Therapeutic Fully Human Monoclonal Antibodies against Vaccina Virus and Smallpox

抗疫苗病毒和天花的治疗性全人单克隆抗体

基本信息

批准号：
7591129
负责人：
Shane P Crotty
金额：
$ 206.85万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591129
关键词：
Adverse effects Affinity Age Animal Model Antibodies Avian Influenza Benchmarking Biological Assay Biology Bioterrorism Breathing Cell Line Characteristics Chinese Hamster Ovary Cell Clinical Research Clinical Trials Combined Modality Therapy Cyclic GMP Development Disease Outbreaks Dose Eczema Vaccinatum Event Fright Funding Future Goals Gold Grant Human Immunization Immunoglobulin G Immunoglobulins Immunotherapy In Vitro Individual Infection Investigational Drugs Investigational New Drug Application Left Licensing Licensure Life M2 protein Measures Military Personnel Modeling Monkeypox Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease Performance Phase Phase I Clinical Trials Population Poxviridae Preclinical Testing Primates Production Prophylactic treatment Readiness Recombinants Replacement Therapy Research Design Research Personnel SCID Mice Safety Schedule Science Smallpox Smallpox Vaccine Smallpox Viruses Specific qualifier value Staging Structure Tail Testing Therapeutic Time TimeLine Tissues Toxicology Transgenic Mice Treatment Protocols Vaccinated Vaccination Vaccines Vaccinia Vaccinia virus Virion Virus Virus Diseases Work Xeno base biodefense blood product cGMP production cross reactivity extracellular human monoclonal antibodies in vitro Assay in vivo interest manufacturing process development mortality mouse model neutralizing monoclonal antibodies novel pre-clinical preclinical study programs research study scale up

项目摘要

DESCRIPTION (provided by applicant): Smallpox is a top bioterrorism concern. Smallpox is a highly lethal viral infection of humans (30% mortality), which can spread rapidly through a population. Furthermore, there is an active smallpox vaccination campaign in the USA military, and VIG (Vaccinia Immune Globulin) is used to treat rare severe side effects of vaccination. VIG can also be used to treat smallpox infections. Problems with VIG-particularly the small number of VIG doses available and their limited potency-have led to great interest in the development of a better anti-vaccinia and anti-smallpox immunotherapy. Indeed, the NIAID High Priority Biodefense Products list includes "High titer/concentrated Vaccinia Immune Globulin (VIG) or replacement product based on monoclonal antibodies (mAbs)" as the first desired biodefense product. Our project goal is to develop a highly efficacious, highly standardized mAb replacement of VIG that can be produced in large quantities and stored long term. Fully human mAbs are the best possible form of mAbs for use in humans, eliminating all xeno / rejection issues. Gemini Science, Inc. has transgenic mice possessing the human immunoglobulin loci and thereby produce fully human antibodies. We have used these mice to develop fully human anti-poxvirus monoclonal antibodies that neutralize vaccinia virus in vitro and are protective in vivo in preliminary experiments. We will now fully demonstrate efficacy of these anti-poxvirus monoclonal antibodies in vitro and in vivo, and scale up production of sufficient mAbs to complete all preclinical testing and IND filing. Licensure of a mAb VIG replacement therapeutic product should be based on a demonstration of equal or better activity ("noninferiority") of the mAbs in the same in vivo and in vitro assays used to validate VIG for licensure, and a demonstration of superiority to VIG in safety, dosing, and product manufacturing features (e.g., ability to standardize the mAb product and produce it in large quantities). Our human anti-poxvirus mAbs are likely to succeed by all of these criteria.

描述（由申请人提供）：天花是最重要的生物恐怖主义。天花是人类高度致命的病毒感染（30％死亡率），可以通过人群迅速传播。此外，美国军方进行了一场主动的天花疫苗接种运动，VIG（Vaccinia Immune Globulin）用于治疗罕见的严重疫苗接种副作用。 VIG也可用于治疗天花感染。 vig局部的问题少数可用的vig剂量及其有限的效力 - 引起了人们对更好的抗Vaccinia和抗Smallpox免疫疗法的极大兴趣。实际上，NIAID高优先级生物固定产品列表包括“基于单克隆抗体（MAB）的高滴度/浓缩疫苗免疫球蛋白（VIG）或替换产品”，作为第一个所需的生物fest素产品。我们的项目目标是开发高效，高度标准化的MAB替换VIG，可以大量生产并长期存储。完全人物mAB是用于人类使用的MAB的最佳形式，消除了所有Xeno /拒绝问题。双子座科学公司具有具有人类免疫球蛋白基因座的转基因小鼠，从而产生了完全人类的抗体。我们已经使用这些小鼠开发了完全人类的抗POXVIRUS单克隆抗体，该抗体在体外中和离子病毒，并且在初步实验中具有保护性。现在，我们将充分证明这些抗PoxVirus单克隆抗体在体外和体内的功效，并扩大足够的单克隆抗体的生产以完成所有临床前测试和IND归档。 MAB VIG替换治疗产品的许可应基于在体内和体内和体外测定中的均等或更好的活动（“非屈服”）的证明，用于验证许可的VIG，以及在安全，剂量和生产制造功能（例如，能够标准化的产品和生产量）中，以vig的优势来证明Mab的优势。通过所有这些标准，我们人类的抗poxvirus mab可能会成功。