Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate
Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate
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DOI：
10.1172/jci.insight.99880
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发表时间：
2018-06-21
期刊：
影响因子：
8
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
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作者：
Panchamoorthy, Govind;Jin, Caining;Kufe, Donald
粘蛋白 1 (MUC1) 是一种异二聚体蛋白，在多种人类癌症表面异常过度表达，是开发基于 mAb 的疗法的一个有吸引力的靶点。然而，针对脱落的 MUC1 N 端亚基的尝试并未成功。我们在这里报告了针对非脱落致癌 MUC1 C 末端 (MUC1-C) 亚基的 mAb 3D1 的生成。我们发现 mAb 3D1 以低 nM 亲和力与限制性 α 3 螺旋处的 MUC1-C 胞外结构域结合。 mAb 3D1 对表达 MUC1-C 的人类癌细胞系和原代癌细胞具有选择性反应性。 mAb 3D1 内化到癌细胞中进一步支持 mAb 3D1 与单甲基 auristatin E (MMAE) 的缀合。 mAb 3D1-MMAE 抗体药物偶联物 (ADC) (a) 在体外杀死 MUC1-C 阳性细胞，(b) 对 MUC1 转基因 (MUC1.Tg) 小鼠无毒，(c) 对人 HCC827 肺肿瘤异种移植物具有活性。与 MMAE 缀合的人源化 mAb (humAb) 3D1 在 (a) MUC1 中也表现出抗肿瘤活性。携带同基因 MC38/MUC1 肿瘤的 Tg 小鼠，(b) 携带人类 ZR-75-1 乳腺肿瘤的裸鼠，以及 (c) 移植了源自患者的三阴性乳腺癌的 NCG 小鼠。这些发现以及不存在相关毒性支持了 humAb 3D1-MMAE ADC 的临床开发，可用于治疗许多 MUC1-C 过度表达的癌症。
Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed on the surface of diverse human carcinomas and is an attractive target for the development of mAb-based therapeutics. However, attempts at targeting the shed MUC1 N-terminal subunit have been unsuccessful. We report here the generation of mAb 3D1 against the nonshed oncogenic MUC1 C-terminal (MUC1-C) subunit. We show that mAb 3D1 binds with low nM affinity to the MUC1-C extracellular domain at the restricted alpha 3 helix. mAb 3D1 reactivity is selective for MUC1-C-expressing human cancer cell lines and primary cancer cells. Internalization of mAb 3D1 into cancer cells further supported the conjugation of mAb 3D1 to monomethyl auristatin E (MMAE). The mAb 3D1-MMAE antibody-drug conjugate (ADC) (a) kills MUC1-C-positive cells in vitro, (b) is nontoxic in MUC1-transgenic (MUC1.Tg) mice, and (c) is active against human HCC827 lung tumor xenografts. Humanized mAb (humAb) 3D1 conjugated to MMAE also exhibited antitumor activity in (a) MUC1. Tg mice harboring syngeneic MC38/MUC1 tumors, (b) nude mice bearing human ZR-75-1 breast tumors, and (c) NCG mice engrafted with a patient-derived triple-negative breast cancer. These findings and the absence of associated toxicities support clinical development of humAb 3D1-MMAE ADCs as a therapeutic for the many cancers with MUC1-C overexpression.