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Antitumor activities of TEM8-Fc: an engineered antibody-like molecule targeting tumor endothelial marker 8.

Abstract
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.
AuthorsHai-Feng Duan, Xian-Wen Hu, Jin-Long Chen, Li-Hua Gao, Yong-Yi Xi, Ying Lu, Jin-Feng Li, Su-Rong Zhao, Jun-Jie Xu, Hui-Peng Chen, Wei Chen, Chu-Tse Wu
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 99 Issue 20 Pg. 1551-5 (Oct 17 2007) ISSN: 1460-2105 [Electronic] United States
PMID17925540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ANTXR1 protein, human
  • Antibodies
  • Antineoplastic Agents
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Membrane Proteins
  • Microfilament Proteins
  • Neoplasm Proteins
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • TEM8-Fc
  • Pyruvate Kinase
Topics
  • Animals
  • Antibodies
  • Antineoplastic Agents (pharmacology)
  • Breast Neoplasms (drug therapy)
  • Cell Line, Tumor
  • Colonic Neoplasms (drug therapy)
  • Drug Design
  • Female
  • Humans
  • Immunoglobulin Fc Fragments (pharmacology)
  • Immunoglobulin G (pharmacology)
  • Immunoprecipitation
  • Liver Neoplasms (drug therapy)
  • Male
  • Membrane Proteins (drug effects, metabolism, pharmacology)
  • Mice
  • Mice, Nude
  • Microfilament Proteins
  • Neoplasm Proteins (drug effects, metabolism)
  • Pyruvate Kinase (drug effects)
  • Receptors, Cell Surface (drug effects, metabolism)
  • Recombinant Fusion Proteins (pharmacology)
  • Transplantation, Heterologous

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