Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells

Mol Ther. 2011 Mar;19(3):507-14. doi: 10.1038/mt.2010.207. Epub 2010 Oct 5.

Abstract

The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cell-specific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor-specific delivery of tumoricidal HSV.

Publication types

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

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / virology
  • Animals
  • Antibody Specificity / genetics
  • Antibody Specificity / immunology
  • CHO Cells
  • Carcinoembryonic Antigen* / immunology
  • Carcinoembryonic Antigen* / metabolism
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cricetinae
  • Cricetulus
  • Gene Order
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • HEK293 Cells
  • Herpesvirus 1, Human / genetics*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nectins
  • Receptors, Tumor Necrosis Factor, Member 14* / genetics
  • Receptors, Tumor Necrosis Factor, Member 14* / metabolism
  • Single-Chain Antibodies* / genetics
  • Single-Chain Antibodies* / metabolism
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / virology

Substances

  • Carcinoembryonic Antigen
  • Cell Adhesion Molecules
  • NECTIN1 protein, human
  • Nectin1 protein, mouse
  • Nectins
  • Receptors, Tumor Necrosis Factor, Member 14
  • Single-Chain Antibodies