Human Monoclonal Antibodies that Bind Botulinum Toxins

结合肉毒杆菌毒素的人单克隆抗体

基本信息

批准号：
8432427
负责人：
SCOTT Kendall DESSAIN
金额：
$ 44.26万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432427
关键词：
Accounting Acute Address Adverse effects Affinity Antibodies Antigens Binding Biological Biological Assay Biological Products Blood Circulation Bontoxilysin Botulinum Toxin Type A Botulinum Toxins Botulism Categories Cell membrane Centers for Disease Control and Prevention (U.S.)Clinical Cloning Communicable Diseases Complex Development Disease Dose Drug Kinetics Enzyme-Linked Immunosorbent Assay Equus caballus Erythrocytes Exposure to Foundations Generations Goals Human Hybridomas Immune Immune Sera Immunotherapeutic agent Infectious Agent Knowledge Measures Mediating Metabolic Clearance Rate Methods Microbe Mus National Institute of Allergy and Infectious Disease Paralysed Passive Immunization Patients Peptides Preparation Problem Solving Production Research Research Priority Risk Serotyping Staging Testing Therapeutic Therapeutic Polyclonal Antibodies Therapeutic antibodies TimeLine Toxin Triplet Multiple Birth Vaccines biodefense cost exposed human population human monoclonal antibodies improved in vivo new technology novel public health relevance research study screening small molecule weapons

项目摘要

DESCRIPTION (provided by applicant): Botulinum neurotoxin (BoNT) is the most potent biological toxin known, the cause of the paralytic disease, botulism, and a potential bioterrorist weapon. Passive immunization with antibody therapeutics is considered to be the ideal countermeasure for a BoNT exposure, and the safest of these would be composed of human monoclonal antibodies. An important obstacle to the production of an effective antibody therapeutic strategy for BoNT is that BoNT exists in at least 7 serotypes, and most of the antibodies cloned thus far are not able to bind more than one serotype. In addition, effective neutralization requires that triplet combinations of antibodies be employed, so that neutralization of 3 toxin serotypes would require at least 9 distinct antibodies. This project addresses this problem by exploring a platform for the creation of human monoclonal antibody therapeutics capable of binding and neutralizing three distinct serotypes of BoNT, A, B, and E. The foundation of the plan is a hybridoma method of human antibody cloning that has generated a number of cross-reactive antibodies. This is combined with a novel means of increasing the in vivo potency of BoNT antibodies using a fusion peptide that may increase the rate of clearance of BoNT from the bloodstream. An important aspect of the study is an ultra-high sensitivity ELISA, developed using human monoclonal antibodies, which will allow pharmacokinetic study of low doses of BoNT bound to antibody:fusion peptide complexes in real-world in vivo exposure scenarios.

描述（由申请人提供）：肉毒神经毒素（BONT）是已知的最有效的生物毒素，是麻痹性疾病，肉毒杆菌和潜在的生物恐怖主义武器的原因。用抗体疗法的被动免疫被认为是暴露于BONT的理想对策，其中最安全的是由人类单克隆抗体组成。生产有效的BONT抗体治疗策略的一个重要障碍是至少7种血清型中存在BONT，到目前为止，克隆的大多数抗体无法绑定多种血清型。此外，有效中和要求使用抗体的三联体组合，以便3种毒素血清型的中和至少需要9种不同的抗体。该项目通过探索建立人类单克隆抗体治疗剂的平台来解决这个问题，该抗体疗法能够结合和中和三种不同的血清型BONT，A，B和E。这与使用融合肽增加体内抗体的体内效力的新型方法相结合，该融合肽可能会增加血液中骨的清除率。该研究的一个重要方面是使用人类单克隆抗体开发的超高灵敏度ELISA，它将允许对与抗体结合的低剂量的BONT：融合肽络合物的药代动力学研究：实际体内暴露情况中的融合肽络合物。