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Infection and Immunity, September 2009, p. 3902-3908, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00200-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Chimpanzee/Human Monoclonal Antibodies That Neutralize Anthrax Lethal Factor, and Evidence for Possible Synergy with Anti-Protective Antigen Antibody {triangledown}

Zhaochun Chen,1,{dagger}* Mahtab Moayeri,2,{dagger} Devorah Crown,2 Suzanne Emerson,1 Inna Gorshkova,3 Peter Schuck,3 Stephen H. Leppla,2,{ddagger} and Robert H. Purcell1,{ddagger}

Laboratory of Infectious Diseases,1 Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases,2 National Institute for Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland3

Received 20 February 2009/ Returned for modification 22 April 2009/ Accepted 4 June 2009

Three chimpanzee Fabs reactive with lethal factor (LF) of anthrax toxin were isolated and converted into complete monoclonal antibodies (MAbs) with human {gamma}1 heavy-chain constant regions. In a macrophage toxicity assay, two of the MAbs, LF10E and LF11H, neutralized lethal toxin (LT), a complex of LF and anthrax protective antigen (PA). LF10E has the highest reported affinity for a neutralizing MAb against LF (dissociation constant of 0.69 nM). This antibody also efficiently neutralized LT in vitro, with a 50% effective concentration (EC50) of 0.1 nM, and provided 100% protection of rats against toxin challenge with a 0.5 submolar ratio relative to LT. LF11H, on the other hand, had a slightly lower binding affinity to LF (dissociation constant of 7.4 nM) and poor neutralization of LT in vitro (EC50 of 400 nM) and offered complete protection in vivo only at an equimolar or higher ratio to toxin. Despite this, LF11H, but not LF10E, provided robust synergistic protection when combined with MAb W1, which neutralizes PA. Epitope mapping and binding assays indicated that both LF10E and LF11H recognize domain I of LF (amino acids 1 to 254). Although domain I is responsible for binding to PA, neither MAb prevented LF from binding to activated PA. Although two unique MAbs could protect against anthrax when used alone, even more efficient and broader protection should be gained by combining them with anti-PA MAbs.

* Corresponding author. Mailing address: Laboratory of Infectious Diseases, National Institutes of Health, 50 South Drive, MSC8009, Bethesda, MD 20892. Phone: (301) 594-2308. Fax: (301) 402-0524. E-mail: ZC20a{at}nih.gov

{triangledown} Published ahead of print on 15 June 2009.

Editor: B. A. McCormick

{dagger} Z.C. and M.M. contributed equally to this work.

{ddagger} S.H.L. and R.H.P. are both senior authors.

Infection and Immunity, September 2009, p. 3902-3908, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00200-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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