Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC).
Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC).
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DOI：
10.18632/oncotarget.4318
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发表时间：
2015-09-08
期刊：
影响因子：
--
通讯作者：
Sharkey RM
中科院分区：
文献类型：
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作者：
Goldenberg DM;Cardillo TM;Govindan SV;Rossi EA;Sharkey RM
Trop-2是ADC治疗的新靶标，因为其在许多实体癌中高表达。IMMU-132的合理开发代表了作为将公知的中度细胞毒性药物SN-38与抗Trop-2抗体结合的ADC的范式转变。体外和体内研究表明，SN-38的疗效增强，而SN-38的逐渐释放有助于整体效果。IMMU-132在7.6：1的高药物：抗体比率（DAR）下最有效，这不影响结合和药代动力学。与SN-38的前药伊立替康相比，它将SN-38靶向至人类癌症异种移植物的靶向量高达136倍。IMMU-132以其最具活性的非葡萄糖醛酸化形式递送SN-38，这可以解释重度腹泻的频率低于伊立替康。因此，这种携带靶向Trop-2的中等毒性药物的ADC代表了一种新型癌症治疗剂，其在患有几种转移性癌症类型的患者中显示出有希望的活性，包括三阴性乳腺癌，非小细胞和小细胞肺癌。
Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti-Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38′s prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers.