Development of antibodies to capsule of carbapenem resistant Klebsiella pneumonia

耐碳青霉烯类肺炎克雷伯菌荚膜抗体的研制

• 批准号: 8839543
• 负责人: Bettina Fries
• 金额: $ 23.7万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839543
• 关键词: Address; Adjuvant Therapy; Aminoglycosides; Anti-Infective Agents; Antibiotics; Antibodies; Antigen Targeting; Bacteria; Binding; Biological Assay; Centers for Disease Control and Prevention (U.S.); Clinical; Communities; Data; Development; Goals; Gram-Negative Bacteria; Healthcare; Human; Hybridomas; Immune response; Immunocompetent; Immunoglobulin G; Immunoglobulin M; In Vitro; Infection; Intoxication; Klebsiella; Klebsiella pneumonia bacterium; Laboratories; Lead; Licensing; Life; Modeling; Molecular; Mus; Patients; Pharmaceutical Preparations; Pneumonia; Polymyxins; Polysaccharides; Prevalence; Regimen; Renal function; Reporting; Resistance; Sepsis; Serum; Solid; Staphylococcal Enterotoxin B; Staphylococcus aureus; Surrogate Markers; Treatment Protocols; Urinary tract infection; Virulence; Vision; Work; alternative treatment; base; capsule; carbapenem resistance; efficacy testing; experience; in vivo; killings; macrophage; mortality; novel; pathogen; patient population; prevent; public health relevance; tigecycline

DESCRIPTION (provided by applicant): Carbapenem resistant Klebsiella pneumonia (CR-Kp) isolates are emerging worldwide including in the US. The CDC has reported an increase in prevalence from 1.6% in 2001 to 10.4% in 2011. CR-Kp causes predominantly pneumonia, sepsis and urinary tract infections. Most patients acquire this pathogen in health care associated settings but infections with CR-Kp have also been observed in healthy people from the community. One problem is that many of the CR-Kp isolates retain full virulence and often become resistant even to aminoglycosides. The 2nd line reserve antibiotics such as Tycycline or Polymyxin either have low efficacy or are very toxic especially in patients with compromised renal function. As a result, the mortality of invasive Cr-Kp infections is high and ranges from 50-80%. New effective drug classes against gram-negative bacteria are not in sight hence alternative treatment regimens have to be explored. This application proposes to generate mAbs to the capsular polysaccharide (CPS) of CR-Kp. Molecular capsule typing of 40 CR-KP isolates demonstrates that despite a common ST258 clonal background the CPS in these isolates is heterogeneous and therefore cross-reactive mAbs will have to be generated in order to successfully cover the variability of clinical isolates. In aim 1 we propose several strategies o generate cross-reactive mAbs and to also increase the number of hybridomas that produce IgG as this isotype is the preferred isotype. In aim 2 we propose to characterize the mAbs with respect to their ability to bind to diverse capsule-types of Cr-Kp and effectively enhance the host response to diverse Cr-Kp isolates. The goal is to generate a rank list of best candidates that are then humanized and further developed.

描述（由申请人提供）：耐碳青霉烯类肺炎克雷伯菌（CR-Kp）分离株正在世界范围内出现，包括在美国。 CDC 报告患病率从 2001 年的 1.6% 上升到 2011 年的 10.4%。CR-Kp 主要引起肺炎、败血症和尿路感染。大多数患者在医疗保健相关环境中感染这种病原体，但在社区健康人群中也观察到 CR-Kp 感染。一个问题是许多 CR-Kp 分离株保留了完整的毒力，甚至常常对氨基糖苷类产生耐药性。二线储备抗生素如泰环素或多粘菌素要么疗效低要么毒性很大，特别是对于肾功能受损的患者。因此，侵袭性 Cr-Kp 感染的死亡率很高，为 50-80%。目前还没有针对革兰氏阴性菌的新有效药物类别，因此必须探索替代治疗方案。本申请提出针对 CR-Kp 的荚膜多糖 (CPS) 生成单克隆抗体。 40 个 CR-KP 分离株的分子胶囊分型表明，尽管具有共同的 ST258 克隆背景，但这些分离株中的 CPS 是异质的，因此必须生成交叉反应性 mAb，才能成功覆盖临床分离株的变异性。在目标 1 中，我们提出了几种策略，以产生交叉反应性单克隆抗体，并增加产生 IgG 的杂交瘤数量，因为该同种型是首选同种型。在目标 2 中，我们建议表征 mAb 与不同胶囊类型的 Cr-Kp 结合的能力，并有效增强宿主的能力 对不同 Cr-Kp 分离株的反应。目标是生成最佳候选人的排名列表，然后将其人性化并进一步开发。