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Molecular Pharmacology

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Research ArticleArticle

Intracellular Dynamics and Fate of a Humanized Anti–Interleukin-6 Receptor Monoclonal Antibody, Tocilizumab

Keiko Fujimoto, Hiroaki Ida, Yuko Hirota, Masaki Ishigai, Jun Amano and Yoshitaka Tanaka
Molecular Pharmacology October 2015, 88 (4) 660-675; DOI: https://doi.org/10.1124/mol.115.099184
Keiko Fujimoto
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences (K.F., H.I., Y.H., Y.T.), and Organelle Homeostasis Research Center (K.F., Y.T.), Kyushu University, Maidashi, Fukuoka, Japan; and Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Komakado, Gotemba-shi, Shizuoka, Japan (M.I., J.A.)
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Hiroaki Ida
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences (K.F., H.I., Y.H., Y.T.), and Organelle Homeostasis Research Center (K.F., Y.T.), Kyushu University, Maidashi, Fukuoka, Japan; and Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Komakado, Gotemba-shi, Shizuoka, Japan (M.I., J.A.)
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Yuko Hirota
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences (K.F., H.I., Y.H., Y.T.), and Organelle Homeostasis Research Center (K.F., Y.T.), Kyushu University, Maidashi, Fukuoka, Japan; and Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Komakado, Gotemba-shi, Shizuoka, Japan (M.I., J.A.)
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Masaki Ishigai
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences (K.F., H.I., Y.H., Y.T.), and Organelle Homeostasis Research Center (K.F., Y.T.), Kyushu University, Maidashi, Fukuoka, Japan; and Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Komakado, Gotemba-shi, Shizuoka, Japan (M.I., J.A.)
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Jun Amano
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences (K.F., H.I., Y.H., Y.T.), and Organelle Homeostasis Research Center (K.F., Y.T.), Kyushu University, Maidashi, Fukuoka, Japan; and Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Komakado, Gotemba-shi, Shizuoka, Japan (M.I., J.A.)
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Yoshitaka Tanaka
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences (K.F., H.I., Y.H., Y.T.), and Organelle Homeostasis Research Center (K.F., Y.T.), Kyushu University, Maidashi, Fukuoka, Japan; and Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Komakado, Gotemba-shi, Shizuoka, Japan (M.I., J.A.)
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Abstract

Tocilizumab (TCZ), a humanized anti–interleukin-6 (IL-6) receptor (IL-6R) monoclonal antibody, abrogates signal transducer protein gp130–mediated IL-6 signaling by competitively inhibiting the binding of IL-6 to the receptor, and shows clinical efficacy in autoimmune and inflammatory diseases. Despite accumulating evidence for therapeutic efficacy, the behavior and fate of TCZ at the cellular level remain largely unknown. To address this, we evaluated the endocytosis and intracellular trafficking of IL-6R in HeLa cells. The results of our study provide evidence that IL-6R is constitutively internalized from the cell surface by ligand or TCZ binding and the expression of gp130 in an independent manner and is targeted via endosomes without being significantly directed to the recycling pathway to, and degraded in, lysosomes. Furthermore, the cytoplasmic tail of IL-6R is required for constitutive endocytosis of the receptor, which is mediated by the clathrin and AP-2 complex. We further demonstrate that FcRn, whose function is to regulate the serum persistence of IgG, is confined primarily to early/recycling endosomes and rapidly transits between these compartments and late endosomes/lysosomes without being degraded. Importantly, the expression of FcRn induces the segregation of TCZ from IL-6R, resulting in extensive colocalization of TCZ and FcRn in IL-6R–depleted endosomal compartments. Collectively, our results suggest that FcRn can accelerate the retrieval of the internalized TCZ, not only from endosomes but also from lysosomes. Our findings provide new insight into the mechanism by which the antibody internalized into cells is rescued from lysosomal degradation and into how its serum levels are maintained.

Footnotes

    • Received March 26, 2015.
    • Accepted July 13, 2015.
  • dx.doi.org/10.1124/mol.115.099184.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (4)
Molecular Pharmacology
Vol. 88, Issue 4
1 Oct 2015
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Research ArticleArticle

Intracellular Dynamics of Tocilizumab by IL-6R and FcRn

Keiko Fujimoto, Hiroaki Ida, Yuko Hirota, Masaki Ishigai, Jun Amano and Yoshitaka Tanaka
Molecular Pharmacology October 1, 2015, 88 (4) 660-675; DOI: https://doi.org/10.1124/mol.115.099184

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Research ArticleArticle

Intracellular Dynamics of Tocilizumab by IL-6R and FcRn

Keiko Fujimoto, Hiroaki Ida, Yuko Hirota, Masaki Ishigai, Jun Amano and Yoshitaka Tanaka
Molecular Pharmacology October 1, 2015, 88 (4) 660-675; DOI: https://doi.org/10.1124/mol.115.099184
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