Highly Enhanced Cytotoxicity of a Dimeric Bispecific Diabody, the hEx3 Tetrabody
| Autor: | Yukiko Sone, Takeshi Nakanishi, Mitsuo Umetsu, Ryutaro Asano, Izumi Kumagai, Yu Katayose, Keiko Ikoma, Michiaki Unno, Hiroko Kawaguchi, Shintaro Taki, Toshio Kudo, Hiroki Hayashi |
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| Rok vydání: | 2010 |
| Předmět: |
Protein Folding
CD3 Complex Light CD3 medicine.medical_treatment Biochemistry law.invention Protein–protein interaction Tetramer Cancer immunotherapy law Neoplasms Antibodies Bispecific medicine Humans Scattering Radiation Epidermal growth factor receptor Antigens Killer Cells Lymphokine-Activated Cytotoxicity Molecular Biology biology Chemistry Cell Biology Surface Plasmon Resonance Molecular biology Recombinant Proteins ErbB Receptors Kinetics Protein Structure and Folding Cancer cell Chromatography Gel biology.protein Recombinant DNA Biophysics Thermodynamics Dimerization Cell Division Software |
| Zdroj: | Journal of Biological Chemistry. 285:20844-20849 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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