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Journal of Virology, September 2007, p. 8989-8995, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00906-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Characterization of Chimpanzee/Human Monoclonal Antibodies to Vaccinia Virus A33 Glycoprotein and Its Variola Virus Homolog In Vitro and in a Vaccinia Virus Mouse Protection Model

Zhaochun Chen,^1,* Patricia Earl,^3, Jeffrey Americo,³ Inger Damon,⁴ Scott K. Smith,⁴ Fujuan Yu,¹ Andrew Sebrell,¹ Suzanne Emerson,² Gary Cohen,⁵ Roselyn J. Eisenberg,⁵ Inna Gorshkova,⁶ Peter Schuck,⁶ William Satterfield,⁷ Bernard Moss,^3, and Robert Purcell^1,

Hepatitis Viruses Section,¹ Molecular Hepatitis Section,² Laboratory of Infectious Diseases, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases,³ Protein Biophysics Resource, National Institute for Biomedical Imaging and Bioengineering, NIH, Bethesda, Maryland 20892,⁶ Centers for Disease Control and Prevention, Atlanta, Georgia 30333,⁴ Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,⁵ Department of Veterinary Sciences, University of Texas, M. D. Anderson Cancer Center, Bastrop, Texas 78602⁷

Received 27 April 2007/ Accepted 11 June 2007

Three distinct chimpanzee Fabs against the A33 envelope glycoprotein of vaccinia virus were isolated and converted into complete monoclonal antibodies (MAbs) with human 1 heavy-chain constant regions. The three MAbs (6C, 12C, and 12F) displayed high binding affinities to A33 (K_d of 0.14 nM to 20 nM) and may recognize the same epitope, which was determined to be conformational and located within amino acid residues 99 to 185 at the C terminus of A33. One or more of the MAbs were shown to reduce the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro and to more effectively protect mice when administered before or 2 days after intranasal challenge with virulent vaccinia virus than a previously isolated mouse anti-A33 MAb (1G10) or vaccinia virus immunoglobulin. The protective efficacy afforded by anti-A33 MAb was comparable to that of a previously isolated chimpanzee/human anti-B5 MAb. The combination of anti-A33 MAb and anti-B5 MAb did not synergize the protective efficacy. These chimpanzee/human anti-A33 MAbs may be useful in the prevention and treatment of vaccinia virus-induced complications of vaccination against smallpox and may also be effective in the immunoprophylaxis and immunotherapy of smallpox and other orthopoxvirus diseases.

Published ahead of print on 20 June 2007.

Z.C. and P.E. contributed equally to this work.

B.M. and R.P. are co-senior authors.