Molecules that selectively activate regulatory t cells for the treatment of autoimmune diseases

Abstract

This invention provides for a fusion protein between an IL2αβγ Selective Agonist protein (IL2 Selective Agonist) and a IgG Fc protein using a linker. The IL2 Selective Agonist moiety provides a therapeutic activity by selectively activating the IL2αβγ form of the receptor, thus selectively stimulating Tregs. The Fc moiety provides a prolonged circulating half-life compared to the circulating half-life of IL-2 or an IL2SA protein.

Description

REFERENCE TO A SEQUENCE LISTING[0001]The Sequence Listing written in file SequenceListing_097584-000400US_ST25.txt created on May 3, 2016, 88,573 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference in its entirety for all purposes.BACKGROUND OF THE INVENTION[0002]The immune system must be able to discriminate between self and non-self. When self / non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity and consequent autoimmune disease. Developing drugs and methods to selectively activate regulatory T cells for the treatment of autoimmune disease is the subject of intense research and, until the development of the present invention, has been largely unsuccessful.[0003]Regulatory T cells (Treg) are a class of CD4+CD25+ T cells that suppress the activity of othe...

AI Technical Summary

Benefits of technology

This patent describes a fusion protein that combines an IL2αβγ Selective Agonist protein (also known as an IL2 Selective Agonist) with a IgG Fc protein. The IL2 agonist is at the N terminus of the molecule and the Fc protein is at the C terminus. The IL2 agonist part of the protein selectively activates the IL2αβγ form of the receptor, which stimulates regulatory T cells (Tregs). The Fc part of the protein increases the molecular size of the fusion protein, which results in a prolonged circulating half-life compared to IL-2 or the IL2 agonist protein. The Fc part also reduces the risk of over-stimulating other immune cells and promotes the potentiation of Tregs, which can help treat autoimmune and inflammatory diseases. The fusion protein is designed to maintain the bioactivity of the IL2 agonist and efficiently promote Tregs function and numbers.

Problems solved by technology

When self / non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases.

While this approach has shown promise in treating animal models of disease and in several early stage human clinical trials, it requires personalized treatment with the patient's own T cells, is invasive, and is technically complex.

), the recombinant form of IL-2 used in these trials, is associated with high toxicity.

Proleukin is approved for the treatment of Metastatic Melanoma and Metastatic Renal Cancer, but its side effects are so severe that its use is only recommended in a hospital setting with access to intensive care (http: / / www.proleukin.com / assets / pdf / proleukin.pdf).

However, even these lower doses resulted in safety and tolerability issues, and the treatments used have employed daily subcutaneous injections, either chronically or in intermittent 5 day treatment courses.

ife. However, construction of such fusion proteins in a manner that ensures robust biological activity of the IL2 Selective Agonist fusion partner can be unpredictable, especially in the case of an IL-2 Selective Agonist, which is a small protein that is defective in binding to one of the receptor subunits and that must assemble a complex of three receptor subunits in order to activate the receptor (Wang, X., et al., 2005, Science 310:1159

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