Adenovirus-mediated delivery of an anti-V antigen monoclonal antibody protects mice against a lethal Yersinia pestis challenge.
Pneumonic plague, caused by inhalation of Yersinia pestis, represents a major bioterrorism threat for which no vaccine is available. Based on the knowledge that genetic delivery of monoclonal antibodies (MAbs) with adenovirus (Ad) gene transfer vectors results in rapid, high-level antibody expression, we evaluated the hypothesis that Ad-mediated delivery of a neutralizing antibody directed against the Y. pestis V antigen would protect mice against a Y. pestis challenge. MAbs specific for the Y. pestis V antigen were generated, and the most effective in protecting mice against a lethal intranasal Y. pestis challenge was chosen for further study. The coding sequences for the heavy and light chains were isolated from the corresponding hybridoma and inserted into a replication-defective serotype 5 human Ad gene transfer vector (AdalphaV). Western analysis of AdalphaV-infected cell supernatants demonstrated completely assembled antibodies reactive with V antigen. Following AdalphaV administration to mice, high levels of anti-V antigen antibody titers were detectable as early as 1 day postadministration, peaked by day 3, and remained detectable through a 12-week time course. When animals that received AdalphaV were challenged with Y. pestis at day 4 post-AdalphaV administration, 80% of the animals were protected, while 0% of control animals survived (P < 0.01). Ad-mediated delivery of a V antigen-neutralizing antibody is an effective therapy against plague in experimental animals and could be developed as a rapidly acting antiplague therapeutic.
Sofer-Podesta
Carolina
C
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA.
Ang
John
J
Hackett
Neil R
NR
Senina
Svetlana
S
Perlin
David
D
Crystal
Ronald G
RG
Boyer
Julie L
JL
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D010930:Plague / Q000276:immunology / Q000382:microbiology / Q000401:mortality* / Q000517:prevention & control; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000276:immunology*; D015010:Yersinia pestis / Q000276:immunology / Q000472:pathogenicity*
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins