title: A humanised murine monoclonal antibody with broad serogroup specificity protects mice from challenge with Venezuelan equine encephalitis virus.
abstract: In murine models of Venezuelan equine encephalitis virus (VEEV) infection, the neutralising monoclonal antibody 1A3B-7 has been shown to be effective in passive protection from challenge by the aerosol route with serogroups I, II and Mucambo virus (formally VEE complex subtype IIIA). This antibody is able to bind to all serogroups of the VEEV complex when used in ELISA and therefore is an excellent candidate for protein engineering in order to derive a humanised molecule suitable for therapeutic use in humans. A Complementarity Determining Region (CDR) grafting approach using human germline IgG frameworks was used to produce a panel of humanised variants of 1A3B-7, from which a single candidate molecule with retained binding specificity was identified. Evaluation of humanised 1A3B-7 (Hu1A3B-7) in in vitro studies indicated that Hu1A3B-7 retained both broad specificity and neutralising activity. Furthermore, in vivo experiments showed that Hu1A3B-7 successfully protected mice against lethal subcutaneous and aerosol challenges with VEEV strain TrD (serogroup I). Hu1A3B-7 is therefore a promising candidate for the future development of a broad-spectrum antiviral therapy to treat VEEV disease in humans.
authors.affiliation: Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. sagoodchild@dstl.gov.uk
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Goodchild
authors.forename: Lyn M
authors.initials: LM
authors.lastname: O'Brien
authors.forename: John
authors.initials: J
authors.lastname: Steven
authors.forename: Mischa R
authors.initials: MR
authors.lastname: Muller
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Lanning
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Logue
authors.forename: Riccardo V
authors.initials: RV
authors.lastname: D'Elia
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Phillpotts
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Perkins
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000276:immunology; D001688:Biological Products / Q000008:administration & dosage* / Q000276:immunology; D004195:Disease Models, Animal; D004666:Encephalitis Virus, Venezuelan Equine / Q000276:immunology*; D004685:Encephalomyelitis, Venezuelan Equine / Q000517:prevention & control*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001688:Biological Products