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Article(id=1198196212521333471, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198196207379120715, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0083.2024.0906, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1705593600000, receivedDateStr=2024-01-19, revisedDate=null, revisedDateStr=null, acceptedDate=1712851200000, acceptedDateStr=2024-04-12, onlineDate=1763601838474, onlineDateStr=2025-11-20, pubDate=1735315200000, pubDateStr=2024-12-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763601838474, onlineIssueDateStr=2025-11-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763601838474, creator=13701087609, updateTime=1763601838474, updator=13701087609, issue=Issue{id=1198196207379120715, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='12', pageStart='1343', pageEnd='1459', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763601837248, creator=13701087609, updateTime=1763603898104, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198204851306988030, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198196207379120715, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198204851306988031, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198196207379120715, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1452, endPage=1459, ext={EN=ArticleExt(id=1198196212898820835, articleId=1198196212521333471, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress on the pathogenesis of interstitial lung disease induced by Trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Trastuzumab deruxtecan (T-DXd) is a new generation of antibody-drug conjugate targeting human epidermal growth factor receptor 2. It has strong antitumor effects and has been recommended by many authoritative guidelines at home and abroad. Drug-induced interstitial lung disease (DILD) is one of the common adverse reactions and causes of death of T-DXd and is an important factor limiting its clinical application. The pathogenesis of DILD induced by T-DXd is still unclear, and the mainstream view holds that it may be related to the non-target-dependent uptake of the drug. Glucocorticoids are an important treatment method for DILD, and other alternative drugs still lack clinical effectiveness evidence. The research progress on the pathogenesis of T-DXd induced DILD was summarized in this review, aiming to provide new ideas for the prevention and treatment of DILD.

, correspAuthors=Yan Zhang, authorNote=null, correspAuthorsNote=
E-mail:
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德曲妥珠单抗(T-DXd)是靶向人表皮生长因子受体2的新一代抗体偶联药物，抗肿瘤作用较强，已获得国内外众多指南推荐。药物相关性间质性肺病(DILD)作为T-DXd的常见不良反应及致死原因之一，是限制其临床应用的重要因素。T-DXd诱导的DILD发病机制尚不明确，主流观点认为可能与药物被非靶点依赖性摄取有关。糖皮质激素是DILD的重要治疗药物，其他替代药物尚缺乏临床有效性证据。本文综述了T-DXd诱导DILD的发病机制研究进展，旨在为DILD的防治研究提供新思路。

, correspAuthors=张妍, authorNote=null, correspAuthorsNote=
张妍，E-mail：
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林清月，主要从事肿瘤内科药物治疗相关的不良反应机制方面的研究

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林清月，主要从事肿瘤内科药物治疗相关的不良反应机制方面的研究

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林清月，主要从事肿瘤内科药物治疗相关的不良反应机制方面的研究

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T-DXd. 德曲妥珠单抗；DXd. 喜树碱合成类似物

, figureFileSmall=PoN2XdVrOci3nxtUwmGdCQ==, figureFileBig=rbUUAF+KU4BUI1VTVnaVDA==, tableContent=null), ArticleFig(id=1198318892172017964, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198196212521333471, language=EN, label=Fig.2, caption=Pathogenesis of interstitial lung disease induced by Trastuzumab deruxtecan, figureFileSmall=okZ3HMn8O2Y92bZ9Std6dQ==, figureFileBig=W3i0u5VrR0xZZss8NlQLkQ==, tableContent=null), ArticleFig(id=1198318892239126832, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198196212521333471, language=CN, label=图2, caption=德曲妥珠单抗诱导间质性肺病的发病机制

