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PNAS:新型人源化单克隆抗体可靶向并杀死癌细胞

日前,加州大学圣地亚哥分校穆尔斯癌症中心(UC San Diego Moores Cancer Center)的研究人员发现了一种人源化单克隆抗体,证实其可以靶向和直接杀死慢性淋巴细胞白血病(CLL)细胞。慢性淋巴细胞白血病是目前最常见的血液癌症类型,新研究为至少部分的慢性淋巴细胞白血病患者提供了一种有潜力的新治疗。相关研究成果在线刊登在近期出版的《PNAS》杂志上。

CLL细胞高水平表达一种细胞表面糖蛋白受体CD44。研究人员发现了一种称作RG7356的单克隆抗体可以特异性靶向CD44,对癌细胞产生直接毒性作用,且对正常B细胞影响甚微。

此外,他们还发现RG7356诱导表达ZAP-70蛋白的CLL细胞发生了程序性细胞死亡。大约一半的CLL患者的淋巴细胞均表达ZAP-70。相比于CLL细胞不表达这种特异蛋白质的患者,这些患者罹患的是更为侵袭性形式的疾病。

在过去的研究中,研究人员曾证实当从身体中移除出CLL细胞,并在实验室培养时,CLL细胞通常会经历自发性或药物诱导性细胞死亡。他们发现在CLL患者体内,CLL细胞接受了来自淋巴结和骨髓中周围非肿瘤细胞的存活信号。其中一个存活信号似乎是通过CD44传递。而当RG7356单克隆抗体与CD44结合时,它似乎转而传递了一种死亡信号给白血病细胞。

研究人员表示,通过靶向CD44,RG7356杀伤了CLL细胞,并且有可能与是否存在足量的“效应细胞”无关,而这通常是其他单克隆抗体杀伤肿瘤细胞的必要条件。

研究人员计划下一步利用这一人源化的抗CD44单克隆抗体启动相关临床试验。

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Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44

PNAS, March 25, 2013 | doi:10.1073/pnas.1221841110

Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cell-surface glycoprotein receptor for hyaluronic acid. We found that a humanized mAb specific for CD44 (RG7356) was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. Moreover, RG7356 could induce CLL cells that expressed the zeta-associated protein of 70 kDa (ZAP-70) to undergo caspase-dependent apoptosis, independent of complement or cytotoxic effector cells. The cytotoxic effect of this mAb was not mitigated when the CLL cells were cocultured with mesenchymal stromal cells (MSCs) or hyaluronic acid or when they were stimulated via ligation of the B-cell receptor with anti-µ. RG7356 induced rapid internalization of CD44 on CLL cells at 37 °C, resulting in reduced expression of ZAP-70, which we found was complexed with CD44. Administration of this mAb at a concentration of 1 mg/kg to immune-deficient mice engrafted with human CLL cells resulted in complete clearance of engrafted leukemia cells. These studies indicate that this mAb might have therapeutic activity, particularly in patients with CLL that express ZAP-70.

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