Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers
Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers
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DOI：
10.1021/acs.bioconjchem.5b00223
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发表时间：
2015-05-01
影响因子：
4.7
通讯作者：
Goldenberg, David M.
中科院分区：
文献类型：
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作者：
Cardillo, Thomas M.;Govindan, Serengulam V.;Goldenberg, David M.
Sacituzumab goitecan(IMMU-132)是由人源化的抗Trop-2单抗(HRS7)与伊立替康的活性代谢产物SN-38偶联而成的抗体药物结合物(ADC)。除了其进一步的特征外，随着IMMU-132的临床应用扩展到表达trop-2的实体肿瘤类型的范围不断扩大，其在新疾病模型中的有效性需要在非临床环境中进行探索。与大多数使用超毒性药物和稳定连接物的ADC不同，IMMU-132使用的是一种中等毒性的药物，在SN-38和连接物之间具有中等稳定的碳酸酯键。流式细胞术和免疫组织化学显示，trop-2在多种肿瘤中都有表达，包括胃、胰腺、三阴性乳腺(TNBC)、结肠、前列腺和肺。虽然细胞结合实验显示IMMU-132和亲本hRS7抗体之间没有显著差异，但使用TROP-2 CMS芯片的表面等离子共振分析表明IMMU-132比hRS7具有显著的结合优势。该结合物保留了与新生儿受体的结合，但与hRS7相比，它失去了60%以上的抗体依赖细胞介导的细胞毒活性。肿瘤细胞暴露在游离SN-38或IMMU-132中显示出相同的信号通路，pJNK1/2和p21(WAF1/Cip1)上调，随后caspase9、7和3被切割，最终导致多聚ADP-核糖聚合酶裂解和双链DNA断裂。完整的ADC在小鼠体内的药代动力学显示平均停留时间(MRT)为15.4h，而载体hRS7抗体的清除速度与未结合抗体相似(MRT类似于300h)。与非特异性对照相比，IMMU-132对荷人胃癌移植瘤小鼠(17.5 mg/kg，每周两次，共4周)有显著的抗肿瘤作用。临床相关的IMMU-132给药方案每隔一周、每周或每两周给药一次，在携带人胰腺癌或胃癌移植瘤的小鼠身上显示出类似的、显著的抗肿瘤作用。目前的I/II期临床试验(ClinicalTrials.gov，NCT01631552)证实了IMMU-132在表达trop-2的癌症中的抗癌活性，包括胃癌和胰腺癌患者。
Sacituzumab govitecan (IMMU-132) is an antibody drug-conjugate (ADC) made from a humanized antiTrop-2 monoclonal antibody (hRS7) conjugated with the active metabolite of irinotecan, SN-38. In addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 antibody, surface plasmon resonance analysis using a Trop-2 CMS chip shows a significant binding advantage for IMMU-132 over hRS7. The conjugate retained binding to the neonatal receptor, but it lost greater than 60% of the antibody-dependent cell-mediated cytotoxicity activity compared to that of hRS7. Exposure of tumor cells to either free SN-38 or IMMU-132 demonstrated the same signaling pathways, with pJNK1/2 and p21(WAF1/Cip1) upregulation followed by cleavage of caspases 9, 7, and 3, ultimately leading to poly-ADP-ribose polymerase cleavage and double-stranded DNA breaks. Pharmacokinetics of the intact ADC in mice reveals a mean residence time (MRT) of 15.4 h, while the carrier hRS7 antibody cleared at a similar rate as that of the unconjugated antibody (MRT similar to 300 h). IMMU-132 treatment of mice bearing human gastric cancer xenografts (17.5 mg/kg; twice weekly X 4 weeks) resulted in significant antitumor effects compared to that of mice treated with a nonspecific control. Clinically relevant dosing schemes of IMMU-132 administered either every other week, weekly, or twice weekly in mice bearing human pancreatic or gastric cancer xenografts demonstrate similar, significant antitumor effects in both models. Current Phase I/II clinical trials (ClinicalTrials.gov, NCT01631552) confirm anticancer activity of IMMU-132 in cancers expressing Trop-2, including gastric and pancreatic cancer patients.