Anti-Autolysin Passive Immunity for MRSA Osteomyelitis

MRSA 骨髓炎的抗自溶素被动免疫

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：最近耐甲氧西林金黄色葡萄球菌（MRSA）已将艾滋病毒作为美国最致命的病原体备，每年占100,000多人死亡。在骨科中，MRSA骨髓炎（OM）已成为患者护理中最大的关注，应该认为，手术技术的改善和侵略性的抗生素预防的改善已将大多数手术的感染率降低到小于1-5％。为了更好地理解OM建立期间病原体宿主相互作用，开发新的干预措施并有效诊断，我们开发了一种新型的植入物与OM的鼠模型，其中不锈钢销涂有金黄色葡萄球菌，并通过胫骨转移经过透射植入。这会导致高度可再现的感染，到第9天的骨溶解，在三周内骨折，在外部固定引脚周围与临床OM非常相似。此外，我们已经开发了实时定量PCR（RTQ-PCR），以确定受感染骨组织中的NUC基因拷贝数，这是准确至〜100份的。和体内生物发光成像，以纵向量化细菌载荷。我们使用该模型来克隆自动蛋白素的葡萄糖氨基酶亚基作为免疫主导抗原，并证明其作为活性疫苗的潜力。但是，由于该疫苗的目标种群是免疫受损或老年患者，CodeVax LLC已开始开发被动免疫，可以在手术前向高危患者提供。目前，该公司具有13种针对葡萄糖酰胺酶的单克隆抗体，它需要筛选以基于以下能力来推导临床试验的主要，次级和第三级候选者：1）在高度关心的域内将表位结合（所有人的100％氨基酸菌株）具有高亲和力（<10-9m9m <10-9m; 2）; 2）; 2）; 2）; 2）; 2）； 2）在体外介导酶抑制，细胞胞菌或细胞溶解； 3）显着保护小鼠免受植入物相关的OM。在这里，我们提出了相应测试这些mAB的关键实验，并得出候选者的发展为MRSA的第一个被动免疫。公共卫生相关性：MRSA骨髓炎甲氧西林抗药性金黄色葡萄球菌（MRSA）的抗氨二糖素免疫免疫已使HIV备受抗空，成为美国最致命的病原体，占每年超过100,000人的死亡。在骨科中，MRSA骨髓炎（OM）已成为患者护理中最关心的问题。为了满足这一需求，CodeVax，Inc。旨在开发第一种被动免疫，以防止接受全体关节置换手术的患者MRSA感染。