶点的药物形式有小分子抑制剂和单克隆抗体等[7]。细胞核内cccDNA降解是HBV治愈的最终目标，但学界对cccDNA降解机制知之甚少,目前尚没有合适的药物形式实现有效干预，因此，cccDNA降解只能作为一个潜在靶点。cccDNA转录为mRNA和pgRNA环节是阻断HBV病毒生命周期的靶点（抗病毒靶点2），靶向于这个靶点的主要药学策略是小干扰RNA（siRNA）药物和反义寡核苷酸（antisense oligonucleotide，ASO）药物[8]。pgRNA需要包装在核衣壳内继续其下一步生命周期，因此衣壳装配（capsid assembly）环节同样是阻断HBV生命周期的靶点（抗病毒靶点3），此靶点的干预药物主要是被称为衣壳装配调节剂（capsid assembly modulators，CAM）的小分子药物[9]。HBV子代病毒形成的逆转录环节也是阻断病毒生命周期的靶点（抗病毒靶点4），这个靶点是目前在用NA药物的设计靶点。NA药物竞争结合HBV聚合酶活性位点，从而破坏5'至3'磷酸二酯键并终止HBV DNA链延伸[10]。值得注意的是，这个靶点在病毒生命周期后期，不直接影响pgRNA转录，也不直接影响整合基因组的HBsAg表达。病毒衣壳要被HBsAg包裹后释放，因而HBsAg合成环节也是治疗靶点（抗病毒靶点5），抑制该靶点可阻断HBV亚病毒颗粒的组装和分泌，目前主要的药学策略是核酸聚合物（nuleic acid polymers，NAP） [11]。
2　CHB免疫治疗药物的靶点
HBV感染后有两种典型临床结局，一种是急性自限性地清除HBV状态；一种是病毒长期存在，疾病迁延不愈，陷入慢性化状态[12]。HBV并不直接杀死肝细胞，其感染导致CHB的主要机制是免疫应答介导的病理过程。在CHB患者中，HBV特异性T淋巴细胞的数量和功能均存在缺陷，主要是异常高水平的病毒粒子和亚病毒粒子通过抗原的持续性刺激，造成T淋巴细胞抗病毒功能降低（即T淋巴细胞耗竭）和数量减少，并伴随免疫检查点分子如程序性死亡受体1（PD-1）、细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和T细胞免疫球蛋白黏蛋白3（TIM-3）表达上调[13]。CHB患者的B淋巴细胞应答同样存在多种缺陷，提示B淋巴细胞应答也是潜在的治疗靶点[14]。此外，CHB也与先天性免疫应答受损有关，特别是Toll样受体（TLR）的下调和功能障碍。研究发现，小部分CHB患者能自发实现对HBV的免疫控制，发生HBeAg血清学转化，甚至达到HBsAg血清转化，这说明免疫力量能够实现CHB自愈。例如，一个接受了白血病骨髓移植治疗的CHB患者的HBsAg和HBV DNA被清除（即实现功能性治愈），证明过继转移抗HBV免疫应答具有治愈CHB的潜力[12]。上述研究提示，靶向于CHB患者缺陷的免疫应答环节、重建或者加强患者的内源性保护性免疫，是治疗CHB的靶点。
CHB新型抗病毒药物研发进展
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针对HBV病毒生命周期中的重要靶点，最近几年有不少药物进入临床试验阶段（见表1），部分药物展现出良好的治疗效果和安全性。
1　HBV入胞抑制剂
HBV进入肝细胞受体NTCP步骤的发现促进了HBV入胞抑制剂药物的研发。该靶点药物的基本机制是通过阻止病毒感染新的肝细胞，阻断HBV再感染，保护新生健康肝细胞。bulevirtide（Hepcludex®，myrcludex B）由美国Gilead公司研发，是一种合成多肽，来源于HBsAg大包膜蛋白的前S1结构域，通过与NTCP结合并使其失活，抑制HBV进入肝细胞[15]。Ⅱ期临床试验数据表明，bulevirtide显示出良好的HBV DNA下降率和ALT复常率，但HBsAg下降幅度有限[15]。另一个类似的入胞抑制剂是贺普拉肽（hepalatide，L47），由我国上海贺普药业研发。贺普拉肽是来自于Pre-S1的47个氨基酸合成肽，可通过与NTCP竞争性结合阻断HBV进入肝细胞[16]。目前，该药已进入Ⅱ期临床试验（NCT04426968）阶段。值得注意的是，NTCP也是丁型肝炎病毒（HDV）的入胞受体，因此，这些药物治疗HDV感染的临床试验同样在推进中。例如，Ⅲ期临床试验显示bulevirtide显著降低慢性丁型肝炎患者HDV RNA和转氨酶水平[17]。另一个阻断HBV入胞的药物策略是抗HBV前S1单克隆抗体，其通过结合亚病毒颗粒来减少循环中的HBsAg。VIR-3434抗体是由美国Vir生物技术公司研发的Fc人源化单克隆抗体，靶向于HBsAg保守抗原环[7]，正处于Ⅱ期临床试验（NCT04856085）阶段。
