P4-IVIG immunotherapy for adjunct treatment of severe respiratory infection

社区获得性肺炎(CAP)是英国感染相关死亡的最常见原因，占重症监护病房入院人数的6%。尽管有抗生素和最佳的支持治疗，需要重症监护的CAP患者的住院死亡率仍为49.4%。类固醇和一些免疫调节疗法已被研究为严重感染的额外治疗方法，但是否有任何生存益处的证据仍存在严重争议。需要新的治疗方法来改善结果，特别是在卫生部强调了英国抗生素耐药感染的紧迫威胁的情况下。这项建议研究了一种策略，通过在与感染细菌结合的抗体的存在下，通过改善吞噬细胞(吞噬和杀灭细菌的白细胞)的功能来刺激严重肺炎患者的肺和血液中的免疫反应。肺炎球菌表面粘附素A(PsaA)是肺炎链球菌的一种表面分子，在细菌黏附中起着至关重要的作用。P4是psaA的28个氨基酸的多肽片段，在实验室实验中能激活人的吞噬细胞(包括巨噬细胞和中性粒细胞)，导致肺炎球菌、葡萄球菌和革兰氏阴性菌的黏附和内化。此外，P4与静脉免疫球蛋白(IVIG)一起注射作为抗细菌抗体的来源，可增加人肺巨噬细胞对肺炎球菌的摄取和杀灭，并通过显著减少或清除肺部和血液中的细菌来显著提高肺炎和感染动物模型的存活率。这一合作伙伴关系旨在开发增强型被动免疫疗法(API)试验，以提高国际电联患者的存活率，特别是严重肺炎的存活率。在这个具体的项目中，我们将采取下一步，合成少量的P4，对其进行毒性筛选，并检查其在既定的实验室检测中是否有效。我们目前的后续重点将是P4和P4/IVIG组合的第一阶段研究。

Community-acquired pneumonia (CAP) is the commonest cause of infection-related death in the UK and accounts for 6% of admissions to Intensive Care. Patients with CAP who require Intensive Care still have a hospital mortality of 49.4%, despite antibiotics and optimal supportive care. Steroids and some immune-modifying treatments have been investigated as additional treatment in severe infection, but evidence for any survival benefit is heavily disputed. New therapies are needed to improve outcome, particularly as the Department of Health has highlighted the urgent threat of antibiotic resistant infections in the UK. This proposal investigates a strategy to stimulate immune responses both in the lung and the blood in patients with severe pneumonia by improving phagocyte (white blood cells that ingest and kill bacteria) function in the presence of antibody binding to the infecting bacteria.Pneumococcal surface adhesin A (PsaA) is a surface molecule of Streptococcus pneumoniae with a vital role in bacterial adherence. P4 is a 28-amino acid peptide fragment of PsaA which activates human phagocytes (both macrophages and neutrophils) resulting in adherence and internalization of pneumococci, staphylococci and gram negative bacteria in laboratory experiments. Furthermore, P4 administered with intravenous immunoglobulin (IVIG) as a source of anti-bacterial antibody increases uptake and killing of pneumococci by human lung macrophages, together with dramatically improving survival in animal models of pneumonia and infection by significantly reducing or clearing bacteria in both lungs and blood.This partnership aims to develop Augmented Passive Immunotherapy (API) trials to improve patient survival in the ITU, particularly from severe pneumonia. In this specific project, we will take the next step by synthesising a small quantity of P4, screening this for toxicity and checking that it works in established laboratory assays. Our immediate follow-on priority will be phase 1 study with both P4 and the P4/IVIG combination.