炎症性肠病生物制剂治疗的前沿进展

更新时间:2022年08月25日阅读量:1875次下载量:517次下载手机版

作者: 李娜 1, 2, 3 叶梅 1, 2, 3

作者单位: 1. 武汉大学中南医院消化内科(武汉 430071) 2. 湖北省肠病医学临床研究中心(武汉 430071) 3. 肠病湖北省重点实验室(武汉 430071)

关键词: 炎症性肠病 生物制剂 小分子药物 治疗

DOI: 10.12173/j.issn.1004-5511.202204037

基金项目: 基金项目: 国家自然科学基金项目(81870391);武汉大学中南医院科技创新培育基金项目(ZNJC201916)

引用格式:李娜, 叶梅. 炎症性肠病生物制剂治疗的前沿进展[J]. 医学新知, 2022, 32(4): 310-320. DOI: 10.12173/j.issn.1004-5511.202204037.

Li N, Ye M. Advances in biological agents in the treatment of inflammatory bowel disease[J]. Yixue Xinzhi Zazhi, 2022, 32(4): 310-320. DOI: 10.12173/j.issn.1004-5511.202204037.[Article in Chinese]

摘要|Abstract

炎症性肠病是一种免疫相关的慢性炎症性疾病,目前难以治愈。传统治疗方法(如氨基水杨酸、糖皮质激素和免疫抑制剂)只能缓解症状,难以阻止疾病进展、改变疾病进程。生物制剂为炎症性肠病的治疗带来转机。随着研究的深入,更多新的生物制剂和小分子药物进入临床开发的各个阶段。本文对目前正在临床应用或研发的生物制剂和小分子药物的作用机制及临床试验结果进行总结,旨在了解本领域最新进展。

全文|Full-text

炎症性肠病(inflammatory bowel disease,IBD)是一组病因不明的胃肠道慢性炎症性疾病,包括克罗恩病(Crohn's disease,CD)和溃疡性结肠炎(ulcerative colitis,UC)[1],目前不可治愈,大多数患者需要长期用药诱导和维持缓解。传统治疗包括氨基水杨酸、糖皮质激素和免疫抑制剂,尽管可控制症状、促进黏膜愈合,但难以阻止疾病进展。生物制剂的问世是IBD治疗的重大突破[2]。目前,用于IBD治疗的生物制剂和小分子药物主要包括抗肿瘤坏死因子(TNF)抗体、抗整合素抗体、抗白细胞介素12/23(IL-12/IL-23)抗体、JAK抑制剂和S1P受体调节剂[3]。但由于原发性无应答、继发性失应答或对治疗不耐受等,许多患者仍需新的治疗方法。随着对IBD发病机制的深入探索,不断有新的生物制剂和小分子药物问世(图1),它们的有效性及安全性也在临床试验中得到评估[4-6]。本文旨在介绍近年来针对CD和UC开发的新型生物制剂及小分子药物,并总结相关的临床试验证据,为临床治疗和药物开发提供参考(表1)。

  • 图1 当前IBD治疗新兴靶点及其作用机制
    Figure1.Current targeted therapies for IBD and their mechanisms of action

  • 表格1 IBD治疗药物研发管线
    Table1.The pipeline of inflammatory bowel disease treatments

1 抗细胞因子类药物

1.1 TNF-α抑制剂

TNF-α是一种可溶性细胞因子,主要由单核细胞、巨噬细胞分泌,是细胞存活和死亡的关键调节因子之一,在维持肠道内环境稳定中发挥着重要作用,但在感染、炎症等病理状态下,TNF-α水平升高,从而促进肠道炎症的发展[8]。抗TNF-α药物是首类被批准用于治疗中重度UC和CD的生物制剂,它彻底改变了IBD的治疗策略,并取得了显著的临床疗效[2]。抗TNF-α药物通过中和可溶性TNF-α和膜结合性TNF-α、抑制T细胞活化和促炎细胞因子释放、诱导抗体或补体依赖性细胞毒作用以及T细胞和巨噬细胞凋亡、增强肠屏障功能、诱导调节性T细胞分化等多种途径发挥抑炎作用[9]。首个用于IBD治疗的TNF-α抑制剂是英夫利昔单抗,随后,其他TNF-α抑制剂如阿达木单抗、戈利木单抗和赛妥珠单抗被陆续批准用于IBD治疗[2]。目前,我国可获得的抗TNF-α单抗包括英夫利昔单抗和阿达木单抗,且均已进入国家医保目录,同时一些英夫利昔单抗和阿达木单抗的生物仿制药也被批准用于临床,大大降低了患者的经济负担[10]。然而,临床应用的抗TNF-α制剂均通过静脉或皮下给药,输注或注射反应及全身副作用风险较高,且增加了注射成本[5]。因此,肠道选择性的口服抗TNF-α药物成为药物研发的新方向。

