Costimulation of T cell proliferation by a chimeric B7-2 antibody fusion protein specifically targeted to cells expressing the erbB2 proto-oncogene.
Costimulation of T cell proliferation by a chimeric B7-2 antibody fusion protein specifically targeted to cells expressing the erbB2 proto-oncogene.
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通过专门针对表达 erbB2 原癌基因的细胞的嵌合 B7-2 抗体融合蛋白共同刺激 T 细胞增殖。
作者：
B. Gerstmayer;U. Altenschmidt;M. Hoffmann;W. Wels
T细胞的激活和克隆性扩增至少需要两种信号。第一个信号的特异性是由T细胞受体与MHC分子中的抗原肽相互作用而启动的。第二，共刺激信号可以由APC上的细胞表面分子提供，如B7-1(CD80)和B7-2(CD86)，它们与T细胞上的对应性受体相互作用。缺乏共刺激信号为肿瘤细胞逃避免疫监视提供了一种可能的机制。在实验模型中，将B7基因导入肿瘤细胞可导致T细胞依赖性肿瘤排斥反应。我们开发了一种新的方法将共刺激B7-2分子定向到靶细胞表面。我们的方法是基于嵌合融合蛋白，该融合蛋白由人B7-2的胞外区与ErbB2蛋白的单链抗体结构域(ScFv)融合而成，ErbB2蛋白是一种I型生长因子受体，在高比例的人类腺癌中过度表达。该B7-2(225)-ScFv(FRP5)分子在毕赤酵母中表达，并从培养上清液中纯化，具有功能活性，并与B7受体和ErbB2结合。B7-2(225)-ScFv(FRP5)特异性地定位于表达ErbB2的靶细胞表面，从而提供协同刺激信号，促进同基因T细胞的增殖。我们的结果表明，通过将嵌合配体靶向肿瘤细胞表面，可以创建用于癌症免疫治疗的有效肿瘤疫苗。
T cells require at least two signals for activation and clonal expansion. The first signal conferring specificity is initiated by interaction of the T cell receptor with antigenic peptides in the context of MHC molecules. The second, costimulatory signal can be provided by cell surface molecules on APCs such as B7-1 (CD80) and B7-2 (CD86), which interact with their counter-receptors on T cells. The absence of costimulatory signals presents one possible mechanism for tumor cells to escape immune surveillance. In experimental models transfection of B7 genes into tumor cells can result in T cell-dependent tumor rejection. We have developed a novel approach to direct the costimulatory B7-2 molecule to the surface of target cells. Our approach is based on a chimeric fusion protein that consists of the extracellular domain of human B7-2 fused to a single-chain Ab domain (scFv) specific for the ErbB2 protein, a type I growth factor receptor overexpressed in a high percentage of human adenocarcinomas. This B7-2(225)-scFv(FRP5) molecule expressed in the yeast Pichia pastoris and purified from culture supernatants is functionally active and binds to B7 counter-receptors and to ErbB2. B7-2(225)-scFv(FRP5) localizes specifically to the surface of ErbB2-expressing target cells, thereby providing a costimulatory signal that results in enhanced proliferation of syngeneic T cells. Our results suggest that effective tumor vaccines for cancer immunotherapy could be created by targeting such chimeric ligands to the surface of tumor cells.