Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor.
Urokinase (uPA) and its receptor (uPAR) play an important role in tumor growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumors. In this study, ATF-Fc, an antibody-like molecule comprising the amino-terminal fragment of human uPA (ATF) linked to the Fc fragment of human IgG1 via a flexible linker was developed. Its antitumor activities were evaluated in vitro and in vivo. The results showed that ATF-Fc had obvious cytotoxic effect on several types of tumor cells, which is dependent on cellular expression of uPAR and its Fc fragment. Treatment with ATF-Fc caused a significant suppression on tumor growth and metastasis of xenograft human tumors (MCF-7 breast cancer and BGC-823 gastric cancer) in athymic nude mice. Furthermore, we demonstrated that ATF-Fc had an anti-angiogenesis activity both in vitro and in vivo. In conclusion, we provided a novel therapeutic antibody-like molecule in the management of a variety of solid tumors by disrupting the uPA/uPAR interaction.
Hu
Xian-Wen
XW
Beijing Institute of Biotechnology (BIB), Fengtai District, Beijing, China. hu.xianwen@tsinghua.org.cn
Duan
Hai-Feng
HF
Gao
Li-Hua
LH
Pan
Shu-Yuan
SY
Li
Yong-Mei
YM
Xi
Yongyi
Y
Zhao
Su-Rong
SR
Yin
Liang
L
Li
Jin-Feng
JF
Chen
Hui-Peng
HP
Wu
Chu-Tse
CT
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry*; D007074:Immunoglobulin G / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000628:therapy*; D009389:Neovascularization, Pathologic; D011956:Receptors, Cell Surface / Q000737:chemistry*; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry*
D000906:Antibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator