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

• 批准号: 8468113
• 负责人: Elijah M. Bolotin
• 金额: $ 30万
• 依托单位: PHARMAIN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-09 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468113
• 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

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

描述（由申请人提供）：Lyso是一种金属内肽酶，对金黄色葡萄球菌具有溶菌作用，是一种潜在的全身疗法，用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）介导的感染，包括心内膜炎、骨髓炎、导管相关感染和MRSA介导的社区获得性真菌病和肺炎。然而，尽管有积极的临床试验数据，但这种酶在体内的半衰期短阻碍了其作为全身治疗的发展。我们的公司PharmaIN开发了一种纳米载体，保护接枝共聚物（PGC），可以可逆地结合肽和/或蛋白质（美国专利#7,138,105），具有可测量的解离常数（Kd）。重要的是，由于其大小，PGC纳米载体集中在血管通透性增加的部位，因此可能在感染部位集中溶酶。我们的目标是开发一种lyso配方，为MRSA提供挽救生命的治疗，并抑制耐药性的出现。我们的初步数据表明，PGC可以与lyso可逆结合，将血液半衰期延长14倍，将体内抗MRSA的功效提高100倍。我们建议制备无内毒素的溶酶酶并建立一个“主细胞系库”（表达溶酶酶的大肠杆菌），该细胞系库将用于：1)本项目提供我们对溶酶酶的需求，2)作为计划中的sbir后IND申请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的变体（至少10种）来优化PGC的结构，目的是将半衰期进一步延长到至少30倍。在我们将大量资源投入到IND之前，这一点很重要。为此，我们将通过对至少10种新的载体变体进行结合研究，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抗生素比较我们的lyso制剂在体内对抗MRSA的有效性。PharmaIN公司