Highly Enhanced Cytotoxicity of a Dimeric Bispecific Diabody,the hEx3 Tetrabody |
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| Authors: | Ryutaro Asano Keiko Ikoma Yukiko Sone Hiroko Kawaguchi Shintaro Taki Hiroki Hayashi Takeshi Nakanishi Mitsuo Umetsu Yu Katayose Michiaki Unno Toshio Kudo Izumi Kumagai |
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| Institution: | From the ‡Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan.;the §Division of Gastroenterological Surgery, Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai 980-8574, Japan, and ;the ¶Cell Resource Center for Biomedical Research, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan |
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| 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. |
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| Keywords: | Antibodies Anticancer Drug Cancer Therapy Protein-Protein Interactions Tyrosine Protein Kinase (Tyrosine Kinase) Bispecific Diabody Bispecific Tetrabody Cancer Immunotherapy ScFv Multimer Small Recombinant Antibody |
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