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单克隆抗体糖基化与糖基化工程抗体 (下)

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重组抗体Fc段聚糖链结构(图中实线为基础糖骨架,虚线为或有或无的糖残基链)

继在上篇中向大家介绍了单克隆抗体的糖基化类型后,本篇中BioEngX将向大家介绍通过对宿主细胞基因的改造获得糖基化工程抗体的一些研究。

1去除岩藻糖(Fuc)侧链提高抗体ADCC效应。绝大多数重组抗体Fc段聚糖链数都含有Fuc侧链,研究证明聚糖链缺少Fuc的抗体所产生的ADCC效应是聚糖链带有Fuc侧链的抗体的10到100倍。通过使宿主细胞过表达GMP3和Golgimannosidase 2两种糖基化相关酶可得到了Fuc缺失的抗体,这种改造可大大提高抗体体内的活性。Gazyva即是由罗氏制药在美罗华(Rituxan)基础上开发的Fuc去除抗体。Rituxan是用于治疗非霍奇金淋巴瘤和慢性淋巴细胞白血病的畅销药物,靶点为B细胞表面的CD20。去除Fuc侧链得到的Gazyva体内活性大大高于Rituxan,使用Gazyva与化疗药物chlorambucil联合治疗的病人获得了23个月的无进展生存期。Gazyva已于2012年获批在日本上市。

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Gazyva的作用机理

2三叉聚糖链提高抗体ADCC效应。CHO细胞表达的抗体糖基化绝大多数为缺少GlcNAc分支的双叉结构。通过向CHO细胞中导入GnTIII酶可获得糖基化为三叉结构的抗体,具有三叉结构糖基链的抗体ADCC活性也更高。瑞士的研究人员通过该技术改造了一种用于生产治疗神经母细胞瘤抗体的宿主细胞,得到的抗体活性也大大提高。

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三叉聚糖链结构

3 聚糖链唾液酸过表达可提高抗体抗炎活性。利用细胞工程生产的重组抗体中Fc聚糖链带唾液酸的抗体只占很少一部分,通过使宿主细胞中过表达唾液酸转移酶可使表达的抗体过唾液酸化。对于用于中和体内因子的抗体,抗体的过唾液酸化可以抑制注射抗体后病人产生的免疫反应。

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过唾液酸化聚糖链

图片来自网络,内容由BioEngX原创,转载请注明!

作者: fiofiona

伦敦大学学院博士,研究方向VLP生产,微藻的基因工程



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