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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5531539?pdf=render |
| _version_ | 1818944592853073920 |
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| author | Victor Vivcharuk Jason Baardsnes Christophe Deprez Traian Sulea Maria Jaramillo Christopher R Corbeil Alaka Mullick Joanne Magoon Anne Marcil Yves Durocher Maureen D O'Connor-McCourt Enrico O Purisima |
| author_facet | Victor Vivcharuk Jason Baardsnes Christophe Deprez Traian Sulea Maria Jaramillo Christopher R Corbeil Alaka Mullick Joanne Magoon Anne Marcil Yves Durocher Maureen D O'Connor-McCourt Enrico O Purisima |
| author_sort | Victor Vivcharuk |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T07:45:41Z |
| format | Article |
| id | doaj.art-eb1db71f334a418297760d9c820583f8 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T07:45:41Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-eb1db71f334a418297760d9c820583f82022-12-21T19:48:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01127e018149010.1371/journal.pone.0181490Assisted Design of Antibody and Protein Therapeutics (ADAPT).Victor VivcharukJason BaardsnesChristophe DeprezTraian SuleaMaria JaramilloChristopher R CorbeilAlaka MullickJoanne MagoonAnne MarcilYves DurocherMaureen D O'Connor-McCourtEnrico O PurisimaEffective 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.http://europepmc.org/articles/PMC5531539?pdf=render |
| spellingShingle | Victor Vivcharuk Jason Baardsnes Christophe Deprez Traian Sulea Maria Jaramillo Christopher R Corbeil Alaka Mullick Joanne Magoon Anne Marcil Yves Durocher Maureen D O'Connor-McCourt Enrico O Purisima Assisted Design of Antibody and Protein Therapeutics (ADAPT). PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC5531539?pdf=render |
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