2　cccDNA转录抑制药物
针对cccDNA转录环节的mRNA和pgRNA靶点，目前有两类药物形式：一类是siRNA，另一类是ASO。siRNA药物可抑制来自整合HBV DNA和cccDNA的HBsAg，而对cccDNA或整合病毒DNA无直接作用。siRNA药物通常靶向于HBV的s基因片段转录物和x基因片段转录物，同时抑制多个病毒基因，敲低从cccDNA表达的所有病毒蛋白和pgRNA；siRNA通过新型结合物GalNAc靶向肝脏[18]。ASO是合成的单链寡核苷酸，与互补的HBV RNA转录物结合，形成ASO-RNA复合物，其被核糖核酸酶H切割[8]。siRNA比ASO具有更长的作用时间，因此所需给药频率较低[8]。
ARC-520是美国Arrowhead公司研发的siRNA药物，该药每月注射一次。在Ⅰ期和Ⅱ期临床试验中，该药降低HBsAg能力有限[19]。RG6346（RO7445482）由瑞士Roche公司研发，是一种GalNAc偶联的双链siRNA药物，靶向于HBV基因组s区；其随机双盲Ⅰ期临床试验数据显示，RG6346治疗可使CHB患者HBsAg水平显著持续性下降[20]。JNJ-3989（JNJ-73763989）是由美国Janssen公司研发的皮下注射siRNA药物，同时靶向于HBV基因组s区和x区，同样使用GalNAc修饰；其Ⅱa临床试验显示，JNJ-3989与NA短期联用可导致HBsAg下降[21]。近期一项多中心、随机双盲Ⅱb临床试验（REEF-1研究）数据显示，JNJ-3989联合核苷酸药物很少导致HBsAg消失，但观察到具有临床意义的HBsAg下降[22]。美国Vir公司研发的VIR-2218靶向于HBV基因组x区域，抑制所有HBV蛋白产生，临床试验显示，其能够剂量依赖性地降低CHB患者血清HBsAg[23]。
bepirovirsen （GSK3228836）是英国GSK公司与Ionis公司联合开发的一款ASO药物，靶向所有HBV RNA，包括HBV信使RNA和前基因组RNA。bepirovirsen的Ⅱb期临床试验（B-Clear）[24]显示，bepirovirsen单药治疗组10%患者、bepirovirsen与NA联合治疗组9%患者，达到了主要终点，即停药24周后HBsAg水平不可测，并且HBV DNA水平低于20 IU·mL-1；在基线HBsAg水平低且未接受NA治疗患者中，有25%达到主要终点，而在接受NA治疗患者中，有16%达到主要终点。早期临床研究发现，HBsAg水平达到最低点后，血清转氨酶水平可能升高[25]。bepirovirsen的Ⅲ期多中心、随机、双盲临床试验（NCT05630820，NCT05630807）已经启动。RO7062931是瑞士Roche公司开发的ASO药物，其在治疗后2~3周HBsAg水平出现反弹，并在第12周恢复到基线水平[26]。由于有效性不及预期，RO7062931研发管线取消。ALG-020572-401是美国Aligos公司开发的ASO药物，在其Ⅰ期临床试验中，报告有患者ALT显著升高的严重不良事件发生[27]，也已经停止研发。
3　CAM
CAM药物是口服小分子，它们通过与核心二聚体的变构结合来干扰衣壳装配，进而误导衣壳形成，并破坏pgRNA包入衣壳的过程。目前，基于该靶点的药物进入临床阶段最多，其中我国广东东阳光药业研发的GLS4已经进入临床试验Ⅲa期（CTR20213273）。Ⅱb期数据显示，GLS4只能小幅降低CHB患者的HBsAg水平（无论患者是否接受过NA治疗）[9]；值得注意的是，GLS4的Ⅲa期临床试验的主要疗效指标并非HBsAg清除，而是HBV DNA抑制。bersacapavir（JNJ-56136379，JNJ-6379）是由美国Janssen公司研发的衣壳组装调节剂药物，Ⅱa期临床试验数据[28]显示其对HBsAg和HBeAg水平影响有限，单药治疗组中观察到与耐药变异相关的病毒突破，该药将不再进行进一步研发。vebicorvir （ABI-H0731）由美国Assembly公司研发，因与其他抗病毒药物联用的试验数据没有达到预期[29]，也已经停止研发。综合来看，CAM药物的缺点是无法降低现有cccDNA水平或抑制cccDNA转录，并且对来自整合HBV基因组的HBsAg没有直接影响，造成HBV RNA和HBcAg在停药后出现反弹。其次，CAM药物可能出现病毒耐药和突破的风险。因此，虽然众多CAM药物进入临床研究，但其在CHB治愈中的作用不容乐观。
