Immune-mediated liver injury of the cancer therapeutic antibody catumaxomab targeting EpCAM, CD3 and Fcγ receptors.
Immune-mediated liver injury of the cancer therapeutic antibody catumaxomab targeting EpCAM, CD3 and Fcγ receptors.
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DOI：
10.18632/oncotarget.8574
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Dittrich C
中科院分区：
文献类型：
--
作者：
Borlak J;Länger F;Spanel R;Schöndorfer G;Dittrich C
免疫治疗性Catumaxomab针对EpCAM阳性癌症，并被批准用于腹膜癌病的治疗。为了评估静脉应用的安全性，启动了一项1期临床试验。使用Catumaxomab治疗EpCAM阳性肿瘤患者导致剂量依赖性肝炎，表现为血清丙氨酸和天冬氨酸氨基转移酶、胆红素、γGT显著升高，以及急性时相C反应蛋白和细胞因子IL 6和IL 8的诱导。第一个接受10μg Catumaxomab的患者发生了致命的急性肝功能衰竭，导致研究终止。免疫病理显示Catumaxomab通过其Fc片段与FcγR阳性的枯否细胞结合，刺激C反应蛋白、趋化因子和细胞因子的释放。在活化的肝巨噬细胞上观察到的CD3+T细胞边集加剧了T细胞介导的细胞毒作用。值得注意的是，Kupffer/T细胞对肝细胞的联合反应并不要求肝细胞为EpCAM阳性。Catumaxomab的非靶向活性包括T细胞介导的颗粒酶B细胞死亡途径的裂解以及肝窦巨噬细胞与T细胞诱导的溶细胞性肝炎的分子相互作用。虽然胆管周围有密集排列的淋巴细胞，但很少有淋巴细胞渗入胆管，提示肝内胆汁淤积是高胆红素血症的原因。最后，一名患者在最后一次注射Catumaxomab六周后死于癌症，观察到了记忆T细胞编程的证据。总之，我们的研究举例说明了分子靶向治疗的非靶点肝毒性，并强调了免疫治疗性抗体临床开发的复杂性。
The immunotherapeutic catumaxomab targets EpCAM positive cancers and is approved for the treatment of peritoneal carcinomatosis. To assess the safety of intravenous applications a phase 1 clinical trial was initiated. Treatment of EpCAM positive tumor patients with catumaxomab caused dose dependent hepatitis as evidenced by significant elevations in serum alanine- and aspartate aminotransferases, bilirubin, γGT and induction of the acute phase C-reactive protein (CRP) and the cytokines IL6 and IL8. The first patient receiving 10μg catumaxomab experienced fatal acute liver failure which led to the termination of the study. Immmunopathology revealed catumaxomab to bind via its Fc-fragment to FcγR-positive Kupffer cells to stimulate CRP, chemokine and cytokine release. The observed CD3+T-cell margination at activated hepatic macrophages exacerbated T-cell mediated cytotoxicity. Strikingly, the combined Kupffer/T-cell responses against liver cells did not require hepatocytes to be EpCAM-positive. Catumaxomab's off-target activity involved T-cell mediated lysis of the granzyme B cell death pathway and the molecular interaction of hepatic sinusoidal macrophages with T-cells induced cytolytic hepatitis. Although the bile ducts were surrounded by densely packed lymphocytes these rarely infiltrated the ducts to suggest an intrahepatic cholestasis as the cause of hyperbilirubinaemia. Lastly, evidence for the programming of memory T-cells was observed with one patient that succumbed to his cancer six weeks after the last catumaxomab infusion. In conclusion, our study exemplifies off-target hepatotoxicity with molecularly targeted therapy and highlights the complexities in the clinical development of immunotherapeutic antibodies.
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