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Related Experiment Videos

Targeting Pseudomonas exotoxin to hematologic malignancies

R J Kreitman1, I Pastan

  • 1Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Seminars in Cancer Biology
|October 1, 1995
PubMed
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Identification of residues in the first cytoplasmic loop of P-glycoprotein involved in the function of chimeric human MDR1-MDR2 transporters.

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Cell-mediated cleavage of Pseudomonas exotoxin between Arg279 and Gly280 generates the enzymatically active fragment which translocates to the cytosol.

The Journal of biological chemistry·1992
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Alanine scanning mutagenesis identifies surface amino acids on domain II of Pseudomonas exotoxin required for cytotoxicity, proper folding, and secretion into periplasm.

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Recombinant toxins containing the variable domains of the anti-Tac monoclonal antibody to the interleukin-2 receptor kill malignant cells from patients with chronic lymphocytic leukemia.

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Pseudomonas exotoxin: recombinant conjugates as therapeutic agents.

Biochemical Society transactions·1992

Targeting malignant hematopoietic cells with Pseudomonas exotoxin (PE) derivatives shows promise. Anti-Tac(Fv)-PE38, an immunotoxin targeting interleukin 2 receptor alpha (IL2Ra), is advancing to clinical trials for leukemia and lymphoma.

Area of Science:

  • Oncology
  • Immunology
  • Biotechnology

Background:

  • Malignant hematopoietic cells overexpress cell surface receptors and antigens compared to normal cells.
  • Targeting these unique markers offers a strategy for selective cancer therapy.
  • Pseudomonas exotoxin (PE) derivatives can be engineered as targeted toxins.

Purpose of the Study:

  • To develop targeted immunotoxins for selective elimination of malignant hematopoietic cells.
  • To evaluate the potential of recombinant immunotoxins targeting specific cell surface antigens.
  • To advance preclinical candidates towards clinical application in hematologic malignancies.

Main Methods:

  • Utilizing Pseudomonas exotoxin (PE) derivatives conjugated to targeting moieties like interleukins or antibody fragments.

Related Experiment Videos

  • Developing single-chain recombinant immunotoxins, such as Anti-Tac(Fv)-PE38, targeting specific receptors like IL2Ra.
  • Conducting preclinical development for immunotoxins targeting IL2Ra, CD22, and other relevant antigens.

    • Main Results:

    • Engineered PE derivatives demonstrate selective targeting of malignant cells expressing specific receptors.
    • Anti-Tac(Fv)-PE38, targeting IL2Ra, has shown significant preclinical development progress.
    • The approach is being prepared for clinical testing in patients with IL2Ra-positive leukemia, lymphoma, and Hodgkin's disease.

    Conclusions:

    • Targeted immunotoxins represent a viable strategy for treating hematologic malignancies.
    • Anti-Tac(Fv)-PE38 is a promising candidate for clinical evaluation in IL2Ra-positive cancers.
    • Further clinical development is warranted to assess the efficacy and safety of these targeted therapies.