Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The design and construction of a new class of recombinant therapeutic agents, receptor-specific cytotoxins, has occurred within the last 5 years. Development of a number of receptor-targeted fusion toxins has been based on a detailed understanding of the structure-function relationships of both diphtheria toxin and Pseudomonas exotoxin A, and availability of the nucleic acid sequences of each structural gene. A variety of fusion toxins in which the native receptor-binding domain of either diphtheria toxin or Pseudomonas exotoxin A has been genetically replaced with either a polypeptide hormone or growth factor have been constructed. These fusion toxins selectively intoxicate receptor-bearing cells in vitro and are active in a variety of animal model systems. DAB486IL-2, and IL-2 receptor targeted cytotoxin, is the first fusion toxin to be evaluated in patients. Phase I/II clinical trials have been performed in refractory leukemia/lymphoma, severe rheumatoid arthritis, and Type 1 diabetes. DAB486IL-2 has been administered to more than 200 patients, has been well tolerated, and has shown encouraging signs of potential efficacy in all three clinical indications. Thus, DAB486IL-2 represents a new class of targeted biological therapeutic response modifiers whose mode of action is based on selective elimination of target cells.
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PMID:Recombinant fusion toxins--a new class of targeted biologic therapeutics. 810 49

To study the structural basis of ligand-induced receptor-mediated internalization of interleukin-2 (IL-2), a strategy has been developed to generate variant T cells that are deficient in internalization of this cytokine. IL-2 receptor (IL-2R) alpha- and beta-bearing EL4 cells, that express high-affinity IL-2R and internalize IL-2, were treated with low doses of IL-2-Pseudomonas exotoxin chimeric protein (IL-2-PE40). This treatment resulted in isolation of a variant (CX1) that was unable to express high-affinity IL-2R or internalize IL-2. Transfection of CX1 with the IL-2R beta cDNA led to surface expression of IL-2R beta and high-affinity IL-2R as well as the ability to internalize IL-2. This finding indicates that the absence of the beta subunit was the sole defect in CX1 responsible for its failure to internalize IL-2. By transfecting CX1 with mutated beta cDNA, several CX1 transfectants were produced that expressed a beta-subunit that lacked all amino acids of the intracytoplasmic region. These transfectants expressed high-affinity IL-2R and internalized IL-2 at a rate comparable to cells expressing wild-type beta-chain. These results demonstrate that internalization of IL-2 is independent of any signals contained in the intracytoplasmic tail of the beta subunit and raise the possibility that such signals may be entirely contained within the gamma subunit.
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PMID:Selection of internalization-deficient cells by interleukin-2-Pseudomonas exotoxin chimeric protein: the cytoplasmic domain of the interleukin-2 receptor beta chain does not contribute to internalization of interleukin-2. 825 33

It has recently been shown that chimeric toxin composed of IL2 fused tp PE40, a mutant form of Pseudomonas Exotoxin A devoid of its native cell recognition and binding domain was cytotoxic to IL2 receptor bearing cells. We here amplified the gene IL-2 (60), which codes for the N-terminal 1-60 amino acids of human IL-2 by PCR. After that, we fused it to PE40 and the new chimeric protein IL-2(60)-PE40 was expressed in E. coli. SDS-PAGE revealed that IL-2(60)-PE40 chimeric protein accounts for more than 18% of total cell proteins. As the region IL-2 binds with its receptor was defined in the N-terminal residues 8-54 of IL-2, such fusion proteins will have the same activity with IL-2-PE40. Following primary purification, IL-2(60)-PE40 was shown to be very toxic to IL-2 receptor-positive cells but non measurable effect on the cells lacking IL-2 receptors. Such a structure has not been reported by now. The fusion protein is useful for suppressing the immune response in cases of rejection of allografts and organ transplants and as therapeutic agents for the treatment of IL-2 receptor related diseases such as autoimmune disease, ATL (adult T-cell leukemia), et al.
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PMID:Cloning and expression of the gene coding for IL-2(60)-PE40, a molecular targeted protein. 858 Apr 81

