Interleukin-2

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Interleukin-2
Interleukin-2
Belt model according to PDB  1m47

Existing structural data : 1m47

Mass / length primary structure 133 amino acids
Precursor 153 amino acids (with signal peptide)
Identifier
Gene name (s) IL2
External IDs
Drug information
ATC code L03 AC01
DrugBank DB00041
Drug class Immune stimulant
Enzyme classification
Substrate IL-2 receptor
Occurrence
Parent taxon Eukaryota

Interleukin-2 ( IL-2 ), also called T-cell growth factor ( engl. T-cell growth factor , TCGF hereinafter) is a peptide hormone of the family of interleukins .

Recombinantly produced human interleukin-2 ( non-proprietary name : Aldesleukin ) is used as a drug for the treatment of renal cell carcinoma . In this indication it is approved in Germany, Austria and Switzerland under the trade name Proleukin (manufacturer: Novartis AG ) .

Layout and function

A human lymphocyte under the scanning electron microscope . The proliferation of lymphocytes is stimulated by interleukin-2.

Interleukin-2 has a molar mass of 15.4  kDa and consists of 133  amino acids . It is released in the body by activated T cells . The gene product originally consists of 153 amino acids. After splitting off a signal peptide made up of 20 amino acids, 133 amino acids remain in the mature form. The molecule contains a disulfide bridge built up via two cysteines , which is essential for the function of the protein. A single, non-essential sugar chain is O-glycosidically bound to threonine .

The mature protein binds to the IL-2 receptor , which is composed of three subunits (α, β and γ) and is mainly expressed by T cells. The β and γ subunits (CD122 and CD132, respectively) are always present on the cell membrane . The α subunit (CD25) is only expressed when an antigen activates the corresponding T cell. Only when all three subunits are present is the affinity of IL-2 sufficiently high to bind to the receptor . After binding to the receptor, a complex signal cascade for the immune response is triggered:

genetics

The human interleukin-2 encoding gene IL2 is on chromosome 4 locus q26-q27. Defects in this gene result in a special form of Severe Combined Immunodeficiency ( dt. "Severe combined immunodeficiency"), a very serious innate immune system disorder.

The gene for the IL-2 receptor is on chromosome 10 .

Aldesleukin (rIL-2)

Aldesleukin (chemical: Interleukin-2 [des-alanyl-1, serin-125]; CAS number [85898-30-2]) is produced biotechnologically by recombinant DNA technology with the help of strains of genetically modified Escherichia coli . The human gene used was modified so that synthetic aldesleukin differs from human interleukin-2 as follows:

As a result, a more homogeneous product with largely the same properties is obtained compared to IL-2.

The amino acid sequence in the one -letter code is:

PTSSSTKKTQ LQLEHLLLDL QMILNGINNY KNPKLTRMLT FKFYMPKKAT
ELKHLQCLEE ELKPLEEVLN LAQSKNFHLR PRDLISNINV IVLELKGSET
TFMCEYADET ATIVEFLNRW ITFAQSIIST LT

Indication and typical dosage

Since 1984, aldesleukin has been tested as a cancer immunotherapeutic agent in a large number of clinical studies . By activating defense cells that are able to switch off tumor cells , aldesleukin is particularly effective in tumors that trigger an immune response in the body. These are mainly renal cell carcinoma and malignant melanoma . For these two cancers, the most promising results have so far been obtained. Aldesleukin is approved in the EU for the treatment of advanced metastatic renal cell carcinoma, where it is used together with interferons and various cytostatics . In all other fields of indication, aldesleukin is only tested in clinical studies. The goals of these studies are the further development of the form of therapy, the reduction of side effects, improved effectiveness in combination with other forms of therapy and the possibility of long-term administration as part of maintenance therapy.

Aldesleukin is usually administered as a continuous infusion over a period of five days for 24 hours. The dosage is usually 1.1 mg active ingredient per day and m² body surface. The same infusion is repeated after a two to six day break. In most cases, this is followed by a three-week treatment break, which concludes the entire induction cycle. Much lower dose maintenance cycles are given to patients who have achieved remission or standstill of the disease.

Pharmacokinetics

With a single intravenous administration, aldesleukin shows a bi-exponential clearance curve. The plasma half-life α is approximately 13 minutes and the plasma half-life β is approximately 85 minutes.

Side effects

The side effects of aldesleukin are significant for patients, especially at high doses. This also leads to a number of contraindications that prohibit the use of aldesleukin in some patients. About 3% of the treated patients died from the side effects of the treatment.

Autoimmune diseases can be aggravated by the systemic administration of aldesleukin. All of these side effects - with the exception of some cases of hypothyroidism - are reversible when the aldesleukin therapy is stopped. X-ray contrast media can cause severe allergic reactions.

Interleukin-2 has also been causally linked to pleural effusion .

The side effects are particularly pronounced with bolus injections - intravenous administration within a few seconds. If aldesleukin is administered subcutaneously or infused slowly, the side effects are significantly reduced with similar effectiveness. The bolus injection is therefore rarely used any more.

