Optimization of therapeutic mAbs to carbapenem resistant Klebsiella clone ST258

针对碳青霉烯类耐药克雷伯菌克隆 ST258 的治疗性单克隆抗体的优化

• 批准号: 9562659
• 负责人: Bettina Fries
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9562659
• 关键词: Address; Affect; Affinity; Animal Model; Anti-Infective Agents; Antibiotics; Antibodies; Antibody Therapy; Applications Grants; Bacteria; Binding; Biological Assay; Catheters; Centers for Disease Control and Prevention (U.S.); Collaborations; Colon; Combined Modality Therapy; Communities; Diagnosis; Disease; Dyes; Epitopes; Exhibits; Goals; Healthcare; Hospitals; Human; Hybridomas; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; In Vitro; Individual; Indwelling Catheter; Infection; Injury; Klebsiella; Klebsiella pneumonia bacterium; Label; Laboratories; Lead; Life; Mesentery; Microbial Biofilms; Military Personnel; Modality; Modeling; Monitor; Monoclonal Antibodies; Multiple Bacterial Drug Resistance; Mus; Patients; Phagocytosis; Pharmacotherapy; Pneumonia; Polymyxins; Polysaccharides; Prevalence; Proteins; Publishing; Rehabilitation Centers; Renal function; Reporting; Resistance; Risk; Sepsis; Soldier; Solid; Techniques; Testing; Therapeutic Monoclonal Antibodies; Time; Urinary tract infection; Vaccination; Vaccines; Variant; Veterans; Virulent; Wound Infection; alternative treatment; base; capsule; carbapenem resistance; combat; cross reactivity; drug standard; efficacy testing; experience; gut colonization; improved outcome; in vivo; intravital microscopy; lead candidate; lead optimization; lymph nodes; mortality; pathogen; patient population; prevent; protective efficacy; receptor; receptor binding; screening; tigecycline

Carbapenem resistant Klebsiella pneumoniae (CR-Kp) bacteria are the most common gram-negative multidrug-resistant bacteria in US hospitals. CR-Kp cause predominantly pneumonia, sepsis and urinary tract infections and, in military personnel, complicated invasive wound infections as well. Most patients acquire this pathogen in health care associated settings. Soldiers are at risk because they commonly have prolonged stays in hospitals and rehabilitation centers when they recover from injuries they sustained in combat. Mortality of invasive CR-Kp infections is high and commonly over 50%. One problem is that most CR-Kp infections are diagnosed too late and empiric treatment with antibiotics like polymyxin is toxic and also compromised by emerging resistance even to these antibiotics. The goal of this application is to optimize two existing lead monoclonal antibodies (mAbs) that bind to the diverse polysaccharide capsule (CPS) of CR-Kp. Both clade 1 and clade 2 CPS-specific IgG mAbs are available and are expected to cover the majority of CR-Kp strains especially those that belong to the more virulent clade 2 of the clonal group CG258 group. Based on others and our published experience we propose several strategies to test these mAbs. Three aims are proposed. In Aim 1 we propose to generate isotype switch variants of CR-Kp specific mAbs and investigate relevance of FcɣR binding in vivo. In Aim 2 we will identify the epitopes of the lead mAbs, and identify the best isotypes of the candidate mAbs with respect to protective efficacy. We will also test combinations of CR-Kp specific mAbs with antibiotics for optimal protection. Finally, in Aim 3 we will use a murine gut colonization model to investigate if antibiotic-induced dissemination in colonized mice can be prevented by treatment with CPS- specific mAbs.

耐碳青霉烯类肺炎克雷伯菌(CR-KP)是最常见的革兰氏阴性菌 美国医院中的多重耐药细菌。CR-KP主要引起肺炎、脓毒症和尿路感染 在军事人员中，还有复杂的侵袭性伤口感染。大多数患者都得了这种病 医疗保健相关环境中的病原体。士兵处于危险之中，因为他们通常有较长的停留时间 在医院和康复中心，当他们从战斗中受伤的康复中恢复时。死亡人数 侵袭性CR-KP感染率很高，通常超过50%。一个问题是，大多数CR-KP感染是 确诊为时已晚，使用多粘菌素等抗生素进行经验性治疗是有毒的，也会受到 甚至对这些抗生素也出现了抗药性。此应用程序目标是优化两个现有的销售线索 与CR-KP的各种多糖胶囊(CP)结合的单抗(MAbs)。两个分支均为1 和分支2 CPS特异性免疫球蛋白单抗已经问世，预计将覆盖大多数CR-KP菌株 尤其是属于克隆组CG258组中毒力更强的分支2的那些。以他人为基础 根据我们已发表的经验，我们提出了几种策略来测试这些单抗。提出了三个目标。在……里面 目的1我们提议产生CR-KP特异性单抗的同型转换变异体并研究其相关性。 FcɣR体内结合。在目标2中，我们将确定主要单抗的表位，并确定最佳的亚型 候选单抗在保护效力方面。我们还将测试CR-KP特异性单抗的组合 使用抗生素以获得最佳保护。最后，在目标3中，我们将使用小鼠肠道定植模型来 研究是否可以通过使用CPS治疗来防止抗生素在被定植的小鼠中的传播 特定单抗。