Development of botulinum neurotoxin immunotherapy, serotypes C, D, F, and G

肉毒杆菌神经毒素免疫疗法（血清型 C、D、F 和 G）的开发

• 批准号: 8547992
• 负责人: James D. Marks
• 金额: $ 8.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547992
• 关键词: Achievement; Affinity; Agreement; Animal Model; Animals; Antibodies; Antibody Affinity; Antitoxins; Binding; Biological Assay; Bioterrorism; Blood Circulation; Bontoxilysin; Botulinum Toxin Type A; Botulism; Categories; Cell Line; Centers for Disease Control and Prevention (U.S.); Chinese Hamster Ovary Cell; Clinical Trials; Communicable Diseases; Complex; Contracts; Country; DNA Fingerprinting; DNA Sequence; Development; Disease; Diversity Library; Engineering; England; Ensure; Epitopes; Fingerprint; Finland; Funding; Generations; Genes; Genetic Polymorphism; Genetic Variation; Goals; Human; Immunization; Immunoglobulin Fragments; Immunoglobulin G; Immunotherapy; In Vitro; Individual; Intensive Care; Intoxication; Italy; Laboratories; Length; Libraries; Light; Medical Research; Microbial Genetics; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Pathway interactions; Pharmacologic Substance; Prevention; Production; Recombinants; Research; Research Institute; Research Personnel; Russia; Serotyping; Staging; Toxin; Toxoids; United States; Western Asia Georgia; Work; Yeasts; antibody engineering; base; botulinum; botulinum toxin type C; cross reactivity; experience; high risk; in vivo; neutralizing antibody; novel; prevent; programs; repository; vaccine development

DESCRIPTION (provided by applicant): Botulinum neurotoxins (BoNTs) are classified by the Centers for Disease Control as one of the 6 highest-risk threat agents for bioterrorism (the "Category A agents"), due to their extreme potency and lethality, ease of production and transport, and need for prolonged intensive care. BoNTs have been produced and weaponized by rogue nations and deployed by terrorist groups. As a result of these threats, specific pharmaceutical agents are needed for prevention and treatment of intoxication. The only near term product for treatment of botulism that has been validated in animals and humans is antitoxin. Under previous NIAID funding, we have generated a potent human compatible recombinant monoclonal antibody based antitoxin for BoNT serotypes A, B, and E. The BoNT/A recombinant antitoxin is currently being developed under separate NIAID funding for human clinical trials. The overall goal of this proposal is to generate novel human compatible monoclonal antibodies (mAbs) that can be used to prevent and treat botulism caused by BoNT serotypes C, D, F, and G. Achievement of this goal requires three components: 1) determination of the extent of BoNT gene diversity of these 4 toxin serotypes (C, D, F, and G); 2) generation of panels of broadly neutralizing human compatible mAbs to the four BoNT serotypes; and 3) in vitro and in vivo characterization of mAbs with respect to serotype cross reactivity and toxin neutralization. These goals will be achieved by an inter-institutional team of botulism experts who have worked in this field for more than 13 years: James D. Marks, antibody engineering and Leonard Smith, BoNT vaccine development, toxin and toxin fragment generation and animal models of toxin neutralization. They will be assisted by an expert in microbial genetic characterization, Karen Hill, at Los Alamos National Laboratory, who will define the extent of toxin diversity to ensure that antibodies neutralize all possible toxin subtypes. At the end of the funding period we anticipate having generated a recombinant antitoxin for BoNT serotypes C, D, F, and G that can be transferred into the manufacturing and late stage development pathway. Combined with previous results, this will make available a safe, efficacious human compatible antitoxin for all seven BoNT serotypes.

描述（由申请人提供）：肉毒神经毒素（BONTS）被疾病控制中心归类为生物恐怖主义的6种最高风险的威胁代理之一（“类别A类药物”），由于其极高的效力和致命性和致命性，生产和运输的易用性，易于生产和运输，并且需要延长延长的重症监护。流氓国家生产和武器，由恐怖组织部署。由于这些威胁，需要特定的药物来预防和治疗中毒。在动物和人类中已验证的肉毒杆菌病治疗的唯一近期产物是抗毒素。在先前的NIAID资金下，我们已经为BONT血清型A，B和E产生了有效的人类兼容的重组单克隆抗体抗体抗体。BONT/A A BONT/A A重组抗毒素目前正在用于人类临床试验的单独的NIAID资金下开发。该提案的总体目标是生成新型的人类兼容的单克隆抗体（mAb），可用于预防和治疗由Bont Perhotypes C，D，F，F和G引起的肉毒杆菌。该目标的实现需要三个组成部分：1）确定这些4 to toxin toxin erstypes toxin Serotypes（c，c，c，c，c，c，c，c）的程度）。 2）与四种BONT血清型的广泛中和人类兼容的mAb的生成； 3）在血清型交叉反应性和毒素中和的体外和体内表征。这些目标将由肉毒杆菌主义专家的机构间团队实现，他们在该领域工作了13年以上：詹姆斯·D·马克斯（James D.洛斯阿拉莫斯国家实验室（Los Alamos National Laboratory）的微生物遗传特征专家Karen Hill将为他们提供协助，他们将定义毒素多样性的程度，以确保抗体中和所有可能的毒素亚型。在资金期结束时，我们预计可以将可以转移到制造和后期开发途径中的BONT血清型C，D，F和G产生重组抗毒素。结合以前的结果，这将使所有七种BONT血清型成为安全，有效的人兼容抗毒素。