scFv-based "Grababody" as a general strategy to improve recruitment of immune effector cells to antibody-targeted tumors.
scFv-based "Grababody" as a general strategy to improve recruitment of immune effector cells to antibody-targeted tumors.
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DOI：
10.1158/0008-5472.can-12-3920
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发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Cai Z;Fu T;Nagai Y;Lam L;Yee M;Zhu Z;Zhang H
将免疫细胞募集至治疗性抗体靶向的肿瘤细胞可提高抗体的抗肿瘤功效。例如，p185 her 2/neu靶向抗体不仅下调p185 her 2/neu激酶（ERBB 2），而且通过抗体Fc区触发补体依赖性细胞毒性（CDC）和抗体依赖性细胞毒性（ADCC）。在这里，我们描述了一种通用的策略，以改善免疫细胞招募到靶向癌细胞，使用修饰的scFv抗体，我们称之为“grababody”，结合靶蛋白和内源性免疫球蛋白。我们用来说明该平台的效用的模型系统识别p185 her 2/neu，并包括IgG结合结构域。所产生的重组scFv grababody募集循环的人IgG，并将携带Fc受体的免疫细胞吸引到表达p185 her 2/neu的肿瘤细胞。IgG结合结构域的存在显著增强CDC和ADCC活性并改善体内抗肿瘤活性。我们的研究结果说明了一种新的一般方法，以改善抗体样蛋白的治疗应用。
Recruitment of immune cells to tumor cells targeted by a therapeutic antibody can heighten the antitumor efficacy of the antibody. For example, p185her2/neu-targeting antibodies not only downregulate the p185her2/neu kinase (ERBB2) but also trigger complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) through the antibody Fc region. Here we describe a generalized strategy to improve immune cell recruitment to targeted cancer cells, using a modified scFv antibody we call a “grababody” that binds the target protein and endogenous immunoglobulins. The model system we used to illustrate the utility of this platform recognizes p185her2/neu and includes an IgG binding domain. The recombinant scFv grababody that was created recruited circulating human IgGs and attracted immune cells carrying Fc receptors to tumor cells that expressed p185her2/neu. The presence of the IgG binding domain significantly enhanced CDC and ADCC activity and improved anti-tumor activity in vivo. Our results illustrate a novel general approach to improve antibody-like proteins for therapeutic applications.