Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders

@article{Turturro2007DenileukinDA,
  title={Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders},
  author={Francesco Turturro},
  journal={Expert Review of Anticancer Therapy},
  year={2007},
  volume={7},
  pages={11 - 17}
}
  • F. Turturro
  • Published 1 January 2007
  • Biology, Medicine
  • Expert Review of Anticancer Therapy
Denileukin diftitox (Ontak®) represents an example of a fused molecule that targets cells bearing high affinity interleukin-2 receptors internalized via receptor-mediated endocytosis in an acidified vesicle. Denileukin diftitox is proteolytically cleaved within the endosome liberating the enzymatically active portion of the diphtheria toxin, the A fragment. Diphtheria toxin fragment A is released into the cytosol inhibiting the protein synthesis through the ADP-ribosylation of the elongation… 
Optimizing denileukin diftitox (Ontak) therapy.
TLDR
This article focuses on the clinical trial that led to the US FDA approval of the drug for cutaneous T- cell lymphoma in 1999, and other investigational studies for hematologic malignancies, recurrent and refractory chronic lymphocytic leukemia, non-Hodgkin B-cell lymphoma, graft-versus-host disease and autoimmune disease, demonstrating the activity and adverse effects of theDrug.
Denileukin diftitox for the treatment of cutaneous T-cell lymphoma
TLDR
Denileukin diftitox (DD) is unique among CTCL therapies in that it is a genetically engineered fusion protein that combines the cytotoxic and membrane translocating domains of the diphtheria toxin with a truncated sequence of human IL-2 that is internalized and blocks protein synthesis.
The co-expression of denileukin diftitox immunotoxin with Artemin: soluble and aggregation analysis in presence of an efficient protein chaperone
TLDR
The results confirmed that the soluble expression of the denileukin diftitox protein significantly increased in the presence of Artemin as a new chaperon protein, and can be utilized for the solubleexpression and production of this protein as a smart and directed toxin for the treatment of recurrent cutaneous T-cell lymphoma (CTCL).
Sensitivity of Cancer Cells to Truncated Diphtheria Toxin
TLDR
It is reported that “receptorless” recombinant DT385 is in fact cytotoxic to a variety of cancer cell lines and possesses anti-angiogenic and anti-tumor activity and may have potential as a therapeutic agent.
Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro
TLDR
This review describes the intracellular transport of ricin and ricin-based immunotoxins and their mechanism of action in different non-malignant and cancer cell lines and their composition, medical applications and side-effects.
The Preclinical and Clinical Evaluation of VB6-845: An Immunotoxin with a De-Immunized Payload for the Systemic Treatment of Solid Tumors
TLDR
Clinical evidence would suggest that the anticancer mechanisms mediated by these antibodies are not on their own sufficient to provide a prolonged clinical benefit, and other strategies have been explored to enhance antibody potency while still exploiting their targeting function.
Recent Advances in the Development of Antineoplastic Agents Derived from Natural Products
TLDR
The review highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells.
Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors
TLDR
Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may haveA role in reducing toxicity in comparative oncologic trials in dogs.
The potential of toxin-based drug delivery systems for enhanced nucleic acid therapeutic delivery
TLDR
The possibility of using attenuated toxins as antisense and siRNA delivery systems has been demonstrated in vitro and systems based upon attenuated anthrax toxin have been shown to have high activity and low toxicity whilst not requiring cationic ‘helpers’ or condensing agents, divorcing these systems from the problems associated with the PEG dilemma.
Molecular Docking and In Silico Study of Denileukin Diftitox: Comparison of Wild Type With C519S Mutant
TLDR
The present study shows that the suggested mutation of this protein can be an acceptable replacement for denileukin diftitox with a similar affinity and a more proper refolding process.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 46 REFERENCES
Denileukin diftitox: a concise clinical review
TLDR
The clinical trials leading to the approval of denileukin diftitox for cutaneous T-cell lymphoma are reviewed, and the potential future role of this novel drug in patients with both malignant and nonmalignant diseases is discussed.
Clinical experience with denileukin diftitox (ONTAK).
  • F. Foss
  • Biology, Medicine
    Seminars in oncology
  • 2006
TLDR
The clinical profile and potential benefits of denileukin diftitox in the treatment of cutaneous T-cell lymphoma and other hematologic disorders are examined.
A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma.
TLDR
The results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexARotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.
Phase II Study of Denileukin Diftitox (Ontak) for Relapsed/Refractory T-Cell Non-Hodgkin’s Lymphoma.
TLDR
While response to denileukin diftitox is seen in both CD25+ and CD25− T-NHL, drug activity in CD25 expressing tumors is particularly striking.
Denileukin diftitox for the treatment of steroid-resistant acute graft-versus-host disease.
  • P. Shaughnessy, C. Bachier, C. LeMaistre
  • Medicine, Biology
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
  • 2005
Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.
  • N. Dang, F. Hagemeister, L. Fayad
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2004
TLDR
Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated.
Confirmation of the activity of the interleukin-2 fusion toxin denileukin diftitox against chemorefractory chronic lymphocytic leukemia, including cases with chromosome 17p deletions and without detectable CD25 expression.
TLDR
The study by Frankel et al. is the first published report of a novel treatment for fludarabine-refractory CD25-positive chronic lymphocytic leukemia using the immunotoxin denileukin diftitox (Ontak) to kill cells expressing the interleukin 2 (IL-2).
DAB(389)IL-2 (denileukin diftitox, ONTAK): review of clinical trials to date.
TLDR
A review of the efficacy and toxicity trials with DAB(389)IL-2 completed to date in cancer, in particular those that involved patients with cutaneous T-cell lymphoma, as well as the rationale for these trials.
Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
TLDR
Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD, and dose level 2 was the maximum tolerated dose (MTD).
A phase II study of denileukin diftitox (ONTAK) in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia
TLDR
A phase II study to evaluate the efficacy and toxicity of ONTAK in patients with fludarabine-refractory CLL and the overall response was 27%, with 1 CR.
...
1
2
3
4
5
...