7-aminocephalosporanic acid derivative as inhibitor of il-15 and il-2 activity

a technology of il-15r and il-2, which is applied in the field of 7aminocephalosporanic acid derivatives, can solve the problems of not being approved for clinical use, affecting the treatment effect, and preventing the progression of illness, so as to facilitate the identification of a chemical compound which will fit in the il-15r receptor

Inactive Publication Date: 2016-08-18
WARSZAWSKI UNIWERSYTET MEDYCZNY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently adopted strategies based on inhibiting IL-15 seem to be effective, but none of them has been approved for clinical use so far.
However, the matter of serious concern is the effect of ‘reverse signaling’ (Budagian V. et al., J. Biol. Chem. (2004)).
Pharmacological treatment of RA, currently available on the medical market, does not remove the cause of the disease.
They suppress the symptoms of the disease, but do not stop the progress of the illness.
However, even in patients responding to the treatment, the disease progresses and diminished medical efficacy is observed after long term treatment.
However, to date there is no available information about the phase III clinical trials.
The introduction of the biologic medical products into rheumatoid arthritis therapy is considered big progress in the RA treatment, but these biologics (usually used in a combination with methotrexate of cytostatic and immunosuppressive properties) are only effective in limiting the disease symptoms and delaying joint degradation in about 30% of treated patients.
Due to the limited therapeutic effects and high production costs of currently available biologic medical products, the demand for an efficacious anti-RA drug of new generation still remains valid.
To date the efficacy of these new compounds has not been proved in clinical studies.
The monoclonal antibodies prevent IL-2 binding, among others, to T lymphocytes, thus hampering IL-2 mediated cell response involved in the process of allograft rejection.

Method used

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  • 7-aminocephalosporanic acid derivative as inhibitor of il-15 and il-2 activity
  • 7-aminocephalosporanic acid derivative as inhibitor of il-15 and il-2 activity
  • 7-aminocephalosporanic acid derivative as inhibitor of il-15 and il-2 activity

Examples

Experimental program
Comparison scheme
Effect test

example 2

Effect of Cefazolin on IL-15 or IL-2-Induced TNF-α Synthesis in PBMC

[0066]The evaluation of TNF-α synthesis in IL-15-stimulated PBMC was performed using the ELISA method and commercially available tests (R&D, USA). The experiment was carried out strictly according to the manufacturer's recommendations.

[0067]The PBMC were seeded in a 24-well plate (2×106 cells in 1 ml of the culture medium / well), treated with the tested compound and after 30 min stimulated with IL-15 (5 ng / ml) or IL-2 (5 ng / ml). After 48 h incubation, the culture medium was collected from each well to determine the TNF-α concentration, cells were harvested and lysed, and the concentration of total protein was measured in cell lysates. The obtained values of TNF-α concentration were calculated for 1 mg of protein. The results are expressed as the percentage change of the concentration of TNF-α synthesized in PBMC with regard to the control cells stimulated with II-15.

[0068]The effect of Cefazolin at different concentr...

example 3

Effect of Cefazolin on IL-15 or IL-2-Induced IL-17 Synthesis in PBMC

[0070]The evaluation of IL-17 synthesis in IL-15 or IL-2-stimulated PBMC was performed using the ELISA method and commercially available tests (R&D, USA). The experiment was carried out strictly according to the manufacturer's recommendations.

[0071]PBMC were seeded in a 24-well plate (2×106 cells in 1 ml of the culture medium / well), treated with the inhibitor, after 30 min. stimulated with IL-15 (5 ng / ml) or IL-2 (5 ng / ml). After 48 h incubation, the culture medium was collected from each well to determine the IL-17 concentration, cells were harvested and lysed, and the concentration of total protein was measured in cell lysates. The obtained values of IL-17 concentration were calculated for 1 mg of protein. The results are expressed as the percentage change of the concentration of IL-17 synthesized in PBMC with regard to the control cells stimulated with 11-15 or IL-2.

[0072]The effect of Cefazolin at different conc...

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Abstract

The invention relates to 7-zminocephalosporanic acid derivative, Cefazolin, for use as the inhibitor of IL-15 and IL-2 receptors in the prevention and treatment of IL-15 and IL-2 overproduction related diseases.

Description

FIELD OF THE INVENTION[0001]The present invention relates to 7-aminocephalosporanic acid derivative for the use in the prevention and treatment of the diseases related to the overproduction of interleukin 15 and interleukin 2, such as, rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.BACKGROUND OF THE INVENTION[0002]Interleukin 15 (IL-15) is the cytokine exerting pleiotropic activity towards immune system cells as well as other cell types. IL-15 exhibits broad spectrum bioactivity, therefore it is placed at the top of the pro-inflammatory cytokines cascade. The impairment of the mechanisms regulating the expression of IL-15 results in the overproduction of this cytokine and contributes directly to the development of such pathologies as inflammatory processes, autoimmune diseases, infections and neoplastic changes. IL-15 is considered a crucial cytokine in the etiology of rheumatoid arthritis (McInnes I. B. et al., Nat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/546A61K9/00
CPCA61K9/0019A61K31/546A61P1/00A61P17/06A61P19/02A61P29/00A61P35/00A61P35/02A61P37/06
Inventor KOZIAK, KATARZYNAZYZYNSKA-GRANICA, BARBARAFILIPEK, SLAWOMIRNIEWIECZERZAL, SZYMONTRZASKOWSKI, BARTOSZZEGROCKA-STENDEL, OLIWIADUTKIEWICZ, MALGORZATAKRZECZYNSKI, PIOTRKACZMAREK, ELZBIETAWINIARSKA, MAGDALENA
Owner WARSZAWSKI UNIWERSYTET MEDYCZNY
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