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Related Experiment Videos

Developing novel oncolytic adenoviruses through bioselection.

Wen Yan1, Galila Kitzes, Farid Dormishian

  • 1ONYX Pharmaceuticals, Inc., 3031 Research Drive, Richmond, CA 94806, USA.

Journal of Virology
|January 29, 2003
PubMed
Summary
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Bioselection created novel human adenovirus 5 (Ad5) mutants, ONYX-201 and ONYX-203, with significantly enhanced oncolytic activity against cancer cells but not normal cells. A specific mutation in the i-leader region proved crucial for this tumor selectivity.

Area of Science:

  • Virology
  • Oncology
  • Molecular Biology

Background:

  • Human adenovirus 5 (Ad5) is a potential oncolytic virus for cancer therapy.
  • Developing tumor-selective oncolytic viruses with enhanced efficacy is crucial for improving cancer treatment outcomes.

Purpose of the Study:

  • To isolate and characterize novel Ad5 mutants with improved oncolytic activity and tumor selectivity using bioselection.
  • To identify the genetic basis for the enhanced oncolytic properties of the selected mutants.

Main Methods:

  • Bioselection of Ad5 mutants by serial passaging in human colorectal cancer cells (HT29).
  • Plaque purification and characterization of ONYX-201 and ONYX-203 mutants.
  • Comparative analysis of viral replication, cell lysis, and cytotoxicity in tumor and normal cells.

Related Experiment Videos

  • Genetic sequencing to identify mutations and mapping of critical mutations.

    • Main Results:

    • Two Ad5 mutants, ONYX-201 and ONYX-203, exhibited significantly enhanced replication and cytolytic activity (up to 1,000-fold) in HT29 and other cancer cell lines compared to wild-type Ad5.
    • The enhanced oncolytic activity was observed at low multiplicities of infection, suggesting efficient viral spread.
    • Cytotoxicity in normal primary human cells remained similar to wild-type Ad5, leading to an improved therapeutic index.
    • Both mutants shared seven single-base-pair mutations, with a key mutation at nucleotide 8350 in the i-leader region responsible for truncating the i-leader protein.

    Conclusions:

    • Bioselection is an effective strategy for generating tumor-selective oncolytic Ad5 viruses.
    • The mutation at nucleotide 8350 is essential for the enhanced oncolytic phenotype and tumor selectivity of ONYX-201 and ONYX-203.
    • These findings support the potential of bioselected Ad5 mutants as novel oncolytic agents for cancer therapy.