HER2. 人表皮生长因子受体2；Fc受体. 免疫球蛋白Fc部分c末端的受体；T-DXd. 德曲妥珠单抗；DXd. 喜树碱合成类似物

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靶向HER2的抗体偶联药德曲妥珠单抗诱导的间质性肺病研究进展
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林清月 , 陈伟 , 裴昕莲 , 邹维 , 张妍 *
解放军医学杂志 | 综述 2024,49(12): 1452-1459
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解放军医学杂志 | 综述 2024, 49(12): 1452-1459
靶向HER2的抗体偶联药德曲妥珠单抗诱导的间质性肺病研究进展
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林清月, 陈伟, 裴昕莲, 邹维, 张妍*
作者信息
  • 解放军联勤保障部队第900医院肿瘤科，福建福州 350025

    • 林清月，主要从事肿瘤内科药物治疗相关的不良反应机制方面的研究

通讯作者:

张妍，E-mail：
Research progress on the pathogenesis of interstitial lung disease induced by Trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2
Qing-Yue Lin, Wei Chen, Xin-Lian Pei, Wei Zou, Yan Zhang*
Affiliations
  • Department of Oncology, the 900th Hospital of Joint Logistic Support Force of Chinese PLA, Fuzhou, Fujian 350025, China
出版时间: 2024-12-28 doi: 10.11855/j.issn.0577-7402.0083.2024.0906
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摘要
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德曲妥珠单抗(T-DXd)是靶向人表皮生长因子受体2的新一代抗体偶联药物，抗肿瘤作用较强，已获得国内外众多指南推荐。药物相关性间质性肺病(DILD)作为T-DXd的常见不良反应及致死原因之一，是限制其临床应用的重要因素。T-DXd诱导的DILD发病机制尚不明确，主流观点认为可能与药物被非靶点依赖性摄取有关。糖皮质激素是DILD的重要治疗药物，其他替代药物尚缺乏临床有效性证据。本文综述了T-DXd诱导DILD的发病机制研究进展，旨在为DILD的防治研究提供新思路。

抗体偶联药物  /  德曲妥珠单抗  /  药物相关性间质性肺病  /  发病机制

Trastuzumab deruxtecan (T-DXd) is a new generation of antibody-drug conjugate targeting human epidermal growth factor receptor 2. It has strong antitumor effects and has been recommended by many authoritative guidelines at home and abroad. Drug-induced interstitial lung disease (DILD) is one of the common adverse reactions and causes of death of T-DXd and is an important factor limiting its clinical application. The pathogenesis of DILD induced by T-DXd is still unclear, and the mainstream view holds that it may be related to the non-target-dependent uptake of the drug. Glucocorticoids are an important treatment method for DILD, and other alternative drugs still lack clinical effectiveness evidence. The research progress on the pathogenesis of T-DXd induced DILD was summarized in this review, aiming to provide new ideas for the prevention and treatment of DILD.

