Hansson J, Ohlsson L, Persson R, Andersson G, Ilbäck N G, Litton M J, Kalland T, Dohlsten M
Lund Research Center, Pharmacia & Upjohn, Sweden.
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2489-94. doi: 10.1073/pnas.94.6.2489.
Superantigens (SAg) are a family of bacterial and viral proteins with strong immunostimulatory properties. SAg bound to major histocompatibility complex (MHC) class II molecules activate a high frequency of T cells and represent the most potent known activators of T cells to date. To explore the use of SAg for T cell-based tumor therapy we have created a tumor-reactive SAg by engineering a fusion protein composed of a tumor-reactive mAb (C215Fab) and the bacterial SAg staphylococcal enterotoxin A (SEA). A point mutation D227A was introduced at the major MHC class II binding site in SEA to reduce systemic toxicity. Treatment of tumor bearing mice with the Fab-SEA D227A fusion protein resulted in profound antitumor effects with a markedly reduced toxicity as compared with the wild-type Fab-SEA fusion protein. The reduced toxicity was probably due to a weak distribution of the SEA D227A fusion protein in tissues with a high MHC class II expression and low systemic cytokine levels as exhibited in mice and rabbits. The data presented demonstrate the efficacy of immunoconjugates containing a mutated SAg in directing a T cell attack against tumor cells with minimal systemic immune activation.
超抗原（SAg）是一类具有强大免疫刺激特性的细菌和病毒蛋白。与主要组织相容性复合体（MHC）II类分子结合的超抗原可激活高频T细胞，是迄今为止已知的最有效的T细胞激活剂。为了探索超抗原在基于T细胞的肿瘤治疗中的应用，我们通过构建一种由肿瘤反应性单克隆抗体（C215Fab）和细菌超抗原葡萄球菌肠毒素A（SEA）组成的融合蛋白，创造了一种肿瘤反应性超抗原。在SEA的主要MHC II类结合位点引入点突变D227A以降低全身毒性。用Fab-SEA D227A融合蛋白治疗荷瘤小鼠产生了显著的抗肿瘤作用，与野生型Fab-SEA融合蛋白相比，毒性明显降低。毒性降低可能是由于SEA D227A融合蛋白在MHC II类表达高和全身细胞因子水平低的组织中分布较弱，如在小鼠和兔子中所示。所呈现的数据证明了含有突变超抗原的免疫缀合物在以最小的全身免疫激活引导T细胞攻击肿瘤细胞方面的有效性。
