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A cell-free nanobody engineering platform rapidly generates SARS-CoV-2 neutralizing nanobodies

Author

Listed:
  • Xun Chen

    (Broad Institute of MIT and Harvard)

  • Matteo Gentili

    (Broad Institute of MIT and Harvard)

  • Nir Hacohen

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Aviv Regev

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Howard Hughes Medical Institute
    Genentech)

Abstract

Antibody engineering technologies face increasing demands for speed, reliability and scale. We develop CeVICA, a cell-free nanobody engineering platform that uses ribosome display for in vitro selection of nanobodies from a library of 1011 randomized sequences. We apply CeVICA to engineer nanobodies against the Receptor Binding Domain (RBD) of SARS-CoV-2 spike protein and identify >800 binder families using a computational pipeline based on CDR-directed clustering. Among 38 experimentally-tested families, 30 are true RBD binders and 11 inhibit SARS-CoV-2 pseudotyped virus infection. Affinity maturation and multivalency engineering increase nanobody binding affinity and yield a virus neutralizer with picomolar IC50. Furthermore, the capability of CeVICA for comprehensive binder prediction allows us to validate the fitness of our nanobody library. CeVICA offers an integrated solution for rapid generation of divergent synthetic nanobodies with tunable affinities in vitro and may serve as the basis for automated and highly parallel nanobody engineering.

Suggested Citation

  • Xun Chen & Matteo Gentili & Nir Hacohen & Aviv Regev, 2021. "A cell-free nanobody engineering platform rapidly generates SARS-CoV-2 neutralizing nanobodies," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25777-z
    DOI: 10.1038/s41467-021-25777-z
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    Cited by:

    1. Thomas Eden & Alessa Z. Schaffrath & Janusz Wesolowski & Tobias Stähler & Natalie Tode & Nathalie Richter & Waldemar Schäfer & Julia Hambach & Irm Hermans-Borgmeyer & Jannis Woens & Camille M. Gall & , 2024. "Generation of nanobodies from transgenic ‘LamaMice’ lacking an endogenous immunoglobulin repertoire," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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