title: A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus.
abstract: A humanized monoclonal antibody (mAb) has been developed and its potential to protect from or cure a Venezuelan equine encephalomyelitis virus (VEEV) infection was evaluated. The VEEV-neutralizing, protective murine mAb 3B4C-4 was humanized using combinatorial antibody libraries and phage-display technology. Humanized VEEV-binding Fabs were evaluated for virus-neutralizing capacity, then selected Fabs were converted to whole immunoglobulin (Ig) G1, and stable cell lines were generated. The humanized mAb Hy4-26C, designated Hy4 IgG, had virus-neutralizing capacity similar to that of 3B4C-4. Passive antibody protection studies with purified Hy4 IgG were performed in adult Swiss Webster mice. As little as 100 ng Hy4 IgG protected 90 % of mice challenged with 100 intraperitoneal (i.p.) mean morbidity (MD(50)) doses of virulent VEEV (Trinidad donkey) 24 h after antibody transfer; also, 500 mug Hy4 IgG protected 80 % of mice inoculated with 100 intranasal MD(50) doses of VEEV. Moreover, 10 mug passive Hy4 IgG protected 70 % of mice from a VEEV challenge dose as great as 10(7) i.p. MD(50). Hy4 IgG also protected mice from challenge with another epizootic VEEV variety, 1C (P676). Importantly, therapeutic administration of the humanized mAb to mice already infected with VEEV cured 90 % of mice treated with Hy4 IgG within 1 h of VEEV inoculation and 75 % of mice treated 24 h after virus infection.
authors.affiliation: Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, US Department of Health and Human Services, PO Box 2087, Fort Collins, CO 80522, USA.
authors.forename: Ann R
authors.initials: AR
authors.lastname: Hunt
authors.affiliation: Alexion Antibody Technologies, San Diego, CA 92121, USA.
authors.forename: Shana
authors.initials: S
authors.lastname: Frederickson
authors.affiliation: Alexion Antibody Technologies, San Diego, CA 92121, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hinkel
authors.affiliation: Alexion Antibody Technologies, San Diego, CA 92121, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Bowdish
authors.affiliation: Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, US Department of Health and Human Services, PO Box 2087, Fort Collins, CO 80522, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Roehrig
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D001483:Base Sequence; D003001:Cloning, Molecular; D004666:Encephalitis Virus, Venezuelan Equine / Q000276:immunology* / Q000472:pathogenicity; D004685:Encephalomyelitis, Venezuelan Equine / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D005803:Genes, Immunoglobulin; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D009838:Oligodeoxyribonucleotides / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides