Antitumor activities of TEM8-Fc: an engineered antibody-like molecule targeting tumor endothelial marker 8.
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.
Duan
Hai-Feng
HF
Beijing Institute of Radiation Medicine, Haidian District, Beijing, China. duanhf0720@yahoo.com.cn
Hu
Xian-Wen
XW
Chen
Jin-Long
JL
Gao
Li-Hua
LH
Xi
Yong-Yi
YY
Lu
Ying
Y
Li
Jin-Feng
JF
Zhao
Su-Rong
SR
Xu
Jun-Jie
JJ
Chen
Hui-Peng
HP
Chen
Wei
W
Wu
Chu-Tse
CT
D000818:Animals; D000906:Antibodies; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D015195:Drug Design; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D011770:Pyruvate Kinase / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014183:Transplantation, Heterologous
C473287:ANTXR1 protein, human; D000906:Antibodies; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C523854:TEM8-Fc; D011770:Pyruvate Kinase