4　新一代NA
NA药物能有效抑制病毒复制，并抑制新的cccDNA分子形成，但对已建立的cccDNA库或新感染细胞cccDNA的形成影响不大。更加高效、低毒的NA药物仍在研究中。如2021年上市的艾米替诺福韦（HS-10234）由豪森公司研发，是新一代单磷酰胺单酯类的替诺福韦前药，具有更好的抗病毒效果和更低的给药剂量[10]。由美国Antios公司研发的ATI-2173是第二代活性位点聚合酶抑制剂核苷酸，该药物提高了靶向肝脏能力，减少全身暴露风险[30]，目前正处于Ⅱ期临床试验（NCT04847440）阶段。
5　HBsAg合成抑制剂
抑制HBsAg的合成产生，能抑制HBV表面抗原亚病毒颗粒的组装和释放，降低血液循环中表面抗原水平。NAP化合物正在开发为HBsAg抑制剂。NAP是两亲性硫代磷酸寡核苷酸，是一种不依赖于序列而发挥其生物学作用的寡核苷酸。REP2139/REP2165是加拿大Replicor公司研制的NAP药物。临床试验数据显示，12例初治HBeAg阳性CHB患者接受REP2139单药治疗后,有9例血清HBsAg较治疗前下降2.79~7.10 log10，其中3例患者出现HBsAg清除[11]。NAP类药物降低HBsAg的能力显著，是目前众多抗HBV新药中降低HBsAg效果最好的，REP 401研究（Ⅱ期临床试验）数据显示,REP2139联合干扰素或NA治疗组的HBsAg清除率均较高，分别为65%和55%[31]。
CHB免疫治疗药物研发进展
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CHB发病与人体免疫控制密切相关，因此通过免疫疗法提高机体对HBV的免疫控制，是理想的治疗目标。干扰素就是通过作用于机体免疫系统发挥治疗作用的，其实现HBeAg血清转化的效果显著高于NA药物，并且在部分患者中显示出了实现功能性治愈的能力。干扰素既能抑制cccDNA向pgRNA和亚基因组RNA转录，也能够导致cccDNA降解。免疫疗法可以与抗病毒药物协同作用，清除感染的肝细胞，阻断新的感染。目前，靶向于CHB患者中各个免疫靶点的药物都在积极推动中，见表2。
1　治疗性疫苗
治疗性疫苗一直是免疫治疗的首选。治疗性疫苗的目的是恢复耗竭的内源性HBV特异性CD4+ T和CD8+ T淋巴细胞以及功能失调的HBsAg特异性记忆B淋巴细胞。在过去20多年，几十种CHB治疗性疫苗进入到临床试验阶段，但多数疫苗临床效果不理想[12]。例如，完成Ⅲ期临床的治疗性乙型肝炎疫苗YIC没有达到主要终点[32]，重组蛋白疫苗GS-4774因在Ⅱ期临床试验中没有显示出降低患者HBsAg水平的能力而终止研发[33]。εPA-44是目前唯一Ⅲ期临床试验在研的治疗性疫苗，它是一个纳米颗粒多肽疫苗，该疫苗能够激活强大的T淋巴细胞应答[34]。εPA-44的Ⅱ期临床数据显示，接受6针900微克εPA-44治疗的CHB患者血清HBeAg转化率达到38.8%；εPA-44疫苗治疗效果长期性良好，没有出现治疗停止后的病毒学复发，εPA-44可能在干扰素和NA治疗无效的患者中有效[34]。该药物具有与众多药物联合使用的潜力，目前正在进行一项εPA-44与恩替卡韦胶囊序贯给药治疗CHB的多中心、随机、双盲双模拟、阳性药对照的Ⅲ期临床试验（ChiCTR2100043708）。ABX-203（HeberNasvac）是古巴研发的一种含有HBsAg和HBcAg的治疗性疫苗，用于鼻内给药，但是Ⅲ期临床试验结果并不令人满意，在降低HBV DNA水平和肝功能正常化方面未观察到显著优势，该疫苗缺少高质量的随机双盲临床试验证实其有效性和安全性[35]。BRII-179是一种基于重组蛋白质的治疗性疫苗，包含3个抗原成分（Pre-S1、Pre-S2、S）的病毒样颗粒，其Ⅰb/Ⅱa期试验显示，BRII-179在患者中诱导HBsAg特异性T淋巴细胞以及抗体免疫应答，支持对其进一步研究[36]。
2　免疫检查点抑制剂
