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Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T-cell epitopes

Cellular & Molecular Immunology volume 17, pages 656–658 (2020)Cite this article

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The clinical efficacy of therapeutic antibodies is recognized in many indications, explaining their rapid rise in the worldwide drug market. However, therapeutic antibodies can be immunogenic by inducing a specific immune response characterized by the production of anti-drug antibodies (ADAs). ADAs can potentially increase the clearance of therapeutic antibodies, decrease their therapeutic effects1 and induce hypersensitivity reactions. Because humans are thought to be tolerant to their own proteins, sequences of the therapeutic antibodies have been humanized or human antibodies have been directly generated by technologies using human sequences. However, human(ized) antibodies exhibit highly variable levels of immunogenicity,1,2 illustrating the poor understanding of the role of sequence humanization in mitigating the immunogenicity of therapeutic antibodies. Multiple lines of evidence highlight the role of CD4 T lymphocytes during the initiation of an ADA response,3 but few T-cell epitopes of marketed therapeutic antibodies have been described to date.

In this study, we identified T-cell epitopes from the human therapeutic antibody adalimumab (Adm) and the humanized antibody natalizumab (Ntz). Adalimumab is a human anti-human TNF-α antibody prescribed for the treatment of different inflammatory diseases and is known to induce ADA responses in many patients.1 Natalizumab targets integrin α4β1 and prevents T lymphocytes from crossing the blood-brain barrier. Treatment with natalizumab efficiently reduces myelin loss in multiple sclerosis patients, but ADA responses are detected in multiple treated patients.

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Acknowledgements

The research leading to these results was supported by the Innovative Medicines Initiative Joint Undertaking ABIRISK project under grant agreement #115303, the resources of which comprise financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and in-kind contributions from EFPIA companies. This work was also supported by the Labex in Research on Medication and Therapeutic Innovation (LERMIT) (to B.M.) and the CEA (to B.M.). The authors thank Pierre Bonnesoeur for his technical help with the HLA binding experiments, as well as Stephan Koepke and Sascha Gottlieb for conducting the MAPP experiments.

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  1. Sebastian Spindeldreher

    Present address: Integrated Biologix GmbH, Basel, Switzerland

Authors and Affiliations

  1. CEA-Saclay, Institut Frederic Joliot, SIMOPRO, Université Paris-Saclay, 91191, Gif sur Yvette, France

    Sylvain Meunier, Moustafa Hamze, Marie de Bourayne, Abdelaziz Gdoura & Bernard Maillère

  2. Novartis Pharma AG, Basel, Switzerland

    Anette Karle & Sebastian Spindeldreher

Authors
  1. Sylvain Meunier
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  2. Moustafa Hamze
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  3. Anette Karle
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  4. Marie de Bourayne
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  5. Abdelaziz Gdoura
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  6. Sebastian Spindeldreher
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  7. Bernard Maillère
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Contributions

S.M., M.H., A.K., M.B., A.G., S.S., and B.M. designed the experiments; S.M., M.H., M.B., and A.G. performed the experiments; S.M., M.H., A.K., M.B., A.G., S.S., and B.M. analyzed the data; and A.G., S.S., and B.M. wrote the paper.

Corresponding author

Correspondence to Bernard Maillère.

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A.K. is full-time employee of and holds shares and stock options in Novartis. S.S. is a former employee and has stocks and stock options in Novartis.

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Meunier, S., Hamze, M., Karle, A. et al. Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T-cell epitopes. Cell Mol Immunol 17, 656–658 (2020). https://doi.org/10.1038/s41423-019-0304-3

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