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:8882238
- 负责人:
- 金额:$ 99.84万
- 依托单位:
- 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 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAffinityAmericanAnimal ModelAnimalsAntibiotic ResistanceAntibiotic TherapyAntibioticsAntibodiesAntibody FormationBacteremiaBacteriaBacterial Antibiotic ResistanceBacterial InfectionsCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeCommunitiesCyclic GMPDataDevelopmentDoseDrug KineticsDrug resistanceEnsureEvaluationGenerationsGrowthHealthcareHumanImmune systemImmunoglobulin GImmunotherapeutic agentIn VitroInfectionInfection preventionInfluenzaInvadedLibrariesLicensingMediator of activation proteinModelingMonoclonal AntibodiesMontanaMorbidity - disease rateMusOsteomyelitisPeptide antibodiesPeptidesPhasePneumoniaPreparationPreventionProductionPropertyPublic HealthRecruitment ActivityResearchResearch InstituteResearch PersonnelResistanceResistance developmentRunningSmall Business Technology Transfer ResearchStaphylococcus aureusSuperbugTechnologyTestingTherapeuticToxic effectUniversitiesValidationVirulenceWorkWound Healingantibody engineeringbasecell bankco-infectioncombatefficacy testinghuman diseasehuman monoclonal antibodieshumanized antibodyin vivomethicillin resistant Staphylococcus aureusmortalitymouse modelnovel strategiespathogenpre-clinicalpressurepreventprophylacticquorum sensingresearch studyscale upstability 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):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、自动诱导肽 (AIP) 产生的小鼠单克隆抗体 (mAb) 证明,金黄色葡萄球菌感染可以在动物挑战模型中预防。这种被称为群体淬灭 (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整体毒力,从而使细菌被细菌清除。宿主的免疫系统;其次,AIP对于细菌本身的生长并不是必需的,因此产生耐药性的选择压力应该大大降低。 Sorrento Therapeutics, Inc. (STI) 已获得 TSRI 的 QQ 技术许可。 STI 将人源化抗 AIP 小鼠单克隆抗体,并从其专有抗体库中分离出全人源抗 AIP2 抗体,然后将其组合到候选产品 STI-001(一种单一四特异性抗体样分子)中,以通过 QQ 预防金黄色葡萄球菌感染。我们在这里概述了 STI-001 的开发和验证实验,STI-001 是一种类似 IgG 的分子,在预防性环境中使用时几乎可以消除发病率和死亡率。在第一阶段,鼠抗 AIP 单克隆抗体 15B4 和 24H11 将被人源化,并在体外和动物模型中进行表征。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 的人 mAb,即 AIP-2。抗 AIP mAb 将被组合成单个 IgG 样分子,即候选产品 STI-001,在体外和体内进行评估,并进入 STTR II 期。在第二阶段,STI-001将大规模生产,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) 和毒理学分析以及剂量研究。我们还将生成主细胞库并准备/启动 IND 填写。这种隔离细菌毒力介质以预防感染的免疫治疗方法将为传统的基于抗生素的治疗提供一种急需的替代方案,以改善金黄色葡萄球菌感染,包括那些对抗生素耐药的感染。
项目成果
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Gunnar Joerg Floris Kaufmann其他文献
Gunnar Joerg Floris Kaufmann的其他文献
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