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Fragment-based computational design of antibodies targeting structured epitopes

Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, View ORCID ProfileStefano Ricagno, View ORCID ProfileJudith Frydman, Michele Vendruscolo, View ORCID ProfilePietro Sormanni
doi: https://doi.org/10.1101/2021.03.02.433360
Mauricio Aguilar Rangel
1Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
3Department of Biology, Stanford University, Stanford, California, USA
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Alice Bedwell
1Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
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Elisa Costanzi
2Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy
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Stefano Ricagno
2Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy
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  • ORCID record for Stefano Ricagno
Judith Frydman
3Department of Biology, Stanford University, Stanford, California, USA
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Michele Vendruscolo
1Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
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  • For correspondence: ps589@cam.ac.uk mv245@cam.ac.uk
Pietro Sormanni
1Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
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  • ORCID record for Pietro Sormanni
  • For correspondence: ps589@cam.ac.uk mv245@cam.ac.uk
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Abstract

De novo design methods hold the promise of reducing the time and cost of antibody discovery, while enabling the facile and precise targeting of specific epitopes. Here we describe a fragment-based method for the combinatorial design of antibody binding loops and their grafting onto antibody scaffolds. We designed and tested six single-domain antibodies targeting different epitopes on three antigens, including the receptor-binding domain of the SARS-CoV-2 spike protein. Biophysical characterisation showed that all designs are highly stable, and bind their intended targets with affinities in the nanomolar range without any in vitro affinity maturation. We further show that a high-resolution input antigen structure is not required, as our method yields similar predictions when the input is a crystal structure or a computer-generated model. This computational procedure, which readily runs on a laptop, provides the starting point for the rapid generation of lead antibodies binding to pre-selected epitopes.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 02, 2021.
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Fragment-based computational design of antibodies targeting structured epitopes
Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, Stefano Ricagno, Judith Frydman, Michele Vendruscolo, Pietro Sormanni
bioRxiv 2021.03.02.433360; doi: https://doi.org/10.1101/2021.03.02.433360
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Fragment-based computational design of antibodies targeting structured epitopes
Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, Stefano Ricagno, Judith Frydman, Michele Vendruscolo, Pietro Sormanni
bioRxiv 2021.03.02.433360; doi: https://doi.org/10.1101/2021.03.02.433360

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