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）： 碳青霉烯耐药肺炎克雷伯菌（CR-Kp）分离株在全球范围内出现，包括美国。疾病预防控制中心报告说，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。大多数患者在卫生保健相关环境中获得这种病原体，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，并且经常甚至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）的疗效较低或毒性很大，尤其是在肾功能受损的患者中。因此，侵袭性Cr-Kp感染的死亡率很高，范围为50- 80%。新的有效的药物类别对革兰氏阴性菌是看不到的，因此替代治疗方案必须探索。本申请提出产生针对CR-Kp的荚膜多糖（CPS）的mAb。40株CR-KP分离株的分子胶囊分型表明，尽管具有共同的ST 258克隆背景，但这些分离株中的CPS是异质性的，因此必须生成交叉反应性mAb，以成功涵盖临床分离株的变异性。在目标1中，我们提出了几种产生交叉反应性mAb的策略，并且还增加了产生IgG的杂交瘤的数量，因为这种同种型是优选的同种型。在目标2中，我们建议表征mAb结合不同胶囊类型的Cr-Kp的能力，并有效地增强宿主的免疫应答。 对不同Cr-Kp分离株的反应。我们的目标是生成一个最佳候选人的排名列表，然后将其人性化并进一步开发。