Epitopes described in "Novel human monoclonal antibody combination effectively neutralizing natural rabies virus variants and individual in vitro escape mutants."

Article Authors:Alexander B H Bakker; Wilfred E Marissen; R Arjen Kramer; Amy B Rice; William C Weldon; Michael Niezgoda; Cathleen A Hanlon; Sandra Thijsse; Harold H J Backus; John de Kruif; Bernhard Dietzschold; Charles E Rupprecht; Jaap Goudsmit
Article Title:Novel human monoclonal antibody combination effectively neutralizing natural rabies virus variants and individual in vitro escape mutants.
Reference Detail
Reference ID:1108
Abstract: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.
Affiliations:Crucell Holland B.V., Archimedesweg 4, P.O. Box 2048, 2301 CA Leiden, The Netherlands.
Reference Type:Literature
PubMed ID:15994800
Journal:J Virol
Journal Volume:79
Article Pages:9062-8
Journal ISSN:1098-5514
Article Chemical List:Antibodies, Monoclonal;Antibodies, Viral;Antigens, Viral;Glycoproteins;Immunoglobulin G;Viral Envelope Proteins;glycoprotein G, Rabies virus
Article MeSH List:Animals; Antibodies, Monoclonal(immunology); Antibodies, Viral(immunology); Antigens, Viral(immunology); Cricetinae; Genotype; Glycoproteins(immunology); Immunoglobulin G(immunology); Mesocricetus; Mice; Mutation; Neutralization Tests; Rabies(prevention & control); Rabies virus(genetics; immunology); Viral Envelope Proteins(immunology)
Curation Last Updated:2015-06-05 00:14:12