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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1429600
This article is part of the Research Topic Safety consideration in the development of anti-tumor monoclonal antibodies during drug development View all 5 articles

In silico evaluation of the role of Fab glycosylation in cetuximab antibody dynamics

Provisionally accepted
Simona Saporiti Simona Saporiti 1Davide Bianchi Davide Bianchi 2Omar Ben Mariem Omar Ben Mariem 2Mara Rossi Mara Rossi 1Uliano Guerrini Uliano Guerrini 2Ivano Eberini Ivano Eberini 2Fabio Centola Fabio Centola 1*
  • 1 Merck (Italy), Rome, Italy
  • 2 University of Milan, Milan, Lombardy, Italy

The final, formatted version of the article will be published soon.

    Introduction: N-glycosylation is a post-translational modification that is highly important for the development of monoclonal antibodies (mAbs), as it regulates their biological activity, particularly in terms of immune effector functions. While typically added at the Fc level, approximately 15-25% of circulating antibodies exhibit glycosylation in the Fab domains as well. To the best of our knowledge, cetuximab (Erbitux®) is the only therapeutic antibody presenting Fab glycosylation approved worldwide targeting the epidermal growth factor receptor for the treatment of metastatic-colorectal and head and neck cancers. Additionally, it can trigger antibody-dependent cell cytotoxicity (ADCC), a response that typically is influenced by N-glycosylation at Fc level. However, the role of Fab glycosylation in cetuximab remains poorly understood. Hence, this study aims to investigate the structural role of Fab glycosylation on the conformational behavior of cetuximab.The study was performed in silico via accelerated molecular dynamics simulations. The commercial cetuximab was compared to its form without Fab glycosylation and structural descriptors were evaluated to establish conformational differences.The results clearly show a correlation between the Fab glycosylation and structural descriptors that may modulate the conformational freedom of the antibody, potentially affecting Fc effector functions, and suggesting a negative role of Fab glycosylation on the interaction with FcγRIIIa. Conclusion: Fab glycosylation of cetuximab is the most critical challenge for biosimilar development, but the differences highlighted in this work with respect to its aglycosylated form can improve the knowledge and represent also a great opportunity to develop novel strategies of biotherapeutics.

    Keywords: N-glycosylation, FAB, cetuximab, molecular dynamics, ADCC, FcγRIIIA

    Received: 08 May 2024; Accepted: 23 Jul 2024.

    Copyright: © 2024 Saporiti, Bianchi, Ben Mariem, Rossi, Guerrini, Eberini and Centola. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Fabio Centola, Merck (Italy), Rome, Italy

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.