1.1.1 皮下注射CT-P13

CT-P13是一种经静脉注射用于IBD治疗的英夫利昔单抗生物仿制药[11]。目前CT-P13皮下剂型(CT-P13 SC)已研发成功并进入临床试验阶段。在一项多中心、随机、开放标签Ⅰ期研究中,对131名活动性IBD患者进行2周的CT-P13静脉诱导治疗后,以1∶1的比例随机分配至皮下治疗组或静脉治疗组,第22周对两组的药物谷浓度进行非劣效性检验,结果显示CT-P13皮下不劣于静脉,在第30周的临床应答率、临床缓解率和黏膜愈合率、不良事件发生率方面,两组均无显著差异[12]。目前,评估CT-P13皮下剂型在UC和CD患者中疗效的Ⅲ期研究正在进行中。

1.1.2 口服TNF抑制剂

AVX-470是一种从TNF免疫的奶牛牛初乳中分离获得的多克隆抗体,可有效降低葡聚糖硫酸钠(dextran sulfate sodium,DSS)或2,4,6-三硝基苯磺酸(2, 4, 6-trinitrobenzenesulfonic acid,TNBS)诱导的结肠炎小鼠的疾病严重程度[13]。在活动性UC患者中进行的Ⅰ期临床研究发现,不同剂量的AVX-470治疗组(0.2 g/d vs. 1.6 g/d vs. 3.5 g/d)中,25.9%的患者在第4周临床应答,而安慰剂组为11.1%,其中3.5 g/d治疗组的疗效最好[14]。

OPRX-106是一种BY-2植物细胞表达的重组抗TNF融合蛋白口服制剂。动物实验显示,OPRX-106可在组织学水平缓解TNBS诱导的结肠炎小鼠肠道炎症[15]。一项纳入25例轻中度UC患者的Ⅱa期临床研究发现,第8周的临床应答率和临床缓解率分别为67%和28%[16]。

V565也是一种新型抗TNF-α抗体口服肠溶片剂,在DSS诱导的结肠炎小鼠和IBD患者的肠道释放并定位于肠黏膜[17-18]。但针对CD患者的一项安慰剂对照Ⅱ期临床研究显示,治疗组第6周临床应答率(35.4%)低于安慰剂组(37.2%)[19]。

目前尚缺乏大规模的临床研究来进一步明确上述口服抗TNF制剂在IBD治疗中的有效性及安全性。

1.2 IL-23抑制剂

IL-23是一种促炎细胞因子,由p19和p40两个亚基组成,在Th17的分化和成熟中发挥重要作用,而活化的Th17细胞可产生多种促炎细胞因子(包括TNF-α、IL-6、IL-22等)从而导致炎症的发生发展[20]。全基因组关联分析确定了IL-23R为IBD易感基因[21]。这些证据表明IL-23可作为IBD潜在治疗靶点之一。

1.2.1 Risankizumab

Risankizumab(RZB,BI-655066)是一种针对IL-23 p19的人源化IgG1单克隆抗体(mAb)。一项纳入中重度CD患者的试验显示,治疗组第12周临床缓解率显著高于安慰剂组[22]。随后研究发现,53%患者在第26周达到临床缓解,71%患者在第52周可维持临床缓解,且未出现严重不良反应,RZB在CD患者中的长期安全性得到了验证[23-24]。针对中重度CD患者的Ⅲ期临床研究显示,600 mg治疗组第12周临床生物标志物应答率、内镜缓解率和内镜下无溃疡率显著高于安慰剂组;随后为期52周的维持性研究发现,治疗组临床生物标志物应答率、内镜应答率、内镜应答维持率、内镜缓解率、内镜缓解维持率、内镜下无溃疡率和深度缓解率均显著高于安慰剂组[25-27]。

