Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site
Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site
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DOI：
10.1126/science.1165480
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发表时间：
2009-03-20
期刊：
影响因子：
56.9
通讯作者：
Fuh, Germaine
中科院分区：
文献类型：
--
作者：
Bostrom, Jenny;Yu, Shang-Fan;Fuh, Germaine
抗体和抗原之间的界面通常被描述为一把锁和钥匙，这表明抗体表面只能容纳一种抗原。在这里，我们描述了一种具有抗原结合位点的抗体，该抗体以高亲和力结合两种不同的蛋白质。我们分离出了赫赛汀的一种变体，这是一种结合人表皮生长因子受体 2 (HER2) 的治疗性单克隆抗体，其基础是它能够同时与血管内皮生长因子 (VEGF) 相互作用。晶体学和诱变研究表明，该抗体的不同氨基酸（称为 bH1）与 HER2 和 VEGF 积极结合，但接触这两种抗原的抗体表面区域之间存在广泛的重叠。 bH1 的亲和力增强版本可抑制 HER2 和 VEGF 介导的体外细胞增殖以及小鼠模型中的肿瘤进展。这种“二合一”抗体挑战了一个结合位点、一种抗原的单克隆抗体范例。它们还可以为基于抗体的治疗提供新的机会。
The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site that binds two distinct proteins with high affinity. We isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the two antigens. An affinity-improved version of bH1 inhibits both HER2-and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. Such "two-in-one" antibodies challenge the monoclonal antibody paradigm of one binding site, one antigen. They could also provide new opportunities for antibody-based therapy.