Characterization of novel murine anti-CD20 monoclonal antibodies and their comparison to 2B8 and c2B8 (rituximab).
Characterization of novel murine anti-CD20 monoclonal antibodies and their comparison to 2B8 and c2B8 (rituximab).
复制标题
DOI：
10.3892/ijo.31.1.29
复制
发表时间：
2007-07
影响因子：
5.2
通讯作者：
Michio Nishida;S. Usuda;M. Okabe;H. Miyakoda;M. Komatsu;Hiroshi Hanaoka;K. Teshigawara;O. Niwa
中科院分区：
文献类型：
--
作者：
Michio Nishida;S. Usuda;M. Okabe;H. Miyakoda;M. Komatsu;Hiroshi Hanaoka;K. Teshigawara;O. Niwa
利妥昔单抗是FDA批准的第一种抗癌抗体，可单独或与化疗药物联合治疗B细胞非霍奇金淋巴瘤(B-NHL)。此外，利妥昔单抗目前正在多种CD20+肿瘤疾病以及B细胞诱导的自身免疫性疾病中进行检测。利妥昔单抗的临床疗效显著，不仅导致肿瘤消退，而且延长了生存期。然而，一部分患者最初对利妥昔单抗没有反应或对其进一步治疗产生抗药性。因此，针对这些患者的替代疗法是非常必要的。利妥昔单抗的活性被认为是通过抗体依赖的细胞毒性、补体依赖的细胞毒性和细胞凋亡，在模型系统中的研究证实了利妥昔单抗在细胞信号诱导的抗凋亡生存通路的扰动中的作用，提示对利妥昔单抗无效的患者可能被其他不同活性的CD20抗体克服。本研究调查了8种针对CD20的新型小鼠抗体的物理和生物学特性，并与2B8和c2B8(利妥昔单抗)进行了比较。这些抗体是通过各种抗原性和免疫程序获得的，并选择用于CD20活性。对这些抗体的分析表明，它们都能与不同的B细胞系和CD20转基因的CHO细胞结合。八种抗体中有六种具有与2B8相似的可变区氨基酸序列，而两种单抗则不同。其中，1K1791具有明显的重链，1K1791和1K1782均具有明显的轻链。不是所有的抗体都抑制细胞生长，只有两个抗体与固定的GST-CD20重组融合蛋白发生反应。值得注意的是，1K1791被发现在没有交联剂的情况下抑制细胞增殖，并诱导caspase非依赖性的细胞凋亡。这些发现确定了具有不同于2B8的特性和表位特异性的新抗体。讨论了这些抗体在治疗B-NHL和利妥昔单抗耐药的B-NHL中的潜在临床应用。
Rituximab is the first anti-cancer antibody approved by the FDA for the treatment of B-cell non-Hodgkin lymphoma (B-NHL), alone or in combination with chemotherapeutic drugs. Further, rituximab is now being examined in a variety of CD20+ neoplastic diseases as well as B-cell-induced autoimmune diseases. The clinical response to rituximab is significant, resulting not only in tumor regression but also prolongation of survival. However, a subset of patients does not initially respond to rituximab or develops resistance to its further treatment. Therefore, alternative therapies for these patients are strongly desired. Rituximab activity has been thought to be by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis, and studies in model systems established the role of rituximab in cell signaling-induced perturbation of anti-apoptotic survival pathways, suggesting that the patients unresponsive to rituximab may be overcome with other CD20 antibodies with different activities. This study investigated eight novel murine antibodies directed against CD20 for their physical and biological properties in comparison with 2B8 and c2B8 (rituximab). These antibodies were derived by various antigenic and immunization procedures and selected for CD20 activity. Analysis of these antibodies revealed that they all bound to various B-cell lines and CD20-transfected CHO cells. Six of the eight antibodies shared similar variable-region amino acid sequences that were also shared by 2B8 while two monoclonal antibodies did not. Of them, 1K1791 has a distinct heavy chain and both 1K1791 and 1K1782 have distinct light chains. Not all of the antibodies inhibited cell growth and only two antibodies reacted with fixed GST-CD20 recombinant fusion protein. Noteworthy, 1K1791 was found to inhibit cell proliferation and also induced caspase-independent apoptosis in the absence of cross-linker. These findings identified new antibodies with properties and epitope specificities different from 2B8. The potential clinical application of such antibodies in the treatment of B-NHL and rituximab-resistant B-NHL is discussed.