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An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma

  • Wei, Mulan (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Liu, Xujie (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Cao, Chunyu (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Yang, Jianlin (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Lv, Yafeng (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Huang, Jiaojiao (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Wang, Yanlin (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Qin, Ye (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College)
  • Received : 2018.04.10
  • Accepted : 2018.06.11
  • Published : 2018.11.30

Abstract

Recent studies showed that the PD-1/PD-L1 checkpoint blockade is a dramatic therapy for melanoma by enhancing antitumor immune activity. Currently, major strategies for the PD-1/PD-L1 blockade have mainly focused on the use of antibodies and compounds. Seeking an alternative approach, others employ endogenous proteins as blocking agents. The extracellular domain of PD-1 (ePD1) includes the binding site with PD-L1. Accordingly, we constructed a PD-1-based recombinantly tailored fusion protein (dFv-ePD1) that consists of bivalent variable fragments (dFv) of an MMP-2/9-targeted antibody and ePD1. The melanoma-binding intensity and antitumor activity were also investigated. We found the intense and selective binding capability of the protein dFv-ePD1 to human melanoma specimens was confirmed by a tissue microarray. In addition, dFv-ePD1 significantly suppressed the migration and invasion of mouse melanoma B16-F1 cells, and displayed cytotoxicity to cancer cells in vitro. Notably, dFv-ePD1 significantly inhibited the growth of mouse melanoma B16-F1 tumor cells in mice and in vivo fluorescence imaging showed that dFv-ePD was gradually accumulated into the B16-F1 tumor. Also the B16-F1 tumor fluorescence intensity at the tumor site was stronger than that of dFv. This study indicates that the recombinant protein dFv-ePD1 has an intensive melanoma-binding capability and exerts potent therapeutic efficacy against melanoma. The novel format of the PD-L1-blocked agent may play an active role in antitumor immunotherapy.

Acknowledgement

Supported by : National Natural Science Foundation of China

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