Interleukin 2

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Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15,5 - 16 kDa protein[1] that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes.

Signaling pathway

IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle; the family also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through the IL-2 receptor, a complex consisting of three chains, termed alpha, beta and gamma. The gamma chain is shared by all family members.[2]

The IL-2 Receptor (IL-2R) α subunit has low affinity for its ligand but has the ability (when bound to the β and ϒ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and ϒ subunits of IL-2R is essential for signalling in T cells.[3][3]

Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints is signaling through TCR receptor, antigen receptor of T-lymphocytes after recognizing MHC-peptide complex. Signaling pathway from TCR then goes through phospholipase-C (PLC) dependent pathway. PLC activates 3 major transcription factors and their pathways: NFAT, NFkB and AP-1. After costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced.

At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation.

NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT is dephosphorylated and therefore translocated to the nucleus.

AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct.

NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter.

Function

IL-2 has essential roles in key functions of the immune system, tolerance and immunity, primarily via its direct effects on T cells. In the thymus, where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen, thus helping the body fight off infections.[2] Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity.[2][4]

Role in disease

While the causes of itchiness are poorly understood, some evidence indicates that IL-2 is involved in itchy psoriasis.[5]

Medical use

Pharmaceutical analogues

Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) and in several European countries for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent doses and has been extensively used in continuous doses.[6][7][8]

Interking is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus.[9]

Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects.[10] It it currently being commercialized into a therapeutic.[11]

Dosage

Various dosages of IL-2 across the United States and across the world are used. The efficiency and side effects of different dosages is often a point of disagreement.

United States

Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects.[12]

A lower dose regimen involves injection of IL-2 under the skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy.[12]

Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.[13]

Toxicity

IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects.[14]

Some common side effects:[12]

More serious and dangerous side effects sometimes are seen, such as capillary leak syndrome, breathing problems, serious infections, seizures, allergic reactions, heart problems or a variety of other possible complications.[12]

Intralesional IL-2 used to treat in-transit melanoma metastases is generally well-tolerated.[13]

Pharmaceutical derivative

Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin.[15] This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T-cell Lymphoma (CTCL).[16]

Clinical research

IL-2 has been used in clinical trials for the treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009.[17] More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis.[18] There are also promising studies looking to use low dose IL-2 in ischaemic heart disease.[19]

History

According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".[20]:712

In the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted lymphocyte proliferation.[21]:16 In the mid-1970s, it was discovered that T-cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin-stimulated normal human lymphocytes.[20]:712 The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980.[22] The gene for human IL-2 was cloned in 1982 after an intense competition.[23]:76

Commercial activity to bring an IL-2 drug to market was intense in the 1980s and '90s. By 1983, Cetus Corporation had created a proprietary recombinant version of IL-2 (Aldesleukin, later branded as Proleukin), with the alanine removed from its N-terminal and residue 125 replaced with serine.[23]:76–77[24]:201[25] Amgen later entered the field with its own proprietary, mutated, recombinant protein and Cetus and Amgen were soon competing scientifically and in the courts; Cetus won the legal battles and forced Amgen out of the field.[23]:151 By 1990 Cetus had gotten aldesleukin approved in nine European countries but in that year, the U.S. Food and Drug Administration (FDA) refused to approve Cetus' application to market IL-2.[8] The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation.[26][27] Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992.[28]

By 1993 aldesleukin was the only approved version of IL-2, but Roche was also developing a proprietary, modified, recombinant IL-2 called teceleukin, with a methionine added at is N-terminal, and Glaxo was developing a version called bioleukin, with a methionine added at is N-terminal and residue 125 replaced with alanine. Dozens of clinical trials had been conducted of recombinant or purified IL-2, alone, in combination with other drugs, or using cell therapies, in which cells were taken from patients, activated with IL-2, then reinfused.[25][29] Novartis acquired Chiron in 2006[30] and sold the aldesleukin business to Prometheus Laboratories in 2010.[31]

