Denileukindiftitox

Denileukindiftitox
Mass / length primary structure	57.6473 kDa
Identifier
External IDs	CAS number : 173146-27-5;
Drug information
ATC code	L01 XX29
DrugBank	DB00004
Drug class	Immunotoxin

Denileukindiftitox , also known as DAB (389) IL-2 , is the international non-proprietary name for an immunotoxin approved in the United States for the treatment of patients with refractory cutaneous T-cell lymphoma .

description

Denileukindiftitox is a recombinant , i.e. genetically engineered , cytotoxic chimeric fusion protein produced in cultures of Escherichia coli . It consists of an interleukin-2 peptide sequence fused with that of the diphtheria toxin . The interleukin-2 binds to the interleukin-2 receptor , which is essentially expressed by T lymphocytes - including malignant T lymphocytes. After binding to the receptor, the immunotoxin is internalized by the cell via receptor-mediated endocytosis . In the endosome , the immunotoxin is cleaved proteolytically , releasing the catalytically active A fragment of the toxin. The enzymatic domain of the toxin (the A fragment) catalyzes the modification of diphthamide , an amino acid formed from histidine , by transferring an ADP - ribose residue from NAD ⁺ with cleavage of nicotinamide to the diphtamide (ADP ribosylation). The elongation factor 2 (EF-2), an enzyme that catalyzes the translation during protein synthesis containing diphthamide. By modifying the diphthamide, EF-2's ability to translate is inhibited and protein synthesis in the cell is interrupted, which ultimately leads to the death of the cell.

Denileukindiftitox was the first immunotoxin to be approved by the FDA in the United States in 1999 . In Europe, however, it is not permitted. Various clinical studies for other indications, such as mycosis fungoides and malignant melanoma , are currently ongoing.

Denileukindiftitox is administered intravenously. The side effects are sometimes considerable. Nausea , vomiting , diarrhea , exhaustion , difficulty breathing , fever , cough , itching and peripheral edema are observed in over 20 percent of patients. Vascular leak syndrome can be observed in over 10 percent . There is some evidence that denileukindiftitox can lead to loss of vision.

Denileukindiftitox has the following protein sequence (in one -letter code ):

  MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK
  YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG
  TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY
  EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS
  EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK
  TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN
  FVESIINLFQVVHNSYNRPAYSPGHKTHAPTSSSTKKTQLQLEHLLLDLQMILNGINNYK
  NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVI
  VLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT

Trade name

Denileukindiftitox is sold under the brand name Ontak in the USA .

literature

JW Eklundm TM Kuzel: Denileukin diftitox: a concise clinical review. In: Expert Review of Anticancer Therapy . 5, 2005, pp. 33-38, PMID 15757436 (review).
CD Carretero-Margolism DP Fivenson: A complete and durable response to denileukin diftitox in a patient with mycosis fungoides. In: Journal of the American Academy of Dermatology 48, 2003, pp. 275-276, PMID 12582402 .
F. Foss: Clinical experience with denileukin diftitox (ONTAK). In: Seminars in Oncology . 33, 2006, pp. S11-16, PMID 16516670 (review).
FM Foss: DAB (389) IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. In: Clin Lymphoma 1, 2000, pp. 110-116, PMID 11707818 (review).
BY Wong et al: Denileukin diftitox as novel targeted therapy for lymphoid malignancies. In: Cancer Invest 25, 2007, pp. 495-501, PMID 17882663 .
M. Duvicm R. Talpur: Optimizing denileukin diftitox (Ontak) therapy. In: Future Oncology . 4, 2008, pp. 457-469. PMID 18684057 (Review).
DP Figgitt et al: Denileukin diftitox. In: American Journal of Clinical Dermatology 1, 2000, pp. 67-72, PMID 11702307 .
MT Litzinger et al: IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. In: Blood 110, 2007, pp. 3192-3201, PMID 17616639 .

Individual evidence

^ ^A ^b F. Turturro: Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. In: Expert Rev Anticancer Ther 7, 2007, pp. 11-17. PMID 17187516 , doi: 10.1586 / 14737140.7.1.11 .
↑ C. Huber (editor) among others: Cancer immunotherapies. Deutscher Ärzteverlag, 2007, ISBN 3-7691-1212-1 , p. 129.
↑ National Cancer Institute: denileukin diftitox. Accessed July 10, 2009.
↑ rxlist.com: ONTAK® (denileukin diftitox). Accessed July 10, 2009.
↑ M. Park et al .: Vision loss following denileukin diftitox treatment: a case report of possible posterior ischemic optic neuropathy. In: Leukemia & Lymphoma . 48, 2007, pp. 808-811, PMID 17454642 .

[PMID17187516-1] A ^b F. Turturro: Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. In: Expert Rev Anticancer Ther 7, 2007, pp. 11-17. PMID 17187516 , doi: 10.1586 / 14737140.7.1.11 .

[huber-2] C. Huber (editor) among others: Cancer immunotherapies. Deutscher Ärzteverlag, 2007, ISBN 3-7691-1212-1 , p. 129.

[3] National Cancer Institute: denileukin diftitox. Accessed July 10, 2009.

[4] rxlist.com: ONTAK® (denileukin diftitox). Accessed July 10, 2009.

[5] M. Park et al .: Vision loss following denileukin diftitox treatment: a case report of possible posterior ischemic optic neuropathy. In: Leukemia & Lymphoma . 48, 2007, pp. 808-811, PMID 17454642 .