Development of novel tetravalent anti-CD20 antibodies with potent antitumor activity
Development of novel tetravalent anti-CD20 antibodies with potent antitumor activity
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DOI：
10.1158/0008-5472.can-07-6663
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Guo, Yajun
中科院分区：
文献类型：
--
作者：
Li, Bohua;Shi, Shu;Guo, Yajun
尽管抗cd20单克隆抗体（mAb）利妥昔单抗（C2B8）治疗b细胞淋巴瘤有效，但其疗效仍然不稳定，通常是适度的。似乎多种机制的结合，如补体依赖性细胞毒性（CDC）和凋亡信号传导，是抗cd20单抗治疗成功的基础。不幸的是，目前所有对CDC有效的抗cd20单克隆抗体在信号细胞死亡中相对不活跃，反之亦然。在这项研究中，我们分别从抗cd20单克隆抗体C2B8和2F2衍生出两种基因工程四价抗体（TetraMcAb）。TetraMcAbs分子质量仅比天然二价抗体（DiMcAb）高25 kDa，不仅与DiMcAbs一样有效地介导对b淋巴瘤细胞的CDC和抗体依赖性细胞毒性，而且具有明显优于DiMcAbs的抗增殖和诱导凋亡活性。有趣的是，尽管2172和C2B8在诱导细胞生长停滞和凋亡方面同样有效，但它们的四价版本2F2(ScFvHL)(4)-Fc和C2B8(ScFvHL)(4)-Fc的功能却有显著差异。2F2(ScFvHL)4-Fc表现出比C2B8(ScFvHL)4-Fc更强的抗增殖和诱导凋亡活性。免疫治疗研究进一步表明，与C2B8、2F2相比，2F2(ScFvHL)4-Fc在延长听力系统性Daudi或Raji肿瘤的严重联合免疫缺陷小鼠的生存期方面更有效。C2B8(ScFvHL)(4)-Fe，提示其可能是一种有前景的b细胞淋巴瘤治疗剂。
Despite the effectiveness of the anti-CD20 monoclonal antibody (mAb) Rituximab (C2B8) in the treatment of B-cell lymphoma, its efficacy remains variable and often modest. It seems likely that a combination of multiple mechanisms, such as complement-dependent cytotoxicity (CDC) and apoptotic signaling, underlies the therapeutic success of anti-CD20 mAbs. Unfortunately, all the current anti-CD20 mAbs effective in CDC are relatively inactive in signaling cell death and vice versa. In this study, we developed two genetically engineered tetravalent antibodies (TetraMcAb) respectively derived from the anti-CD20 mAbs C2B8 and 2F2. TetraMcAbs, with a molecular mass only 25 kDa higher than native divalent antibodies (DiMcAb), were shown not only to be as effective in mediating CDC and antibody-dependent cellular cytotoxicity against B-lymphoma cells as DiMcAbs but also to have antiproliferative and apoptosis-inducing activity markedly superior to that of DiMcAbs. Interestingly, whereas 2172 and C2B8 were equally effective in inducing cell growth arrest and apoptosis, the functions of their tetravalent versions, 2F2(ScFvHL)(4)-Fc and C2B8(ScFvHL)(4)-Fc, were significantly different. 2F2(ScFvHL)4-Fc exhibited exceptionally more potent antiproliferative and apoptosis-inducing activity than that of C2B8(ScFvHL)4-Fc. Immunotherapeutic studies further showed that 2F2(ScFvHL)4-Fc was far more effective in prolonging the survival of severe combined immunodeficient mice hearing systemic Daudi or Raji tumors than C2B8, 2F2. and C2B8(ScFvHL)(4)-Fe, suggesting that it might he a promising therapeutic agent for B-cell lymphoma.