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The rapid and highly parallel identification of antibodies with defined biological activities by SLISY

Author

Listed:
  • Steve Lu

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • Austin K. Mattox

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • P. Aitana Azurmendi

    (Johns Hopkins University School of Medicine)

  • Ilias Christodoulou

    (Johns Hopkins University School of Medicine)

  • Katharine M. Wright

    (Johns Hopkins University School of Medicine)

  • Maria Popoli

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • Zan Chen

    (Johns Hopkins University School of Medicine)

  • Surojit Sur

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • Yana Li

    (Johns Hopkins University School of Medicine)

  • Challice L. Bonifant

    (Johns Hopkins University School of Medicine)

  • Chetan Bettegowda

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Nickolas Papadopoulos

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Shibin Zhou

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Sandra B. Gabelli

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Bert Vogelstein

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • Kenneth W. Kinzler

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

The therapeutic applications of antibodies are manifold and the emergence of SARS-CoV-2 provides a cogent example of the value of rapidly identifying biologically active antibodies. We describe an approach called SLISY (Sequencing-Linked ImmunoSorbent assaY) that in a single experiment can assess the binding specificity of millions of clones, be applied to any screen that links DNA sequence to a potential binding moiety, and requires only a single round of biopanning. We demonstrate this approach using an scFv library applied to cellular and protein targets to identify specific or broadly reacting antibodies. For a cellular target, we use paired HLA knockout cell lines to identify a panel of antibodies specific to HLA-A3. For a protein target, SLISY identifies 1279 clones that bound to the Receptor Binding Domain of the SARS-CoV-2 spike protein, with >40% of tested clones also neutralizing its interaction with ACE2 in in vitro assays. Using a multi-comparison SLISY against the Beta, Gamma, and Delta variants, we recovered clones that exhibited broad-spectrum neutralizing potential in vitro. By evaluating millions of scFvs simultaneously against multiple targets, SLISY allows the rapid identification of candidate scFvs with defined binding profiles facilitating the identification of antibodies with the desired biological activity.

Suggested Citation

  • Steve Lu & Austin K. Mattox & P. Aitana Azurmendi & Ilias Christodoulou & Katharine M. Wright & Maria Popoli & Zan Chen & Surojit Sur & Yana Li & Challice L. Bonifant & Chetan Bettegowda & Nickolas Pa, 2023. "The rapid and highly parallel identification of antibodies with defined biological activities by SLISY," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35668-6
    DOI: 10.1038/s41467-022-35668-6
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