Anti-Pseudomonas Immunotherapy and Targeted Drug Delivery

抗假单胞菌免疫治疗和靶向药物递送

• 批准号: 8785992
• 负责人: Gunnar Joerg Floris Kaufmann
• 金额: $ 29.87万
• 依托单位: SORRENTO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785992
• 关键词: Acute; Affinity; Antibiotics; Antibodies; Antibody Therapy; Antigen Targeting; Antitoxins; Applications Grants; Azithromycin; Bacteria; Bacterial Infections; Binding; Biochemical; Biological Assay; Cells; Chronic; Clinical; Clinical Trials; Colistin; Data; Deltastab; Development; Drug Delivery Systems; Drug resistance; Equus caballus; Evaluation; Family suidae; Future; Generations; Growth; Human; Immune; Immune Sera; Immunotherapy; In Vitro; Infection; Inorganic Sulfates; Laboratories; Lead; Libraries; Link; Lung; Mediating; Membrane Proteins; Methodology; Micelles; Microbial Biofilms; Modeling; Monoclonal Antibodies; Mus; Ohio; Organ failure; Passive Immunotherapy; Patients; Pharmaceutical Preparations; Phase; Prevention; Property; Pseudomonas; Pseudomonas aeruginosa; Safety; Serum; Small Business Technology Transfer Research; Technology; Therapeutic; Treatment Efficacy; Universities; Unspecified or Sulfate Ion Sulfates; Vaccine Antigen; analytical method; base; biophysical properties; capsule; cost; drug resistant bacteria; efficacy evaluation; high risk; human monoclonal antibodies; in vivo; killings; member; method development; particle; pathogen; pre-clinical; prevent; public health relevance; small molecule; wound

DESCRIPTION (provided by applicant): Antibody therapy for serious bacterial infections using polyclonal immune antitoxin or anti-capsule horse serum actually predates small molecule antibiotic use. However, for reasons of safety, convenient empirical use, and cost, the development of broader-spectrum antibiotics rapidly supplanted the use of immune serum. But drug resistance is quickly reducing the number of effective antibiotics available for treatment of severe bacterial infections while advances in human monoclonal antibody (mAb) technologies have led to reconsideration of immunotherapies. Therefore, passive immunotherapies could be effective in preventing or treating high-risk infections caused by drug-resistant bacterial pathogens, such as Pseudomonas aeruginosa, a highly adaptable opportunistic bacterium. Our target antigens for this proposal, the outer membrane proteins OprF and OprI, were chosen because of sequence conservation among clinical isolates and their use as vaccine antigens in several clinical trials. Sorrento Therapeutics, Inc. has developed proprietary technologies, namely its G-MAB(R) library for selection of fully human antibodies as well as "antibody formulated drug conjugate" (AfDC) methodology for generation of targeted micelles. We propose to generate and evaluate anti-OpfF/I mAbs as well as AfDCs, i.e. colistin sulfate/azithromycin-containing micelles linked to selected anti-P. aeruginosa mAbs. The studies will be performed together with our academic collaborator Dr. Daniel Wozniak (Ohio State University). The most promising mAbs and AfDCs will be thoroughly evaluated in vitro and in vivo for their ability to prevent and/or treat local as well as systemic P. aeruginosa infection. Specifically, the projects of our STTR Advanced Technology Phase I grant application are: Project 1 - In vitro evaluation and prioritization of the selected human anti-OprF/I mAbs; Project 2 - Generation and in vitro evaluation of anti-Pseudomonas AfDCs; Project 3 - In vivo evaluation of mAbs/AfDCs in murine and porcine P. aeruginosa infection models. The proposed product, a fully human anti-P. aeruginosa mAb immunotherapy or an AfDC as targeted antibiotic delivery vehicle, would be an effective and safe stand-alone and/or member of a "cocktail" therapeutic option for prevention or treatment of P. aeruginosa infections.

描述(申请人提供)：使用多克隆免疫抗毒素或抗胶囊马血清对严重细菌感染进行抗体治疗实际上早于使用小分子抗生素。然而，出于安全、方便的经验性使用和成本的原因，广谱抗生素的开发迅速取代了免疫血清的使用。但耐药性正在迅速减少可用于治疗严重细菌感染的有效抗生素的数量，而人类单抗(MAb)技术的进步已导致对免疫疗法的重新考虑。因此，被动免疫疗法可以有效地预防或治疗由耐药细菌病原体引起的高危感染，如高度适应性的机会细菌铜绿假单胞菌。我们选择的目标抗原是外膜蛋白OprF和OprI，因为它们在临床分离株中具有序列保守性，并在几个临床试验中用作疫苗抗原。索伦托治疗公司开发了专利技术，即用于选择完全人类抗体的G-MAB(R)库，以及用于产生靶向胶束的“抗体制剂药物结合物”(AFDC)方法。我们建议制备和评估抗OpfF/I单抗和AFDCs，即与选定的抗P。铜绿假单抗。这些研究将与我们的学术合作者丹尼尔·沃兹尼亚克博士(俄亥俄州立大学)一起进行。最有希望的单抗和AFDCS将在体外和体内彻底评估它们预防和/或治疗局部和系统性铜绿假单胞菌感染的能力。具体地说，我们的STTR先进技术第一阶段拨款申请的项目是：项目1-选定的人源性抗OprF/I单抗的体外评估和优先顺序；项目2-抗假单胞菌AFDCS的产生和体外评估；项目3-在小鼠和猪铜绿假单胞菌感染模型中对单抗/AFDCS的体内评估。建议的产品是一种完全人源性的抗P。铜绿假单抗免疫疗法或AFDC作为靶向抗生素输送载体，将是预防或治疗铜绿假单胞菌感染的有效和安全的独立治疗方案和/或“鸡尾酒”疗法的成员。