Highly enhanced cytotoxicity of a dimeric bispecific diabody, the hEx3 tetrabody

Ryutaro Asano, Keiko Ikoma, Yukiko Sone, Hiroko Kawaguchi, Shintaro Taki, Hiroki Hayashi, Takeshi Nakanishi, Mitsuo Umetsu, Yu Katayose, Michiaki Unno, Toshio Kudo, Izumi Kumagai

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We previously reported the utility for cancer immunotherapy of a humanized bispecific diabody (hEx3) that targets epidermal growth factor receptor and CD3. Here, we used dynamic and static light scattering measurements to show that the multimer fraction observed in hEx3 in solution is a monodisperse tetramer. The multimerization into tetramers increased the inhibition of cancer cell growth by the hEx3 diabody. Furthermore, 1:2 stoichiometric binding for both antigens was observed in a thermodynamic analysis, indicating that the tetramer has bivalent binding activity for each target, and the structure may be in a circular configuration, as is the case for the single-chain Fv tetrabody. In addition to enhanced cytotoxicity, the functional affinity and stability of the hEx3 tetrabody were superior to those of the hEx3 diabody. The increase in molecular weight is also expected to improve the pharmacokinetics of the bispecific diabody, making the hEx3 tetrabody attractive as a therapeutic antibody fragment for cancer immunotherapy.

Original languageEnglish
Pages (from-to)20844-20849
Number of pages6
JournalJournal of Biological Chemistry
Volume285
Issue number27
DOIs
Publication statusPublished - 2010 Jul 2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Asano, R., Ikoma, K., Sone, Y., Kawaguchi, H., Taki, S., Hayashi, H., Nakanishi, T., Umetsu, M., Katayose, Y., Unno, M., Kudo, T., & Kumagai, I. (2010). Highly enhanced cytotoxicity of a dimeric bispecific diabody, the hEx3 tetrabody. Journal of Biological Chemistry, 285(27), 20844-20849. https://doi.org/10.1074/jbc.M110.120444