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Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein × anti-CD3 diabody

Leukemia volume 18, pages 513–520 (2004)Cite this article

Abstract

Overexpressing of P-glycoprotein (Pgp) has been shown to be responsible for cancer resistance to multiple chemotherapeutic agents. Immunotherapy with biological agents, such as bispecific antibodies (BsAbs), may represent a promising approach to overcome the emergence of drug resistance. Here we constructed a recombinant BsAb, a diabody, with specificities to both CD3 on human T-lymphocyte and Pgp on cancer cells. The diabody was produced in Escherichia coli in a soluble functional form and purified by an affinity chromatography with a yield of >4 mg/l culture medium in shaker flask. The diabody binds to both CD3 on T-lymphocytes and Pgp on multidrug-resistant (MDR) tumor cells with affinities that are comparable to its respective parental single chain Fv molecules. In the presence of activated human peripheral blood lymphocytes (PBLs), the diabody mediates effectively the lysis of the Pgp-overexpressing human leukemia K562/A02 and epidermoid carcinoma KBv200 cells, but is much less potent in mediating the lysis of the parent K562 and KB cells. Further, the diabody localized selectively within the K562/A02 xenografts in mice. When combined with activated PBL, the diabody significantly inhibited the growth of K562/A02 and KBv200, but had no effect on K562 and KB xenografts. In contrast, treatment with doxorubicin, a standard chemotherapeutic agent, only inhibited the growth of K562 and KB, but had no effect on K562/A02 and KBv200 xenografts. Taken together, our results suggest that the anti-Pgp × anti-CD3 diabody may have a great potential in the treatment of various MDR cancers.

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Acknowledgements

This work was supported by grants from The Natural Science Foundation of China (NSFC) – General Projects (Grant number: 39900186) and from the ‘National High Technology Research and Development Program (863 Program)’ of the Chinese Government (Grant number: 2002AA2Z346D).

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Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Tianjin Union Medical College, Tianjin, China

    Y Gao, D Xiong, M Yang, H Liu, H Peng, X Shao, Y Xu, C Xu, D Fan, C Yang & Z Zhu

  2. Department of Nuclear Medicine, First Central Hospital of Tianjin, Tianjin, China

    L Qin

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  1. Y Gao
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Correspondence to C Yang or Z Zhu.

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Gao, Y., Xiong, D., Yang, M. et al. Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein × anti-CD3 diabody. Leukemia 18, 513–520 (2004). https://doi.org/10.1038/sj.leu.2403267

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