Antibody-based bacterial cytotoxicity mediated by mechanisms independent of CDC and ADCC

由独立于 CDC 和 ADCC 的机制介导的基于抗体的细菌细胞毒性

• 批准号: 2243-2009
• 负责人: Hall, JChristopher
• 金额: $ 4.08万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=520461
• 关键词: Antibody; based; bacterial; cytotoxicity; mediated

In addition to their well-characterized functions of antigen recognition for destruction of specific targets through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), numerous antibodies, termed Abzymes, have been found to possess catalytic abilities such as hydrolysis of nucleotides, proteins, and polysaccharides, phosphorylation of proteins and lipids, and generation of free radicals. We have found that a monoclonal antibody (mAb), namely anti-Pseudomonas aeruginosa O6ad lipopolysaccaride (LPS) IgG1, and its recombinant antibody (rAb) fragments (Fab and scFv) exhibit cytotoxic activities against their specific target bacterium independent of ADCC and CDC. Our preliminary unpublished data indicate that this mAb has co-evolved two functions onto one molecule: specific binding to the surface of a pathogen, and the ability to kill it per se. We propose a five-year research program to test the hypothesis that this mAb and its fragments are catalytic in nature, and to elucidate the specific killing mechanism through experimentation involving biochemical, molecular, physiological, structural, analytic, immunological, genetic, and pharmacological techniques. We will also search for other antibodies with specific bactericidal characteristics, and to compare killing mechanisms for further understanding of this phenomenon. It is anticipated that research outcomes will result in greater understanding a novel mechanism of cytotoxicity with tremendous potential for further development of applications in medicine and health.

除了它们通过抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）破坏特异性靶标的抗原识别功能之外，已经发现许多抗体（称为Abzymes）具有催化能力，例如核苷酸、蛋白质和多糖的水解，蛋白质和脂质的磷酸化以及自由基的产生。我们发现抗铜绿假单胞菌O6ad脂多糖（LPS）的单克隆抗体（mAb）IgG1及其重组抗体（rAb）片段（Fab和scFv）对它们的特异性靶细菌具有不依赖ADCC和CDC的细胞毒活性。我们初步未发表的数据表明，这种mAb已经共同进化到一个分子上的两种功能：特异性结合病原体表面，以及杀死病原体本身的能力。我们提出了一个为期五年的研究计划，以测试的假设，这种单克隆抗体及其片段是催化的性质，并阐明具体的杀伤机制，通过实验涉及生化，分子，生理，结构，分析，免疫学，遗传学和药理学技术。我们还将寻找具有特定杀菌特性的其他抗体，并比较其杀伤机制，以进一步了解这种现象。预计研究成果将导致更好地理解细胞毒性的新机制，具有进一步开发医学和健康应用的巨大潜力。