Nishida Michio, Usuda Sadakazu, Okabe Masato, Miyakoda Hiroko, Komatsu Midori, Hanaoka Hiroshi, Teshigawara Keisuke, Niwa Otsura
Late Effects Studies, Radiation Biology Center, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Int J Oncol. 2007 Jul;31(1):29-40.
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.
利妥昔单抗是美国食品药品监督管理局（FDA）批准的首个用于治疗B细胞非霍奇金淋巴瘤（B-NHL）的抗癌抗体，可单独使用或与化疗药物联合使用。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研究。利妥昔单抗的临床反应显著，不仅导致肿瘤消退，还延长了生存期。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耐药性。因此，强烈需要为这些患者提供替代疗法。利妥昔单抗的活性被认为是通过抗体依赖性细胞毒性、补体依赖性细胞毒性和凋亡实现的，并且在模型系统中的研究确定了利妥昔单抗在细胞信号传导诱导的抗凋亡生存途径扰动中的作用，这表明对利妥昔单抗无反应的患者可能可以用具有不同活性的其他CD20抗体来克服。本研究调查了八种针对CD20的新型鼠源抗体与2B8和c2B8（利妥昔单抗）相比的物理和生物学特性。这些抗体通过各种抗原和免疫程序获得，并选择具有CD20活性。对这些抗体的分析表明，它们都与各种B细胞系和CD20转染的CHO细胞结合。八种抗体中的六种具有相似的可变区氨基酸序列，2B8也具有这些序列，而两种单克隆抗体则没有。其中，1K1791具有独特的重链，1K1791和1K1782都具有独特的轻链。并非所有抗体都能抑制细胞生长，只有两种抗体与固定的GST-CD20重组融合蛋白反应。值得注意的是，发现1K1791在没有交联剂的情况下能抑制细胞增殖并诱导不依赖半胱天冬酶的凋亡。这些发现鉴定出了具有与2B8不同特性和表位特异性的新抗体。讨论了此类抗体在治疗B-NHL和利妥昔单抗耐药的B-NHL中的潜在临床应用。
