Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system.
It is a 15.5–16 kDa protein[5] 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 signals through a IL-2 receptor, a complex consisting of three chains, termed alpha (CD25), beta (CD122) and gamma (CD132).
Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold.
This phosphorylation recruits STAT transcription factors, predominantly STAT5, which dimerize and migrate to the cell nucleus where they bind to DNA.
One of the checkpoints (in other words one of the things which needs to be done before IL-2 is expressed) is that there must be signaling through a conjunction of a T Cell Receptor (a TCR) and an HLA-peptide complex.
[11] 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.
[15][24] As has been found in some studies on mammalian IL-2,[25] data suggest that fish IL-2 can form homodimers and that this is an ancient property of the IL-2/15/15L-family cytokines.
It has been approved by the Food and Drug Administration (FDA) with a black box warning 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.
The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy.
Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health.
[33] Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.
Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients.
In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy [37] Systemic IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects.
Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema.
[39] Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses.
[37] 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.
In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL).
[44] More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis.
On the other hand, IL-2/JES6-1 highly selectively stimulate regulatory T cells and they could be potentially useful for transplantations and in treatment of autoimmune diseases.
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.
[54][55] Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992.
[56] 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.