Article: In-silico rituximab protein engineering to improve humanisation and reduce immunogenicity Journal: International Journal of Bioinformatics Research and Applications (IJBRA) 2024 Vol.20 No.2 pp.142 - 160 Abstract: Rituximab is a monoclonal antibody with a high degree of specificity towards the CD20 antigen, found on the surface of B lymphocytes used in the treatment of diverse B cell lymphomas and autoimmune disorders. Rituximab is a chimeric monoclonal antibody that reported adverse effects due to the presence of non-human sequences. Here, we attempted to improve the humanness score of rituximab using a computational approach by using combinatorial mutations at the sequence patches. These changes were imposed in: a) CDR; b) non-CDR; c) CDR + non-CDR mutants at Ala49 → Gly, Thr50 → Ala, and Leu53 → Arg, Ser5 → Thr, Ala9 → Gly, and Ile10 → Thr. These mutations did not affect the structural stability that was interpreted from the MD simulation analysis. However, non-CDR mutants showed marginally higher structural variation compared to CDR mutants and native rituximab. It is suggested in this study that this rational design can improve the humanness characteristics of rituximab without affecting its structural and therapeutic behaviour. Inderscience Publishers - linking academia, business and industry through research

Title: In-silico rituximab protein engineering to improve humanisation and reduce immunogenicity

Authors: Harit Kasana; Harish Chander; Ashwani Mathur

Addresses: National Institute of Biologicals, Ministry of Health and Family Welfare, A-32, Sector-62, Noida-201 309, India; Department of Biotechnology, Jaypee Institute of Information Technology Noida, A-10, Sector-62, Noida, 201309, Uttar Pradesh, India ' National Institute of Biologicals, Ministry of Health and Family Welfare, A-32, Sector-62, Noida-201 309, India ' Department of Biotechnology, Jaypee Institute of Information Technology Noida, A-10, Sector-62, Noida, 201309, Uttar Pradesh, India

Abstract: Rituximab is a monoclonal antibody with a high degree of specificity towards the CD20 antigen, found on the surface of B lymphocytes used in the treatment of diverse B cell lymphomas and autoimmune disorders. Rituximab is a chimeric monoclonal antibody that reported adverse effects due to the presence of non-human sequences. Here, we attempted to improve the humanness score of rituximab using a computational approach by using combinatorial mutations at the sequence patches. These changes were imposed in: a) CDR; b) non-CDR; c) CDR + non-CDR mutants at Ala⁴⁹ → Gly, Thr⁵⁰ → Ala, and Leu⁵³ → Arg, Ser⁵ → Thr, Ala⁹ → Gly, and Ile¹⁰ → Thr. These mutations did not affect the structural stability that was interpreted from the MD simulation analysis. However, non-CDR mutants showed marginally higher structural variation compared to CDR mutants and native rituximab. It is suggested in this study that this rational design can improve the humanness characteristics of rituximab without affecting its structural and therapeutic behaviour.

Keywords: rituximab; protein engineering; immunogenicity; molecular docking; molecular dynamic simulation.

DOI: 10.1504/IJBRA.2024.138716

International Journal of Bioinformatics Research and Applications, 2024 Vol.20 No.2, pp.142 - 160

Received: 22 Jun 2023
Accepted: 07 Oct 2023
Published online: 29 May 2024 *

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Title: In-silico rituximab protein engineering to improve humanisation and reduce immunogenicity

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