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Tumor necrosis therapy antibody interleukin-2 fusion protein elicits prolonged and targeted antitumor effects in vivo

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Abstract

Interleukin-2 (IL-2) is one of the most successful cytokines applied in tumor immunotherapy because of its ability to stimulate potent cellular immune response. The life-threatening toxicity of vascular leak syndrome (VLS) associated with the high-dose IL-2 treatment regimen has limited its use in tumor immunotherapy. To reverse this situation, a tumor-targeted fusion protein, recombinant human TNT-IL2 (rhTNT-IL2), was generated with both the cytokine activity of IL-2 and the tumor-targeting ability of TNT antibody. TNT is a human tumor necrosis therapy monoclonal antibody capable of binding intracellular antigens which are accessible and abundant in necrotic regions of tumors. The immunotherapeutic potential of this fusion protein was tested in murine melanoma and lung cancer models, and tumor-bearing mice showed satisfied tumor regressions after rhTNT-IL2 immunotherapy. Immunohistochemical study showed a distinct penetration of IL-2 in tumors in mice treated with rhTNT-IL2, indicating its evident tumor-targeting activity. Moreover, the rhTNT-IL2 was well tolerated in cynomolgus monkeys in a 12-week long-term repeated toxicity study. These studies indicate that the targeting of IL-2 to necrotic areas of tumors might be a new approach for the immunotherapy of solid tumors.

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Acknowledgments

This work was supported by Shanghai Science and Technology funds (11431920104), National Science and Technology Major Project for Drug Discovery of the Ministry of Science and Technology of China (2011ZX09102-001-27), and Shanghai Health Bureau funds (2010035). This study was also supported by Shanghai MediPharm Biotech Co. Ltd, Shanghai, China.

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Authors and Affiliations

  1. Department of Biosynthesis & Key Lab of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai, 201203, China

    Li Ye, Jiajun Fan, Xunlong Shi, Zongshu Xian, Xian Zeng, Yubin Li & Dianwen Ju

  2. Shanghai MediPharm Biotech Co. Ltd, Shanghai, 201203, China

    Qun Tao & Dan Ye

  3. Department of Biosynthesis, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai, 201203, China

    Meiqing Feng

Authors
  1. Li Ye
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  2. Jiajun Fan
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  3. Xunlong Shi
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  4. Qun Tao
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  5. Dan Ye
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  6. Zongshu Xian
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  7. Xian Zeng
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  8. Yubin Li
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  9. Meiqing Feng
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  10. Dianwen Ju
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Correspondence to Meiqing Feng or Dianwen Ju.

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Li Ye and Jiajun Fan contributed equally to this work.

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Ye, L., Fan, J., Shi, X. et al. Tumor necrosis therapy antibody interleukin-2 fusion protein elicits prolonged and targeted antitumor effects in vivo. Appl Microbiol Biotechnol 98, 4053–4061 (2014). https://doi.org/10.1007/s00253-013-5349-0

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  • DOI: https://doi.org/10.1007/s00253-013-5349-0

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