内源性HBV特异性T淋巴细胞受到程序性死亡受体1（PD-1）等检查点限制，因此免疫检查点抑制剂药物具有治疗CHB的潜力。在肿瘤免疫治疗中获得巨大成功的纳武利尤单抗（nivolumab）能够降低CHB患者血清的HBsAg水平[37] ，但其进一步的临床试验进展缓慢。由我国歌礼制药研发的恩沃利单抗（envafolimab，ASC22）是PD-L1单抗，Ⅱb临床试验显示其联合NA可有效降低患者HBsAg水平[38]，是否展开进一步临床试验未知。
3　固有免疫激动剂
TLR是抵御入侵病原体的第一道防线，在功能上参与识别自身和非自身抗原、树突状细胞成熟以及抗原特异性适应性免疫应答启动。TLR7激动剂和TLR8激动剂参与内源性干扰素的产生及特异性适应性免疫应答调控。vesatolimod（GS-9620）是美国Gilead公司研发的一种TLR7激动剂，可增加T细胞和NK细胞应答；目前处于Ⅱ期临床试验阶段，但未观察到患者HBsAg显著下降，与其他抗病毒药物联合的抗病毒疗效尚待验证[39]。RG7854（RO7020531）是罗氏公司开发的一款TLR7激动剂，现已经完成Ⅰ期临床试验，目前正在Ⅱ期临床试验中进一步研究其与恩替卡韦联合治疗实现HBV功能性治愈的潜力[40]。selgantolimod（GS-9688）是一种TLR8激动剂，也是由美国Gilead公司研发，目前Ⅱ期临床试验在研；Ⅰb期临床结果显示，该药治疗的患者HBsAg呈现小幅但一致的下降[41]，提示其具有进一步展开联合治疗的潜力。
4　其他免疫疗法
IMC-I109V是由英国Immunocore公司研发的一种T细胞受体双特异性抗体，可重定向未耗竭的效应T淋巴细胞，消除病毒感染的肝细胞。IMC-I109V的Ⅰ期临床试验显示，CHB患者接受极低剂量IMC-I109V治疗，出现HBsAg下降及ALT升高[42]。
小结与展望
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CHB是影响人类健康的重大疾病，全世界各大科研机构和药物公司在过去10年时间开展了广泛的新药研发。很大比例的药物由于安全性问题和疗效问题倒在了研发的各个阶段。如美国Spring Bank公司研发的视黄酸诱导基因蛋白-Ⅰ（RIG-Ⅰ）激动剂inarigivir（SB9200）在Ⅱb期出现严重不良事件，终止研发；美国Gilead公司的GS-4774因Ⅱ期临床试验中未到达主要终点而停止研发。这些案例凸显了CHB治疗新药研发的难度。肝细胞cccDNA的双重来源及其较长的半衰期，解释了为什么患者经多年抗病毒治疗，cccDNA浓度也很少下降。基因编辑已被提出作为消除或永久沉默cccDNA和整合HBV DNA的手段，但其在脱靶效应和递送问题方面仍存在重大挑战。因此，实现CHB的完全治愈，甚至是功能性治愈，非常具有挑战性。CHB的功能性治愈，需要同时从抗病毒药物和免疫治疗两个层面入手。不同机制的CHB治疗药物的合理联用可能是实现CHB治愈的关键途径。
基金
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  • 国家自然科学基金(32270987)
  • 国家自然科学基金(31900672)
  • 陆军军医大学红医人才支持经费(2022-23)
文献
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doi: 10.14109/j.cnki.xyylc.2024.10.02
  • 接收时间：2023-11-28
  • 首发时间：2026-03-17
  • 出版时间：2024-10-25
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  • 收稿日期：2023-11-28
  • 录用日期：2024-08-12
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国家自然科学基金(32270987)
国家自然科学基金(31900672)
陆军军医大学红医人才支持经费(2022-23)
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    中国人民解放军陆军军医大学 全军免疫学研究所，重庆　400038

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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