title: Synthetic antibodies with a human framework that protect mice from lethal Sudan ebolavirus challenge.
abstract: The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection.
authors.affiliation: Banting and Best Department of Medical Research, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, ON, Canada M5S 3E1.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Jayne F
authors.initials: JF
authors.lastname: Koellhoffer
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Zak
authors.forename: Julia C
authors.initials: JC
authors.lastname: Frei
authors.forename: Nina
authors.initials: N
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Long
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.forename: Kaajal
authors.initials: K
authors.lastname: Nagar
authors.forename: Guohua
authors.initials: G
authors.lastname: Pan
authors.forename: Kartik
authors.initials: K
authors.lastname: Chandran
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology*; D029043:Ebolavirus / Q000276:immunology / Q000472:pathogenicity*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D019151:Peptide Library; D011487:Protein Conformation; D017471:Receptors, Interferon / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D013397:Sudan; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D000939:Epitopes; D019151:Peptide Library; D017471:Receptors, Interferon; D014759:Viral Envelope Proteins