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- Title
Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin.
- Authors
Garcia-Rodriguez, Consuelo; Levy, Raphael; Arndt, Joseph W; Forsyth, Charles M; Razai, Ali; Lou, Jianlong; Geren, Isin; Stevens, Raymond C; Marks, James D
- Abstract
Broadening antibody specificity without compromising affinity should facilitate detection and neutralization of toxin and viral subtypes. We used yeast display and a co-selection strategy to increase cross-reactivity of a single chain (sc) Fv antibody to botulinum neurotoxin type A (BoNT/A). Starting with a scFv that binds the BoNT/A1 subtype with high affinity (136 pM) and the BoNT/A2 subtype with low affinity (109 nM), we increased its affinity for BoNT/A2 1,250-fold, to 87 pM, while maintaining high-affinity binding to BoNT/A1 (115 pM). To find the molecular basis for improved cross-reactivity, we determined the X-ray co-crystal structures of wild-type and cross-reactive antibodies complexed to BoNT/A1 at resolutions up to 2.6 A, and measured the thermodynamic contribution of BoNT/A1 and A2 amino acids to wild-type and cross-reactive antibody binding. The results show how an antibody can be engineered to bind two different antigens despite structural differences in the antigen-antibody interface and may provide a general strategy for tuning antibody specificity and cross-reactivity.
- Publication
Nature biotechnology, 2007, Vol 25, Issue 1, p107
- ISSN
1087-0156
- Publication type
Journal Article
- DOI
10.1038/nbt1269