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

• 批准号: 8882238
• 负责人: Gunnar Joerg Floris Kaufmann
• 金额: $ 99.84万
• 依托单位: SORRENTO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882238
• 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; Superbug; Technology; Testing; Therapeutic; Toxic effect; Universities; Validation; Virulence; Work; Wound Healing; antibody engineering; base; cell bank; co-infection; 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

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)：斯克里普斯研究所(TSRI)的研究人员利用针对群体感应(QS)媒介--自动诱导肽(AIP)的鼠单抗(MAbs)，证明了在动物挑战模型中可以预防金黄色葡萄球菌感染。这种被称为群体猝灭(QQ)的方法至少在两个重要方面是独特的：第一，QQ方法不是消除与感染相关的细菌，而是调节入侵病原体的全球毒力，从而允许细菌被宿主的免疫系统清除；第二，AIP对细菌本身的生长不是必不可少的，因此应该大大降低产生耐药性的选择压力。索伦托治疗公司(STI)已经从TSRI获得了QQ技术的许可。STI将人源化抗AIP小鼠单抗，并从其专有抗体库中分离出全人抗AIP2抗体，然后将其结合到产品候选STI-001中，这是一个单一的四特异性抗体样分子，通过QQ预防金黄色葡萄球菌感染。我们在这里概述了开发和验证STI-001的实验，STI-001是一种类似免疫球蛋白的分子，当用于预防环境时，几乎可以消除发病率和死亡率。在第一阶段，小鼠抗AIP单抗15B4和24H11将人源化，并在体外和动物模型中进行鉴定。此外，还将从STI的抗体库中鉴定并产生一种针对TSRI单抗中未涵盖的剩余AIP的人源性mAb，即AIP-2。抗AIP单抗将结合成单一的类免疫球蛋白分子，即候选产品STI-001，进行体外和体内评估，并进入STTR第二阶段。在第二阶段，STI-001将大规模生产，用于其他动物模型的测试和临床前开发，例如药代动力学(PK)、动力学(PD)和毒理学分析以及剂量研究。我们还将生成一个主细胞库，并准备/启动IND填充。这种隔离细菌毒力介质以防止感染的免疫治疗方法将提供一种亟需的替代传统抗生素治疗的方法，以改善金黄色葡萄球菌感染，包括那些对抗生素具有耐药性的感染。