Antibody therapy of MRSA colonization and infection

MRSA 定植和感染的抗体治疗

基本信息

批准号：
10307576
负责人：
Dominique M. Missiakas
金额：
$ 52.42万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-13 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307576
关键词：
American Amino Acid Substitution Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antibody Response Antibody Suppression Antibody Therapy B Cell Proliferation B-Cell Antigen Receptor B-Lymphocytes Bacteria Bacterial Interference Binding Blood Clinical Communities Community Hospitals Complement 1q Cultured Cells Disease Engineering Excision Gastrointestinal tract structure Generations Genus staphylococcus Half-Life Hospitals Human Human Engineering IgG1 Immune Immune Evasion Immunity Immunoglobulin G Immunoglobulin M Immunoglobulin binding proteins Immunoglobulins Immunotherapeutic agent Individual Infection Ligands Monoclonal Antibodies Morbidity - disease rate Mucous Membrane Mus Nasopharynx Nosocomial Infections Outcome Plasma Pre-Clinical Model Preclinical Testing Production Proteins Recurrence Recurrent disease Relapse Reporting Research Personnel Resistance Risk Factors Sepsis Serum Staphylococcal Protein A Staphylococcus aureus Staphylococcus aureus infection Superantigens Surface Antigens Testing Tissues Treatment Failure Variant base community-level factor crosslink glycosylation human monoclonal antibodies improved outcome in vivo individual patient insight intravenous administration methicillin resistant Staphylococcus aureus mortality neutralizing monoclonal antibodies novel therapeutics prevent research clinical testing skills standard of care vaccine development

项目摘要

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) colonize the nasopharynx and GI tract of healthy individuals and of patients admitted to hospitals. Colonization is the key risk factor for community-acquired and hospital-acquired MRSA invasive diseases. MRSA infection is associated with treatment failure, increased morbidity, and increased mortality. Prior attempts to develop vaccines or immune therapeutics that can prevent MRSA colonization or invasive disease or that improve the outcome of MRSA infections have failed. Infected individuals cannot develop protective antibody responses (immunity), which enables MRSA to persist within host tissues and to cause recurrent disease. MRSA immune escape is based on immunoglobulinbinding proteins, specifically staphylococcal protein A (SpA) and staphylococcal binder of immunoglobulin (Sbi). SpA and Sbi block effector functions of human IgG by binding to the Fcγ domain of antibodies. SpA also binds to the variant heavy chains of VH3-idiotypic immunoglobulin and crosslinks IgM B cell receptors, thereby activating B cell proliferation and the secretion of VH3-clonal antibodies that fail to recognize MRSA. This B cell superantigen activity (BCSA) of SpA is essential for the diversion of antibody responses during MRSA colonization and invasive disease. Here we describe a monoclonal antibody, MAb 3F6, that binds and neutralizes SpA and Sbi. We show that MAb 3F6 galactosylation at Fcγ promotes C1q binding, MAb 3F6- dependent opsonophagocytic killing (OPK) of MRSA and protection of mice against MRSA bloodstream infection. Further, we isolated amino acid substitutions in Fcγ that abolish SpA and Sbi binding and enhance the OPK activity of variant MAb 3F6. We also report that SpA is essential for suppression of antibody responses (BCSA) against bacterial colonization factors, thereby enabling S. aureus persistence in the nasopharynx and GI tract. Intravenous administration of MAb 3F6 into mice neutralizes circulating SpA and blocks its BCSA, thereby promoting antibody responses against bacterial surface antigens and the removal of S. aureus from the nasopharynx and GI tract. Here, we will test the hypotheses that intravenous administration of glyco- and Fcγ-engineered human 3F6-IgG1 in preclinical models a) elicits broad spectrum antibody responses against S. aureus, b) promotes decolonization of MSSA and MRSA, c) induces immunity to prevent re-colonization as well as invasive MSSA and MRSA disease, and d) improves the outcome of MRSA bloodstream infections. Glyco- and Fcγengineered 3F6 antibodies that achieve such product profile can be developed further for clinical testing to prevent and treat MRSA infections in American hospitals.

抽象的耐甲氧西林金黄色葡萄球菌 (MRSA) 定植于健康人的鼻咽部和胃肠道定植是社区获得性和住院患者的关键危险因素。医院获得性MRSA感染与治疗失败增加有关。发病率和死亡率增加之前尝试开发可以预防的疫苗或免疫疗法。 MRSA 定植或侵袭性疾病或改善 MRSA 感染的结果均已失败。个体无法产生保护性抗体反应（免疫），这使得 MRSA 能够在体内持续存在宿主组织并导致复发性疾病的 MRSA 免疫逃逸是基于免疫球蛋白结合。蛋白质，特别是葡萄球菌蛋白 A (SpA) 和葡萄球菌免疫球蛋白结合物 (Sbi)。 Sbi 通过与抗体的 Fcγ 结构域结合来阻断人 IgG 的效应子功能。 VH3-独特型免疫球蛋白的变异重链并交联 IgM B 细胞受体，从而激活 B 细胞增殖和无法识别 MRSA 的 VH3 克隆抗体的分泌。 SpA 的超抗原活性 (BCSA) 对于 MRSA 期间抗体反应的转移至关重要在这里，我们描述了一种单克隆抗体 MAb 3F6，它可以结合并抑制侵袭性疾病。中和 SpA 和 Sbi 我们发现 MAb 3F6 Fcγ 处的半乳糖基化促进 C1q 结合，MAb 3F6- MRSA 的依赖性调理吞噬杀伤 (OPK) 和保护小鼠免受 MRSA 血流影响此外，我们分离了 Fcγ 中的氨基酸取代，这些取代消除了 SpA 和 Sbi 的结合并增强了这种结合。我们还报道了变体 MAb 3F6 的 OPK 活性，SpA 对于抑制抗体至关重要。针对细菌定植因子的反应（BCSA），从而使金黄色葡萄球菌能够在向小鼠静脉注射 MAb 3F6 可中和循环 SpA 和阻断其 BCSA，从而促进针对细菌表面抗原的抗体反应并去除来自鼻咽和胃肠道的金黄色葡萄球菌在这里，我们将检验静脉注射的假设。糖基和 Fcγ 工程改造的人 3F6-IgG1 在临床前模型中的作用 a) 引发广谱抗体针对金黄色葡萄球菌的反应，b) 促进 MSSA 和 MRSA 的去定植，c) 诱导免疫以预防重新定植以及侵袭性 MSSA 和 MRSA 疾病，并且 d) 改善 MRSA 的结果实现此类产品特征的糖基和 Fcγ 工程化 3F6 抗体可以是进一步开发用于临床测试，以预防和治疗美国医院的 MRSA 感染。