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

Author

Listed:
  • Alessandro Angelini

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Ca’ Foscari University of Venice)

  • Yoshishige Miyabe

    (Harvard Medical School)

  • Daniel Newsted

    (Massachusetts Institute of Technology)

  • Byron H. Kwan

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Chie Miyabe

    (Harvard Medical School)

  • Ryan L. Kelly

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Misha N. Jamy

    (Massachusetts Institute of Technology)

  • Andrew D. Luster

    (Harvard Medical School)

  • K. Dane Wittrup

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

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.

Suggested Citation

  • Alessandro Angelini & Yoshishige Miyabe & Daniel Newsted & Byron H. Kwan & Chie Miyabe & Ryan L. Kelly & Misha N. Jamy & Andrew D. Luster & K. Dane Wittrup, 2018. "Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03687-x
    DOI: 10.1038/s41467-018-03687-x
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    Cited by:

    1. Serena Vales & Jhanna Kryukova & Soumyanetra Chandra & Gintare Smagurauskaite & Megan Payne & Charlie J. Clark & Katrin Hafner & Philomena Mburu & Stepan Denisov & Graham Davies & Carlos Outeiral & Ch, 2023. "Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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