Modified IL-2 variants that selectively activate regulatory T cells for the treatment of autoimmune diseases

A technology of IL-2 and variants, applied in allergic diseases, chemical instruments and methods, carrier binding/immobilizing peptides, etc., can solve problems such as protein aggregation, inappropriateness, and protein misfolding

Active Publication Date: 2017-08-29
DELINIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Engineering new free cysteines into proteins carries the risk that the introduced new cysteines may form inappropriate intrachain disulfide bonds with other cysteines, leading to misfolding of the protein, or may Forms interchain disulfide bonds with other molecules, leading to protein aggregation

Method used

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  • Modified IL-2 variants that selectively activate regulatory T cells for the treatment of autoimmune diseases
  • Modified IL-2 variants that selectively activate regulatory T cells for the treatment of autoimmune diseases
  • Modified IL-2 variants that selectively activate regulatory T cells for the treatment of autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0088] The following examples are offered by way of illustration only and not by way of limitation. Those skilled in the art will readily recognize that various noncritical parameters can be changed or modified to produce substantially similar results.

[0089] 1. Prediction of candidate PEG attachment sites in IL-2

[0090] To select candidate sites for conjugation of PEG to IL-2, amino acid residues that were exposed to solvent and did not appear to directly or sterically interfere with IL-2 binding to IL-2Rαβγ were identified. strategy in figure 2 displayed in the diagram. Examination of the published crystal structure of IL-2 in complex with the extracellular domain of the IL-2Rαβγ receptor (Wang, X., et al., 2005, Science 310:1159-63, Stauber, D.J., et al., 2006, Proc. Natl Acad Sci 103:2788-93) identified the following residues: S6, K8, K48, K49, T51, E52, K54, K97, G98, F103, M104, E106, D109 and T133 ( image 3 ). Additional amino acid residues that were not visi...

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Abstract

The invention described herein is a novel IL-2 protein with selective agonist activity for Regulatory T cells and with an additional amino acid substitution that enable chemical conjugation with Polyethyene Glycol (PEG) that increase circulating half-life compared to the IL-2 selective agonist alone. A preferred IL-2 selective agonist variant is IL2 / N88R / C125S / D109C.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 62 / 070,016, filed August 11, 2014, the contents of which are hereby incorporated by reference. Background of the invention [0003] The immune system must be able to distinguish self from non-self. When the self / non-self distinction fails, the immune system destroys the body's cells and tissues and thus leads to autoimmune disease. Regulatory T cells actively suppress the activation of the immune system and prevent pathological autoreactivity and resulting autoimmune disease. The development of drugs and methods for selectively activating regulatory T cells for the treatment of autoimmune diseases has been the subject of intensive research and, until the development of the present invention, was largely unsuccessful. [0004] Regulatory T cells (Treg) are a class of CD4+CD25+ T cells that suppress the activity of other immune cells. Tregs are ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20C07K14/55C07K17/08
CPCA61K38/00A61K38/2013A61K47/60A61P37/06A61P43/00C07K14/55
Inventor 杰弗里·格雷夫
Owner DELINIA
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