antibody-drug conjugate  /  Trastuzumab deruxtecan  /  drug-induced interstitial lung disease  /  pathogenesis
林清月, 陈伟, 裴昕莲, 邹维, 张妍. 靶向HER2的抗体偶联药德曲妥珠单抗诱导的间质性肺病研究进展. 解放军医学杂志, 2024 , 49 (12) : 1452 -1459 . DOI: 10.11855/j.issn.0577-7402.0083.2024.0906
Qing-Yue Lin, Wei Chen, Xin-Lian Pei, Wei Zou, Yan Zhang. Research progress on the pathogenesis of interstitial lung disease induced by Trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (12) : 1452 -1459 . DOI: 10.11855/j.issn.0577-7402.0083.2024.0906
正文
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德曲妥珠单抗(Trastuzumab deruxtecan，DS-8201/T-DXd)是靶向人表皮生长因子受体2(human epidermal growth factor receptor 2，HER2)的新型抗体偶联药物(antibody-drug conjugate，ADC)，是使用酶可裂解肽基连接子将人源化的抗HER2抗体曲妥珠单抗与喜树碱类细胞毒性药物DXd结合制备而成[1]。因同时拥有单克隆抗体的特异性和小分子药物的细胞毒性，T-DXd已成为HER2基因相关肿瘤精准医学和联合治疗的重要药物，也是目前肿瘤治疗研究的热点之一。药物相关性间质性肺病(drug-induced interstitial lung disease，DILD)是指药物导致的肺间质炎症和纤维化[2]。可能诱发DILD的抗肿瘤药物种类众多，其中应用ADC类药物后的发生率为1.9%~15.8%[3]。目前，T-DXd诱发的DILD已被美国食品药品监督管理局(FDA)列入黑框警告[4]，成为限制其临床应用的重要因素。因此，探究T-DXd诱发DILD的发病机制具有重要意义。本文对T-DXd诱发的DILD的流行病学、治疗策略和发病机制研究进展进行综述，旨在为该药的临床合理应用和相关不良反应研究提供参考。
1 HER2与T-DXd
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HER2是表皮生长因子受体(epidermal growth factor receptors，EGFR)家族的一员；HER2基因突变、扩增、过表达会过度传递信号，刺激癌细胞增殖[5-6]。HER2基因的致癌潜能及其激活已在几种人类恶性肿瘤中得到较好的验证，尤其是在乳腺癌、胃癌和胃食管交界处癌中。在这些癌症中，HER2激活的主要机制是HER2基因扩增导致HER2蛋白在细胞膜上过表达。近年来，HER2的其他基因组改变也被发现可导致蛋白激活，其中HER2基因突变是最重要的形式。HER2突变通常为激活型，大多数没有HER2基因的同时扩增。在前列腺神经内分泌癌、转移性皮肤鳞状细胞癌和尿路上皮性膀胱癌中，HER2突变的发生率较高。此外，HER2突变在常见的癌症如肺癌、结直肠癌和乳腺癌中也有报道，提示HER2靶向治疗在这些癌症中也具有一定潜力。HER2突变在某些特定的组织学亚型中富集，如乳腺浸润性小叶癌和肺腺癌。近期有研究发现，在微卫星不稳定型结直肠癌中的HER2突变较微卫星稳定型更频繁[7]。
