Zhu Mei, Zhou Lei, Hu Shangjiu, Miao Qingfang, Gong Jianhua, Zhang Na, Zhang Guoning, Wang Minghua, Wang Juxian, He Hongwei, Wang Yucheng
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
J Med Chem. 2022 May 26;65(10):7141-7153. doi: 10.1021/acs.jmedchem.1c01920. Epub 2022 May 6.
By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-(-maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody-drug conjugate LR-DM1 with an appropriate drug-antibody ratio of 3.6. LR-DM1, which was targeted toward the epidermal growth factor receptor for pancreatic cancer, exhibited potent antiproliferation activity with a half-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibition under 20 mg/kg LR-DM1 dosage in a single administration or multiple administrations without apparent abnormality of pathological observation. Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned.
通过不可裂解的连接子琥珀酰亚胺基-4-（-马来酰亚胺甲基）-环己烷-1-羧酸酯将有效载荷DM1与单克隆抗体LR004连接起来，我们设计并评估了一种药物抗体比为3.6的抗体药物偶联物LR-DM1。靶向胰腺癌表皮生长因子受体的LR-DM1对Capan-2细胞表现出强大的抗增殖活性，其半数最大抑制浓度值为7.03 nM。特别地，在单次给药或多次给药20 mg/kg LR-DM1剂量下，它显示出显著的肿瘤生长抑制作用，且病理观察无明显异常。此外，LR-DM1具有相对较宽的治疗指数，半数致死剂量高于300 mg/kg，比最高给药剂量20 mg/kg高出15倍以上。这项关于LR-DM1的初步研究为进一步开发一种对相关患者治疗具有变革性的新型抗体药物偶联物带来了希望。
