Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies.
Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies.
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治疗性 ipilimumab 和 tremelimumab 抗体的 CTLA-4 结合特性非常相似
DOI：
10.18632/oncotarget.18004
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Gao GF
中科院分区：
文献类型：
--
作者：
He M;Chai Y;Qi J;Zhang CWH;Tong Z;Shi Y;Yan J;Tan S;Gao GF
基于单克隆抗体的免疫检查点阻断疗法在恶性肿瘤的管理中取得了临床成功。随着第一个针对免疫检查点分子的单克隆抗体进入临床，基于伊匹单抗的抗CTLA-4阻断作用的分子基础尚未完全清楚。在本研究中，我们报告了易普利姆玛和CTLA-4的复合物结构。复合物结构显示来自易普利姆玛的VH和VL在与CTLA-4前β折叠链的结合中的相似贡献。伊匹单抗的阻断机制是CTLA-4中有助于与B7-1或B7-2结合的链被伊匹单抗占据，然后阻止B7-1或B7-2与CTLA-4结合。尽管伊匹单抗与CTLA-4上的曲美木单抗以相似的结合亲和力结合相同的表位，但伊匹单抗的较高解离速率可能表明与CTLA-4的动态结合，这可能影响其药代动力学。基于ipilimumab的抗CTLA-4阻断的分子基础以及ipilimumab和tremelimumab结合特性的比较研究将为发现小分子抑制剂和基于结构的单克隆抗体优化或新的生物制剂提供启示。
Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.
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DOI：
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期刊：
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影响因子：
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发表时间：
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期刊：
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影响因子：
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DOI：
10.1073/pnas.1417320112
发表时间：
2015-05-12
影响因子：
11.1
作者：
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通讯作者：
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