Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis

Nat Commun. 2018 Apr 13;9(1):1461. doi: 10.1038/s41467-018-03687-x.

Abstract

Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR+ CXC chemokines. The engineered molecules recognize functional epitopes of ELR+ CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / chemistry*
  • Arthritis / immunology
  • Arthritis / therapy*
  • Autoantibodies / chemistry
  • Binding, Competitive
  • Biotinylation
  • Calcium / chemistry
  • Chemokines / metabolism*
  • Directed Molecular Evolution*
  • Epitope Mapping
  • Epitopes / chemistry
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis, Site-Directed
  • Neutrophils / cytology
  • Neutrophils / metabolism
  • Protein Binding
  • Signal Transduction
  • Surface Properties
  • Synovial Fluid / metabolism
  • Transgenes

Substances

  • Antibodies, Blocking
  • Autoantibodies
  • Chemokines
  • Epitopes
  • Calcium