IL-2-PE664Glu is a chimeric cytotoxin consisting of interleukin-2 (IL-2) fused to a mutant form of Pseudomonas exotoxin (PE664Glu). The chimeric cytotoxin has been previously shown to be extremely toxic to both phytohaemagglutinin blasts and mixed leukocyte reaction blasts prepared from monkey and human lymphocytes. To explore the possible clinical utility of IL-2-PE664Glu for autoimmune diseases, particularly in which B cells are involved, we tested the sensitivity of B cell lines derived from myasthenia gravis patients to this chimeric cytotoxin. 65% (15 out of 23) of the tested B cell lines were sensitive to IL-2-PE664Glu mediated cytotoxicity. B cell lines from control donors as well as from patients with another autoimmune disease, multiple sclerosis, were much less sensitive to IL-2-PE664Glu cytotoxicity. Moreover, a control protein lacking the IL-2 as the targeting moiety of the chimera, had no effect toward all B cell lines tested, thus establishing its specific activity. A detailed study of the IL-2 receptor of the patients' B cells, using the PCR technique and FACS analysis, showed that the cells express mainly the beta and gamma chains and at a lower level also the alpha-chain of the IL-2 receptor. Our results suggest that IL-2-PE664Glu could be effective for selective targeted immunotherapy of myasthenia gravis patients.
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PMID:Interleukin-2 Pseudomonas exotoxin chimeric protein is cytotoxic to B cell cultures derived from myasthenia gravis patients. 858 24

Haploidentical bone marrow transplantation (BMT) is associated with a high risk of severe graft-versus-host disease (GVHD). While pan-T cell depletion of the graft is the most effective means of preventing severe GVHD, it is associated with delayed recovery of T cell function leading to fatal infections. We used two related Pseudomonas exotoxin-based immunotoxins, anti-Tac(Fv)-PE38 and anti-Tac(Fv)-PE38KDEL, that both target the IL-2 receptor on activated T cells, to specifically deplete alloreactive lymphocytes against haploidentical stimulators. The functional capacity of the remaining lymphocytes was tested in proliferative assays against the original haploidentical stimulator and pooled cells from other mismatched donors (third party). We varied the recombinant toxin concentration and schedule to determine the optimum conditions for selective depletion. In 10 experiments, the mean residual reactivity after depletion was 7.6 +/- 1.4% against the haploidentical stimulator and 64.2 +/- 5% against the third party, expressed as a percentage of the undepleted response to the same stimulators. Depletion was shown to be specific for mixed lymphocyte culture (MLC)-activated lymphocytes. The immunotoxin did not affect CFU-GM growth of normal BM cells. This selective depletion of haploidentical alloreactivity could be used to prevent GVHD while conserving immune recovery following haploidentical BMT.
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PMID:Specific depletion of alloreactivity against haplotype mismatched related individuals by a recombinant immunotoxin: a new approach to graft-versus-host disease prophylaxis in haploidentical bone marrow transplantation. 873