T-DXd的设计理念源于20世纪初Paul Ehrlich提出的“魔术子弹”概念，他假设某些细胞毒性药物可直接作用于细胞内的某些预期靶点，从而治愈疾病[8-9]。T-DXd在与靶标肿瘤细胞上的HER2特异性结合后被内化，连接子则在细胞内被溶酶体酶裂解，细胞毒性药物DXd得以释放，后者可结合并抑制拓扑异构酶Ⅰ-DNA复合物，导致DNA复制抑制、细胞周期阻滞和肿瘤细胞凋亡[10](图1)。由于细胞毒性药物DXd具有膜通透性，可诱导旁观者效应而增强疗效。此外，T-DXd与靶标肿瘤细胞结合后，其Fc端招募效应细胞(如自然杀伤细胞、巨噬细胞)并与其表面的Fcγ受体结合，启动抗体依赖性细胞介导的细胞毒性(antibody-dependent cell-mediated cytotoxicity，ADCC)，使免疫效应细胞分泌穿孔素和颗粒酶来诱导肿瘤细胞凋亡[11]。T-DXd还能通过调节肿瘤微环境中免疫细胞和基质细胞的相互作用，增强对肿瘤细胞的攻击能力，发挥辅助治疗的作用[12]。综上所述，T-DXd可通过多种机制发挥抗肿瘤作用，已成为HER2相关肿瘤的重要治疗手段之一。
目前，FDA已先后批准T-DXd用于多种HER2阳性实体瘤的治疗。2023年2月，基于DESTINY-Breast 03试验数据，T-DXd在我国获批上市，首个适应证为既往接受过≥一种HER2药物治疗的不可切除或转移性HER2阳性乳腺癌；2023年7月，其再次获批用于治疗既往在转移性疾病阶段接受过至少一种系统治疗，或在辅助化疗期间或完成辅助化疗之后6个月内复发的不可切除或转移性HER2低表达成人乳腺癌。这是国内首个有助于HER2低表达转移性乳腺癌患者延缓疾病进展和延长生存期的创新靶向疗法。目前正在开展的T-DXd相关临床试验正在不断拓宽其适应证。
2 T-DXd诱发DILD的研究进展
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2.1 流行病学
T-DXd在多数相关研究中呈现出一定程度的肺毒性，但其发生率与严重程度并不一致。在DESTINY-Breast 01(NCT03248492)临床试验中，接受5.4 mg/kg T-DXd治疗的184例乳腺癌中DILD发生率为15.2%，病死率2.7%，中位发生时间为193 d[13]。而在DESTINY-Lung 01(NCT03505710)研究中，91例非小细胞肺癌接受6.4 mg/kg T-DXd治疗，DILD发生率为26.4%，病死率2.2%，中位发生时间为141 d[14]。美国西奈山医学院研究人员对T-DXd单药治疗的9项Ⅰ期和Ⅱ期临床试验进行了汇总分析，发现1150例受试者中DILD发生率为15.4%，大多数为低级别反应，其中1－2级为11.9%，5级为2.2%；DILD主要发生于治疗开始后的12个月内，中位发生时间162 d；该研究经Cox回归分析确定与DILD风险增加相关的基线因素为年龄<65岁、并发肺病、既往肺部治疗史、中重度肾功能不全、T-DXd剂量>6.4 mg/kg、血氧饱和度<0.95、日本人群、确诊癌症>4年[15]。
2.2 发病机制
据报道，在给猕猴注射6.4 mg/kg T-DXd(使用放射性碳元素标记)后，24 h定量全身放射性自显影显示，除大肠内容物外，血液中放射性水平最高，其次为肺、肾、肾上腺、肝、脾，这为T-DXd诱导DILD提供了药代动力学基础[16]。根据T-DXd相关DILD发病场所的不同，可初步分为“靶向”和“脱靶”。其中，靶点依赖性与细胞表面的受体结合蛋白有关；脱靶相关机制则更为复杂，T-DXd的单克隆抗体、连接子及连接方式、细胞毒性药物各个环节都有可能导致DILD的发生。以下为T-DXd诱发DILD的几种发病机制(图2)。
2.3 靶点依赖性
