Antibody therapy for pneumococcal disease

摘要 肺炎球菌多糖(PPS)结合疫苗(PCV)在预防 侵袭性肺炎球菌病(IPD)，但在肺炎球菌的治疗和预防方面仍存在差距 目前的疫苗对肺炎的疗效不如IPD，对大多数患者的免疫原性也较低 有得病的危险。我的团队长期以来一直对疫苗引发的PPS抗体及其作用方式感兴趣。 我们发现，虽然一些PPS3单抗(MAb)可以保护 血清3型肺炎球菌(ST3)的小鼠在体外介导对ST3的吞噬细胞杀伤(Opsonic)，其他小鼠则不能 (非Opsonic)。这些单抗类型具有不同的PPS3特异性，并且需要不同的效应器和FcγR来 保护小鼠免受ST3肺炎的侵袭。光学抗体诱导早期肺部细菌清除，但非光学抗体 单抗不起作用，相反，它们可以减少肺部炎症。这些发现挑战了流行的疫苗教条 疗效仅仅是光学抗体的一种功能，这表明关于PPS如何 抗体起到保护作用。这项应用的目标是制造人类单抗(HuMAbs)。 治疗ST3肺炎。最终，我们希望开发一种多ST huMAb鸡尾酒，但ST3将是我们的第一款 作为PCV13的目标对ST3的效果较差，ST3是肺炎的重要原因，死亡风险仍较高 而不是其他性传播疾病。我们假设平衡ST3清除和控制宿主炎症的HuMAb将 提供最多的保护。我们将从肺炎球菌疫苗接受者那里生成PPS3 huMAb，使用 用于确定huMAb PPS3表位的新型ST3糖链阵列，并测定其体外和体外功能活性 在正常人和人(HU)FcγR体内的定植、肺炎和脓毒症模型中对st3的疗效 转基因小鼠。这将确定用于治疗的候选HuMAb，揭示潜在的新相关性 并确定潜在的辅助PPS3抗原，以增强肺炎疫苗的效力。这 该项目将促进对抗体作用机制的理解，并对临床产生重大影响 清除防治肺炎肺炎的障碍，医药与公共卫生 具有可以应用于任何病原体的想法和方法。

ABSTRACT Pneumococcal polysaccharide (PPS conjugate vaccines (PCV) have had remarkable impact in preventing invasive pneumococcal disease (IPD), but there is still a gap in treatment and prevention of pneumococcal disease as current vaccines are less effective for pneumonia than IPD and less immunogenic in patients most at risk for disease. My group has a longstanding interest in vaccine-elicited PPS antibodies and how they work. We made the paradigm-shifting discovery that while some PPS3 monoclonal antibodies (MAbs) that protect mice from serotype 3 (ST3) pneumococcus mediate phagocyte killing of ST3 in vitro (opsonic), others do not (non-opsonic). These MAb types have distinct PPS3 specificities and require different effectors and FcγRs to protect mice from ST3 pneumonia. Opsonic antibodies induce early lung bacterial clearance, but non-opsonic MAbs do not, instead they reduce lung inflammation. These findings challenge prevailing dogma that vaccine efficacy is solely a function of opsonic antibodies and show there is still much to learn about how PPS antibodies mediate protection. The goal of this application is to make human monoclonal antibodies (huMAbs) to treat ST3 pneumonia. Ultimately, we wish to develop a multi-ST huMAb cocktail, but ST3 will be our first target as PCV13 is less effective for ST3, an important cause of pneumonia that still carries higher risk of death than other STs. We hypothesize huMAbs that balance ST3 clearance and control of host inflammation will provide the most protection. We will generate PPS3 huMAbs from pneumococcal vaccine recipients, use a novel ST3 glycan array to identify huMAb PPS3 epitopes, and determine their functional activities in vitro and efficacies against ST3 in vivo in colonization, pneumonia, and sepsis models in normal and human (hu)FcγR transgenic mice. This will identify candidate huMAbs to advance for therapy, reveal potentially new correlates of protection, and identify potential adjunctive PPS3 antigens to enhance vaccine efficacy for pneumonia. This project will advance understanding of mechanisms of antibody action and have a major impact on clinical medicine and public health by removing roadblocks to prevention and treatment of pneumococcal pneumonia with ideas and an approach that can be applied to any pathogen.