The data of a closed phase I/II trial in patients with resistant Hodgkin's lymphoma indicate promising results using a chemically linked anti-CD25 ricin-A immunotoxin (IT) (RFT5-SMPT-dgA). This IT is based on the high-affinity moab RFT5. Since recombinant DNA technology permits the readier production of large amounts of ITs, we constructed a new RFT5-based fusion toxin [RFT5(scFv)-ETA']. We isolated mRNA from the hybridoma cell line RFT5, synthesized first strand cDNA and performed RT-PCR. Amplified coding regions of the light and heavy chain variable domains were joined together with a synthetic (Gly4-Ser)3 linker. The resulting single chain variable fragment (scFv) was fused to a modified Pseudomonas aeruginosa exotoxin A (ETA') lacking its cell-binding domain I. After IPTG-induced expression in Escherichia coli, the 70 kDa His-tagged fusion protein [RFT5(scFv)-ETA'] was isolated by osmotic shock and sonication under denaturing conditions. The recombinant toxin was purified on a Ni2+-NTA chelating sepharose and eluted with 250 mM imidazole. Pooled protein was renatured, dialyzed and concentrated by precipitation. Binding properties of RFT5(scFv)-ETA' were assessed on the CD25-expressing cell line L540cy by ELISA, immunohistochemistry and FACS analysis. CD25-specific binding was confirmed by immunoprecipitation experiments with recombinant human IL-2 receptor alpha. The in vitro toxicity of the chimeric protein was tested on the Hodgkin-derived cell lines L540cy, L428, L1236, a monocyte cell line U937 and a Burkitt lymphoma cell line BL38. RFT5(scFv)-ETA' inhibited protein biosynthesis of L540cy and L428 cells by 50% at concentrations (IC50) of 18 and 12 ng/ml, respectively. CD25-specific toxicity was confirmed by competitive toxicity assays. These data confirm for the first time binding specificity and toxicity of a recombinant anti-CD25 immunotoxin, against Hodgkin-derived cell lines; its applicability on Hodgkin's lymphoma needs yet to be evaluated in vivo.
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PMID:Construction and in vitro evaluation of RFT5(scFv)-ETA', a new recombinant single-chain immunotoxin with specific cytotoxicity toward CD25+ Hodgkin-derived cell lines. 985 27

Graft-versus-host disease (GVHD), due to the presence of recipient-reactive T cells, limits the usefulness of bone marrow transplantation (BMT) and is a major contributor to patient mortality. To prevent GVHD, murine and human T cells were activated by antigen or mitogens and treated with a genetically engineered form of Pseudomonas exotoxin A (PE) directed against the IL-2 receptor. Treatment with the chimeric toxin eliminated alloreactive cytotoxic T lymphocytes (CTL) as determined by cytotoxicity and mixed lymphocyte culture assays. Precursor frequencies of alloreactive cytotoxic T cells and proliferative T cells were reduced up to 100-fold as shown by limiting dilution assays. Flow cytometric analyses revealed that treatment with the chimeric toxin completely eliminated CD25+ cells from the cultures. Toxin treatment had no significant effect on hematopoietic stem and progenitor cells as determined in vitro by colony-forming assays and in vivo by long-term hematopoietic recovery after 950 rad irradiation. Toxin treatment decreased GVHD in transplanted mice to less than 10% (as compared to 88% in untreated controls). Thus, it is possible to prevent life-threatening GVHD after BMT by using a CD25 receptor-directed toxin to eliminate host-reactive T cells from bone marrow grafts.
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PMID:Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor. 1019 98

Both severe combined immunodeficiency (SCID) and cystic fibrosis (CF) may present in infancy with a history of respiratory infections and failure to thrive. Elevated sweat chloride levels on multiple sweat tests is diagnostic of CF; transient elevation of sweat chloride has been reported in patients with hypogammaglobulinemia and antibody deficiency without CF. This article presents a case report of a 5-month-old boy with recurrent respiratory infections, failure to thrive, and two borderline elevated sweat test levels. Laboratory evaluation including testing for CF as well as immune deficiency was performed in this patient. Two borderline abnormal sweat chloride tests together with isolation of Pseudomonas from the airway caused clinicians initially to suspect CF; however, mutation in gene coding for the gamma-chain of the IL-2 receptor and a negative CF genetic mutation analysis ultimately led to the final diagnosis of SCID. It is essential to make the diagnosis of SCID as early as possible because infants with SCID who do not undergo reconstitution of their immune system universally die in infancy because of infection. Early diagnosis and intervention can lead to an excellent prognosis in a previously fatal disease.
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PMID:A 5-month-old boy with recurrent respiratory infections, failure to thrive, and borderline elevated sweat chloride levels. 1691 75


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