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: 10265325
• 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/10265325
• 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; Label; Laboratories; Lead; Life; 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; emerging pathogen; experience; gut colonization; improved outcome; in vivo; intravital microscopy; lead candidate; lead optimization; mesenteric lymph node; mortality; pathogen; patient population; prevent; protective efficacy; receptor; receptor binding; resistant Klebsiella pneumoniae; 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) 细菌是最常见的革兰氏阴性菌 美国医院中的多重耐药细菌主要导致肺炎、败血症和尿路感染。 感染，并且在军事人员中，大多数患者也会出现复杂的侵袭性伤口感染。 卫生保健相关环境中的病原体存在风险，因为他们通常会长时间停留。 当他们从战斗中受伤后康复时，他们会在医院和康复中心接受治疗。 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 感染都是侵袭性的。 诊断得太晚，使用多粘菌素等抗生素进行经验性治疗是有毒的，而且还会受到以下因素的影响： 甚至对这些抗生素也出现了耐药性。该应用的目标是优化两个现有的先导化合物。 与 CR-Kp 的多种多糖胶囊 (CPS) 结合的单克隆抗体 (mAb) 均为进化枝 1。 和 clade 2 CPS 特异性 IgG mAb 已上市，预计覆盖大多数 CR-Kp 菌株 特别是那些属于克隆群 CG258 组的毒性更强的进化枝 2 的病毒。 根据我们发表的经验，我们提出了几种测试这些单克隆抗体的策略。 目标 1 我们建议生成 CR-Kp 特异性 mAb 的同种型转换变体并研究相关性 FcɣR 体内结合 在目标 2 中，我们将鉴定先导单克隆抗体的表位，并鉴定最佳同种型。 我们还将测试 CR-Kp 特异性单克隆抗体的组合。 最后，在目标 3 中，我们将使用小鼠肠道定植模型来实现最佳保护。 研究是否可以通过 CPS- 治疗来预防抗生素诱导的定植小鼠传播 特定的单克隆抗体。