References

  1. ↑ Arenas-Ramirez, Natalia; Woytschak, Janine; Boyman, Onur (December 2015). "Interleukin-2: Biology, Design and Application". Trends in Immunology. 36 (12): 763–777. doi:10.1016/j.it.2015.10.003. ISSN 1471-4906.
  2. ↑ 2.0 2.1 2.2 Liao W, Lin JX, Leonard WJ (October 2011). "IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation". Current Opinion in Immunology. 23 (5): 598–604. doi:10.1016/j.coi.2011.08.003. PMC 3405730. PMID 21889323.
  3. ↑ 3.0 3.1 Gaffen SL, Liu KD (November 2004). "Overview of interleukin-2 function, production and clinical applications". Cytokine. 28 (3): 109–23. doi:10.1016/j.cyto.2004.06.010. PMID 15473953.
  4. ↑ Malek TR, Castro I (August 2010). "Interleukin-2 receptor signaling: at the interface between tolerance and immunity". Immunity. 33 (2): 153–65. doi:10.1016/j.immuni.2010.08.004. PMC 2946796. PMID 20732639.
  5. ↑ Reich A, Szepietowski JC (2007). "Mediators of pruritus in psoriasis". Mediators of Inflammation. 2007: 64727. doi:10.1155/2007/64727. PMC 2221678. PMID 18288273.
  6. ↑ Noble S, Goa KL (May 1997). "Aldesleukin (recombinant interleukin-2)". BioDrugs. 7 (5): 394–422. doi:10.2165/00063030-199707050-00007. PMID 18031103.
  7. ↑ Bhatia S, Tykodi SS, Thompson JA (May 2009). "Treatment of metastatic melanoma: an overview". Oncology. 23 (6): 488–96. PMC 2737459. PMID 19544689.
  8. ↑ 8.0 8.1 Pollack A (July 31, 1990). "Cetus Drug Is Blocked By F.D.A." New York Times. This source mentions approval in 9 European countries.
  9. ↑ Bloombert BusinessWeek. Last updated March 3, 2014 Shenzhen Neptunus Interlng-H
  10. ↑ Baker, David; Garcia, K. Christopher; Dougan, Michael; Bernardes, Gonçalo J. L.; Pepper, Marion; Riddell, Stanley R.; Stewart, Lance; Carter, Lauren; Castellanos, Javier (January 2019). "De novo design of potent and selective mimics of IL-2 and IL-15". Nature. 565 (7738): 186–191. doi:10.1038/s41586-018-0830-7. ISSN 1476-4687.
  11. ↑ "Neoleukin Therapeutics". neoleukin.com. Retrieved 2019-01-14.
  12. ↑ 12.0 12.1 12.2 12.3 American Cancer Society. Interleukin-2 (Aldesleukin). Date accessed: 07 Nov 10.
  13. ↑ 13.0 13.1 Shi VY, Tran K, Patel F, Leventhal J, Konia T, Fung MA, Wilken R, Garcia MS, Fitzmaurice SD, Joo J, Monjazeb AM, Burrall BA, King B, Martinez S, Christensen SD, Maverakis E (October 2015). "100% Complete response rate in patients with cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid combination therapy: results of a case series". Journal of the American Academy of Dermatology. 73 (4): 645–54. doi:10.1016/j.jaad.2015.06.060. PMID 26259990.
  14. ↑ Shaker MA, Younes HM (July 2009). "Interleukin-2: evaluation of routes of administration and current delivery systems in cancer therapy". Journal of Pharmaceutical Sciences. 98 (7): 2268–98. doi:10.1002/jps.21596. PMID 19009549.
  15. ↑ Figgitt DP, Lamb HM, Goa KL (2000). "Denileukin diftitox". American Journal of Clinical Dermatology. 1 (1): 67–72, discussion 73. doi:10.2165/00128071-200001010-00008. PMID 11702307.
  16. ↑ "Changes in the Ontak (denileukin diftitiox)". Package Insert to Include a Description of Ophthalmologic Adverse Events ]. FDA. May 11, 2009.
  17. ↑ "IL-2 Immunotherapy Fails to Benefit HIV-Infected Individuals Already Taking Antiretrovirals". News Release. National Institutes of Health (NIH). February 10, 2009.
  18. ↑ Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, Fonfrede M, Rosenzwajg M, Bernard C, Klatzmann D (December 2013). "Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial". The Lancet. Diabetes & Endocrinology. 1 (4): 295–305. doi:10.1016/S2213-8587(13)70113-X. PMID 24622415.
  19. ↑ Clinical trial number NCT03113773 for "Low Dose Interleukin-2 in Patients With Stable Ischaemic Heart Disease and Acute Coronary Syndromes (LILACS)" at ClinicalTrials.gov
  20. ↑ 20.0 20.1 Paul WE (2008). Fundamental immunology (6th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-0-7817-6519-0.
  21. ↑ Chavez AR, Buchser W, Basse PH, Liang X, Appleman LJ, Maranchie JK, Zeh H, de Vera ME, Lotze MT (December 2009). "Pharmacologic administration of interleukin-2". Annals of the New York Academy of Sciences. 1182: 14–27. doi:10.1111/j.1749-6632.2009.05160.x. PMID 20074271.
  22. ↑ Welte K, Wang CY, Mertelsmann R, Venuta S, Feldman SP, Moore MA (August 1982). "Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity". The Journal of Experimental Medicine. 156 (2): 454–64. doi:10.1084/jem.156.2.454. PMC 2186775. PMID 6980256.
  23. ↑ 23.0 23.1 23.2 Rabinow P (1997). Making PCR: A story of biotechnology (Paperback ed.). Chicago, IL, USA: University of Chicago Press. ISBN 978-0226701479.
  24. ↑ Almeida H (April–June 2011). "Drugs obtained by biotechnology processing" (PDF). Brazilian Journal of Pharmaceutical Sciences. 47 (2): 199–207. doi:10.1590/s1984-82502011000200002.
  25. ↑ 25.0 25.1 Whittington R, Faulds D (September 1993). "Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer". Drugs. 46 (3): 446–514. doi:10.2165/00003495-199346030-00009. PMID 7693434.
  26. ↑ Pollack A (July 23, 1991). "2 Biotech Pioneers To Merge". New York Times.
  27. ↑ Lehrman S (January 20, 1992). "Cetus: A Collision Course With Failure". The Scientist Magazine.
  28. ↑ Dutcher JP (November 2002). "Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma". Oncology. 16 (11 Suppl 13): 4–10. PMID 12469934.
  29. ↑ "D02749 (Teceleukin)". KEGG drug.
  30. ↑ "Chiron shareholders approve Novartis deal". SWI swissinfo.ch. Apr 19, 2006.
  31. ↑ "Novartis sells rights to Proleukin in the USA to Prometheus; gets license for vaccine from IIG; and pleads guilty over Trileptal". Pharmaletter. January 27, 2010.

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