PNAS：人源化CD44单克隆抗体可直接杀死白血病细胞

在一项新的研究中,来自加州大学圣地亚哥分校摩尔癌症中心(Moores Cancer Center)的研究人员鉴定出一种人化单克隆抗体(humanized monoclonal antibody)能够靶向和直接杀死慢性淋巴细胞白血病(chronic lymphocytic leukemia, CLL)细胞.相关研究结果于2013年3月25日在线发表在PNAS期刊上,论文标题为"Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44".这一发现代表着一种潜在的新疗法来治疗至少一些CLL患者,其中在美国,CLL是一种最为常见性的血癌.

CLL细胞表达高水平的细胞表面糖蛋白受体CD44.论文通信作者Thomas Kipps博士和同事们鉴定出一种被称作RG7356的人化单克隆抗体特异性地靶向CD44,因而直接毒杀癌细胞,但是对正常的B细胞几乎没有什么影响.

再者,他们发现RG7356诱导表达蛋白ZAP-70的CLL细胞经历凋亡或者说程序性细胞死亡.大约一半的CLL患者携带表达ZAP-70的白血病细胞,而且这些患者的病情通常要比那些携带不表达这种特异性蛋白的CLL细胞的患者更为严重.

Kipps和其他人之前的研究已证实当CLL细胞从体内被提取出并在实验室条件下培养时,它们通常发生自发性或药物诱导的细胞死亡.他们在体内研究中发现存在于CLL患者的淋巴结和骨髓中的非肿瘤细胞给周围的CLL细胞发送存活信号.这些存活信号中的一种似乎是通过CD44发送的.然而,当CD44被单克隆抗体RG7356结合时,它似乎传送死亡信号给这种白血病细胞.

Kipps说,"无论是否存在数量充足的效应细胞(effector cell),人们都可能通过靶向CD44来杀死CLL细胞,而通常这种情形下,还需其他的单克隆抗体来杀死肿瘤细胞.我们计划在不远的未来利用这种人化的抗CD44单克隆抗体进行临床试验."(生物谷Bioon.com）

doi:10.1073/pnas.1221841110
PMC:
PMID:

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

Suping Zhanga, Christina C. N. Wu, Jessie-F. Fecteau, Bing Cui, Liguang Chen, Ling Zhang, Rongrong Wu, Laura Rassenti, Fitzgerald Lao, Stefan Weigand, and Thomas J. Kipps

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.

(责任编辑：lili.zhao)