Labetuzumab govitecan (IMMU-130), an antibody–drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ∼500 or ∼16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130–treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196–203. ©2017 AACR.

中文翻译：

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使用 CEACAM5 靶向抗体-药物偶联物 (ADC)、labetuzumab govitecan (IMMU-130) 选择性和集中增加 SN-38

Labetuzumab govitecan (IMMU-130) 是一种抗体药物偶联物 (ADC)，平均为 7.6 SN-38/IgG，评估了其增强 SN-38 向人结肠肿瘤异种移植物递送的潜力。携带 LS174T 或 GW-39 人类结肠肿瘤异种移植物的小鼠注射伊立替康或 IMMU-130（SN-38 等效物分别为~500 或~16 μg）。提取肿瘤、肝脏和小肠的血清和匀浆，并通过反相 HPLC 测定 SN-38、SN-38G（葡糖醛酸化 SN-38）和伊立替康的浓度。伊立替康从血清中快速清除，5 分钟后仅注射剂量 1% 至 2%/mL；总体而言，大约 20% 被转换为 SN-38 和 SN-38G。在使用 IMMU-130 1 小时时，血清中 45% 至 63% 注射剂量/mL 的 SN-38，在 3 天内与 ADC 结合 >90%，并且 SN-38G 水平较低。SN-38 的总水平比 IgG 下降得更快，证实 SN-38 从 ADC 中逐渐释放。AUC 分析发现，在 IMMU-130 治疗的动物中，LS174T 和 GW-39 肿瘤中的 SN-38 水平分别高约 11 倍和 16 倍。当标准化为为每个产品注射的 SN-38 等价物时，这种递送优势被放大 > 30 倍。给予 IMMU-130 的动物肝脏和小肠内容物中的 SN-38 和 SN-38G 水平明显较低。在给予的 SN-38 等价物的基础上，与伊立替康相比，IMMU-130 可能向产生 CEA 的肿瘤输送超过 300 倍的 SN-38，同时还降低了正常组织中 SN-38 和 SN-38G 的水平。这些观察结果与显示疗效和安全性提高的临床前和临床数据一致。摩尔癌症治疗; 17(1); 196-203。