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Antibody Response Against Betaferon® in Immune Tolerant Mice: Involvement of Marginal Zone B-cells and CD4+ T-cells and Apparent Lack of Immunological Memory

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Abstract

Purpose

The immunological processes underlying immunogenicity of recombinant human therapeutics are poorly understood. Using an immune tolerant mouse model we previously demonstrated that aggregates are a major trigger of the antidrug antibody (ADA) response against recombinant human interferon beta (rhIFNβ) products including Betaferon®, and that immunological memory seems to be lacking after a rechallenge with non-aggregated rhIFNβ. The apparent absence of immunological memory indicates a CD4+ T-cell independent (Tind) immune response underlying ADA formation against Betaferon®. This hypothesis was tested.

Methods

Using the immune tolerant mouse model we first validated that rechallenge with highly aggregated rhIFNβ (Betaferon®) does not lead to a subsequent fast increase in ADA titers, suggesting a lack of immunological memory. Next we assessed whether Betaferon® could act as Tind antigen by inactivation of marginal zone (MZ) B-cells during treatment. MZ B-cells are major effector cells involved in a Tind immune response. In a following experiment we depleted the mice from CD4+ T-cells to test their involvement in the ADA response against Betaferon®.

Results

Inactivation of MZ B-cells at the start of Betaferon® treatment drastically lowered ADA levels, suggesting a Tind immune response. However, persistent depletion of CD4+ T-cells before and during Betaferon® treatment abolished the ADA response in almost all mice.

Conclusion

The immune response against rhIFNβ in immune tolerant mice is neither a T-cell independent nor a classical T-cell dependent immune response. Further studies are needed to confirm absence of immunological memory (cells).

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Acknowledgements

This research was financially supported by the European Community under its 6th Framework (project NABINMS, contract number 018926). The authors would like to thank Darren Baker and Susan Goelz from Biogen Idec Inc for kindly supplying bulk recombinant human interferon beta 1a.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Author notes

  1. Miranda M. C. van Beers

    Present address: Bioprocessing Technology Institute, A*STAR, Singapore, Singapore

Authors and Affiliations

  1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands

    Melody Sauerborn, Miranda M. C. van Beers, Grzegorz M. Kijanka, Huub Schellekens & Vera Brinks

  2. Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University, Leiden, 2300 RA, the Netherlands

    Miranda M. C. van Beers & Wim Jiskoot

  3. Department of Innovation and Environmental Sciences, Utrecht University, P.O. box 80115, Utrecht, 3508 TC, the Netherlands

    Huub Schellekens

  4. Bioceros, Utrecht, 3584 CM, the Netherlands

    Louis Boon

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  1. Melody Sauerborn
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Correspondence to Vera Brinks.

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Sauerborn, M., van Beers, M.M.C., Jiskoot, W. et al. Antibody Response Against Betaferon® in Immune Tolerant Mice: Involvement of Marginal Zone B-cells and CD4+ T-cells and Apparent Lack of Immunological Memory. J Clin Immunol 33, 255–263 (2013). https://doi.org/10.1007/s10875-012-9783-z

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  • DOI: https://doi.org/10.1007/s10875-012-9783-z

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