Functional and structural characterization of a two-MAb cocktail for delayed treatment of enterovirus D68 infections

• Published in: Nature communications Vol. 12; no. 1; pp. 2904 - 16
• Main Authors: Zhang, Chao, Xu, Cong, Dai, Wenlong, Wang, Yifan, Liu, Zhi, Zhang, Xueyang, Wang, Xuesong, Wang, Haikun, Gong, Sitang, Cong, Yao, Huang, Zhong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 147/28; 631/154; 631/326/596; 631/535; 692/699/255/2514; Acids; Animals; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antigens; Binding; Binding sites; Canyons; Cell Line, Tumor; Chemical compounds; Cryoelectron Microscopy; Enterovirus D, Human - drug effects; Enterovirus D, Human - immunology; Enterovirus D, Human - physiology; Enterovirus Infections - drug therapy; Enterovirus Infections - immunology; Enterovirus Infections - virology; Enteroviruses; Epidemics; Female; Humanities and Social Sciences; Humans; Infections; Laboratories; Mice; Mice, Inbred BALB C; Monoclonal antibodies; multidisciplinary; Myelitis; Neutralization; Neutralizing; Pharmacology; Protein Binding - drug effects; Receptors; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; Respiratory diseases; Science; Science (multidisciplinary); Signs and symptoms; Steric hindrance; Structural analysis; Structure-function relationships; Time-to-Treatment; Treatment Outcome; Uncoating; Virion - drug effects; Virion - immunology; Virion - metabolism; Virion - ultrastructure; Virions; Virus Uncoating - drug effects; Virus-like particles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23199-5

Enterovirus D68 (EV-D68) is an emerging pathogen associated with respiratory diseases and/or acute flaccid myelitis. Here, two MAbs, 2H12 and 8F12, raised against EV-D68 virus-like particle (VLP), show distinct preference in binding VLP and virion and in neutralizing different EV-D68 strains. A combination of 2H12 and 8F12 exhibits balanced and potent neutralization effects and confers broader protection in mice than single MAbs when given at onset of symptoms. Cryo-EM structures of EV-D68 virion complexed with 2H12 or 8F12 show that both antibodies bind to the canyon region of the virion, creating steric hindrance for sialic acid receptor binding. Additionally, 2H12 binding can impair virion integrity and trigger premature viral uncoating. We also capture an uncoating intermediate induced by 2H12 binding, not previously described for picornaviruses. Our study elucidates the structural basis and neutralizing mechanisms of the 2H12 and 8F12 MAbs and supports further development of the 2H12/8F12 cocktail as a broad-spectrum therapeutic agent against EV-D68 infections in humans. Although enterovirus D68 poses a major global threat to children, neither vaccines nor therapeutics are currently available. Using Cryo-EM, Zhang et al. show that two murine-derived monoclonal antibodies with therapeutic efficacy neutralize virions via binding to the canyon region, creating steric hindrance for sialic acid receptor binding.