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Assisted Design of Antibody and Protein Therapeutics (ADAPT)

Effective biologic therapeutics require binding affinities that are fine-tuned to their disease-related molecular target. The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform aids in the selection of mutants that improve/modulate the affinity of antibodies and other biologics. I...

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Autores principales: Vivcharuk, Victor, Baardsnes, Jason, Deprez, Christophe, Sulea, Traian, Jaramillo, Maria, Corbeil, Christopher R., Mullick, Alaka, Magoon, Joanne, Marcil, Anne, Durocher, Yves, O’Connor-McCourt, Maureen D., Purisima, Enrico O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531539/
https://www.ncbi.nlm.nih.gov/pubmed/28750054
http://dx.doi.org/10.1371/journal.pone.0181490
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author Vivcharuk, Victor
Baardsnes, Jason
Deprez, Christophe
Sulea, Traian
Jaramillo, Maria
Corbeil, Christopher R.
Mullick, Alaka
Magoon, Joanne
Marcil, Anne
Durocher, Yves
O’Connor-McCourt, Maureen D.
Purisima, Enrico O.
author_facet Vivcharuk, Victor
Baardsnes, Jason
Deprez, Christophe
Sulea, Traian
Jaramillo, Maria
Corbeil, Christopher R.
Mullick, Alaka
Magoon, Joanne
Marcil, Anne
Durocher, Yves
O’Connor-McCourt, Maureen D.
Purisima, Enrico O.
author_sort Vivcharuk, Victor
collection PubMed
description Effective biologic therapeutics require binding affinities that are fine-tuned to their disease-related molecular target. The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform aids in the selection of mutants that improve/modulate the affinity of antibodies and other biologics. It uses a consensus z-score from three scoring functions and interleaves computational predictions with experimental validation, significantly enhancing the robustness of the design and selection of mutants. The platform was tested on three antibody Fab-antigen systems that spanned a wide range of initial binding affinities: bH1-VEGF-A (44 nM), bH1-HER2 (3.6 nM) and Herceptin-HER2 (0.058 nM). Novel triple mutants were obtained that exhibited 104-, 46- and 32-fold improvements in binding affinity for each system, respectively. Moreover, for all three antibody-antigen systems over 90% of all the intermediate single and double mutants that were designed and tested showed higher affinities than the parent sequence. The contributions of the individual mutants to the change in binding affinity appear to be roughly additive when combined to form double and triple mutants. The new interactions introduced by the affinity-enhancing mutants included long-range electrostatics as well as short-range nonpolar interactions. This diversity in the types of new interactions formed by the mutants was reflected in SPR kinetics that showed that the enhancements in affinities arose from increasing on-rates, decreasing off-rates or a combination of the two effects, depending on the mutation. ADAPT is a very focused search of sequence space and required only 20–30 mutants for each system to be made and tested to achieve the affinity enhancements mentioned above.
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spelling pubmed-55315392017-08-07 Assisted Design of Antibody and Protein Therapeutics (ADAPT) Vivcharuk, Victor Baardsnes, Jason Deprez, Christophe Sulea, Traian Jaramillo, Maria Corbeil, Christopher R. Mullick, Alaka Magoon, Joanne Marcil, Anne Durocher, Yves O’Connor-McCourt, Maureen D. Purisima, Enrico O. PLoS One Research Article Effective biologic therapeutics require binding affinities that are fine-tuned to their disease-related molecular target. The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform aids in the selection of mutants that improve/modulate the affinity of antibodies and other biologics. It uses a consensus z-score from three scoring functions and interleaves computational predictions with experimental validation, significantly enhancing the robustness of the design and selection of mutants. The platform was tested on three antibody Fab-antigen systems that spanned a wide range of initial binding affinities: bH1-VEGF-A (44 nM), bH1-HER2 (3.6 nM) and Herceptin-HER2 (0.058 nM). Novel triple mutants were obtained that exhibited 104-, 46- and 32-fold improvements in binding affinity for each system, respectively. Moreover, for all three antibody-antigen systems over 90% of all the intermediate single and double mutants that were designed and tested showed higher affinities than the parent sequence. The contributions of the individual mutants to the change in binding affinity appear to be roughly additive when combined to form double and triple mutants. The new interactions introduced by the affinity-enhancing mutants included long-range electrostatics as well as short-range nonpolar interactions. This diversity in the types of new interactions formed by the mutants was reflected in SPR kinetics that showed that the enhancements in affinities arose from increasing on-rates, decreasing off-rates or a combination of the two effects, depending on the mutation. ADAPT is a very focused search of sequence space and required only 20–30 mutants for each system to be made and tested to achieve the affinity enhancements mentioned above. Public Library of Science 2017-07-27 /pmc/articles/PMC5531539/ /pubmed/28750054 http://dx.doi.org/10.1371/journal.pone.0181490 Text en © 2017 Vivcharuk et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Vivcharuk, Victor
Baardsnes, Jason
Deprez, Christophe
Sulea, Traian
Jaramillo, Maria
Corbeil, Christopher R.
Mullick, Alaka
Magoon, Joanne
Marcil, Anne
Durocher, Yves
O’Connor-McCourt, Maureen D.
Purisima, Enrico O.
Assisted Design of Antibody and Protein Therapeutics (ADAPT)
title Assisted Design of Antibody and Protein Therapeutics (ADAPT)
title_full Assisted Design of Antibody and Protein Therapeutics (ADAPT)
title_fullStr Assisted Design of Antibody and Protein Therapeutics (ADAPT)
title_full_unstemmed Assisted Design of Antibody and Protein Therapeutics (ADAPT)
title_short Assisted Design of Antibody and Protein Therapeutics (ADAPT)
title_sort assisted design of antibody and protein therapeutics (adapt)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531539/
https://www.ncbi.nlm.nih.gov/pubmed/28750054
http://dx.doi.org/10.1371/journal.pone.0181490
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