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J Pharm Sci. 2019 Jul;108(7):2358-2366. doi: 10.1016/j.xphs.2019.02.011. Epub 2019 Feb 21.

Evaluation of a 3D Human Artificial Lymph Node as Test Model for the Assessment of Immunogenicity of Protein Aggregates.

Author information

1
Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-Universität München, Butenandtstr.5, D-81377 Munich, Germany. Electronic address: teresa.kraus@cup.uni-muenchen.de.
2
ProBioGen AG, Department Cell and Tissue Services, Goethestraße 54, D-13086 Berlin, Germany.
3
Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-Universität München, Butenandtstr.5, D-81377 Munich, Germany.

Abstract

The immunogenicity of protein aggregates has been investigated in numerous studies. Nevertheless, it is still unknown which kind of protein aggregates enhance immunogenicity the most. The ability of the currently used in vitro and in vivo systems regarding their predictability of immunogenicity in humans is often questionable, and results are partially contradictive. In this study, we used a 2D in vitro assay and a complex 3D human artificial lymph node model to predict the immunogenicity of protein aggregates of bevacizumab and adalimumab. The monoclonal antibodies were exposed to different stress conditions such as light, heat, and mechanical stress to trigger the formation of protein aggregates and particles, and samples were analyzed thoroughly. Cells and culture supernatants were harvested and analyzed for dendritic cell marker and cytokines. Our study in the artificial lymph node model revealed that bevacizumab after exposure to heat triggered a TH1- and proinflammatory immune response, whereas no trend of immune responses was seen for adalimumab after exposure to different stress conditions. The human artificial lymph node model represents a new test model for testing the immunogenicity of protein aggregates combining the relevance of a 3D human system with the rather easy handling of an in vitro setup.

KEYWORDS:

immunogenicity; immunology; in vitro models; protein aggregation; protein(s)

PMID:
30797781
DOI:
10.1016/j.xphs.2019.02.011

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