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Improvement of tumor targeting and antitumor activity by a disulphide bond stabilized diabody expressed in Escherichia coli

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Abstract

We have generated an anti-Pgp/anti-CD3 diabody which can effectively inhibit the growth of multidrug-resistant human tumors. However, the two chains of the diabody are associated non-covalently and are therefore capable of dissociation. Cysteine residues were introduced into the V-domains to promote disulphide cross-linking of the dimer as secreted by Escherichia coli. Compared with the parent diabody, the ds-Diabody obtained was more stable in human serum at 37°C, without loss of affinity or cytotoxicity activity in vitro. Furthermore, the ds-Diabody showed improved tumor localization and a twofold improved antitumor activity over the parent diabody in nude mice bearing Pgp-overexpressing K562/A02 xenografts. Our data demonstrate that ds-Diabody may be more useful in therapeutic applications than the parent diabody.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant number: 30400558) and from the Natural Science Foundation of Tianjin (Grant number: 08ZCKFSH04100, 05YFJZJC01200).

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Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 300020, Tianjin, People’s Republic of China

    Juanni Liu, Ming Yang, Jinhong Wang, Yuanfu Xu, Xiaofeng Shao, Chunzheng Yang, Yingdai Gao & Dongsheng Xiong

  2. Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 300192, Tianjin, People’s Republic of China

    Yan Wang

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  1. Juanni Liu
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  2. Ming Yang
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Correspondence to Yingdai Gao or Dongsheng Xiong.

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Liu, J., Yang, M., Wang, J. et al. Improvement of tumor targeting and antitumor activity by a disulphide bond stabilized diabody expressed in Escherichia coli . Cancer Immunol Immunother 58, 1761–1769 (2009). https://doi.org/10.1007/s00262-009-0684-9

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  • DOI: https://doi.org/10.1007/s00262-009-0684-9

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