作为肝胆系统一种高度致命的腺癌，胆管癌（CCA）患者的预后仍然非常糟糕，5年存活率低于10%，这是因为缺乏有效的治疗方法。胆管癌的靶向治疗有限，手术切除胆管癌常常存在高复发率的问题。本研究报道了胆管癌的两种有效的靶向治疗方法。我们首先在一系列人类胆管癌细胞系中，采用定量和无偏的流式细胞术筛选肿瘤相关抗原，鉴定出细胞间粘附分子-1（ICAM1）作为胆管癌的治疗靶点。在确定ICAM1具有高效介导抗体内化的能力后，我们通过可切割的化学连接物，将ICAM1抗体与不同的细胞毒性药物载体结合，构建了两种ICAM1抗体药物联合物（ADCs）。与一线化疗药物吉西他滨进行体外和体内比较，两种ICAM1 ADC在抑制肿瘤方面表现出了卓越的疗效。总之，本研究为开发胆管癌的有前景的靶向治疗药物候选剂铺平了道路。© 2023年，自然出版集团（英国）。

As a highly lethal adenocarcinoma of the hepatobiliary system, outcomes for cholangiocarcinoma (CCA) patients remain prominently poor with a 5-year survival of <10% due to the lack of effective treatment modalities. Targeted therapeutics for CCA are limited and surgical resection of CCA frequently suffers from a high recurrence rate. Here we report two effective targeted therapeutics in this preclinical study for CCA. We first performed a quantitative and unbiased screening of cancer-related antigens using comparative flow cytometry in a panel of human CCA cell lines, and identified intercellular adhesion molecule-1 (ICAM1) as a therapeutic target for CCA. After determining that ICAM1 has the ability to efficiently mediate antibody internalization, we constructed two ICAM1 antibody-drug conjugates (ADCs) by conjugating ICAM1 antibodies to different cytotoxic payloads through cleavable chemical linkers. The efficacies of two ICAM1 ADCs have been evaluated in comparison with the first-line chemodrug Gemcitabine in vitro and in vivo, and ICAM1 antibodies coupled with warhead DX-8951 derivative (DXd) or monomethyl auristatin E (MMAE) elicit a potent and consistent tumor attenuation. In summary, this study paves the road for developing a promising targeted therapeutic candidate for clinical treatment of CCA.© 2023. Nature Publishing Group UK.