Anti-Autolysin Passive Immunity for MRSA Osteomyelitis

MRSA 骨髓炎的抗自溶素被动免疫

• 批准号: 7999014
• 负责人: John Linforth Daiss
• 金额: $ 32.62万
• 依托单位: CODEVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999014
• 关键词: Accounting; Address; Affinity; Amino Acids; Animals; Antibiotic Prophylaxis; Antibodies; Antigens; Autolysin; Bacteria; Binding; Biological Assay; Bioluminescence; Bone Tissue; Cell Wall; Cell division; Cells; Cessation of life; Clinical; Clinical Trials; Complement; Cytolysis; Development; Diagnostic; Digestion; Effectiveness; Elderly; Enzyme Inhibition; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Fracture; Gene Dosage; Glucosaminidase; Goals; Grant; Growth; HIV; Haemophilus influenzae; Haemophilus influenzae type b bacteria; Human Papillomavirus; Image; Immune; Immune response; Immunization; Immunoglobulin G; Implant; In Vitro; Infection; Infection prevention; Intervention; Length; Measurement; Mediating; Medical center; Metaphysics; Metaphysis; Methods; Microbial Biofilms; Mission; Mitosis; Modeling; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Orthopedics; Osteolysis; Osteomyelitis; Passive Immunity; Passive Immunization; Passive Transfer of Immunity; Patient Care; Patients; Phase; Placebos; Procedures; Publishing; Replacement Arthroplasty; Research Personnel; Risk; Serum; Stainless Steel; Staphylococcus aureus; Structure; Surface; Surface Plasmon Resonance; Surgeon; Target Populations; Techniques; Technology; Testing; Time; United States; Universities; Vaccines; Work; base; candidate identification; cytotoxicity; effective intervention; high risk; in vivo; instrument; methicillin resistant Staphylococcus aureus; minimally invasive; novel; older patient; pathogen; periplasm; prevent; prophylactic; public health relevance; research study; sample fixation; septic; success; vaccine development

DESCRIPTION (provided by applicant): Recently methicillin resistant Staphylococcus aureus (MRSA) has surpased HIV as the most deadly pathogen in the United States, accounting for over 100,000 deaths per year. In Orthopaedics, MRSA osteomyelitis (OM) has become the greatest concern in patient care, desite the fact that improvements in surgical technique and aggressive antibiotic prophylaxis have decreased the infection rate for most procedures to less than 1-5%. In order to better understand pathogen-host interactions during the establishment of OM, develop new interventions and an effective diagnostic, we have developed a novel murine model of implant- associated OM in which a stainless steel pin is coated with S. aureus and implanted transcortically through the tibial metaphysis. This leads to a highly reproducible infection with osteolysis by day 9, fractures within three weeks, and closely resembles clinical OM around an external fixation pin. Furthermore, we have developed real time quantitative-PCR (RTQ-PCR) to determine nuc gene copy number in infected bone tissue, which is accurate to ~100 copies; and in vivo bioluminescence imaging to quantify the bacterial load longitudinally. We used this model to clone the glucosaminidase subunit of autolysin as an immuno-dominant antigen and demonstrated its potential as an active vaccine. However, as the target populations for this vaccine are immuno-compromised or elderly patients, Codevax LLC has initiated development of a passive immunization that can be given to high-risk patients prior to surgery. Currently, the company has 13 monoclonal antibodies against glucosaminidase that it needs to screen to derive a primary, secondary and tertiary candidate for clinical trials based on their ability to: 1) bind an epitope within a highly concerned domain (100%amino acid identity of all know S. aureus strains) with high affinity (<10-9M; 2); 2) mediate enzyme inhibition, cytostasis or cytolysis of the bacteria in vitro; and 3) significantly protect mice from implant associated OM. Here we propose the pivotal experiments to test these mAbs accordingly, and derive the candidates to be developed as the first passive immunization for MRSA. PUBLIC HEALTH RELEVANCE: Anti-Autolysin Passive Immunity for MRSA Osteomyelitis Methicillin resistant Staphylococcus aureus (MRSA) has surpased HIV as the most deadly pathogen in the United States, accounting for over 100,000 deaths per year. In Orthopaedics, MRSA osteomyelitis (OM) has become the greatest concern in patient care. To address this need, Codevax, Inc. aims to develop the first passive immunization to prevent MRSA infections in patients undergoing total joint replacement surgery.

描述(申请人提供)：最近，耐甲氧西林金黄色葡萄球菌(MRSA)已超过艾滋病毒成为美国最致命的病原体，每年导致超过10万人死亡。在骨科，MRSA骨髓炎(OM)已成为患者护理中最令人担忧的问题，尽管手术技术的改进和积极的抗生素预防已将大多数手术的感染率降至1-5%以下。为了更好地了解OM建立过程中病原体-宿主的相互作用，开发新的干预措施和有效的诊断方法，我们建立了一种新的植入性OM小鼠模型，在该模型中，不锈钢针包被金黄色葡萄球菌，并通过胫骨干骺端经皮下植入。这会导致高度可重复性的感染，在第9天骨溶解，在三周内骨折，非常类似于临床上外固定钉周围的OM。此外，我们还开发了实时定量-聚合酶链式反应(RTQ-PCR)来检测感染骨组织中nuc基因的拷贝数，其准确度为~100拷贝；体内生物发光成像技术用于纵向定量细菌载量。我们利用这个模型克隆了自溶素的氨基葡萄糖苷酶亚基作为免疫优势抗原，并展示了它作为活性疫苗的潜力。然而，由于这种疫苗的目标人群是免疫受损或老年患者，Codevax LLC已经开始开发一种被动免疫，可以在手术前给予高危患者。 目前，该公司有13种抗氨基葡萄糖苷酶的单抗需要进行筛选，以获得临床试验的一级、二级和三级候选抗体，其依据是：1)与高度关注的区域(所有已知金黄色葡萄球菌菌株的氨基酸同一性为100%)内的高亲和力(10-9M；2)结合表位；2)在体外介导细菌的酶抑制、细胞停滞或细胞溶解；以及3)显著保护小鼠免受植入相关OM的影响。在这里，我们提出了关键的实验来测试这些单抗，并得出了作为MRSA的第一个被动免疫的候选方案。 公共卫生相关性：耐甲氧西林金黄色葡萄球菌(MRSA)骨髓炎的抗自溶素被动免疫已超过艾滋病毒，成为美国最致命的病原体，每年造成超过10万人死亡。在骨科，MRSA骨髓炎(OM)已成为患者护理中最受关注的问题。为了满足这一需求，Codevax公司的目标是开发第一种被动免疫，以防止接受全关节置换手术的患者感染MRSA。