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Molecular evolution of antibody cross-reactivity for two subtypes of type a botulinum neurotoxin

Academic Article
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Overview

authors

  • Garcia-Rodriguez, C.
  • Levy, R.
  • Arndt, J. W.
  • Forsyth, C. M.
  • Razai, A.
  • Lou, J. L.
  • Geren, I.
  • Stevens, Raymond
  • Marks, J. D.

publication date

  • January 2007

journal

  • Nature Biotechnology  Journal

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.

subject areas

  • Antibodies, Monoclonal
  • Binding Sites
  • Botulinum Toxins, Type A
  • Drug Design
  • Epitope Mapping
  • Protein Binding
  • Protein Engineering
  • Protein Interaction Mapping
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Identity

International Standard Serial Number (ISSN)

  • 1087-0156

Digital Object Identifier (DOI)

  • 10.1038/nbt1269

PubMed ID

  • 17173035
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Additional Document Info

start page

  • 107

end page

  • 116

volume

  • 25

issue

  • 1

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