IL-2 receptor antagonists

IL-1 receptor antagonist Anakinra A naturally occurring complete antagonist, effective in rheumatoid arthritis. 

The interleukin-1 (EL-1) family of proteins currently comprises IL-1 a, IL-1 (3, and the IL-1 receptor antagonist (IL-1RA). The biological activities of EL-1 are shared by IL-1 a and IL-1 (3, whereas IL-1RA is a true receptor antagonist. IL-1 is a key player in acute and chronic inflammatory diseases. Whether IL-1 has a role in normal physiology is still unresolved. IL-1 can... 

Anakinra/Kineret, an IL-1 receptor antagonist approved for use in rheumatoid arthritis, was recently evaluated in a small phase II trial. When initiated within 6 hours after stroke onset, Anakinra treatment yielded promising preliminary results it was deemed safe with demonstrable biologic activity and likely favorable clinical outcome." ... 

IP4 Inositol tetrakisphosphate IPF Idiopathic pulmonary fibrosis IPO Intestinal peroxidase IpOCOCq Isopropylidene OCOCq I/R Ischaemia-reperfusion IRAP IL-1 receptor antagonist protein IRF-1 Interferon regulatory factor 1 la Short-circuit current ISCOM Immune-stimulating complexes... 

Anakinra is a recombinant form of human IL-1 receptor antagonist. Anakinra inhibits the activity of IL-1 by binding to it and preventing cell signaling.28 Patients must administer a subcutaneous injection every day, which may be less desirable than other treatment options. Anakinra may be used in combination with other DMARDs in patients not responding to or unable to tolerate DMARDs or TNF antagonists.21 Anakinra should not be used in combination with TNF antagonists due to the increased risk of infection.21... 

In addition to IL-la and -1(3, a third IL-l-like protein has been identified, termed IL-1 receptor antagonist (IL-IRa). As its name suggests, this molecule appears to be capable of binding to the IL-1 receptors without triggering an intracellular response. 

Kineret is the tradename given to a recently approved product based on the latter strategy. Indicated in the treatment of rheumatoid arthritis, the product consists of a recombinant form of the human IL-1 receptor antagonist. The 17.3 kDa, 153 amino acid product is produced in engineered E. coli and differs from the native human molecule in that it is non-glycosylated and contains an additional N-terminal methionine residue (a consequence of its prokaryotic expression system). 

Sepsis involves a complex interaction of proinflammatory (e.g., tumor necrosis factor-a [TNF-a] interleukin [IL]-1, IL-6) and antiinflammatory mediators (e.g., IL-1 receptor antagonist, IL-4, and IL-10). IL-8, plateletactivating factor, and a variety of prostaglandins, leukotrienes, and thromboxanes are also important. 

Antiinflammatory mediators including IL-1 receptor antagonist, IL-4, and IL-10 are also produced in sepsis and inhibit production of proinflammatory cytokines. The net effect can vary depending on the state of activation of the target cell, and the ability of the target cell to release mediators that... 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

Nesic, O. et al. IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J. Neurotrauma 18, 947, 2001. 

Horai, R. et al., Production of mice deficient in genes for interleukin (IL)-la, IL-ip, and IL-1 receptor antagonist shows that IL-lp is crucial in turpentine-induced fever development and glucocorticoid secretion, J. Exp. Med., 187, 1463, 1998. 

Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA 2003 100 5986-5990. 

Vannier E, Dinarello CA Histamine enhances interleukin (IL)-l-induced IL-1 gene expression and protein synthesis via Hj receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist. J Clin Invest 1993 92 281-287. 

The IL-1 receptor antagonist (IL-lra) is present in human milk. IL-lra limits inflammation by competing with IL-1 (pro-inflammatory cytokine) for receptor binding (Dinarello, 1995). The reduced inflammatory response in rats with colitis fed human milk compared to chow or formula was similar to the inflammatory response in rats fed infant formula supplemented with IL-lra (Grazioso et al., 1997). These results suggest that the IL-lra content of human milk contributes to its anti-inflammatory properties. 

IL-1 occurs as two polypeptides, IL-la and IL-ip, and produces many of the same effects as TNF-a. An 80-kDa type 1 IL-1 receptor and a 68-kDa type 2 IL-1 receptor found on the surface of some cell types bind both forms of IL-1. An endogenous 17-kDa IL-1 receptor antagonist (IL-lra) competes for binding with IL-1 and counterbalances the inflammatory response. 

Anakinra is a nonglycosylated form of the human IL-1 receptor antagonist (IL-lra). It is produced in a recombinant Escherichia coli expression system and has an additional methionine residue at its amino terminus. In rheumatoid arthritis patients, the amount of naturally occurring IL-lra in the synovial fluid is not sufhcient to counteract the high levels of locally produced IL-1. Anakinra acts as a competitive antagonist of the type 1 IL-1 receptor and decreases the pain and inflammation produced by IL-1. It is administered as a daily subcutaneous injection. 

WARNING Associated w/ T incidence of serious Infxn D/C w/ serious Infxn Uses Reduce S/Sxs of mod/severe active RA, failed 1 or more DMARD Action Human IL-1 receptor antagonist Dose 100 mg SQ daily w/ CrCl <30... 

Kineret is a human IL-1 receptor antagonist and is produced by recombinant DNA technology. It is nonglycosylated and is made up of 153 amino acids. With the exception of an additional methionine residue, it is similar to native human IL-lRa. Human IL-lRa is a naturally occurring IL-1 receptor antagonist, a 17-kDa protein, which competes with IL-1 for receptor binding and blocks the activity of IL-1. 

The studies from our group showed that curcumin inhibited pancreatic cancer in patients. Twenty-five patients were enrolled in this study. Patients received 8 g of curcumin orally daily until disease progression, with restaging every 2 months. Serum cytokine levels for IL-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell (PBMC) expression of NF-kB and COX-2 were monitored. Out of 25 patients, 21 were evaluable for... 

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