Recombinant interleukins

Interleukin-2 (recombinant human) [94218-72-1] Mr-15,000, amorphous. Purified by reverse phase HPLC. [Weir and Sparks Biochem J 245 85 1 987 Robb et al. Proc Natl Acad Sci USA 81 6486 1984.]... 

Interleukin-2 (recombinant human) [NAM SY] T-cell growth factor [NAM SY]... 

Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d lmmunotherapie. N Engl J Med 1998 338(18) 1272-8. 

Therapeutics. Therapeutic materials represent a class of polypeptides that are a low volume, high value product. The production system need not be very efficient but the quaHty of the recombinant protein has to be extremely pure (33,34). Thus high cost mammalian production systems can be tolerated. However, some of the therapeutic proteins such as insulin, human growth hormone, interleukins, interferon, and streptokinase are produced microbially. 

One component of the age-ielated decline in immune function is decreased production of the lymphokine that promotes the growth of T-ceUs, interleukin 2 (IL-2). Administration of recombinant-derived IL-2, both in vitro and in vivo, appears to restore certain immune functions in aged mice. Recovery of T-regulatory effects on B-ceU differentiation has been reported in human cells from elderly patients treated with IL-1 and/or IL-2 (42). Similar effects have been observed in the presence of the pentapeptide thymopentin [69558-55-0] (Arg Lys Asp Val Tyr), a weU-known IL-2 inducer. Recombinant IL-2 adrninistered to aged mice for three weeks has been shown to correct the T-ceU functional deficiency associated with antigen-specific immunoglobulin production by certain lymphoid tissue (43). 

Recombinant human DL-1 receptor antagonist (Anakinra, Kineret ) blocks the biological activity of interleukin-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. Thereby it reduces the pro-inflammatory activities of IL-1 including cartilage destiuction and bone resorption. Side effects include an increased risk of infections and neutropenia. 

Thrombopoietic factors (no recombinant TPO product in clinical use at this time IL-11 [recombinant product oprelvekin] has marketing approval) stimulate the production of megakaryocyte precursors, megakaryocytes, and platelets [8]. Interleukin-11 has many effects on multiple tissues, and can interact with IL-3, TPO, and SCF. AMG 531, a recombinant peptibody in that binds to the thrombopoetin receptor Mpl and stimulates the production of platelets, is in phase 1 and 2 studies and has been shown to safely increase platelet counts in patients with immune thrombocytopenic purpura [9]. 

The first etCCR application has been reported for a partially C— N-labeled phosphotyrosine peptide derived from interleukin-4 receptor ligated to STAT-6 [107] and subsequent studies involve nucleotide cofactors ligated to human recombinant deoxycytidine kinase [108] and epothilone A bound to tubulin [109]. Since etCCR usually involves isotope-labeling schemes for the ligand, its applicability is limited to specific molecular classes. 

The purported prophylactic use of Japanese herbal medicines to combat neuronal ageing has been related to their free-radical scavenging activity (Hiramatsu a al., 1992). Inhibition of the pro-inflammatory effects of cytokine interleukin-1 by recombinant endogenous interleukin-1 receptor antagonist in experimental rats is associated with alleviation of excitotoxic neuronal damage, an action which has also been related to the antiinflammatory effect of lipocortin 1 (Relton and Roth well, 1992). 

Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin 2 therapy in patients with metastatic melanoma Long-term survival update. Cancer J Sci Am. 2000 6(suppl 1) SI 1-14. 

C25. Cross, A. S., Sadoff, J. C., Kelly, N., Bemton, E., and Gemski, P., Pretreatment with recombinant murine tumor necrosis factor-alpha/cachectin and murine interleukin 1 -alpha protects mice from lethal bacterial infection. J. Exp. Med. 169,2021-2027 (1989). 

Recombinant tumor necrosis factor and interleukin 1 enhance slow-wave sleep. Am. J. Physiol. 253, R142-9. 

Johnson BJ et al. Differential gene expression in response to adjunctive recombinant human interleukin-2 immunotherapy in multidrug-resistant tuberculosis patients. Infect Immunity 1998 66 2426-2433. 

Kratje, R. B., and Wagner, R., Evaluation of Production of Recombinant Human Interleukin-2 in Fluidized Bed Bioreactor, Biotechnol. Bioeng., 39 233... 

