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Monoclonal Antibody Dimers Induced by Low pH, Heat, or Light Exposure Are Not Immunogenic Upon Subcutaneous Administration in a Mouse Model.

Authors
  • Kijanka, Grzegorz1
  • Bee, Jared S2
  • Schenerman, Mark A2
  • Korman, Samuel A2
  • Wu, Yuling3
  • Slütter, Bram1
  • Jiskoot, Wim4
  • 1 Division of BioTherapeutics, Leiden University, Leiden, the Netherlands. , (Netherlands)
  • 2 Analytical Sciences, MedImmune LLC, Gaithersburg, Maryland 20878.
  • 3 Clinical Pharmacology and DMPK, MedImmune LLC, Gaithersburg, Maryland 20878.
  • 4 Division of BioTherapeutics, Leiden University, Leiden, the Netherlands. Electronic address: [email protected] , (Netherlands)
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Jan 01, 2020
Volume
109
Issue
1
Pages
730–738
Identifiers
DOI: 10.1016/j.xphs.2019.04.021
PMID: 31029572
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The presence of protein aggregates is commonly believed to be an important risk factor for immunogenicity of therapeutic proteins. Among all types of aggregates, dimers are relatively abundant in most commercialized monoclonal antibody (mAb) products. The aim of this study was to investigate the immunogenicity of artificially created mAb dimers relative to that of unstressed and stressed mAb monomers. A monoclonal murine IgG1 (mIgG1) antibody was exposed to low pH, elevated temperature, or UV irradiation to induce dimerization. Dimers and monomers were purified via size-exclusion chromatography. Physicochemical analysis revealed that upon all stress conditions, new deamidation or oxidation or both of amino acids occurred. Nevertheless, the secondary and tertiary structures of all obtained dimers were similar to those of unstressed mIgG1. Isolated dimers were administered subcutaneously in Balb/c mice, and development of antidrug antibodies and accumulation of follicular T helper cells in draining lymph nodes and spleens were determined. None of the tested dimers or stressed monomers were found to be more immunogenic than the unstressed control in our mouse model. In conclusion, both dimers and monomers generated by using 3 different stress factors have a low immunogenicity similar to that of the unstressed monomers. Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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