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

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 Papadopoulos, Shibin Zhou, Sandra B. Gabelli, Bert Vogelstein and Kenneth W. Kinzler ()
Additional contact information
Steve Lu: Johns Hopkins University School of Medicine
Austin K. Mattox: Johns Hopkins University School of Medicine
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
Zan Chen: Johns Hopkins University School of Medicine
Surojit Sur: Johns Hopkins University School of Medicine
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
Nickolas Papadopoulos: Johns Hopkins University School of Medicine
Shibin Zhou: Johns Hopkins University School of Medicine
Sandra B. Gabelli: Johns Hopkins University School of Medicine
Bert Vogelstein: Johns Hopkins University School of Medicine
Kenneth W. Kinzler: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35668-6

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