1.2.2 Brazikumab

Brazikumab(MEDI 2070)是一种人源性IgG1 mAb,可选择性结合IL-23 p19亚基。与RZB类似,Brazikumab在诱导期是通过静脉给药,维持期则是皮下注射[28]。一项针对抗TNF失败的中重度CD患者研究发现,诱导阶段700 mg治疗组第8周临床应答率显著高于安慰剂组(49.2% vs. 26.7%);第8周开始,两组患者均接受每4周一次皮下注射210 mg治疗,第24周原治疗组与安慰剂组分别有53.8%、57.7%的患者获得临床应答[28]。

1.2.3 Mirikizumab

Mirikizumab(miri,LY3074828)也是一种选择性结合IL-23 p19亚基的IgG4变异抗体 mAb。一项针对中重度活动期UC患者的Ⅱ期临床试验显示,Mirikizumab可有效诱导临床应答和临床缓解[29],在第52周,65.8%患者临床应答、26.3%临床缓解,且未发现新的安全事件[30]。而针对中重度UC患者的Ⅲ期研究显示,治疗组12周临床缓解率显著高于安慰剂组,两组不良反应发生率相似[31]。在CD患者中进行的Ⅱ期临床试验也显示,第12周600 mg和1 000 mg治疗组内镜缓解率显著高于安慰剂组,而不良反应发生率两组相似[32];第52周两组内镜应答率分别为58.5%和58.7%[33]。目前,针对UC和CD的Ⅲ期临床研究以及针对儿童IBD患者的临床研究正在进行中。

1.2.4 Guselkumab

Guselkumab(GUS)是一种抗IL-23 p19的IgG1 mAb,已被批准用于治疗斑块型银屑病[4]。一项针对中重度CD患者的Ⅱ期临床研究显示,不同剂量治疗组(200 mg、600 mg、1 200 mg,第0、4、8周静脉注射)第12周的临床应答率、实验室应答率、内镜应答率均显著高于安慰剂组,且各组之间不良事件发生率相似[34];第48周,各治疗组临床缓解率分别为63.9%、73.0%和57.4%,临床应答率分别为73.8%、84.1%和67.2%,安全性方面与现有结果一致[35]。针对中重度UC患者的一项Ⅱb期研究显示,静脉注射200 mg和400 mg治疗组第12周临床应答率分别为61.4%和60.7%,安慰剂组仅为27.6%,差异有统计学意义(P<0.001),治疗组发生不良反应的比例并未高于安慰剂组[36]。

1.3 IL-12/IL-23抑制剂

构成IL-23的p40亚基与p35亚基共同构成IL-12,IL-12可通过上调转录因子STAT4和T-bet,介导初始T细胞分化成为辅助性T细胞1(Th1)并产生IFN-γ,进而介导炎症的发生发展[37]。因此,阻断IL-12/IL-23可同时阻断Th1、Th17在IBD发病机制中发挥重要作用的细胞通路[38]。

乌司奴单抗(ustekinumab,UST)是靶向p40的IL-12/IL-23抑制剂,目前已被批准用于中重度UC和CD患者的治疗,在我国获批CD适应证,并已进入国家医保目录[39-40]。针对中重度CD患者的Ⅲ期研究以及最近发表的研究均显示出UST对CD患者有效且安全[39, 41]。一项真实世界研究显示,难治性CD患者UST谷浓度在1.12 μg/mL以上与16或24周内镜缓解有关[42]。而一项中重度UC患者的Ⅲ期研究结果显示,UST可诱导并维持缓解,且严重不良事件发生率与安慰剂组相似[40]。一项意大利的多中心真实世界研究显示,在68例接受UST治疗的中重度UC患者中,分别有31%和50%的患者在第24周和第52周达到无激素临床缓解,84%和82%的患者达到临床应答,仅有1例发生不良反应[43]。

