Human monoclonal antibodies for prevention of S. aureus infections

用于预防金黄色葡萄球菌感染的人单克隆抗体

基本信息

批准号：
8851014
负责人：
Gunnar Joerg Floris Kaufmann
金额：
$ 99.92万
依托单位：
SORRENTO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-06 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851014
关键词：
AIDS/HIV problem Affinity American Animal Model Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antibody Formation Bacteremia Bacteria Bacterial Antibiotic Resistance Bacterial Infections Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Communities Cyclic GMP Data Development Dose Drug Kinetics Drug resistance Ensure Evaluation Generations Growth Healthcare Human Immune system Immunoglobulin G Immunotherapeutic agent In Vitro Infection Infection prevention Influenza Invaded Libraries Licensing Mediator of activation protein Modeling Monoclonal Antibodies Montana Morbidity - disease rate Mus Osteomyelitis Peptide antibodies Peptides Phase Pneumonia Preparation Prevention Production Property Public Health Recruitment Activity Research Research Institute Research Personnel Resistance Resistance development Running Small Business Technology Transfer Research Staphylococcus aureus Technology Testing Therapeutic Toxic effect Universities Validation Virulence Work Wound Healing antibody engineering base cell bank combat efficacy testing human disease human monoclonal antibodies humanized antibody in vivo methicillin resistant Staphylococcus aureus mortality mouse model novel strategies pathogen pre-clinical pressure prevent prophylactic quorum sensing research study scale up stability testing

项目摘要

DESCRIPTION (provided by applicant): Using mouse monoclonal antibodies (mAbs) raised against the mediators of quorum sensing (QS), the Auto-Inducing Peptides (AIPs), researchers at The Scripps Research Institute (TSRI) have demonstrated that S. aureus infections can be prevented in animal challenge models. This approach, known as quorum quenching (QQ) is unique in at least two significant ways: first, rather than eliminating bacteria associated with infection, the QQ approach modulates the global virulence of the invading pathogens, thus allowing the bacteria to be cleared by the host's immune system; second, the AIPs are not essential for the growth of the bacteria per se, so the selective pressure for the generation of resistance should be greatly reduced. Sorrento Therapeutics, Inc. (STI) has licensed QQ technology from TSRI. STI will humanize anti-AIP mouse mAbs and isolate a fully human anti-AIP2 antibody from its proprietary antibody library then combine them into the product candidate STI-001, a single tetraspecific antibody-like molecule, to prevent S. aureus infections through QQ. We here outline experiments for the development and validation of STI-001, an IgG-like molecule that would virtually eliminate morbidity and mortality when used in prophylactic settings. In Phase I, the murine anti-AIP mAbs 15B4 and 24H11 will be humanized, and characterized in vitro as well as in animal models. In addition, a human mAb against the remaining AIP not covered by the TSRI mAbs, namely AIP-2, will be identified from STI's antibody library and also generated. The anti-AIP mAbs will be combined into a single IgG-like molecule, namely product candidate STI-001, evaluated in vitro as well as in vivo and taken into STTR Phase II. In Phase II, STI-001 will be produced in large scale for testing in additional animal models and preclinical development, e.g. pharmacokinetic (PK), -dynamic (PD) and toxicological analyses as well as dosing studies. We will also generate a master cell bank and prepare/initiate IND filling. This immunotherapeutic approach of sequestering the mediators of bacterial virulence in order to prevent infection will provide a much needed alternative to traditional antibiotic-based treatments to ameliorate S. aureus infections, including those resistant to antibiotics.

描述（由申请人提供）：使用针对群体传感介质（QS），自动诱导肽（AIPS）提出的小鼠单克隆抗体（MAB），Scripps研究所（TSRI）的研究人员证明，S. Aureus感染可以在动物挑战模型中预防。这种称为法定淬灭（QQ）的方法至少在两种重要方面是独一无二的：首先，而不是消除与感染相关的细菌，而是调节了入侵病原体的全局毒力，从而使细菌可以由宿主的免疫系统清除；其次，AIP对于细菌本身的生长不是必不可少的，因此应大大降低产生抗性的选择性压力。 Sorrento Therapeutics，Inc。（STI）已获得TSRI的QQ技术。 STI将使抗AIP小鼠mAb人体化并从其专有抗体文库中分离出完全人类的抗AIP2抗体，然后将它们合并到产物候选STI-001（一种单个四种抗体样分子）中，以防止金黄色葡萄球菌通过QQ进行。我们在这里概述了STI-001的开发和验证的实验，STI-001是一种类似IgG的分子，在预防性环境中使用时实际上可以消除发病率和死亡率。在第一阶段，鼠类抗AIP mAb 15B4和24H11将被人性化，并在体外和动物模型中被表征。此外，将从STI的抗体库中鉴定出对TSRI mABS（即AIP-2）未覆盖的剩余AIP的mAb，也将生成。抗AIP mAB将合并为单个IgG样分子，即产品候选STI-001，在体外和体内进行了评估，并将其分为STTR II期。在第二阶段，将大规模生产STI-001，以在其他动物模型和临床前开发中进行测试，例如药代动力学（PK）， - 动力学（PD）和毒理学分析以及给药研究。我们还将生成一个主电池库，并准备/启动IND填充。为了防止感染的细菌毒力介质的这种免疫治疗方法将为传统的基于抗生素的疗法提供急需的替代方法，以减轻金黄色葡萄球菌感染，包括那些对抗生素耐药性的感染。