Monoclonal Antibody Dimers Induced by Low pH, Heat, or Light Exposure Are Not Immunogenic Upon Subcutaneous Administration in a Mouse Model.
| Autor: | Kijanka G; Division of BioTherapeutics, Leiden University, Leiden, the Netherlands., Bee JS; Analytical Sciences, MedImmune LLC, Gaithersburg, Maryland 20878., Schenerman MA; Analytical Sciences, MedImmune LLC, Gaithersburg, Maryland 20878., Korman SA; Analytical Sciences, MedImmune LLC, Gaithersburg, Maryland 20878., Wu Y; Clinical Pharmacology and DMPK, MedImmune LLC, Gaithersburg, Maryland 20878., Slütter B; Division of BioTherapeutics, Leiden University, Leiden, the Netherlands., Jiskoot W; Division of BioTherapeutics, Leiden University, Leiden, the Netherlands. Electronic address: w.jiskoot@lacdr.leidenuniv.nl. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of pharmaceutical sciences [J Pharm Sci] 2020 Jan; Vol. 109 (1), pp. 730-738. Date of Electronic Publication: 2019 Apr 25. |
| DOI: | 10.1016/j.xphs.2019.04.021 |
| Abstrakt: | 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.) |
| Databáze: | MEDLINE |
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