从ADC的药物设计理念出发，理想的靶点应在肿瘤细胞中高表达而在正常细胞中低表达或不表达[17]；然而，包括HER2在内的几乎所有靶点蛋白在正常细胞中均有表达。HER2在肺支气管上皮存在表达，稳定的偶联技术将有效载荷带到支气管上皮细胞中，肺作为相对富血供器官，血液滞留时间长，在肺内发生的有效载荷被不良摄取较多[18]，从而造成损伤。BR-96 DOX(靶向Lewis肺癌的一种ADC)的临床发展是ADC药物存在靶点相关性毒性的重要例子。在BR-96 DOX的Ⅰ期临床试验中出现较多的不良反应为胃肠道反应，包括出血性胃炎，其主要原因可能与胃黏膜细胞上的Lewis抗原表达有关[19]。更为极端的案例是，接受ADC药物Bivatuzumab mertansine(由靶向CD44的抗人CD44v6抗体与DM1连接)治疗的患者中近80%出现皮肤毒性，甚至发生致命的表皮松懈症；免疫组化结果显示CD44v6表达于角质形成细胞和角膜及扁桃体上皮细胞[20]，考虑皮肤毒性与靶蛋白的表达有关。曲妥珠单抗作为第一个用于治疗实体瘤的人源化单克隆抗体，与ADC药物开发早期阶段使用鼠源性抗体相比，其免疫原性已明显降低，但截至目前，依旧没有可准确分析抗体免疫原性的方法[21-22]。Kanbayashi等[23]利用日本药物警戒数据库进行曲妥珠单抗导致肺损害的研究，结果显示，DILD是最多见的肺毒性表现(61.8%)，是曲妥珠单抗好发且强信号的不良事件，这与T-DXd存在一致性；同时曲妥珠单抗所致DILD发生率未呈现剂量依赖性递增的规律，提示其发病机制可能与免疫反应有关。Miettinen等[24]认为DILD的发病机制之一可能是由于EGFR由2型肺泡上皮细胞表达，可参与肺泡壁的修复，而EGFR的抑制会中断肺泡壁的恢复，从而导致肺纤维化。
从理论上推测，由靶向摄取带来的ADC药物不良反应与靶点的表达水平相关。尽管肾可大量表达HER2，但在临床应用中却鲜有证据显示HER2靶向药相关的肾毒性[25]，这似乎反驳了T-DXd诱导DILD的靶点依赖性机制。另一不支持靶点依赖性机制的证据是，同为治疗HER2晚期乳腺癌的恩美曲妥珠单抗诱发DILD的发生率仅0.5%，远低于T-DXd诱发的DILD发生率[26]，提示T-DXd所致DILD可能与单克隆抗体无关。目前关于T-DXd诱发DILD的靶点依赖性机制是否参与发病，学术界并无定论，也未见针对T-DXd的研究验证。通过分析众多的临床试验数据，大多认为靶点依赖性机制并非T-DXd诱发DILD的决定性发病机制，但尚不能完全排除其发挥一定致病作用的可能。
2.4 非靶点依赖性
2.4.1 Fc介导的非依赖性摄取
免疫球蛋白G(immunoglobulin G，IgG)作为免疫系统的一部分，通过与在免疫细胞表面表达的可结合IgG的Fc区域受体(如Fcγ受体、新生儿Fc受体、C型凝集素受体)相互作用，与不同类型的免疫细胞进行通信。这些通信可激活IgG介导的免疫效应攻击靶目标，同时也可能导致Fc介导的非靶点依赖性摄取。支持非靶点依赖性摄取理论的证据较多来自于恩美曲妥珠单抗(同为抗HER2的ADC药物)诱导血小板减少机制的探究。Uppal等[27]评估了恩美曲妥珠单抗和DM1(恩美曲妥珠单抗包含的细胞毒药物)对从正常供体分离的血小板功能的影响，发现曲妥珠单抗、恩美曲妥珠单抗和含DM1的对照ADC均被巨核细胞内化，而HER2在巨核细胞或血小板上是不表达的；该内化可通过使用抗CD32阻断FcγRⅡa之间的相互作用或使用不能结合FcγR的FcγRⅡa突变体曲妥珠单抗-DANA来抑制。肺泡巨噬细胞恰恰有高表达Fcγ受体、低表达HER2的特点[28]，因此，大胆推测Fc介导的非靶点依赖性摄取完整T-DXd或游离DXd可能是T-DXd诱发DILD发病的重要因素。
