Methods of Using Interleukin-10 for Treating Diseases and Disorders

Abstract

Methods of modulating immune responses in subjects having oncology- and immune-related diseases, disorders and conditions by the administration of an IL-10 agent, including pegylated IL-10.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]The present application claims priority benefit of U.S. provisional application Ser. No. 62 / 167,699, filed May 28, 2015, which application is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This invention relates to methods of using IL-10 agents to modulate immune responses in the treatment or prevention of oncology- and immune-related diseases, disorders and conditions.INTRODUCTION[0003]The cytokine interleukin-10 (IL-10) is a pleiotropic cytokine that regulates multiple immune responses through actions on T cells, B cells, macrophages, and antigen presenting cells (APC). IL-10 can suppress immune responses by inhibiting expression of IL-1α, IL-1β, IL-6, IL-8, TNF-α, GM-CSF and G-CSF in activated monocytes and activated macrophages, and it also suppresses IFN-γ production by NK cells. Although IL-10 is predominantly expressed in macrophages, expression has also been detected in activated T cells, B cells, mast...

AI Technical Summary

Benefits of technology

[0012]In certain embodiments of the present disclosure, the IL-10 agent enhances the function of activated memory CD8+ T cells. In other embodiments, the amount of the IL-10 agent administered is sufficient to enhance cytotoxic function.

[0042]In still further embodiments, the present disclosure provides methods of enhancing the function of a CAR-T T cell, comprising a) genetically engineering a T cell to express a CAR, thereby generating a CAR-T T cell; and b) modulating the CAR-T T cell with an agent (e.g., a small interfering RNA (siRNA)) that reduces the amount of at least one cytokine secreted by the CAR-T T cell. Examples of cytokines include, but are not limited to, members of the tumor necrosis factor family or the transforming growth factor beta superfamily (e.g., TGF-β). Embodiments are contemplated wherein reducing the amount of TGF-β reduces the proliferation of T regulatory cells.

Problems solved by technology

Following amplification ex vivo to a sufficient number, the autologous cells are infused back into the patient, resulting in the antigen-specific destruction of the cancer.

As discussed further hereafter, treatment with CAR-T cell therapy has, in part, been limited by both the induction of antigen-specific toxicities targeting normal tissues expressing the target-antigen, and the extreme potency of CAR-T cell treatments resulting in life-threatening cytokine-release syndromes.

In particular, it has been observed that high affinity T cell receptor interactions with significant antigen burden can lead to activation-induced cell death.

However, that steady state serum trough concentration cannot be achieved until approximately 30 days after initiation of dosing at 0.1 mg / kg / day (and also after any loading dose(s)).

Indeed, the amount of the secreted IL-10 agent necessary to achieve the aforementioned effects may be undetectable in the serum.

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