Historical

Interleukin-2 was the first interleukin to be discovered. In 1976 Doris Morgan , Frank Ruscetti and Robert Charles Gallo described a new glycoprotein that is able to grow T lymphocytes from human bone marrow in vitro . In 1983, Interleukin-2 was cloned and sequenced for the first time.

Aldesleukin was made by the US company Cetus Corp. - Chiron Corporation today - after it was acquired  and approved by the FDA in 1992 for the treatment of metastatic renal cell carcinoma. In 1998, the indication was expanded to include the treatment of metastatic malignant melanoma.

In Europe, approval for the treatment of metastatic renal cell carcinoma was granted in 1989 in the Netherlands, then in other countries (e.g. Germany: 1989, Austria: 1998).

literature

Web links

  • Proleukin on the Internet Drug Index (English)

Individual evidence

  1. ^ T. Dingermann et al. a .: Pharmaceutical biology. Verlag Springer, 2002, ISBN 3-540-42844-5 , pp. 211-214.
  2. ^ Roche Lexicon Medicine. Edition 5. Verlag Urban & Fischer, ISBN 3-437-15150-9 , p. 935.
  3. ↑ T. Shows u. a .: Interleukin 2 (IL2) is assigned to human chromosome 4. In: Somat Cell Molec Genet. 10, 1984, pp. 315-318. PMID 6609441
  4. ↑ T. Fujita et al. a .: Structure of the human interleukin 2 gene. In: PNAS. 80, 1983, pp. 7437-7441. PMID 6324170
  5. ↑ K. Weinberg, R. Parkman: Severe combined immunodeficiency due to a specific defect in the production of interleukin-2. In: NEJM. 322, 1990, pp. 1718-1723. PMID 2342538
  6. ^ WJ Leonard et al. a .: Localization of the gene encoding the human interleukin-2 receptor on chromosome 10. In: Science. 228, 1985, pp. 1547-1549. PMID 3925551
  7. ^ SA Rosenberg u. a .: Biological activity of recombinant human interleukin-2 produced in Escherichia coli. In: Science. 223, 1984, pp. 1412-1415. PMID 6367046
  8. ↑ MV Doyle et al. a .: Comparison of the biological activities of human recombinant interleukin-2125 and native interleukin-2. In: J Biol Response Mod. 4, 1985, pp. 96-109. PMID 3920358
  9. ↑ a b c Immunotherapies for cancer - Cytokines in cancer therapy - Interleukins: helping the immune system on the jumps. Cancer information service of the German Cancer Research Center (DKFZ), Heidelberg. September 28, 2010. Last accessed September 4, 2014.
  10. ↑ a b c d e Specialist information: Proleukin ( Memento of the original from January 18, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. January 2012. @1@ 2Template: Webachiv / IABot / www.diagnosia.com
  11. ↑ open drug database: Specialist information on Proleukin®. ( Memento of the original from March 31, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved June 18, 2009. @1@ 2Template: Webachiv / IABot / ch.oddb.org
  12. ↑  ( page no longer available , search in web archives ) Interactions between contrast media and other drugs. (PDF) Aarau Cantonal Hospital; Retrieved June 18, 2009.@1@ 2Template: Dead Link / www.ksa.ch
  13. ↑ Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.
  14. ↑ J. Gordon, LD Maclean: A Lymphocyte-stimulating Factor produced in vitro. In: Nature. 208, 1965, pp. 795-796. doi: 10.1038 / 208795a0 PMID 4223737
  15. ↑ S. Kasakura, L. Lowenstein: A factor stimulating DNA synthesis derived from the medium of leukocyte cultures. In: Nature. 208, 1965, pp. 794-795. doi: 10.1038 / 208794a0 PMID 5868897
  16. ↑ J. Bubeník: Interleukin-2 therapy of cancer. (PDF; 195 kB) In: Folia Biol (Praha). 50, 2004, pp. 120-130. PMID 15373345 (Review).
  17. ↑ DA Morgan et al. a .: Selective in vitro growth of T lymphocytes from normal human bone marrows. In: Science. 193, 1976, pp. 1007-1008. PMID 181845 .
  18. ↑ T. Taniguchi et al. a .: Structure and expression of a cloned cDNA for human interleukin-2. In: Nature. 302, 1983, pp. 305-310. PMID 6403867
  19. ↑ Biotechnology in a Global Economy (PDF; 5.31 MB) accessed on June 18, 2009.
  20. ↑ Geneesmiddeleninformatiebank , accessed on April 20 of 2019.
  21. ^ List of nationally authorized medicinal products. Active substance: aldesleukin . EMA, September 6, 2018.
  22. ↑ Product information PROLEUKIN S 18 x 10 6 IU powder for solution for injection or infusion , Novartis Pharma GmbH, Nuremberg.
  23. ↑ Technical information PROLEUKIN S 18 x 10 6 IU powder for the preparation of a solution for injection or infusion , Novartis Pharma GmbH, Vienna.