另一项支持肺泡巨噬细胞在T-DXd诱发DILD发病中有重要作用的证据是，Kumagai等[29]在成年猕猴中建立T-DXd诱发的DILD模型，免疫组化检测并未显示DXd在支气管上皮内表达，这与以往报道中人肺HER2大多表达于支气管上皮的结论[30]不相符，提示T-DXd诱导的肺毒性与肺上皮细胞通过HER2的靶摄取可能无关；同时还发现DXd主要定位于肺泡巨噬细胞，提示T-DXd被肺泡巨噬细胞非靶摄取并可能参与了发病过程，肺泡巨噬细胞或许是T-DXd诱导DILD的关键细胞；此外，组织蛋白酶B免疫组化检测结果显示，肺泡巨噬细胞的阳性染色强度最强，推测DILD的发病机制可能与肺泡巨噬细胞表达组织蛋白酶B有关。组织蛋白酶B是一种溶酶体半胱氨酸蛋白酶，被认为是裂解T-DXd连接子的酶之一，这就导致完整的T-DXd在进入肺泡巨噬细胞后可发生解偶联，释放DXd产生细胞毒性作用。研究显示，单独接受高剂量小分子DXd的猴并未出现肺部不良反应，即使DXd血浆暴露水平高于T-DXd(考虑与T-DXd中的连接结构在血浆中相对稳定有关)，但尚不排除这可能与物种差异、疾病易感性及基因变异等有关[31-32]。总之，Fc介导的非靶点依赖性摄取是目前学界较为认可的DILD发病机制之一，针对此机制开展阻断Fcγ受体的研究可能有助于确定Fcγ受体在T-DXd诱发DILD中的作用。
2.4.2 非特异性内化
在识别并附着于靶标后，ADC-抗原复合物通过抗原介导的内吞作用内化进入细胞，内化通过3种不同的途径发生：网格蛋白介导的内吞作用(细胞摄取ADC的主要途径)，小泡介导的内吞作用，以及胞饮作用。其中网格蛋白和小泡介导的内吞作用是抗原依赖性的，而胞饮作用是抗原非依赖性的[33]。Boswell等[34]发现，IgG抗体净正电荷的增加可导致血浆清除率增高，组织分布增多；等电点至少一个单位或更多的变化足以产生可测量的组织分布和药代动力学变化。这些结论也适用于ADC，支持T-DXd在体内发生电荷改变后可能影响正常细胞的非特异性内吞作用的假设。除电荷性外，另一不可忽视的影响因素是ADC的疏水性。用作T-DXd有效载荷的细胞毒性小分子药物是细胞毒性拓扑异构酶Ⅰ抑制剂，其在本质上是疏水的。DXd赋予了抗体显著的疏水性，特别是对于具有高药物抗体比(drug-to-antibody ratio，DAR)的T-DXd[35]。显著的疏水性使T-DXd可能被具有高非特异性内吞能力的正常细胞(包括肺泡巨噬细胞)迅速清除，从而导致非靶标毒性。关于ADC疏水性与药物暴露的关系，Nagai等[16]对恩美曲妥珠单抗(DAR为3.5)和T-DXd(DAR为8)的ADC药物暴露率进行比较，发现T-DXd中更稳定的连接体和有效载荷DXd更高的血浆清除率均有助于药物暴露率的提高。对非特异性内化机制的相关影响因素进行研究是改进ADC药物以减轻其全身毒性的重要途径。
2.4.3 旁观者杀伤效应
抗原阳性的靶细胞将ADC药物摄取进入细胞内，经溶酶体分解等作用后在细胞质中自由释放细胞毒性药物，而后通过靶细胞介导的毒性作用使细胞毒性药物被运转到细胞外，或在靶细胞死亡后直接释放，细胞毒性药物被抗原阴性或低表达的正常细胞吸收，进而导致细胞凋亡，被称之为“旁观者杀伤效应”[25]。一项评估T-DXd与恩美曲妥珠单抗旁观者杀伤效应的研究显示，T-DXd在共培养条件下能够同时损伤HER2阳性和HER2阴性细胞，提示T-DXd存在旁观者杀伤效应[36-37]。Suzuki等[38]在HER2异质性模型中也发现，曲妥珠单抗分布与HER2表达一致，而DXd在周围的HER2阴性区域也有分布；由于DXd在与HER2阳性肿瘤分开移植的HER2阴性肿瘤中没有分布，推测DXd在HER2阴性区域的分布要求该区域与HER2阳性区域相邻，甚至可能是异质性混合区域(即HER2阳性和HER2阴性组成的“混合肿瘤”)。
Li等[39]的体内外实验结果显示，虽然旁观者杀伤效应需要抗原阳性细胞的启动，但与靶向细胞表面抗原的表达量无关。这些结果提示T-DXd在HER2选择性分布后，对HER2阳性(无论表达程度如何)或阴性的细胞都可能产生细胞毒性。
2.4.4 连接子和(或)连接方式不稳定
