Hybridoma (Monoclonal Antibody) Core

杂交瘤（单克隆抗体）核心

• 批准号: 7706296
• 负责人: MATTHEW D SCHARFF
• 金额: $ 36.01万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706296
• 关键词: Affinity; Antibodies; Antigens; Antitoxins; Antiviral Agents; Ascites; Autoimmunity; Bacillus anthracis; Biological; Bioterrorism; Cancer Center; Cells; Cloning; Commit; Communicable Diseases; Country; Decision Making; Diphtheria Toxin; E protein; Enterotoxins; Epidemic; Faculty; Fiber; Freezing; Funding; Generations; Goals; Human; Human Resources; Hybridomas; Immune Sera; Immunity; Immunization; Immunoglobulin Somatic Hypermutation; In Vitro; Individual; Institution; Learning; Liquid substance; Malignant Neoplasms; Mediating; Medicine; Monoclonal Antibodies; Morbidity - disease rate; Mus; Numbers; Persons; Process; Production; Productivity; Property; Protein Subunits; Proteins; Public Health; Rate; Rattus; Research Personnel; SCID Mice; Screening procedure; Serum; Staphylococcus aureus; Technology; Testing; Tetanus; Therapeutic; Therapeutic antibodies; Time; Toxin; Training; United States; Viral; Virus; West Nile virus; Work; activation-induced cytidine deaminase; anthrax lethal factor; anthrax toxin; college; edema factor; flasks; in vivo; member; mortality; neutralizing antibody; passive antibodies; pressure; prophylactic; size; tissue culture; virus envelope

Passive antibody administration is the only strategy available for conferring immediate immunity to individuals exposed to biological weapons. Furthermore, toxin-specific antibodies are toxin neutralizing agents par excellence and currently constitute the only means of neutralizing toxins in the human host. The efficacy of antitoxin sera in human therapy is known since the 1890s when Behring and Kitasato developed antisera to tetanus and diphtheria toxins and demonstrated their prophylactic and therapeutic properties. However, despite a century of immunological study we know relatively little about what antibody properties are important for antitoxin efficacy and the mechanisms involved in toxin neutralization are largely conjecture. This application is focused on the generation of antibodies to four toxins: B. anthracis toxins (protective antigen, lethal factor, and edema factor protein subunits) and Staphylococcus aureus enterotoxin with the goal of generating therapeutic antibodies to protect against biological attack with these agents. In addition we will generate neutralizing antibodies to West Nile Virus (WNV). The United States is currently in the midst of an unfolding WNV epidemic and there has been some concern that this agent was deliberately introduced into this country in an act of bioterrorism. While this is unlikely, the morbidity and mortality associated with WNV remain a significant public health concern. Four Specific Aims are proposed: 1) To generate neutralizing (murine and human) mononclonal antibodies to anthrax toxin protein components, S. aureus enterotroxin, and WNV envelope (E) protein; 2) To identify the antibody attributes necessary for optimal toxin and viral neutralizing activity; 3) To generate very high affinity derivatives of neutralizing antitoxin and antiviral mAbs by increasing the rate of somatic hypermutation in selected hybridomas through expression of activation induced deaminase (AID); 4) To identify the mechanism(s) of antibody-mediated toxin and virus neutralization.

被动抗体给药是唯一可用于赋予立即免疫的策略， 暴露在生物武器下的人。此外，毒素特异性抗体是毒素中和性的。 这些药剂是最优秀的，目前是中和人体内毒素的唯一手段。的 自19世纪90年代Behring和Kitasato开发出抗毒素血清以来， 破伤风和白喉毒素的抗血清，并证明了其预防和治疗特性。 然而，尽管经过了世纪的免疫学研究， 对于抗毒素功效是重要的，并且毒素中和中涉及的机制主要是 猜想本申请集中于产生针对以下四种毒素的抗体：B。炭疽毒素 （保护性抗原、致死因子和水肿因子蛋白亚基）和金黄色葡萄球菌肠毒素 目的是产生治疗性抗体以防止这些试剂的生物攻击。在 此外，我们将产生西尼罗河病毒（WNV）的中和抗体。美国目前在 西尼罗河病毒正在蔓延，有人担心这种病毒是故意传播的。 在生物恐怖活动中被引入这个国家虽然这不太可能，但发病率和死亡率 与西尼罗河病毒相关的疾病仍然是一个重大的公共卫生问题。提出了四个具体目标：1） 产生针对炭疽毒素蛋白组分的中和性（鼠和人）单克隆抗体，S. 金黄色葡萄球菌肠营养素和WNV包膜（E）蛋白; 2）为了鉴定 最佳的毒素和病毒中和活性; 3）产生非常高亲和力的中和衍生物， 抗毒素和抗病毒mAb，通过增加选定杂交瘤中的体细胞超突变率， 活化诱导的脱氨酶（AID）的表达; 4）为了鉴定抗体介导的脱氨酶的机制， 毒素和病毒中和。