Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells
Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells
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DOI：
10.1038/leu.2011.362
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发表时间：
2012-06-01
期刊：
影响因子：
11.4
通讯作者：
Mellstedt, H.
中科院分区：
文献类型：
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作者：
Daneshmanesh, A. H.;Hojjat-Farsangi, M.;Mellstedt, H.
ROR 1是一种受体酪氨酸激酶（RTK），最近发现在慢性淋巴细胞白血病（CLL）中在基因和蛋白水平上过度表达。RTKs单克隆抗体已成功应用于实体瘤的治疗。我们分别针对ROR 1的胞外部分的IG（n = 1）、富含半胱氨酸（CRD）（n = 2）和kringle（KNG）（n = 2）结构域产生了五种单克隆抗体。所有CLL患者（n = 20）的白血病细胞的表面上表达ROR 1。发现进展性疾病患者与非进展性疾病患者以及未突变IgVH基因与突变IgVH基因患者的ROR 1表达频率显着更高。所有五种单克隆抗体单独诱导CLL细胞但不诱导正常B细胞在不存在补体或添加效应细胞（膜联蛋白-V和MTT，以及聚-（ADP核糖）-聚合酶、半胱天冬酶-8和半胱天冬酶-9的裂解）的情况下的凋亡。最有效的是抗CRD和KNG的单克隆抗体，显著上级优于利妥昔单抗（P
ROR1 is a receptor tyrosine kinase (RTK) recently identified to be overexpressed at the gene and protein levels in chronic lymphocytic leukemia (CLL). Monoclonal antibodies (MAbs) against RTKs have been successfully applied for therapy of solid tumors. We generated five MAbs against the Ig (n = 1), cysteine-rich (CRD) (n = 2) and kringle (KNG) (n = 2) domains, respectively, of the extracellular part of ROR1. All CLL patients (n = 20) expressed ROR1 on the surface of the leukemic cells. A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. All five MAbs alone induced apoptosis in the absence of complement or added effector cells (Annexin-V and MTT, as well as cleavage of poly-(ADP ribose)-polymerase, caspase-8 and caspase-9) of CLL cells but not of normal B cells. Most effective were MAbs against CRD and KNG, significantly superior to rituximab (P