title: Chimpanzee-human monoclonal antibodies for treatment of chronic poliovirus excretors and emergency postexposure prophylaxis.
abstract: Six poliovirus-neutralizing Fabs were recovered from a combinatorial Fab phage display library constructed from bone marrow-derived lymphocytes of immunized chimpanzees. The chimeric chimpanzee-human full-length IgGs (hereinafter called monoclonal antibodies [MAbs]) were generated by combining a chimpanzee IgG light chain and a variable domain of heavy chain with a human constant Fc region. The six MAbs neutralized vaccine strains and virulent strains of poliovirus. Five MAbs were serotype specific, while one MAb cross-neutralized serotypes 1 and 2. Epitope mapping performed by selecting and sequencing antibody-resistant viral variants indicated that the cross-neutralizing MAb bound between antigenic sites 1 and 2, thereby covering the canyon region containing the receptor-binding site. Another serotype 1-specific MAb recognized a region located between antigenic sites 2 and 3 that included parts of capsid proteins VP1 and VP3. Both serotype 2-specific antibodies recognized antigenic site 1. No escape mutants to serotype 3-specific MAbs could be generated. The administration of a serotype 1-specific MAb to transgenic mice susceptible to poliovirus at a dose of 5 μg/mouse completely protected them from paralysis after challenge with a lethal dose of wild-type poliovirus. Moreover, MAb injection 6 or 12 h after virus infection provided significant protection. The MAbs described here could be tested in clinical trials to determine whether they might be useful for treatment of immunocompromised chronic virus excretors and for emergency protection of contacts of a paralytic poliomyelitis case.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Zhaochun
authors.initials: Z
authors.lastname: Chen
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chumakov
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dragunsky
authors.forename: Diana
authors.initials: D
authors.lastname: Kouiavskaia
authors.forename: Michelle
authors.initials: M
authors.lastname: Makiya
authors.forename: Alexander
authors.initials: A
authors.lastname: Neverov
authors.forename: Gennady
authors.initials: G
authors.lastname: Rezapkin
authors.forename: Andrew
authors.initials: A
authors.lastname: Sebrell
authors.forename: Robert
authors.initials: R
authors.lastname: Purcell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D003429:Cross Reactions; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D002679:Pan troglodytes; D011051:Poliomyelitis / Q000517:prevention & control*; D017955:Poliovirus / Q000145:classification / Q000276:immunology*; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012703:Serotyping
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D007074:Immunoglobulin G; D011994:Recombinant Proteins