Tuftsin-based, EGFR-targeting fusion protein and its enediyne-energized analog show high antitumor efficacy associated with CD47 down-regulation.

Abstract

Tuftsin (TF) is an immunomodulator tetrapeptide (Thr-Lys-Pro-Arg) that binds to the receptor neuropilin-1 (Nrp1) on the surface of cells. Many reports have described anti-tumor activity of tuftsin to relate with nonspecific activation of the host immune system. Lidamycin (LDM) that displays extremely potent cytotoxicity to cancer cells is composed of an apoprotein (LDP) and an enediyne chromophore (AE). In addition, Ec is an EGFR-targeting oligopeptide. In the present study, LDP was used as protein scaffold and the specific carrier for the highly potent AE. Genetically engineered fusion proteins LDP-TF and Ec-LDP-TF were prepared; then, the enediyne-energized fusion protein Ec-LDM-TF was generated by integration of AE into Ec-LDP-TF. The tuftsin-based fusion proteins LDP-TF and Ec-LDP-TF significantly enhanced the phagocytotic activity of macrophages as compared with LDP (P < 0.05). Ec-LDP-TF effectively bound to tumor cells and macrophages; furthermore, it markedly suppressed the growth of human epidermoid carcinoma A431 xenograft in athymic mice by 84.2 % (P < 0.05) with up-regulated expression of TNF-α and IFN-γ. Ec-LDM-TF further augmented the therapeutic efficacy, inhibiting the growth of A431 xenograft by 90.9 % (P < 0.05); notably, the Ec-LDM-TF caused marked down-regulation of CD47 in A431 cells. Moreover, the best therapeutic effect was recorded in the group of animals treated with the combination of Ec-LDP-TF with Ec-LDM-TF. The results suggest that tuftsin-based, enediyne-energized, and EGFR-targeting fusion proteins exert highly antitumor efficacy with CD47 modulation. Tuftsin-based fusion proteins are potentially useful for treatment of EGFR- and CD47-overexpressing cancers.

• Authors: Wen-Juan Liu, Xiu-Jun Liu, Liang Li, Yi Li, Sheng-Hua Zhang, Yong-Su Zhen
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 63 Issue 12 Pg. 1261-72 (Dec 2014) ISSN: 1432-0851 [Electronic] Germany
• PMID: 25164878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD47 Antigen
• Enediynes
• Immunotoxins
• Recombinant Fusion Proteins
• ErbB Receptors
• Tuftsin

Topics

• Animals
• CD47 Antigen (immunology)
• Carcinoma, Squamous Cell (immunology, therapy)
• Cell Communication
• Cell Line, Tumor
• Down-Regulation
• Enediynes (chemistry, pharmacology)
• ErbB Receptors (immunology)
• Female
• Humans
• Immunotoxins (chemistry, immunology, pharmacology)
• Mice
• Mice, Inbred BALB C
• Murine pneumonia virus
• Recombinant Fusion Proteins (chemistry, immunology, pharmacology)
• Tuftsin (chemistry, immunology, pharmacology)
• Xenograft Model Antitumor Assays