RESUMO
Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.
Assuntos
Anticorpos Antivirais , Especificidade de Anticorpos , Vírus da Influenza A , Vírus da Influenza B , Vacinas contra Influenza , Influenza Humana , Mimetismo Molecular , Neuraminidase , Animais , Humanos , Camundongos , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Especificidade de Anticorpos/imunologia , Arginina/química , Domínio Catalítico , Hemaglutininas Virais/imunologia , Vírus da Influenza A/classificação , Vírus da Influenza A/enzimologia , Vírus da Influenza A/imunologia , Vírus da Influenza A Subtipo H3N2/enzimologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/classificação , Vírus da Influenza B/enzimologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/química , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Neuraminidase/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Estações do Ano , Ácidos Siálicos/químicaRESUMO
Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood. Robust antibacterial vaccines have prevented and reduced resistance suggesting a pivotal role for immunity in deterring antibiotic resistance. Here, we show the increased prevalence of Klebsiella pneumoniae lipopolysaccharide O2 serotype strains in all major drug resistance groups correlating with a paucity of anti-O2 antibodies in human B cell repertoires. We identify human monoclonal antibodies to O-antigens that are highly protective in mouse models of infection, even against heavily encapsulated strains. These antibodies, including a rare anti-O2 specific antibody, synergistically protect against drug-resistant strains in adjunctive therapy with meropenem, a standard-of-care antibiotic, confirming the importance of immune assistance in antibiotic therapy. These findings support an antibody-based immunotherapeutic strategy even for highly resistant K. pneumoniae infections, and underscore the effect humoral immunity has on evolving drug resistance.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Infecções por Klebsiella/terapia , Klebsiella pneumoniae/fisiologia , Antígenos O/imunologia , Animais , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/imunologia , Linhagem Celular , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/genética , Farmacorresistência Bacteriana Múltipla/imunologia , Humanos , Imunidade Humoral , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/mortalidade , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Sorogrupo , Taxa de Sobrevida , Tienamicinas/uso terapêuticoRESUMO
Monoclonal antibodies (mAbs) have revolutionized the diagnosis and treatment of many human diseases and the application of combinations of mAbs has demonstrated improved therapeutic activity in both preclinical and clinical testing. Combinations of antibodies have several advantages such as the capacities to target multiple and mutating antigens in complex pathogens and to engage varied epitopes on multiple disease-related antigens (e.g. receptors) to overcome heterogeneity and plasticity. Oligoclonal antibodies are an emerging therapeutic format in which a novel antibody combination is developed as a single drug product. Here, we will provide historical context on the use of oligoclonal antibodies in oncology and infectious diseases and will highlight practical considerations related to their preclinical and clinical development programs.