Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter

Cancer Res. 2007 Jun 1;67(11):5354-61. doi: 10.1158/0008-5472.CAN-06-4679.

Abstract

Adenovirus vectors have a number of advantages for gene therapy. However, because of their lack of tumor tropism and their preference for liver infection following systemic administration, they cannot be used for systemic attack on metastatic disease. Many epithelial tumors (e.g., colon, lung, and breast) express carcinoembryonic antigen (CEA). To block the natural hepatic tropism of adenovirus and to "retarget" the virus to CEA-expressing tumors, we used a bispecific adapter protein (sCAR-MFE), which fuses the ectodomain of the coxsackie/adenovirus receptor (sCAR) with a single-chain anti-CEA antibody (MFE-23). sCAR-MFE untargets adenovirus-directed luciferase transgene expression in the liver by >90% following systemic vector administration. Moreover, sCAR-MFE can "retarget" adenovirus to CEA-positive epithelial tumor cells in cell culture, in s.c. tumor grafts, and in hepatic tumor grafts. The sCAR-MFE bispecific adapter should, therefore, be a powerful agent to retarget adenovirus vectors to epithelial tumor metastases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism
  • Adenoviridae / physiology*
  • Animals
  • Carcinoembryonic Antigen / immunology*
  • Cell Line
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Gene Targeting / methods*
  • Genetic Therapy / methods*
  • Genetic Vectors / genetics
  • Immunoglobulin Fragments / immunology
  • Immunoglobulin Fragments / metabolism
  • Immunoglobulin Fragments / pharmacology*
  • Liver / immunology
  • Liver / metabolism
  • Liver / virology
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / immunology
  • Liver Neoplasms, Experimental / therapy*
  • Liver Neoplasms, Experimental / virology
  • Mice
  • Mice, Nude
  • Receptors, Virus / biosynthesis
  • Receptors, Virus / metabolism*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology*
  • Transfection

Substances

  • CLMP protein, human
  • CLMP protein, mouse
  • Carcinoembryonic Antigen
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Immunoglobulin Fragments
  • MFE-23 protein, human
  • Receptors, Virus
  • Recombinant Fusion Proteins