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Dual interleukin-2/TNF receptor agonists for use in therapy

An agonist, human interleukin technology, used in non-central analgesics, recombinant DNA technology, DNA/RNA fragments, etc., can solve problems such as reducing disease activity and increasing the number of Treg cells

Pending Publication Date: 2022-08-05
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Low-dose IL-2 has been clinically evaluated for the treatment of several inflammatory diseases, such as chronic graft-versus-host disease (GVHD), T1D, and SLE, and has been shown to increase Treg cell numbers while reducing disease activity

Method used

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  • Dual interleukin-2/TNF receptor agonists for use in therapy
  • Dual interleukin-2/TNF receptor agonists for use in therapy
  • Dual interleukin-2/TNF receptor agonists for use in therapy

Examples

Experimental program
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Effect test

example

[0170] The following examples (both actual and predicted) are provided to illustrate specific embodiments or features of the invention, and not to limit its scope.

example 1

[0171] Example 1 - Combined Agonism of TNFR and IL-2R Promotes Treg Cell Expansion

[0172] To determine the effects of TNFR and IL-2R stimulation, human peripheral blood mononuclear cells were labeled with cellular microviolet and treated with various TNFR agonists (anti-OX40, anti-DR3, TNF) and IL-2, and analyzed 4 days later . Cells stimulated with anti-CD3 showed robust proliferation and served as a positive control for the assay. Stimulation with IL2 or control IgG did not result in any CTV dilution. No proliferation was observed with any of the indicated TNFR agonists alone. As shown by CTV dilution, stimulation with a combination of anti-OX40 and IL2 can lead to Treg cell proliferation.

[0173] PBMCs from healthy human donors were labeled with Cell Micro Violet (Invitrogen) and cultured in x-vivo 15 medium (Lonza) according to the manufacturer's instructions. Reagents were obtained from the following sources: TNF (R&D Systems), anti-DR3 (BioLegend) and anti-OX40 (w...

example 2

[0175] Example 2 - In vivo study of combined agonism of TNFR and IL-2R to promote Treg cell expansion

[0176] C57 / Bl6 mice (n=6) were administered 1 mg / kg of murine IL-2 mutein, anti-OX40 or anti-OX40-IL2 and on day 4 (n=3) or day 15 (n=3) Spleen, lymph nodes and lungs were harvested. Examples of molecules produced in this study are Image 6 shown. Molecule #3 was used for the specific study herein. PBS-treated mice were used as controls. The effect of these treatments on the frequency of indicator cell populations was investigated. Tregs were identified as CD4+Foxp3+, activated T cells were identified as CD4+Foxp3-CD25+, activated CD8s were identified as CD8+CD44+, and NK / ILCs were identified as CD4-CD8-NK1.1+. Results are representative of two independent experiments. Data are shown as fold amplification relative to control (value set to 1).

[0177] Results are shown in Figure 7 middle. Treatment with IL2 alone resulted in the expansion of Treg cells in several t...

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Abstract

Provided herein are combinations of IL-2 molecules or muteins with TNFR agonists, as well as complexes comprising IL-2 / TNFR agonist molecules, such as Fc-binding IL-2 / TNFR agonist molecules that preferentially expand and activate regulatory T cells and are readily producible in large scale. Also provided herein are methods of making and using the compositions of the present disclosure.

Description

Background technique [0001] Regulatory T (Treg) cells, specified by the expression of the transcription factor Foxp3, are a subset of CD4 T cells specialized to suppress the activation and response of innate and adaptive immune cells. Deletion or loss-of-function mutations in the Foxp3 gene cause an early-onset autoimmune disease in both humans and mice, termed IPEX (X-linked polyendocrine enteropathy with immune dysregulation syndrome), manifesting with multiorgan involvement, and is usually fatal. The spontaneous dysregulation of different types of inflammatory responses in Foxp3-deficient animals suggests that Treg cells are required to maintain normal immune homeostasis. Several human autoimmune diseases, such as type I diabetes (T1D), multiple sclerosis (MS) and systemic lupus erythematosus (SLE), have defects in the number or suppressive function of Treg cells isolated from peripheral blood. Because Treg cells can influence immune responses in a dominant manner, active...

Claims

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Application Information

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IPC IPC(8): C07K16/24C07K14/55C07K16/28
CPCC07K16/2878C07K14/55C07K2319/75C07K2317/75A61K2039/505C07K2319/30C12N5/0637C12N2501/2302C12N2501/25A61K38/2013A61K38/191A61K39/39A61P37/04C07K14/525A61K2300/00C12N15/62A61P29/00A61P37/00A61K47/6425A61K47/642A61P37/06A61K38/00C12N15/85
Inventor A·乔德瑞W·欧阳
Owner AMGEN INC