Identification of the molecular mechanism that leads to a resistance against pseudomonas exotoxin A based immunotoxins

鉴定导致对基于假单胞菌外毒素 A 的免疫毒素产生抗性的分子机制

• 批准号: 234512553
• 负责人: Dr. Fabian Müller
• 金额: --
• 依托单位: Laboratory of Biochemistry and Molecular Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234512553?language=en
• 关键词: Identification; molecular; mechanism; leads; resistance

During the last decades, a vast variety of different immunotoxins were developed by fusing bacterial toxin components like the catalytic domain of pseudomonas exotoxin A (PE) to antibodies or receptor-binding ligands. A broadly evaluated representative of such targeted therapeutics is the fusion protein HA22 which is a combination of a CD22-binding FAB and PE which is effective in many B-cell lymphomas by ADP-ribosylation of the elongation factor 2 (EF2) and subsequently by inhibition of protein biosynthesis. Due to this event, the cell is driven into programmed cell death. Some lymphoma cells are resistant to the immunotoxin a priori. The group of Ira Pastan discovered HA22-resistant cells in which the EF2 gets ADP-ribosylated and protein synthesis stops, but the cells do not undergo apoptosis. Some of these primary HA22-resistant cells can be sensitized to HA22 by specific small molecule compounds. In the project proposed here, we will compare the protein expression profile of primary resistant, secondarily sensitized and primary sensitive cells with each other to elucidate the underling molecular mechanism behind this resistance. This knowledge will be used to predict response to therapy and thus save patients from ineffective treatment and, in addition, to boost the effects of ADP-ribosylating toxins.Since the broadly used ADP-ribosylating immunotoxins diphtheria toxin, cholix toxin, ricin, and pseudomonas exotoxin share a common apoptosis-inducing mechanism, this work is of great interest for numerous targeted therapies in modern oncology.

在过去的几十年中，通过将细菌毒素组分如假单胞菌外毒素A（PE）的催化结构域融合到抗体或受体结合配体来开发出各种不同的免疫毒素。 这种靶向治疗剂的广泛评价的代表是融合蛋白HA 22，其是CD 22结合FAB和PE的组合，其通过延伸因子2（EF 2）的ADP-核糖基化并随后通过抑制蛋白质生物合成在许多B细胞淋巴瘤中有效。 由于该事件，细胞被驱使进入程序性细胞死亡。 一些淋巴瘤细胞先验地对免疫毒素具有抗性。 伊拉·帕斯坦的研究小组发现了HA 22抗性细胞，其中EF 2被ADP核糖基化，蛋白质合成停止，但细胞不发生凋亡。 这些原代HA 22抗性细胞中的一些可以通过特定的小分子化合物对HA 22敏化。 在这里提出的项目中，我们将比较原发性耐药、继发性致敏和原发性敏感细胞的蛋白质表达谱，以阐明这种耐药背后的分子机制。 这方面的知识将被用来预测治疗反应，从而挽救无效的治疗患者，此外，以提高ADP-核糖基化的免疫毒素白喉毒素，胆毒素，蓖麻毒素，和假单胞菌外毒素广泛使用的效果，因为有一个共同的肿瘤诱导机制，这项工作是在现代肿瘤学的许多靶向治疗的极大兴趣。