Knauf MJ, Bell DP, Hirtzer P, Luo ZP, Young JD, Katre NV (1988) Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biol Chem 263 15064—15070... 

Goodson, R.J., and Katre, N.V. (1990) Site-directed pegylation of recombinant interleukin-2 at its glyco-sylation site. Bio/Technology 8, 343-346. 

Calcium oxalate monohydrate responsible for the formation of most kidney stones significantly increased mitochondrial superoxide production in renal epithelial cells [42], Recombinant human interleukin IL-(3 induced oxygen radical generation in alveolar epithelial cells, which was suppressed by mitochondrial inhibitors 4 -hydroxy-3 -methoxyacetophe-none and diphenylene iodonium [43]. Espositio et al. [44] found that mitochondrial oxygen radical formation depended on the expression of adenine nucleotide translocator Anti. Correspondingly, mitochondria from skeletal muscle, heart, and brain from the Antl-deficient mice sharply increased the production of hydrogen peroxide. 

It overcomes the problem of source availability. Many proteins of therapeutic potential are produced naturally in the body in minute quantities. Examples include interferons (Chapter 8), interleukins (Chapter 9) and colony-stimulating factors (CSFs Chapter 10). This rendered impractical their direct extraction from native source material in quantities sufficient to meet likely clinical demand. Recombinant production (Chapters 3 and 5) allows the manufacture of any protein in whatever quantity it is required. 

Jeal, W. and Goa, K. 1997. Aldesleukin (recombinant interleukin-2) a review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. Biodrugs 7(4), 285-317. 

Hora et al. [3.19] described the complexity of protein stabilization by the example of recombinant, human Interleukin-2 (rhIL-2). Formulations with amino acids and mannitol/ sucrose are sensitive to mechanical stress e. g. by pumping. Hydroxypropyl-beta-cyclodextrin (HPcD) provides stability, but increases the sensitivity to oxygen. Polysor-bate 80 forms a mechanically stable product, but results in oxidation. In both cases contamination in the HPcD or traces of H202 in the Polysorbate may have been the starter for the oxidation. Brewster [3.20] reports, that HPcD stabilizes interleukin without forming aggregations and this results in 100 % biopotency. 

Prestrelski, S. J., Pikal, K., Arakawa, T. Optimization of lyophilization conditions for recombinant interleukin-2 by dried state conformational analysis using Fourier-transform infrared spectroscopy. Pharm. Res. 12 (9), p. 1250-1259, 1995... 

Sarmiento, U.M. et al., Biologic effects of recombinant human interleukin-12 in squirrel monkeys (Sciureau saimiri), Lab. Invest., 71, 862, 1994. 

Talmadge, J.E. et al., Systematic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease, Cancer Res, 47, 5725, 1987. 

Lotze, M.T. et al., High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings, JAMA, 256, 3117, 1986. 

Interleukin-1 (IL-1) produced by monocytes and several other cell types [70, 146] has a wide array of biological properties, including T cell activation and inflammatory interactions with muscle, liver, fibroblasts, brain and bone [70, 146], IL-1, both natural and recombinant, has been shown to release histamine from human basophils and from human adenoidal mast cells [70,146,151] and this release was abolished by an IL-1 antibody. However, the average release produced by 10 units of IL-1 was less than 20% and there was considerable variability between populations of basophils in the extent of histamine release. Moreover, the secretory response elicited was quite slow (within 15 min) compared with that of other peptides [151]. Desensitization of the basophils by anti-IgE serum had no effect on the subsequent IL-1 response, suggesting different mechanisms of action [ 151], as has been the case with other peptides. Interestingly, the portion of the IL-1 molecule that is responsible for its immu-nostimulatory activity appears to be separate from that portion responsible for its proinflammatory effects [152]. However, that portion of the molecule responsible for eliciting basophil and mast-cell histamine release has not as yet been defined. 

Examples of the early application of recombinant DNA technology in medicine are the development of recombinant human growth hormone human insulin human interferons, thought to have anticancer activity in addition to antiviral activity interleukins (regulatory proteins from lymphocytes that are believed to be important in the treatment of immunodeficiency diseases and cancer) tumor necrosis factor epidermal and bone marrow progenitor cell growth factors and the production of vaccines (Table 12.1). 

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