Anti-Pseudomonas Immunotherapy and Targeted Drug Delivery

描述（由申请人提供）：使用多克隆免疫抗毒素或抗胶囊马血清进行严重细菌感染的抗体治疗实际上早于小分子抗生素的使用。然而，出于安全性、经验性使用方便和成本等原因，广谱抗生素的开发迅速取代了免疫血清的使用。但是，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，而人类单克隆抗体（mAb）技术的进步已经导致重新考虑免疫疗法。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风险感染，如铜绿假单胞菌，一种高度适应性的机会性细菌。我们的目标抗原是外膜蛋白OprF和OprI，之所以选择它们，是因为它们在临床分离株中序列保守，并且在一些临床试验中用作疫苗抗原。Sorrento Therapeutics, Inc.开发了专有技术，即用于选择全人抗体的G-MAB(R)文库，以及用于生成靶向胶束的“抗体配制药物偶联物”（AfDC）方法。我们建议生成和评估抗opff /I单克隆抗体以及afdc，即与选定的抗p连接的含有粘菌素/阿奇霉素的胶束。绿脓杆菌马伯。这些研究将与我们的学术合作者Daniel Wozniak博士（俄亥俄州立大学）一起进行。最有希望的单克隆抗体和afdc将在体外和体内进行全面评估，以评估它们预防和/或治疗局部和全身铜绿假单胞菌感染的能力。具体而言，我们的STTR先进技术I期资助申请项目包括：项目1 -选定的人类抗oprf /I单克隆抗体的体外评估和优先排序；项目2 -抗假单胞菌afdc的制备及体外评价项目3 -单抗/ afdc在小鼠和猪铜绿假单胞菌感染模型中的体内评价。拟议的产品是一种全人体抗p。铜绿单抗免疫疗法或AfDC作为靶向抗生素递送载体，将是预防或治疗铜绿假单胞菌感染的有效和安全的独立和/或“鸡尾酒”治疗选择的成员。

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.