A biparatopic anti-EGFR nanobody efficiently inhibits solid tumour growth.
A biparatopic anti-EGFR nanobody efficiently inhibits solid tumour growth.
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DOI：
10.1002/ijc.26145
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发表时间：
2011-10-15
影响因子：
6.4
通讯作者：
Henegouwen, Paul M. P. van Bergen En
中科院分区：
文献类型：
--
作者：
Roovers, Rob C.;Vosjan, Maria J. W. D.;Laeremans, Toon;el Khoulati, Rachid;de Bruin, Renee C. G.;Ferguson, Kathryn M.;Verkleij, Arie J.;van Dongen, Guus A. M. S.;Henegouwen, Paul M. P. van Bergen En
表皮生长因子受体 (EGFR) 已被证明是基于抗体的治疗的有效癌症靶点。目前，已有多种抗EGFR单克隆抗体（mAb）成功使用，其中包括西妥昔单抗和马妥珠单抗。 X 射线晶体学数据显示，这些抗体与 EGFR 胞外域上的不同表位结合，为联合使用这两种抗体特异性提供了理论依据。我们之前曾报道过拮抗性抗 EGFR 纳米抗体的成功分离。在本研究中，我们旨在通过将具有与西妥昔单抗和马妥珠单抗相似的特异性的纳米抗体组合成单个双互补位分子来改进这些分子。精心设计的噬菌体纳米抗体选择产生了两组纳米抗体，它们特异性阻断马妥珠单抗或西妥昔单抗与 EGFR 的结合，并且不竞争彼此的结合。来自两个表位组的纳米抗体组合成双互补位纳米抗体 CONAN-1 被证明比单价或二价（单特异性）纳米抗体更有效地阻止 EGFR 激活。此外，这种双互补位纳米抗体可有效抑制 EGF 依赖性细胞增殖。重要的是，在携带 A431 异种移植物的无胸腺小鼠体内模型中，CONAN-1 抑制肿瘤生长的效力与整个 mAb 西妥昔单抗几乎相似，尽管 CONAN-1 缺乏可介导免疫效应器功能的 Fc 部分。与使用二价、单特异性纳米抗体的治疗相比，CONAN-1 在肿瘤生长抑制方面显然更有效。这些结果表明，基于双互补位纳米抗体的抗癌疗法的合理设计可能会产生用于进一步开发的有效先导分子。
The epidermal growth factor receptor (EGFR) has been shown to be a valid cancer target for antibody-based therapy. At present, several anti-EGFR monoclonal antibodies (mAbs) have been successfully used, among which cetuximab and matuzumab. X-ray crystallography data show that these antibodies bind to different epitopes on the ecto-domain of EGFR, providing a rationale for the combined use of these two antibody specificities. We have previously reported on the successful isolation of antagonistic anti-EGFR nanobodies. In the present study, we aimed to improve on these molecules by combining nanobodies with specificities similar to both cetuximab and matuzumab into a single bi-paratopic molecule. Carefully designed phage nanobody selections resulted in two sets of nanobodies that specifically blocked the binding of either matuzumab or of cetuximab to EGFR and that did not compete for each others binding. A combination of nanobodies from both epitope groups into the bi-paratopic nanobody CONAN-1 was shown to block EGFR activation more efficiently than monovalent or bivalent (monospecific) nanobodies. In addition, this bi-paratopic nanobody potently inhibited EGF-dependent cell proliferation. Importantly, in an in vivo model of athymic mice bearing A431 xenografts, CONAN-1 inhibited tumour outgrowth with an almost similar potency as the whole mAb cetuximab, despite the fact that CONAN-1 is devoid of an Fc portion that could mediate immune effector functions. Compared to therapy using bivalent, mono-specific nanobodies, CONAN-1 was clearly more potent in tumour growth inhibition. These results show that the rational design of bi-paratopic nanobody-based anti-cancer therapeutics may yield potent lead molecules for further development.
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