Construction and Characterization of a Bispecific Anti-CD20 Antibody with Potent Antitumor Activity against B-Cell Lymphoma
Construction and Characterization of a Bispecific Anti-CD20 Antibody with Potent Antitumor Activity against B-Cell Lymphoma
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具有有效抗 B 细胞淋巴瘤活性的双特异性抗 CD20 抗体的构建和表征
DOI：
10.1158/0008-5472.can-10-0009
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Guo, Yajun
中科院分区：
文献类型：
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作者：
Li, Bohua;Zhang, Xunming;Guo, Yajun
为了开发更有效的b细胞淋巴瘤抗cd20试剂，我们设计并构建了双特异性四价抗cd20抗体11B8/2F2(ScFvHL)(4)-Fc，该抗体来源于两种完整的人源单克隆抗体2F2和11B8。2F2是I型CD20单抗，在补体依赖性细胞毒性（CDC）试验中有效，但在诱导细胞凋亡方面较差，而11B8是II型CD20单抗，在诱导细胞凋亡方面有效，但在CDC试验中无效。结果表明，11B8/2F2(ScFvHL)(4)-Fc具有明显优于2F2的诱导凋亡活性，甚至是11B8、11B8 + 2F2和2F2(ScFvHL)(4)-Fc，这是一种由2F2衍生的单特异性四价抗体。有趣的是，11B8/2F2(ScFvHL)(4)-Fc显示出与2F2(ScFvHL)(4)-Fc相似的介导CDC的能力，尽管其四个抗原结合臂中有两个起源于11B8。为了探究11B8/2F2(ScFvHL)(4)-Fc在CDC和凋亡活性中如此有效的原因，我们构建了一种由2F2和11B8组成的双特异性二价抗体，命名为11B8/2F2- scfvfc。我们的研究结果部分解释了11B8/2F2(ScFvHL)(4)-Fc具有强CDC和诱导凋亡活性的原因。进一步的体内治疗研究表明，与2F2、11B8、2F2 + 11B8和2F2(ScFvHL)(4)-Fc相比，11B8/2F2 (ScFvHL)(4)-Fc具有更强的抗肿瘤活性。这些数据提示11B8/2F2(ScFvHL)(4)-Fc可能作为b细胞淋巴瘤的潜在治疗剂。癌症Res;70 (15);6293 - 302。(c) 2010年aacr。
To develop more effective anti-CD20 reagents for B-cell lymphoma, we designed and constructed a bispecific tetravalent anti-CD20 antibody, 11B8/2F2(ScFvHL)(4)-Fc, derived from two fully human monoclonal antibodies (mAb), 2F2 and 11B8. 2F2 is a type I CD20 mAb, which is potent in complement-dependent cytotoxicity (CDC) assays but poor at inducing apoptosis, whereas 11B8 is a type II CD20 mAb, which is effective in induction of apoptosis but ineffective in CDC. Our results showed that 11B8/2F2(ScFvHL)(4)-Fc possessed apoptosis-inducing activity markedly superior to that of 2F2, and even 11B8, 11B8 plus 2F2, and 2F2(ScFvHL)(4)-Fc, a 2F2-derived monospecific tetravalent antibody developed previously. Interestingly, 11B8/2F2(ScFvHL)(4)-Fc displayed a similar ability to mediate CDC as 2F2(ScFvHL)(4)-Fc, although two of its four antigen-binding arms originated from 11B8. To explore why 11B8/2F2(ScFvHL)(4)-Fc was so potent in both CDC and apoptotic activity, a bispecific divalent antibody composed of 2F2 and 11B8, denoted as 11B8/2F2-ScFvFc, was constructed and characterized. Our results partially explained the reason for the potent CDC and apoptosis-inducing activity of 11B8/2F2(ScFvHL)(4)-Fc. Further in vivo therapy studies showed that 11B8/2F2 (ScFvHL)(4)-Fc had a significantly more potent antitumor activity compared with 2F2, 11B8, 2F2 plus 11B8, and 2F2(ScFvHL)(4)-Fc. These data suggest that 11B8/2F2(ScFvHL)(4)-Fc may serve as a potential therapeutic agent for B-cell lymphoma. Cancer Res; 70(15); 6293-302. (C) 2010 AACR.