Influence of pH on Heat-Induced Aggregation and Degradation of Therapeutic Monoclonal Antibodies

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  • Ishikawa Tomoyoshi
    Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd. Department of Chemistry and Chemical Biology, Graduate School of Engineering, Gunma University
  • Ito Takahiko
    Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd.
  • Endo Ryosuke
    Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd.
  • Nakagawa Keiko
    Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd.
  • Sawa Eiji
    Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd.
  • Wakamatsu Kaori
    Department of Chemistry and Chemical Biology, Graduate School of Engineering, Gunma University

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Monoclonal antibodies are widely used for the treatment of various diseases, and because therapeutic monoclonal antibodies are stored in an aqueous solution or in a lyophilized state, the preparation of a stabilizing formulation that prevents their deterioration (degradation and aggregation) is crucial. Given the structural similarities of the immunoglobulin G (IgG) framework regions and a diversity of only four subclasses, we aimed to find common conditions that stabilize many different antibodies. In this study, we analyzed the effect of pH (the most critical factor in establishing a stable formulation) on human monoclonal antibodies from subclasses IgG1, IgG2, and IgG4, all of which have been utilized in antibody therapeutics. We found that human IgGs are stable with minimal heat-induced degradation and aggregation at pH 5.0—5.5 irrespective of their subclass. We also found that IgG1 is more susceptible to fragmentation, whereas IgG4 is more susceptible to aggregation. This basic information emphasizing the influence of pH on IgG stability should facilitate the optimization of formulation conditions tailored to individual antibodies for specific uses.

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