Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE
Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE
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DOI：
10.1016/j.toxlet.2019.12.027
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发表时间：
2020-05-15
影响因子：
3.5
通讯作者：
Chen, Fang
中科院分区：
文献类型：
--
作者：
Jiang, Jing;Li, Shenjun;Chen, Fang
HER 2通路在细胞增殖和分化中起关键作用，而由HER 2基因扩增引起的受体过表达与多种肿瘤的生长相关。先前发表的临床试验已经证明，对于相同的靶点，与单独的抗体相比，抗体缀合的药物（ADC）显著改善了临床效果。为了提供更有效的药物，我们基于ADC开发了Disitamab vedotin。抗体部分为靶向HER 2的人源化单克隆抗体，小分子毒素为人工合成的抗HER 2药物单甲基澳瑞他汀E（MMAE）。蛋白酶可切割接头将MMAE共价连接至抗体。在本研究中，我们通过猴单次和重复给药毒性研究表征了Disitamab vedotin的毒性特征。在这些研究中还评估了小分子和裸抗体（Disitamab）的毒性。猴对6 mg/kg剂量的Disitamab vedotin耐受良好，而等效MMAE导致重度骨髓抑制。这一发现证明ADC可以提高治疗效果。此外，Disitamab vedotin和MMAE的安全性特征相似，且与MMAE的激活机制一致。毒理学发现包括骨髓/血液学毒性和淋巴器官毒性，而在裸抗体处理的动物中未观察到显著毒性。发现这些副作用与从接受Disitamab vedotin治疗的临床I/II期患者中获得的数据一致。
The HER2 pathway plays a pivotal role in cell proliferation and differentiation, while the receptor overexpression caused by amplification of HER2 gene is associated with the growth of several tumors. Previously published clinical trials have demonstrated that antibody-conjugated drugs (ADCs) remarkably improved clinical effects compared with antibodies alone for the same target. In order to provide more effective drugs, we developed Disitamab vedotin based on ADC. The antibody part was a humanized monoclonal antibody targeting HER2, the small molecule toxin was monomethyl auristatin E (MMAE), a synthetic antineoplastic agent. A protease cleavable linker covalently attached MMAE to the antibody. In this study, we characterized the toxicity profile of Disitamab vedotin through single- and repeat-dose toxicity studies in monkeys. The toxicities of small molecules and naked antibody (Disitamab) were also assessed in these studies. Monkeys were well tolerated with Disitamab vedotin at doses of 6 mg/kg, while equivalent MMAEs resulted in severe myelosuppression. This finding proves that ADCs improve the therapeutic effect. In addition, the safety profiles of Disitamab vedotin and MMAE were similar and consistent with the activation mechanism of MMAE. Toxicology finding included bone marrow/hematology toxicity and lymphoid organ toxicity, while no significant toxicity was observed in animals treated with naked antibody. These side effects were found to be consistent with data acquired from clinical phase I/II patients treated with Disitamab vedotin.