Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment
Recent development of monoclonal antibodies as mainstream anticancer agents demands further optimization of their safety for use in humans. Potent targeting and/or effector activities on normal tissues is an obvious toxicity concern. Optimization of specific tumor targeting could be achieved by taki...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2019.1682866 |
| _version_ | 1817987886641840128 |
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| author | Traian Sulea Nazanin Rohani Jason Baardsnes Christopher R. Corbeil Christophe Deprez Yuneivy Cepero-Donates Alma Robert Joseph D. Schrag Marie Parat Mélanie Duchesne Maria L. Jaramillo Enrico O. Purisima John C. Zwaagstra |
| author_facet | Traian Sulea Nazanin Rohani Jason Baardsnes Christopher R. Corbeil Christophe Deprez Yuneivy Cepero-Donates Alma Robert Joseph D. Schrag Marie Parat Mélanie Duchesne Maria L. Jaramillo Enrico O. Purisima John C. Zwaagstra |
| author_sort | Traian Sulea |
| collection | DOAJ |
| description | Recent development of monoclonal antibodies as mainstream anticancer agents demands further optimization of their safety for use in humans. Potent targeting and/or effector activities on normal tissues is an obvious toxicity concern. Optimization of specific tumor targeting could be achieved by taking advantage of the extracellular acidity of solid tumors relative to normal tissues. Here, we applied a structure-based computational approach to engineer anti-human epidermal growth factor receptor 2 (Her2) antibodies with selective binding in the acidic tumor microenvironment. We used an affinity maturation platform in which dual-pH histidine-scanning mutagenesis was implemented for pH selectivity optimization. Testing of a small set of designs for binding to the recombinant Her2 ectodomain led to the identification of antigen-binding fragment (Fab) variants with the desired pH-dependent binding behavior. Binding selectivity toward acidic pH was improved by as much as 25-fold relative to the parental bH1-Fab. In vitro experiments on cells expressing intact Her2 confirmed that designed variants formatted as IgG1/k full-size antibodies have high affinity and inhibit the growth of tumor spheroids at a level comparable to that of the benchmark anti-Her2 antibody trastuzumab (Herceptin®) at acidic pH, whereas these effects were significantly reduced at physiological pH. In contrast, both Herceptin and the parental bH1 antibody exhibited strong cell binding and growth inhibition irrespective of pH. This work demonstrates the feasibility of computational optimization of antibodies for selective targeting of the acidic environment such as that found in many solid tumors. |
| first_indexed | 2024-04-14T00:27:56Z |
| format | Article |
| id | doaj.art-f7e7bbaa010a45d39cfc5376757156e7 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-14T00:27:56Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-f7e7bbaa010a45d39cfc5376757156e72022-12-22T02:22:40ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2019.1682866Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironmentTraian Sulea0Nazanin Rohani1Jason Baardsnes2Christopher R. Corbeil3Christophe Deprez4Yuneivy Cepero-Donates5Alma Robert6Joseph D. Schrag7Marie Parat8Mélanie Duchesne9Maria L. Jaramillo10Enrico O. Purisima11John C. Zwaagstra12Human Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaRecent development of monoclonal antibodies as mainstream anticancer agents demands further optimization of their safety for use in humans. Potent targeting and/or effector activities on normal tissues is an obvious toxicity concern. Optimization of specific tumor targeting could be achieved by taking advantage of the extracellular acidity of solid tumors relative to normal tissues. Here, we applied a structure-based computational approach to engineer anti-human epidermal growth factor receptor 2 (Her2) antibodies with selective binding in the acidic tumor microenvironment. We used an affinity maturation platform in which dual-pH histidine-scanning mutagenesis was implemented for pH selectivity optimization. Testing of a small set of designs for binding to the recombinant Her2 ectodomain led to the identification of antigen-binding fragment (Fab) variants with the desired pH-dependent binding behavior. Binding selectivity toward acidic pH was improved by as much as 25-fold relative to the parental bH1-Fab. In vitro experiments on cells expressing intact Her2 confirmed that designed variants formatted as IgG1/k full-size antibodies have high affinity and inhibit the growth of tumor spheroids at a level comparable to that of the benchmark anti-Her2 antibody trastuzumab (Herceptin®) at acidic pH, whereas these effects were significantly reduced at physiological pH. In contrast, both Herceptin and the parental bH1 antibody exhibited strong cell binding and growth inhibition irrespective of pH. This work demonstrates the feasibility of computational optimization of antibodies for selective targeting of the acidic environment such as that found in many solid tumors.https://www.tandfonline.com/doi/10.1080/19420862.2019.1682866Virtual histidine scanningacidic pH selectivitycell bindingspheroid growthtumor targeting |
| spellingShingle | Traian Sulea Nazanin Rohani Jason Baardsnes Christopher R. Corbeil Christophe Deprez Yuneivy Cepero-Donates Alma Robert Joseph D. Schrag Marie Parat Mélanie Duchesne Maria L. Jaramillo Enrico O. Purisima John C. Zwaagstra Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment mAbs Virtual histidine scanning acidic pH selectivity cell binding spheroid growth tumor targeting |
| title | Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment |
| title_full | Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment |
| title_fullStr | Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment |
| title_full_unstemmed | Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment |
| title_short | Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment |
| title_sort | structure based engineering of ph dependent antibody binding for selective targeting of solid tumor microenvironment |
| topic | Virtual histidine scanning acidic pH selectivity cell binding spheroid growth tumor targeting |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2019.1682866 |
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