2 JAK通路抑制剂

活化的炎症细胞释放细胞因子,与特定受体结合发挥促炎促细胞分化等效应。其中,Ⅰ型和Ⅱ型细胞因子受体被认为在肠道内白细胞活化和细胞炎症中发挥关键作用[44]。细胞因子与Ⅰ型和Ⅱ型细胞因子受体结合可激活细胞内关键激酶——Janus激酶(JAKs)。JAKs特异性结合到细胞因子受体信号链的胞内结构域,并催化配体诱导自身磷酸化,进而催化受体胞内段上的酪氨酸残基磷酸化,形成STAT结合位点而诱导靶基因转录[45]。JAK-STAT通路是介导各种细胞外细胞因子反应的中枢,参与多种人类疾病的发病,如类风湿关节炎(rheumatoid arthritis,RA)、自身免疫性皮肤病、IBD等。因此,JAKs已成为治疗IBD的一个潜在靶点。

2.1 托法替布

托法替布(Tofacitinib)是一种口服非选择性JAK抑制剂,在临床前研究中,托法替布在多种炎症模型中表现出剂量依赖性的治疗效果,已在多国获批用于活动性RA的治疗[46]。针对中重度UC患者进行的多中心Ⅲ期临床试验发现,治疗组(10 mg,bid)第8周临床缓解率显著高于安慰剂组,治疗组(5 mg,bid;10 mg,bid)第52周时分别有34.3%和40.6%的患者达到临床缓解,而安慰剂组为11.1% (P<0.001);安全性分析显示,治疗组感染率和严重感染率高于安慰剂组[47]。2018年5月美国FDA批准托法替布用于传统治疗或应用TNF抑制剂失败的中重度UC患者的诱导和维持治疗。然而,此后研究表明,与TNF抑制剂相比,接受托法替布治疗与RA患者主要不良心血管事件、恶性肿瘤、静脉血栓栓塞和病死率的风险增加相关,因此,FDA已将托法替布的使用限制在抗TNF治疗失败的UC患者中[48]。在针对中重度活动性CD患者的Ⅱ期临床试验中,托法替布并未显示出显著的临床疗效。

2.2 Filgotinib

Filgotinib是一种每日口服一次的选择性JAK1抑制剂,在欧洲和日本被批准用于治疗RA[49-50],目前正在被开发用于UC和CD的治疗。一项在中重度UC患者中进行的多中心、随机、双盲、安慰剂对照的Ⅱb/Ⅲ期临床试验显示,200 mg治疗组第10周临床缓解率较安慰剂组高,而100 mg治疗组与安慰剂组相比无差异;为期58周的维持期中,各治疗组临床缓解率均高于安慰剂组;该项研究中大多数不良事件为轻或中度,各组间不良事件发生率基本一致[51]。针对78名累及小肠的CD患者开展的Ⅱ期临床试验未发现Filgotinib的明确疗效[52],一项评估Filgotinib治疗合并肛瘘CD患者的有效性及安全性Ⅱ期研究显示,200 mg治疗组第24周复合瘘管应答率、复合瘘管愈合率均高于安慰剂组,但差异不具有统计学意义[53]。

2.3 Upadacitinib

Upadacitinib(ABT-494)是另一种对JAK1具有高度选择性的口服JAK抑制剂,已被FDA批准用于中重度RA的治疗[4]。最近完成的针对中重度UC的Ⅲ期临床试验报告显示,治疗组(45 mg/d)第8周临床缓解率(33.5%)、内镜应答率(44%)、内镜缓解率(18.2%)、组织学改善率(62.2%)、黏膜愈合率(13.5%)均显著高于安慰剂组;治疗组、安慰剂组分别有3.2%和4.5%的患者发生严重不良反应;在为期8周的延长诱导治疗结束后,48.3%的患者临床应答[54]。另一项研究中,30 mg治疗组第52周临床应答率(66.75%)、临床缓解率(33.3%)、内镜改善率(37.5%)均高于15 mg治疗组,且在第52周的肠外表现改善率显著高于安慰剂组[55-56]。

