抗體偶聯藥物的肝毒性研究進展

摘要 惡性腫瘤是全球威脅生命的重要疾病。近年來，腫瘤的精準治療逐漸興起，靶向藥物、免疫檢查點抑制劑以及新興的抗體偶聯藥物（ADC）取得巨大成功。ADC藥物發展迅猛，全球獲批上市者已多達15種，其肝毒性也逐漸引起重視，且已出現致死性肝毒性事件的報道。本文旨在梳理上述上市ADC藥物，對目前臨床試驗報道的ADC藥物肝臟相關不良事件和肝毒性表現進行總結，并搜集整理肝毒性機制相關研究，旨在幫助臨床醫師了解和掌握ADC藥物的肝毒性特征，及時識別具有潛在肝毒性風險的患者并采取有效管理措施，從而減少和避免嚴重不良事件發生。

關鍵詞 抗體偶聯藥物； 肝毒性； 惡性腫瘤； 臨床試驗

Hepatotoxicity of Antibody?drug Conjugates DONG Yinuo， ZHI Yang， LI Xiaoyun， LEI Xiaohong， TANG Jieting， MAO Yimin. Division of Gastroenterology and Hepatology， Renji Hospital， School of Medicine， Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; Shanghai Research Center for Diagnosis and Treatment of Fatty Liver Disease， Shanghai （200001）

Correspondence to： MAO Yimin， maoym11968@163.com

Abstract Cancer has become a major life?threatening disease globally. In recent years， precision therapy for cancer has gradually emerged， and significant success has been achieved with targeted therapies， immune checkpoint inhibitors， and the newly emerging antibody?drug conjugates （ADC）. The development of ADC has been rapid， with up to 15 ADC drugs currently approved worldwide. However， the hepatotoxicity of ADC has gained increasing attention， with reports of fatal hepatotoxic events. In this article， we briefly reviewed the ADC approved globally， summarized the liver?related adverse events and hepatotoxic manifestations reported in current clinical trials of ADC， and compiled research on possible hepatotoxicity mechanisms. Our aim is to assist clinicians in understanding and managing the hepatotoxicity characteristics of ADC， enabling timely identification of patients at risk of hepatotoxicity and implementing effective measures to manage these risks， thus reducing and preventing serious adverse events.

Key words Antibody?Drug Conjugates; Hepatotoxicity; Cancer; Clinical Trials

惡性腫瘤每年在全球造成近1 000萬人死亡，是威脅生命的重要疾病[1]。近年來，腫瘤的精準治療逐漸興起，腫瘤治療藥物歷經演變后，靶向藥物、免疫檢查點抑制劑以及新興的抗體偶聯藥物（antibody?drug conjugate， ADC）取得了巨大的成功。ADC藥物系由靶向特異性抗原的單克隆抗體、細胞毒性有效載荷（小分子毒素）和連接子組成，自2000年美國食品和藥品管理局（FDA）批準首個ADC藥物gemtuzumab ozogamicin（GO; Mylotarg?， Pfizer Inc.）用于成人急性髓系白血病的治療以來[2]，ADC藥物發展迅猛。

隨著ADC藥物在腫瘤治療中的廣泛應用，其肝毒性也逐漸引起重視，且已出現致死性肝毒性事件的報道[3?4]。本文就現有的15種全球獲批上市ADC藥物引起的肝毒性進行總結分析，以期幫助臨床醫師了解和掌握ADC藥物的肝毒性特征，及時識別具有潛在肝毒性風險的患者并采取有效管理措施，從而減少和避免嚴重不良事件發生。……