Intracellular dynamics and fate of a humanized anti-interleukin-6 receptor monoclonal antibody, Tocilizumab

Keiko Fujimoto, Hiroaki Ida, Yuko Hirota, Masaki Ishigai, Jun Amano, Yoshitaka Tanaka

研究成果: ジャーナルへの寄稿学術誌査読

14 被引用数 (Scopus)


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.

ジャーナルMolecular Pharmacology
出版ステータス出版済み - 10月 1 2015

!!!All Science Journal Classification (ASJC) codes

  • 分子医療
  • 薬理学


「Intracellular dynamics and fate of a humanized anti-interleukin-6 receptor monoclonal antibody, Tocilizumab」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。