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Journal of Virology, July 2005, p. 9062-9068, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.9062-9068.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Novel Human Monoclonal Antibody Combination Effectively Neutralizing Natural Rabies Virus Variants and Individual In Vitro Escape Mutants

Alexander B. H. Bakker,1,{dagger} Wilfred E. Marissen,1,{dagger} R. Arjen Kramer,1 Amy B. Rice,2 William C. Weldon,3 Michael Niezgoda,3 Cathleen A. Hanlon,3 Sandra Thijsse,1 Harold H. J. Backus,1 John de Kruif,1 Bernhard Dietzschold,2 Charles E. Rupprecht,3 and Jaap Goudsmit1*

Crucell Holland BV, Leiden, The Netherlands,1 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania,2 Centers for Disease Control and Prevention, Division of Viral and Rickettsial Diseases, Rabies Section, Atlanta, Georgia3

Received 16 February 2005/ Accepted 1 April 2005

The need to replace rabies immune globulin (RIG) as an essential component of rabies postexposure prophylaxis is widely acknowledged. We set out to discover a unique combination of human monoclonal antibodies (MAbs) able to replace RIG. Stringent criteria concerning neutralizing potency, affinity, breadth of neutralization, and coverage of natural rabies virus (RV) isolates and in vitro escape mutants were set for each individual antibody, and the complementarities of the two MAbs were defined at the onset. First, we identified and characterized one human MAb (CR57) with high in vitro and in vivo neutralizing potency and a broad neutralization spectrum. The linear antibody binding site was mapped on the RV glycoprotein as antigenic site I by characterizing CR57 escape mutants. Secondly, we selected using phage display a complementing antibody (CR4098) that recognized a distinct, nonoverlapping epitope (antigenic site III), showed similar neutralizing potency and breadth as CR57, and neutralized CR57 escape mutants. Reciprocally, CR57 neutralized RV variants escaping CR4098. Analysis of glycoprotein sequences of natural RV isolates revealed that the majority of strains contain both intact epitopes, and the few remaining strains contain at least one of the two. In vitro exposure of RV to the combination of CR57 and CR4098 yielded no escape mutants. In conclusion, a novel combination of human MAbs was discovered suitable to replace RIG.

* Corresponding author. Mailing address: Crucell Holland B.V., Archimedesweg 4, P.O. Box 2048, 2301 CA Leiden, The Netherlands. Phone: 31 71 5248701. Fax: 31 71 5248702. E-mail: j.goudsmit{at}crucell.com.

{dagger} A.B.H.B. and W.E.M. contributed equally to this work.

Journal of Virology, July 2005, p. 9062-9068, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.9062-9068.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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