3 S1P受体调节剂

鞘氨醇-1-磷酸(S1P)是由鞘氨醇激酶(SphKs)磷酸化鞘氨醇产生的具有生物活性的鞘脂代谢产物,SphKs通过与5种特异性G蛋白偶联受体S1P1-S1P5相互作用,调节血管发育、心脏功能、淋巴细胞运输和炎症等生理过程[57]。S1P与S1P受体结合,引导淋巴细胞从胸腺和次级淋巴结以S1P梯度依赖的方式迁移至淋巴结,导致循环血中淋巴细胞增加;同时S1P抑制T细胞从炎症组织中流出,促进T细胞在炎症组织聚集以及炎症反应的发生发展[58]。

3.1 Ozanimod

Ozanimod是一种新型的口服选择性S1P1和S1P5受体调节剂,通过直接与S1P受体结合发挥作用,是目前唯一一种被FDA批准用于成年中重度活动性UC患者诱导缓解和维持缓解的S1P受体调节剂[3]。一项在中重度UC患者中进行的Ⅲ期临床试验表明,无论是在诱导治疗或在维持治疗中,0.92 mg/d治疗组的临床缓解率及临床应答率均显著高于安慰剂组[59-60]。一项纳入69例中重度CD患者的多中心、非对照观察性Ⅱ期试验显示,Ozanimod治疗后第12周内镜、组织学和临床活动性均有所改善[61]。

3.2 Etrasimod

Etrasimod(APD334)是一种选择性S1P1/S1P4/S1P5受体调节剂,在实验性自身免疫性脑脊髓炎小鼠模型和大鼠胶原诱导性关节炎模型中发挥抗炎效应[62]。在T细胞过继转移性结肠炎小鼠模型中,Etrasimod(3 mg·kg-1·d-1)可显著抑制体重减轻和结肠炎症[63]。针对中重度UC患者为期12周的Ⅱ期临床试验显示,与安慰剂组相比,2 mg治疗组在内镜改善(43.2% vs. 16.3%)、组织学改善(31.7% vs. 10.2%)、组织学缓解(19.5% vs. 6.1%)和黏膜愈合(19.5% vs. 4.1%)方面均有显著疗效,而1 mg治疗组疗效并不显著[64]。随后的一项开放标签研究显示64%的患者临床应答,33%的患者临床缓解,43%的患者内镜改善[65]。

4 整合素相关抑制剂

α4β1和α4β7整合素与内皮细胞表面的黏附分子,即血管细胞黏附分子-1(VCAM-1)和黏膜地址素细胞黏附分子-1(MAdCAM-1)之间相互作用,诱导炎症细胞从血液循环迁移至胃肠道,这是IBD患者肠道慢性炎症启动和持续的重要机制之一[66]。因此,通过阻断α4β1和α4β7整合素与其配体的相互作用来抑制淋巴细胞转运已成为治疗IBD的重要途径。那他珠单抗是一种人源性IgG4 mAb,靶向淋巴细胞表面的α4β1和α4β7的α4亚基,是首个获准用于治疗CD的此类药物,但由于发生进行性多灶性白质脑病的风险较高,其使用受到限制[67-69]。维得利珠单抗(Vedolizumab,VDZ)是一种针对α4β7的肠道选择性人源性IgG1 mAb,可阻止白细胞迁移到肠道,其静脉剂型在2014年已被批准用于UC和CD的治疗[5, 69-70]。

4.1 维得利珠单抗

一项中重度UC患者的双盲、双模拟Ⅲ期临床试验显示,患者在第0周和第2周接受静脉注射VDZ 300 mg治疗,在第6周有临床应答的患者进入维持治疗,并随机分配至每2周皮下注射108 mg组(SC组)、每8周静脉注射300 mg组(Ⅳ组)或安慰剂组。在第52周,SC组、Ⅳ组和安慰剂组的临床缓解率分别为46.2%、42.6%和14.3%;与安慰剂组相比,SC组临床缓解率、内镜改善率更高,临床应答更持久;SC组注射部位局部反应的发生率(10.4%)高于另外两组,但大多数比较轻微,并未导致治疗中断,皮下注射和静脉注射组安全性曲线相似[71]。此研究表明,在静脉注射诱导缓解后,皮下注射作为UC的维持治疗是有效的且耐受性良好。如果患者希望避免长期静脉注射治疗,皮下剂型将提供替代选择。

