Humanized anti-CD271 monoclonal antibody exerts an anti-tumor effect by depleting cancer stem cells
Humanized anti-CD271 monoclonal antibody exerts an anti-tumor effect by depleting cancer stem cells
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DOI：
10.1016/j.canlet.2019.07.011
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Tamai, Keiichi
中科院分区：
文献类型：
--
作者：
Morita, Shinkichi;Mochizuki, Mai;Tamai, Keiichi
CD271是一种神经营养素受体，在下咽癌(HPC)和黑色素瘤等多种癌症中均有表达。我们最近报道CD271是HPC的一个肿瘤干细胞生物标志物，它的表达对癌细胞的增殖是必不可少的，并与该病的不良预后相关。为了研制针对CD271的治疗性抗体，我们建立了人源化的抗CD271单抗(HCD271 MA B)。HCD271 mA b与人CD271富含半胱氨酸的结构域1(CRD1)具有高亲和力(K-D=1.697×10(-9)M)。在体外，hCD271 mAb对人CD271转导的小鼠细胞株SP2/0-CD271具有抗体依赖的细胞介导的细胞毒(ADCC)活性。HCD271 mAb还在小鼠三种细胞系(HPCM2(下咽癌患者来源的异种移植细胞系)、MeWo-Luc(黑色素瘤细胞系)和SP2/0-CD271)的移植模型中发挥了抗肿瘤活性，导致与对照组相比肿瘤较小，CD271阳性细胞的数量减少。总而言之，这些数据表明，针对CD271的抗体是一种有前途的治疗策略。
CD271, known as a neurotrophin receptor, is expressed in various cancers such as hypopharyngeal cancer (HPC) and melanoma. We recently reported that CD271 is a cancer-stem-cell biomarker of HPC, and that its expression is essential for cancer-cell proliferation and is correlated with a poor prognosis in this disease. Here, to develop a therapeutic antibody to CD271, we established a humanized anti-CD271 monoclonal antibody (hCD271 mA b). hCD271 mA b bound to the cysteine-rich domain 1 (CRD1) of human CD271 with high affinity (K-D = 1.697 x 10(-9)M). In vitro, hCD271 mA b exerted antibody-dependent cell-mediated cytotoxicity (ADCC) activity against SP2/0-CD271 (human CD271-transduced mouse cell line). Treatment with hCD271 mA b also exerted anti-tumor activity in graft models of three cell lines (HPCM2 (patient-derived xenograft cell line of hypopharyngeal cancer), MeWo-Luc (melanoma cell line), and SP2/0-CD271) in mice, resulting in smaller tumors compared to controls and reduced numbers of CD271-positive cells. Collectively, these data suggest that an antibody targeting CD271 is a promising therapeutic strategy.