Protection against anthrax toxin by recombinant antibody fragments correlates with antigen affinity

Nat Biotechnol. 2002 Jun;20(6):597-601. doi: 10.1038/nbt0602-597.

Abstract

The tripartite toxin produced by Bacillus anthracis is the key determinant in the etiology of anthrax. We have engineered a panel of toxin-neutralizing antibodies, including single-chain variable fragments (scFvs) and scFvs fused to a human constant kappa domain (scAbs), that bind to the protective antigen subunit of the toxin with equilibrium dissociation constants (K(d)) between 63 nM and 0.25 nM. The entire antibody panel showed high serum, thermal, and denaturant stability. In vitro, post-challenge protection of macrophages from the action of the holotoxin correlated with the K(d) of the scFv variants. Strong correlations among antibody construct affinity, serum half-life, and protection were also observed in a rat model of toxin challenge. High-affinity toxin-neutralizing antibodies may be of therapeutic value for alleviating the symptoms of anthrax toxin in infected individuals and for medium-term prophylaxis to infection.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anthrax / drug therapy
  • Anthrax / immunology
  • Antibodies, Bacterial / biosynthesis*
  • Antibodies, Bacterial / genetics*
  • Antibodies, Bacterial / immunology
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / genetics*
  • Antibody Affinity / immunology*
  • Antigens, Bacterial / drug effects
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / immunology
  • Bacillus anthracis / drug effects
  • Bacillus anthracis / immunology
  • Bacterial Toxins / immunology*
  • Binding, Competitive / genetics
  • Binding, Competitive / immunology
  • Gene Expression Regulation
  • Humans
  • Immunoglobulin Fragments / genetics
  • Immunoglobulin Fragments / immunology
  • Immunoglobulin Fragments / therapeutic use
  • Immunoglobulin kappa-Chains / genetics
  • Immunoglobulin kappa-Chains / immunology
  • Mice
  • Molecular Sequence Data
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Protein Engineering
  • Rats
  • Rats, Inbred F344
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / biosynthesis*
  • Recombinant Proteins / genetics

Substances

  • Antibodies, Bacterial
  • Antibodies, Monoclonal
  • Antigens, Bacterial
  • Bacterial Toxins
  • Immunoglobulin Fragments
  • Immunoglobulin kappa-Chains
  • Recombinant Proteins
  • anthrax toxin
  • immunoglobulin Fv