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Immunomodulating polypeptides derived from IL-2 and use thereof in cancer and chronic infections

一种IL-2、免疫调节的技术，应用在免疫学领域

Active Publication Date: 2012-09-12
CENT DE INMUNOLOGIA MOLECULAR CENT DE INMUNOLO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to the best of our knowledge, there are no reports of such IL-2 mutants in the literature: supporting the possibility that they could be used to selectively or preferentially regulate the activity of regulatory T cells

Method used

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  • Immunomodulating polypeptides derived from IL-2 and use thereof in cancer and chronic infections
  • Immunomodulating polypeptides derived from IL-2 and use thereof in cancer and chronic infections
  • Immunomodulating polypeptides derived from IL-2 and use thereof in cancer and chronic infections

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Using Wang, X., Rickert, M. and Garcia, K.C. in Structure of the quaternary complex of interleukin-2 with it salpha, beta, and gamma receptors.Science, 2005.310(5751):p.1159-63 reported Using the quaternary structure of the complex of human IL-2 coupled to the receptor as a basis, and the energy calculation algorithms for protein-ligand interactions in the public domain, mutants were designed in silico by bioinformatics techniques. It was initially predicted that different variants of the mutein would not affect the ability to bind to the alpha and beta chains of the receptor. These muteins were expressed in E. coli from a genetic construct of the pET28a vector, which includes the identified sequence of six histidines at the amino terminus. Use invert ( figure 1 ) to purify the mutant protein to high purity (>95%). The muteins obtained were selected according to their properties in vitro. Among the constructed muteins shown in Table 1, a set of specific mutations wit...

Embodiment 2

[0044] Selected muteins retain the ability to bind to different components of the IL2 receptor, particularly the alpha and beta chains of the receptor. figure 2 Show: use ELISA test, several mutants shown in table 1 keep intact with the α chain of IL-2 human receptor substantially (see figure 2 ) and β chain ( figure 2 b) Ability to bind. image 3 showed further confirmation of the binding of these mutants to receptors on the cell surface (see image 3 a), and this binding can be gradually replaced by the addition of native IL-2 ( image 3 b).

Embodiment 3

[0046] The ability of selected muteins to signal through the IL-2 receptor is significantly reduced. image 3 CTLL2 cell lines were stimulated to grow by measuring their growth from total splenic lymphocytes ( Figure 4 a) or stimulate NK cell differentiation from total splenic lymphocytes ( Figure 4 b) proves this. At high concentrations, these muteins inhibit ( Figure 5 a) and on NK cells ( Figure 5 b) Activity of native IL-2.

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Abstract

The invention relates in general to polypeptides having a primary sequence that is highly homologous with the sequence of human interleukin-2 (IL-2) with some punctual mutations in the sequence of native IL-2. The polypeptides of the invention have an immunomodulating effect on the immune system, which is selective / preferential in relation to regulatory T cells. The invention also relates to specific polypeptides of which the amino acid sequence is disclosed in the present invention. The invention further relates to pharmaceutical compositions containing the disclosed polypeptides as an active principle. Finally, the invention relates to the therapeutic use of said polypeptides and pharmaceutical compositions, given the immune-system-modulating effect thereof on pathologies such as cancer and chronic infectious diseases.

Description

technical field [0001] The present invention relates to the field of biotechnology, especially immunology. The present invention relates to technical solutions with therapeutic applications for human health. The invention particularly relates to the therapeutic modulation of the immune system using analogs of natural molecules. Background technique [0002] Interleukin 2 (IL-2) was the first growth factor described for T cells. Since its discovery, it has shown a strong ability to promote T cell proliferation and survival in vitro (Smith, KA (1988) Science.240, 1169-76) and enhance T cell immune response in vivo under the condition of virus infection. capacity (Blattman, JN, et al. (2003) Nat Med 9, 540-7) or in the case of vaccines (Fishman, M., et al. (2008) J Immunother. 31, 72-80, Kudo- Saito, C., et al. (2007) Cancer Immunol Immunother. 56, 1897-910; Lin, CT, et al. (2007) Immunol Lett. 114, 86-93). Recently, however, multiple experimental data have questioned this ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20C07K14/55
CPCA61K38/00C07K14/55C07K2319/30C07K2319/31A61P31/00A61P35/00A61P37/00A61P37/02A61P37/04A61K38/20
Inventor K·里昂蒙松T·卡尔梅纳特波蒂利亚K·加西亚马丁内斯A·B·拉赫戴维拉S·佩雷斯罗德里格斯D·冈萨雷斯罗切G·马克斯佩雷拉
Owner CENT DE INMUNOLOGIA MOLECULAR CENT DE INMUNOLO
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