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

doi:10.3390/antib11010006

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

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Protein Engineering, SystImmune, Inc., 15318 NE 95th St., Redmond, WA 98052, USA

Process Development, SystImmune, Inc., 15318 NE 95th St., Redmond, WA 98052, USA

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Academic Editor: Christian Kellner

Antibodies 2022, 11(1), 6; https://doi.org/10.3390/antib11010006

Received: 25 November 2021 / Revised: 12 December 2021 / Accepted: 5 January 2022 / Published: 13 January 2022

(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy Series II)

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Abstract

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. View Full-Text

Keywords: cetuximab; antibody engineering; humanization; glycosylation; post-translational modifications; stability; aggregation; immunogenicity; modeling; binding kinetics

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Goulet, D.R.; Chatterjee, S.; Lee, W.-P.; Waight, A.B.; Zhu, Y.; Mak, A.N.-S. Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability. Antibodies 2022, 11, 6. https://doi.org/10.3390/antib11010006

AMA Style

Goulet DR, Chatterjee S, Lee W-P, Waight AB, Zhu Y, Mak AN-S. Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability. Antibodies. 2022; 11(1):6. https://doi.org/10.3390/antib11010006

Chicago/Turabian Style

Goulet, Dennis R., Soumili Chatterjee, Wai-Ping Lee, Andrew B. Waight, Yi Zhu, and Amanda N.-S. Mak. 2022. "Engineering an Enhanced EGFR Engager: Humanization of Cetuximab for Improved Developability" Antibodies 11, no. 1: 6. https://doi.org/10.3390/antib11010006

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

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