ADC药物的连接子和连接方式的稳定性是药物安全性的重要影响因素。理想的连接子不应诱导ADC的聚集，并能够确保有效载荷在血液和非癌组织中仍然附着在单克隆抗体主链上，避免细胞毒性药物的过早释放。T-DXd使用的是一种可裂解四肽连接子，它将马来酸连接到曲妥珠单抗，然后通过叔丁氧羰基甘氨酰甘氨酰苯丙胺基甘氨酸(BOC-GGFG-OH)连接到甲磺酸Exatecan衍生物DXd，减少了抗体链间的二硫键。连接子本质上是一种肽，属于溶酶体蛋白酶敏感连接物；尽管该偶联技术在血浆中较稳定，但难以完全摆脱在血流中被裂解酶或难以预测的化学反应解偶联的噩运，造成细胞毒性药物脱靶释放，因而增加了全身毒性并降低了抗肿瘤的有效性[40]。已知有效载荷DXd的疏水性可影响T-DXd的物理和化学性质，过多的疏水细胞毒性分子(T-DXd拥有高DAR)与单克隆抗体结构耦合，会使T-DXd容易聚集并变得不稳定。这不仅是因为DXd的疏水性，还因为抗体二、三级结构的变化以及由此产生的构象稳定性的影响[35]。无论游离DXd以何种途径进入血液循环中，但由于有效载荷具有膜透性[41]，DXd可被动扩散进入组织细胞中，包括富血供的肺部，进而导致肺组织细胞的损伤、坏死及凋亡。
2.5 治疗策略
2.5.1 糖皮质激素
糖皮质激素是目前治疗T-DXd相关DILD的主要手段，其剂量应根据事件的严重程度(可分为无症状、中等或严重)进行调整。对于无症状病例(CTCAE 1级)，可考虑保留T-DXd；对于中重度病例(CTCAE 2级及以上)，建议永久停用T-DXd，同时使用泼尼松或等效制剂开始治疗[3,42]。需要强调的是，糖皮质激素治疗后临床症状及影像学表现改善并不能明确T-DXd诱发DILD的诊断。因为其他与T-DXd治疗无关的肺部疾病(如基础存在的间质性肺炎、放射性肺炎等)亦可对糖皮质激素治疗作出应答；患者临床症状及影像学表现改善也可能是自限性疾病(如吸入性肺炎、病毒性肺炎等)病程进入恢复期而导致的巧合事件。在无法明确诊断的情况下，T-DXd治疗过程中出现严重或进行性肺损伤且缺乏更好的替代解释时，对糖皮质激素治疗的反应可支持T-DXd诱发DILD的诊断。
2.5.2 其他治疗
当出现类固醇难治性DILD或并发症限制糖皮质激素应用时，可考虑其他药物替代治疗。肺纤维化是DILD的重要病理表现，目前批准用于治疗肺纤维化的药物有吡非尼酮和尼达尼布。吡非尼酮被证实具有抗炎和抗纤维化作用，但其确切作用机制尚不完全清楚，可能是通过JAK2/STAT3信号通路抑制肺巨噬细胞极化，从而延缓病变肺的纤维化[43]。另一种已获批准的抗纤维化药物尼达尼布为小分子酪氨酸激酶抑制剂，可通过抑制转化生长因子β(TGF-β)、纤维母细胞生长因子(FGF)、血小板衍生生长因子(PDGF)和血管内皮生长因子(VEGF)等的信号传递来限制成纤维细胞的迁移和增殖[44-45]。但抗纤维化药物的作用仅限于延缓疾病进展，并不能终止或逆转疾病。目前已报道的T-DXd诱发的DILD中，鲜有应用抗纤维化药物治疗的案例，其疗效仍有待临床验证。
一项关于类固醇难治性免疫检查点抑制剂相关性肺炎患者的全面队列研究显示，在静脉注射免疫球蛋白(intravenous immunoglobulin，IVIG)、英夫利昔单抗或两者联合应用时，患者呈现出明显不同的临床病程，其中接受IVIG治疗的患者可获得较好的疗效，而使用含英夫利昔单抗治疗方案的患者并发症发生率及病死率更高[46]。此外，Wiertz等[47]还尝试使用肺功能检测指标描述环磷酰胺治疗类固醇难治性免疫检查点抑制剂相关性肺炎的临床改善作用。现阶段对于T-DXd诱发的类固醇难治性DILD尚缺乏理想的免疫抑制治疗方案。
3 总结与展望
