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Novel Oxygen-Dependent Degradable Immunotoxin Regulated by the Ubiquitin-Proteasome System Reduces Nonspecific

Min Wei1, Anxiang Chen1, Jian Zhang1

  • 1State Key Laboratory of Bioreactor Engineering, New World Institute of Biotechnology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.

Molecular Pharmaceutics
|October 28, 2022
PubMed

Insights

Engineered immunotoxins fuse bacterial toxins with oxygen-sensing domains to target cancer cells. This approach reduces side effects by degrading the toxin in normal cells, offering a promising cancer therapy.

Area of Science:

  • Biotechnology
  • Molecular Biology
  • Cancer Research

Background:

  • Bacterial toxins and immunotoxins are explored as antitumor agents.
  • Immunotoxins show potent tumor cell killing but cause nonspecific toxicity.
  • Hypoxia-inducible factor 1α (HIF-1α) indicates cancer cell hypoxia.

Purpose of the Study:

  • To engineer an oxygen-dependent degradable immunotoxin (DS-ODDD) for cancer therapy.
  • To reduce nonspecific toxicity of immunotoxins in normal cells.
  • To investigate the degradation mechanism and therapeutic potential of the engineered immunotoxin.

Main Methods:

  • Fusion of immunotoxin DAB389-4D5 scFv (DS) with HIF-1α's oxygen-dependent degradation domain (ODDD).
  • Construction and testing of the engineered fusion protein DSO-2 with a (G4S)3 linker.
  • Analysis of DSO-2 degradation via ubiquitin-proteasome pathway and its effect on apoptosis-related molecules.

Main Results:

  • DSO-2 demonstrated potent cancer cell killing under hypoxia.
  • DSO-2 exhibited significantly reduced nonspecific toxicity to normal cells under normoxic conditions.
  • DSO-2 degradation is regulated by an oxygen-sensitive ubiquitin-proteasome pathway, decreasing apoptosis in normal cells.

Conclusions:

  • The engineered oxygen-sensing immunotoxin DSO-2 is a potential therapeutic agent for cancer treatment.
  • Targeted degradation of immunotoxins based on cellular oxygen levels can minimize side effects.
  • This strategy offers a novel approach to enhance the safety and efficacy of immunotoxin-based cancer therapies.
Keywords:
HIF1-α oxygen-dependent degradation domaincancer therapyhypoxiarecombinant immunotoxinubiquitin−proteasome

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