4.2 Etrolizumab

Etrolizumab(rhuMAb β7, anti-β7, PRO145223)是一种皮下注射的人源性抗整合素单克隆抗体,可选择性结合α4β7和αEβ7整合素的β7亚基,以阻止免疫细胞进入肠道[72]。在未使用过抗TNF治疗的中重度UC患者中进行的Ⅲ期临床试验发现,每4周接受一次105 mg皮下注射治疗,60%的患者在第10周出现临床应答,将其纳入随后进行的为期62周的双盲、安慰剂对照维持期研究中,治疗组(105 mg,每4周一次)在第62周的临床缓解率(29.6%)与安慰剂组(20.6%)相比差异无统计学意义(P=0.19)[73]。纳入未接受过抗TNF治疗患者的Ⅲ期研究发现,Etrolizumab的治疗效果并不优于阿达木单抗[74],与英夫利昔单抗的差异不显著[75]。既往接受过抗TNF治疗的中重度UC患者Ⅲ期研究显示,Etrolizumab治疗组在第14周的临床缓解率显著高于安慰剂组(18.5% vs. 6.3%),但第66周的差异并不显著(24.1% vs. 20.2%)[75]。针对中重度CD患者的Ⅱ期临床试验显示,与安慰剂组相比,210 mg(0、2、4、8、12周)和105 mg治疗组(每4周一次)的患者在第14周达到临床缓解、内镜应答的比例更高[76]。在儿童IBD患者中开展的Ⅰ期临床试验表明,不论是以1.5 mg/kg(每4周一次)给药,还是以3.0 mg/kg(每8周一次)给药,均可达到完全或接近完全的β7受体占位,与成人血药浓度的关系类似,约60%的患者达到临床应答且耐受性良好[77]。

4.3 Ontamalimab

Ontamalimab(PF-00547659,SHP647)是一种皮下注射的人源性IgG2 mAb,可竞争性结合MAdCAM-1,减少淋巴细胞向肠道的迁移。由于MAdCAM-1主要表达于肠黏膜及其相关淋巴组织的血管内皮细胞表面,所以Ontamalimab具有较高的肠道选择性[78]。对UC患者的Ⅲ期临床试验发现,75 mg治疗组12周缓解率显著高于25 mg治疗组、安慰剂组,而25 mg治疗组与安慰剂组未见差异[79]。另一项研究结果显示,25 mg和75 mg治疗组52周缓解率均高于其各自的安慰剂组[80]。一项针对中重度CD患者的Ⅱ期临床试验结果发现,不论在第8周还是第12周,不同剂量治疗组(22.5 mg,75 mg,225 mg)和安慰剂组之间的活动指数CDAI应答率相比无统计学意义[81]。随后的开放标签、单臂Ⅱ期临床试验发现,接受75 mg维持治疗的患者不良反应发生率为92.9%,19.8%因不良反应退出研究,29.9%发生严重不良反应[82]。

5 结语

随着IBD发病机制的研究不断深入,越来越多的新靶点和治疗药物陆续开发,致力于优化IBD治疗方案,为患者提供更多的治疗选择。但这些药物能否真正改善IBD患者的治疗结局仍未可知,仍需多中心、大样本的随机对照试验以及头对头试验进行进一步评估。由于环境因素、遗传基因多态性等方面的差异,在欧美国家取得成效的药物是否对我国患者同样有效也需进一步探讨。总之,未来应重视药物在我国患者人群中的真实世界应用情况,加强治疗监测,做到个体化、精准化治疗,力争患者收益最大化。

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《医学新知》由国家新闻出版总署批准,中国农工民主党湖北省委主管,武汉大学中南医院和中国农工民主党湖北省委医药卫生工作委员会主办的综合性医学学术期刊,国内外公开发行。

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