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: 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
• 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

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）的研究人员使用针对群体感应（QS）介质（自诱导肽（AIP））的小鼠单克隆抗体（mAb）证明了S。在动物攻击模型中可以预防金黄色葡萄球菌感染。这种称为群体淬灭（QQ）的方法至少在两个重要方面是独特的：首先，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局毒力，从而允许细菌被宿主的免疫系统清除;其次，AIP本身不是细菌生长所必需的，因此产生耐药性的选择压力应大大降低。Sorrento Therapeutics，Inc. (STI)已经从TSRI获得了QQ技术的授权。STI将人源化抗AIP小鼠mAb，并从其专有抗体库中分离全人抗AIP 2抗体，然后将它们联合收割机组合成候选产品STI-001，一种单一的四特异性抗体样分子，以预防S.通过QQ感染金黄色葡萄球菌。我们在这里概述了STI-001的开发和验证实验，STI-001是一种IgG样分子，当用于预防性治疗时，几乎可以消除发病率和死亡率。在I期，鼠抗AIP mAb 15 B4和24 H11将被人源化，并在体外以及动物模型中表征。此外，还将从STI的抗体库中鉴定并生成针对TSRI mAb未涵盖的剩余AIP（即AIP-2）的人mAb。将抗AIP mAb组合成单个IgG样分子，即候选产品STI-001，进行体外和体内评价，并纳入STTR II期。在II期，将大规模生产STI-001，用于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。我们还将生成主细胞库并准备/启动IND灌装。这种隔离细菌毒力介质以预防感染的免疫方法将为传统的基于抗生素的治疗提供急需的替代方案，以改善S。金黄色葡萄球菌感染，包括对抗生素耐药的感染。