Antigen-dependent internalization is related to rapid elimination from plasma of humanized anti-HM1.24 monoclonal antibody

Jun Amano, Naoko Masuyama, Yuko Hirota, Yoshitaka Tanaka, Yuriko Igawa, Rie Shiokawa, Taichi Okutani, Takashi Miyayama, Masahiko Nanami, Masaki Ishigai

研究成果: Contribution to journalArticle

13 被引用数 (Scopus)

抄録

Anti-HM1.24 monoclonal antibody (AHM) is a humanized anti-HM1.24 monoclonal antibody that binds to the HM1.24 antigen, a protein that is highly expressed in multiple myeloma cells. The pharmacokinetics of AHM was determined in experiments in which AHM was administered intravenously to cynomolgus monkeys. The area under the plasma concentration-time curve increased by more than the dose ratio between 2 and 20 mg/kg, and nonlinear pharmacokinetics was observed. The elimination half-life of AHM from the plasma was 7.56 h at 2 mg/kg and 28.6 h at 20 mg/kg, which was shorter than that observed for other therapeutic humanized monoclonal antibodies, such as trastuzumab and bevacizumab. Although antibodies to AHM were detected in all monkeys on or after 10 days of administration, there was a temporal disassociation between the rapid elimination of AHM and the appearance of anti-AHM antibodies. HM1.24 antigen-dependent internalization and intracellular metabolism of AHM were investigated in peripheral blood mononuclear, KPMM2, and U937 cells. In all cases, AHM was rapidly internalized from the cell surface; this internalization was significantly prevented by phenylarsine oxide in KPMM2 cells, an inhibitor of receptor-mediated endocytosis, and the internalized AHM was subsequently degraded within the cells. Furthermore, immunofluorescence microscopy revealed that the internalized AHM is delivered to and degraded in late endosomes/lysosomes. Taken together, our results suggest that the rapid elimination of AHM from plasma in monkey is due to HM1.24 antigen-dependent internalization followed by delivery to the lysosomes.

本文言語英語
ページ(範囲)2339-2346
ページ数8
ジャーナルDrug Metabolism and Disposition
38
12
DOI
出版ステータス出版済み - 12 2010

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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