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Effect of Treatment Regimen on the Immunogenicity of Human Interferon Beta in Immune Tolerant Mice

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Abstract

Purpose

Interferon beta is commonly used as therapeutic in the first line of therapy for multiple sclerosis. However, depending on the product, it induces an antibody response in up to 60% of patients. This study evaluated the impact of therapy related factors like dose, route of administration and administration frequency on the immunogenicity of one of the originator interferon beta drugs (Betaferon®) in an immune tolerant transgenic mouse model.

Methods

Immune tolerant transgenic mice received injections with Betaferon® via different routes, doses and injection frequencies. Anti-drug antibody (ADA) production was measured by ELISA to assess immunogenicity.

Results

A single injection of Betaferon® was found to be sufficient for the induction of ADAs. The antibody titer was enhanced with increasing dose and treatment frequency. Among the tested administration routes, the intravenous route was the most immunogenic one, which is in contradiction with one of the dogma in immunogenicity research according to which subcutaneous administration is the most immunogenic route. Intramuscular, intraperitoneal and subcutaneous injections resulted in comparable immunogenicity.

Conclusion

This study shows that treatment related factors affect significantly immunogenicity of Betaseron® and therefore substantiate the need for further studies on these factors in patients.

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Abbreviations

ADAs:

anti-drug antibodies

ELISA:

enzyme-linked immunosorbent assay

IM:

intramuscular

IP:

intraperitoneal

IV:

intravenous

MS:

multiple sclerosis

non-Tg:

non-transgenic

PCR:

polymerase chain reaction

PEG:

poly(ethylene glycol)

rhIFNβ:

recombinant human interferon beta

SC:

subcutaneous

Tg:

transgenic

TNFα:

tumor necrosis factor α

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Acknowledgments and Disclosures

We acknowledge Darren P. Baker, Ph.D. from BiogenIdec for kindly providing the IFNβ-1a (Avonex® drug substance) which we used in the ELISA to detect ADAs. We thank Abdul Basmeleh for performing the ELISAs described in this article.

GK, WJ and VB declare no financial and commercial conflict of interest. HS has participated in meeting and publications sponsored by Amgen, Johnson & Johnson, Roche, Sandoz and Hospira. Part of his research is directly or indirectly sponsored by Roche and Amgen.

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Authors and Affiliations

  1. Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, David de Wied Building, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands

    Grzegorz Kijanka, Huub Schellekens & Vera Brinks

  2. Division of Drug Delivery Technology Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University, Gorlaeus Laboratories Einsteinweg 55, Leiden, 2333 CC, The Netherlands

    Wim Jiskoot

  3. Department of Innovation Management, Utrecht University, Willem C. Van Unnikgebouw Heidelberglaan 2, Utrecht, 3584 CS, The Netherlands

    Huub Schellekens

Authors
  1. Grzegorz Kijanka
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  2. Wim Jiskoot
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  3. Huub Schellekens
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  4. Vera Brinks
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Correspondence to Grzegorz Kijanka.

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Kijanka, G., Jiskoot, W., Schellekens, H. et al. Effect of Treatment Regimen on the Immunogenicity of Human Interferon Beta in Immune Tolerant Mice. Pharm Res 30, 1553–1560 (2013). https://doi.org/10.1007/s11095-013-0992-9

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  • DOI: https://doi.org/10.1007/s11095-013-0992-9

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