Nanocarrier formulated enzyme for the treatment of S. aureus infection

纳米载体配制的酶用于治疗金黄色葡萄球菌感染

基本信息

批准号：
8392195
负责人：
Elijah M. Bolotin
金额：
$ 30万
依托单位：
PHARMAIN CORPORATION
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：
2012-05-09 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8392195
关键词：
Affinity Animals Antibiotics Area Under Curve Back Bacteria Binding Biodistribution Biological Assay Blood Blood Circulation Time Cell Line Cells Clinical Clinical Trials Cloning Communities Coupled Cyclic GMP Daptomycin Data Development Dissociation Drug Combinations Drug Formulations Drug Interactions Drug Kinetics Effectiveness Endocarditis Endotoxins Enzyme-Linked Immunosorbent Assay Enzymes Escherichia coli Evaluation Feasibility Studies Figs - dietary Freedom Funding Furunculosis Generations Goals Half-Life Hour In Vitro Infection Inflammation Instruction Intention Legal patent Letters Licensing Life Linezolid Lysostaphin Measurable Mediating Metalloendopeptidases Modeling Mus Osteomyelitis Peptides Phase Pneumonia Preparation Production Proteins Recombinants Recovery Resistance Resources Secure Serum Site Small Business Innovation Research Grant Speed Staphylococcal Infections Staphylococcus aureus Structure Systemic Therapy Testing Thigh structure Time Toxicology Vancomycin Variant Vascular Permeabilities Work catheter related infection chemical synthesis copolymer cost design immunogenicity improved in vivo killings methicillin resistant Staphylococcus aureus nanocarrier phase 2 study pre-clinical prevent residence success

项目摘要

DESCRIPTION (provided by applicant): Lyso, a metalloendopeptidase that is bacteriolytic for S. aureus, is a potential systemic therapy for treating methicillin-resistant S. aureus (MRSA) mediated infections including endocarditis, osteomyelitis, catheter related infections, and MRSA-mediated community acquired furunculosis and pneumonia. However, the short half-life of this enzyme in vivo has precluded its development thus far as a systemic therapy, despite positive clinical trial data. Our company, PharmaIN, has developed a nanocarrier, Protected Graft Copolymers (PGC), that can reversibly bind peptides and/or proteins (US patent #7,138,105) with measurable dissociation constant (Kd). Importantly, because of its size, PGC nanocarrier concentrates at sites of increased vascular permeability and thus can potentially concentrate lyso at the site of infection. Our goal is to develop a formulation of lyso to provide life-saving treatment against MRSA and to suppress the emergence of resistance. Our preliminary data demonstrates that PGC can reversibly associate with lyso, increase blood half-life 14-fold, and increase its in vivo efficacy against MRSA by 100-fold. We propose to prepare endotoxin- free lyso and create a "master cell-line bank" (E. coli expressing lyso) that will be used for: 1) this project to supply our lyso needs, and 2) as reference cells for the planned post-SBIR IND filing and clinical trial. We will also optimize the structure of PGC by synthesizing variations (at least 10) of the effective PGC shown in the preliminary data with the intention to further extend the half-life to at least 30 fold. This is important before we put a lot of resource towards IND. To this end, we will continue the development of PGC-lyso formulation by doing binding studies of at least 10 new carrier variations. We will do PKs and biodistribution studies on at least 6 selected lyso formulations. We will determine and compare with commercially available antibiotics the effectiveness of our lyso formulation in vivo against MRSA. PharmaIN Corp. Confidential PUBLIC HEALTH RELEVANCE: We will develop a formulation of lysostaphin (lyso) to provide a life-saving treatment against MRSA and to suppress the emergence of resistance. To this end, we will optimize the structure of PGC to extend lyso blood residence time by 30 fold and effectiveness in vivo against MRSA by more than 100-fold. We also propose to prepare endotoxin-free lyso and create a "master cell-line bank" (E. coli expressing lyso) that will be used for: 1) this project to supply our lyso needs, and 2) as reference cells for the planned post-SBIR IND filing and clinical trial. PharmaIN Corp. Confidential

描述（由申请人提供）：Lyso是一种用于金黄色葡萄球菌的细菌型的冶金肽酶，是一种用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）介导的感染的潜在全身治疗，包括心内膜炎，骨髓性相关感染，MRSA相关感染，以及MRSA介导的社区依从性的依uncectied Furunconia和Preunconia和Preunconia和PeNeumania。然而，尽管临床试验阳性数据呈阳性，但该酶在体内的短期半衰期一直排除到全身治疗。我们的公司Pharmain已开发了一种纳米载体，受保护的移植共聚物（PGC），可以可逆地结合肽和/或蛋白质（美国专利＃7,138,105），可测量的解离常数（KD）。重要的是，由于其大小，PGC纳米载体浓缩在增加血管通透性的部位，因此可能会在感染部位浓缩Lyso。我们的目标是开发一种溶血的表述，以提供对MRSA的生命疗法并抑制抗药性的出现。我们的初步数据表明，PGC可以与LYSO可逆地关联，增加半衰期14倍，并使对MRSA对MRSA的体内疗效提高100倍。我们建议准备无内毒素 - 无毒素溶血液，并创建一个“主细胞系库”（大肠杆菌表达溶血），该库将用于：1）该项目以满足我们的LYSO需求，而2）作为计划的Sbir IND IND档案和临床试验的参考细胞。我们还将通过合成初步数据中显示的有效PGC的变化（至少10个）来优化PGC的结构，以进一步将半衰期扩展到至少30倍。在我们将大量资源投入IND之前，这一点很重要。为此，我们将通过对至少10种新的载体变化进行结合研究来继续开发PGC-Lyso配方。我们将对至少6种选定的LYSO制剂进行PKS和生物分布研究。我们将确定并与市售的抗生素进行比较，即我们在体内对MRSA的液体配方的有效性。 Pharmain Corp.机密公共卫生相关性：我们将开发一种乳子磷脂（LYSO）的表述，以提供对MRSA的救生治疗，并抑制抵抗的出现。为此，我们将优化PGC的结构，以将Lyso血液停留时间延长30倍，并在体内对MRSA的有效性增加100倍以上。我们还建议准备无内毒素的LYSO，并创建一个“主细胞系库”（大肠杆菌表达Lyso），该库将用于：1）该项目以满足我们的溶解需求，而2）作为计划的后SBIR IND IND FIL和临床试验的参考细胞。 Pharmain Corp.机密