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目前，HER2已成为癌症治疗的重要靶点，T-DXd作为重要的抗HER2药物，正受到越来越多的关注。但T-DXd复杂的结构和药理作用以及严重的DILD不良事件，给治疗带来了诸多不确定性。T-DXd诱发DILD的发病机制尚不明确，且相关临床研究十分匮乏。基于T-DXd具有靶向性这一重要药理特性，由靶点依赖引起的DILD不良事件首先受到了学界的关注；对临床数据的分析显示，剂量限制性毒性在不良事件发生机制中可能发挥了更重要的作用，这与靶向抗原和治疗的癌症类型无关；剂量限制性毒性通常与不表达靶向抗原(即非靶点依赖)的细胞和组织相关。针对T-DXd诱发DILD的非靶点依赖发病机制，研究较多的主要有：(1)在免疫激活时由Fc介导的非依赖性摄取完整的T-DXd或游离DXd，肺泡巨噬细胞凭借高表达Fcγ受体的特性在其中发挥重要作用；(2)T-DXd拥有敏感的电荷性和显著的疏水性，导致其可能被肺泡巨噬细胞非特异性内化，从而引起非靶标毒性；(3)旁观者杀伤效应对于T-DXd是一把“双刃剑”，是其拓宽HER2阴性肿瘤适应证的利器，与此同时对正常细胞的杀伤作用也是其导致不良事件的机制之一；(4)连接子和连接方式的不稳定导致细胞毒药物DXd在血液中暴露，随血液循环到达肺组织并被动扩散进入细胞中，是导致药物治疗指数降低及全身毒性增加的重要原因。
基于上述不良事件的发生机制，已提出多种改进ADC药物的方法，部分已进入开发阶段。例如，进行抗体修饰，开发探针药物偶联物(probody drug conjugates，PDC)或针对两种抗原的双特异性抗体；改善修饰偶联技术，降低ADC的疏水性从而降低毒性；通过位点定向诱变，将有效载荷与结构域特定位置进行连锁增加稳定性；实行有效载荷结合抗体的“反向靶向”策略，将有效载荷结合抗体片段与ADC共同施用，以实现血浆中释放的有效载荷的结合、中和和清除，减少组织中与ADC毒性相关的有效载荷的暴露。ADC领域的研究焦点正在转向不良事件的发生机制，旨在减轻ADC的毒性以扩大治疗窗口，增加药物最大耐受剂量并改善临床结果。
基金
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  • 福建中医药大学科研课题临床专项课题(XB2023180)
文献
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参考文献 引证文献
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2024年第49卷第12期
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doi: 10.11855/j.issn.0577-7402.0083.2024.0906
  • 接收时间：2024-01-19
  • 首发时间：2025-11-20
  • 出版时间：2024-12-28
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  • 收稿日期：2024-01-19
  • 录用日期：2024-04-12
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Clinical Special Program of Scientific Research Project of Fujian University of Traditional Chinese Medicine(XB2023180)
福建中医药大学科研课题临床专项课题(XB2023180)
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    解放军联勤保障部队第900医院肿瘤科，福建福州 350025

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张妍，E-mail：
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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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