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Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose proliferative effects can contribute to the development of many types of solid tumors when overexpressed. For this reason, EGFR inhibitors such as cetuximab can play an important role in treating cancers such as colorect...

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Autores principales: Goulet, Dennis R., Chatterjee, Soumili, Lee, Wai-Ping, Waight, Andrew B., Zhu, Yi, Mak, Amanda Nga-Sze
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788544/
https://www.ncbi.nlm.nih.gov/pubmed/35076451
http://dx.doi.org/10.3390/antib11010006
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author Goulet, Dennis R.
Chatterjee, Soumili
Lee, Wai-Ping
Waight, Andrew B.
Zhu, Yi
Mak, Amanda Nga-Sze
author_facet Goulet, Dennis R.
Chatterjee, Soumili
Lee, Wai-Ping
Waight, Andrew B.
Zhu, Yi
Mak, Amanda Nga-Sze
author_sort Goulet, Dennis R.
collection PubMed
description The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose proliferative effects can contribute to the development of many types of solid tumors when overexpressed. For this reason, EGFR inhibitors such as cetuximab can play an important role in treating cancers such as colorectal cancer and head and neck cancer. Cetuximab is a chimeric monoclonal antibody containing mouse variable regions that bind to EGFR and prevent it from signaling. Although cetuximab has been used clinically since 2004 to successfully control solid tumors, advances in protein engineering have created the opportunity to address some of its shortcomings. In particular, the presence of mouse sequences could contribute to immunogenicity in the form of anti-cetuximab antibodies, and an occupied glycosylation site in FR3 can contribute to hypersensitivity reactions and product heterogeneity. Using simple framework graft or sequence-/structure-guided approaches, cetuximab was humanized onto 11 new frameworks. In addition to increasing humanness and removing the VH glycosylation site, dynamic light scattering revealed increases in stability, and bio-layer interferometry confirmed minimal changes in binding affinity, with patterns emerging across the humanization method. This work demonstrates the potential to improve the biophysical and clinical properties of first-generation protein therapeutics and highlights the advantages of computationally guided engineering.
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spelling pubmed-87885442022-01-26 Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability Goulet, Dennis R. Chatterjee, Soumili Lee, Wai-Ping Waight, Andrew B. Zhu, Yi Mak, Amanda Nga-Sze Antibodies (Basel) Article The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase whose proliferative effects can contribute to the development of many types of solid tumors when overexpressed. For this reason, EGFR inhibitors such as cetuximab can play an important role in treating cancers such as colorectal cancer and head and neck cancer. Cetuximab is a chimeric monoclonal antibody containing mouse variable regions that bind to EGFR and prevent it from signaling. Although cetuximab has been used clinically since 2004 to successfully control solid tumors, advances in protein engineering have created the opportunity to address some of its shortcomings. In particular, the presence of mouse sequences could contribute to immunogenicity in the form of anti-cetuximab antibodies, and an occupied glycosylation site in FR3 can contribute to hypersensitivity reactions and product heterogeneity. Using simple framework graft or sequence-/structure-guided approaches, cetuximab was humanized onto 11 new frameworks. In addition to increasing humanness and removing the VH glycosylation site, dynamic light scattering revealed increases in stability, and bio-layer interferometry confirmed minimal changes in binding affinity, with patterns emerging across the humanization method. This work demonstrates the potential to improve the biophysical and clinical properties of first-generation protein therapeutics and highlights the advantages of computationally guided engineering. MDPI 2022-01-13 /pmc/articles/PMC8788544/ /pubmed/35076451 http://dx.doi.org/10.3390/antib11010006 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Goulet, Dennis R.
Chatterjee, Soumili
Lee, Wai-Ping
Waight, Andrew B.
Zhu, Yi
Mak, Amanda Nga-Sze
Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
title Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
title_full Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
title_fullStr Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
title_full_unstemmed Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
title_short Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability
title_sort engineering an enhanced egfr engager: humanization of cetuximab for improved developability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788544/
https://www.ncbi.nlm.nih.gov/pubmed/35076451
http://dx.doi.org/10.3390/antib11010006
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