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Molecular Targets for Therapy (MTT)

Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity

Leukemia volume 17, pages 604–611 (2003)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. We recently showed that certain ‘liquid’ tumors such as leukemia not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. A chimeric anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-1C11, was shown to be able to inhibit VEGF-induced proliferation of human leukemia cells in vitro, and to prolong survival of nonobese diabetic-severe combined immune deficient (NOD-SCID) mice inoculated with human leukemia cells. Here we produced two fully human anti-KDR antibodies (IgG1), IMC-2C6 and IMC-1121, from Fab fragments originally isolated from a large antibody phage display library. These antibodies bind specifically to KDR with high affinities: 50 and 200 pM for IMC-1121 and IMC-2C6, respectively, as compared to 270 pM for IMC-1C11. Like IMC-1C11, both human antibodies block VEGF/KDR interaction with an IC50 of approximately 1 nM, but IMC-1121 is a more potent inhibitor to VEGF-stimulated proliferation of human endothelial cells. These anti-KDR antibodies strongly inhibited VEGF-induced migration of human leukemia cells in vitro, and when administered in vivo, significantly prolonged survival of NOD-SCID mice inoculated with human leukemia cells. It is noteworthy that the mice treated with antibody of the highest affinity, IMC-1121, survived the longest period of time, followed by mice treated with IMC-2C6 and IMC-1C11. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and leukemia. It further underscores the efforts to identify antibodies of high affinity for enhanced antiangiogenic and antitumor activities.

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Acknowledgements

This work was supported in part by grants from Leukemia and Lymphoma Society and American Cancer Society to S. R.

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Authors and Affiliations

  1. Department of Antibody Technology, ImClone Systems Incorporated, New York, NY, USA

    Z Zhu, H Zhang, D Lu & M Liu

  2. Division of Hematology-Oncology, Cornell University Weill Medical College, New York, NY, USA

    K Hattori, S Dias, R Tejada, M Friedrich & S Rafii

  3. Department of Molecular and Cell Biology, ImClone Systems Incorporated, New York, NY, USA

    X Jimenez, D L Ludwig, H Koo & L Witte

  4. Department of Protein Chemistry, ImClone Systems Incorporated, New York, NY, USA

    P Kussie & H J Kim

  5. Department of Research, ImClone Systems Incorporated, New York, NY, USA

    P Bohlen

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Zhu, Z., Hattori, K., Zhang, H. et al. Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. Leukemia 17, 604–611 (2003). https://doi.org/10.1038/sj.leu.2402831

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