Journal of the National Cancer Institute Advance Access originally published online on October 9, 2007
JNCI Journal of the National Cancer Institute 2007 99(20):1551-1555; doi:10.1093/jnci/djm132
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2007. Published by Oxford University Press.
BRIEF COMMUNICATION |
Antitumor Activities of TEM8-Fc: An Engineered Antibody-like Molecule Targeting Tumor Endothelial Marker 8
Affiliations of authors: Beijing Institute of Radiation Medicine, Haidian District, Beijing, China (HFD, JLC, JFL, SRZ, CTW); Beijing Institute of Biotechnology, Fengtai District, Beijing, China (XWH, LHG, YYX, HPC); Affiliated Hospital, Academy of Military Medical Sciences, Beijing, China (YL); Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, China (JJX, WC)
Correspondence to: Xian-Wen Hu, PhD, Beijing Institute of Biotechnology, No. 20, Dongdajie St, Fengtai District, Beijing 100071, China (e-mail: hu.xianwen{at}tsinghua.org.cn) or Hai-Feng Duan, PhD, Beijing Institute of Radiation Medicine, No. 27, Taiping Rd, Haidian District, Beijing 100850, China (e-mail: duanhf0720{at}yahoo.com.cn).
Tumor endothelial marker 8 (TEM8) was discovered as a cell membrane protein that is predominantly expressed in tumor endothelium and identified as a receptor for anthrax toxin. We developed an antibody-like molecule that consists of the protective antigen (PA)–binding domain of human TEM8 linked to the Fc portion of human immunoglobulin G1 (TEM8-Fc). This engineered protein bound to PA in a divalent cation–dependent manner and efficiently protected J774A.1 macrophage-like cells against anthrax toxin challenge in a dose-dependent manner. TEM8-Fc suppressed the growth and metastasis of xenograft human tumors in athymic nude mice (control versus 10 mg/kg TEM8-Fc, mean tumor weight: LS-180, 1.72 versus 0.16 g, difference = 1.56 g, 95% confidence interval [CI] = 0.96 to 2.16 g; P<.001; MCF-7, 1.12 versus 0.08 g, difference = 1.04 g, 95% CI = 0.77 to 1.31 g; P<.001; HepG2, 1.28 versus 0.35 g, difference = 0.93 g, 95% CI = 0.60 to 1.25 g; P<.001). Furthermore, TEM8 interacted with the M2 isoenzyme of pyruvate kinase (M2-PK), which has an important role in tumor growth and metastasis. TEM8-Fc is a novel therapeutic antibody-like agent in the management of solid tumors that may act by trapping M2-PK.
| CONTEXT AND CAVEATS Prior knowledge Tumor endothelial marker 8 (TEM8) is an anthrax toxin receptor that is expressed on the plasma membrane of tumor endothelial cells. Study design TEM8-Fc, an antibody-like molecule that contains the protective antigen (PA) domain of TEM8 fused to the Fc portion of human immunoglobulin G1 was synthesized, and PA functions were assayed. Tumor growth and metastasis were compared in TEM8-Fc–treated and control athymic mice carrying xenograft tumors derived from human cell lines. Immunoprecipitation with TEM8-Fc was performed using tumor homogenates. Contributions TEM8-Fc retained properties of the PA-binding domain and reduced tumor growth and metastasis in the mice carrying xenograft tumors. TEM8-Fc bound to the M2 isoenzyme of pyruvate kinase (M2-PK), which is involved in tumor growth and metastasis. Implications TEM8-Fc is an antibody-like molecule that may suppress tumor growth and metastasis by trapping the M2-PK. Limitations It is unknown whether TEM8-Fc would be a useful therapeutic agent in human cancer.
|
Manuscript received March 13, 2007; revised July 25, 2007; accepted July 31, 2007.
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 1497.