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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：
10525253
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/10525253
关键词：
American Amino Acid Substitution Animal Experiments Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antibody Response Antibody Suppression Antibody Therapy B Cell Proliferation B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes Bacteria Bacterial Interference Binding Blood Clinical Communities Complement 1q Cultured Cells Disease Engineering Excision Gastrointestinal tract structure Generations Genus staphylococcus Glycoengineering Half-Life Hospitals Human Human Engineering IgG1 Immune Immune Evasion Immunity Immunoglobulin G Immunoglobulin Idiotypes Immunoglobulin M Immunoglobulin binding proteins Immunoglobulins Immunotherapeutic agent Individual Infection Ligands Monoclonal Antibodies Morbidity - disease rate Mucous Membrane Mus Nasopharynx Nosocomial Infections Outcome Patient Admission 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 community-level factor crosslink glycosylation human monoclonal antibodies improved outcome in vivo 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.

摘要