Human Monoclonal Antibodies that Bind Botulinum Toxins

结合肉毒杆菌毒素的人单克隆抗体

• 批准号: 7597256
• 负责人: SCOTT Kendall DESSAIN
• 金额: $ 20.77万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7597256
• 关键词: Amino Acid Sequence; Antibodies; Antibody Formation; B-Lymphocytes; Binding; Biological Assay; Bontoxilysin; Botulinum Toxin Type A; Botulinum Toxins; Categories; Cell Line; Cloning; Complex; Development; Epitopes; Gene Family; General Population; Heparin; Human; Human Cloning; Hybridomas; In Vitro; Individual; Interleukin-6; Methods; Military Personnel; Monoclonal Antibodies; Mus; Names; National Institute of Allergy and Infectious Disease; Neuromuscular Blocking Agents; Peripheral Blood Lymphocyte; Platelet Factor 4; Polysaccharides; Process; Protocols documentation; Publishing; Purpose; Research Personnel; Screening procedure; Seminal; Serotyping; Somatic Mutation; Sorting - Cell Movement; Source; State Government; Streptococcus pneumoniae; Telomerase; Testing; Therapeutic; Therapeutic antibodies; Toxin; Toxoids; United States; Vaccinated; Vaccination; Vaccines; Vaccinia virus; Viral Antigens; Work; base; botulinum; botulinum toxin type B; chimeric antibody; human monoclonal antibodies; in vivo; neutralizing antibody; novel; novel therapeutics; programs; research study; response; volunteer

DESCRIPTION (provided by applicant): Botulinum neurotoxin (BoNT) is an extremely potent neuromuscular blocker that has been designated a category A select bioterror agent by the United States Government because of its extreme lethality and its availability from environmental sources. Current countermeasures for BoNT exposure are insufficient, and there is an urgent need for therapeutic antibodies able to counteract the effects of BoNT exposure. Our working hypothesis is that a combination of human antibodies that bind BoNT will potently protect individuals from the complications of BoNT exposure. We have recently developed a novel hybridoma protocol for the cloning of human antibodies and have used it to clone antibodies that bind BoNT serotypes A and B. One of the serotype A antibodies is neutralizing in vivo. We plan to use our method to clone native human antibodies that bind and neutralize botulinum toxin serotypes A and B. For this purpose we will obtain peripheral blood lymphocytes from individuals vaccinated with the botulinum toxoid vaccine. We will assess in vitro and in vivo neutralizing activities of the cloned antibodies, singly and in combination. We will characterize the binding and primary sequences of the antibodies to determine the features that correlate with the ability to neutralize toxin and to cooperate synergistically in toxin neutralization. The primary result of these experiments will be the creation of combinations of cloned human antibodies that can effectively counteract BoNT/A and BoNT/B exposure.

描述（由申请人提供）：肉毒杆菌神经毒素（BoNT）是一种极其有效的神经肌肉阻滞剂，由于其极高的杀伤力和可从环境来源获得，已被美国政府指定为 A 类精选生物恐怖剂。目前针对 BoNT 暴露的对策还不够，迫切需要能够抵消 BoNT 暴露影响的治疗性抗体。我们的工作假设是，结合 BoNT 的人类抗体组合将有效保护个体免受 BoNT 暴露的并发症。我们最近开发了一种用于克隆人类抗体的新型杂交瘤方案，并用它来克隆结合 BoNT 血清型 A 和 B 的抗体。其中一种血清型 A 抗体在体内具有中和作用。我们计划使用我们的方法来克隆结合并中和肉毒杆菌毒素血清型 A 和 B 的天然人类抗体。为此，我们将从接种肉毒杆菌毒素疫苗的个体中获得外周血淋巴细胞。我们将评估克隆抗体的单独和组合的体外和体内中和活性。我们将表征抗体的结合序列和一级序列，以确定与中和毒素的能力相关的特征以及在毒素中和中协同合作的能力。这些实验的主要结果将是创建能够有效抵消 BoNT/A 和 BoNT/B 暴露的克隆人类抗体组合。