Regulatory B cells (tBREGS) and their use

Inventors

Arya, Bira • Olkhanud, Purevdorj B. • Bodogai, Monica

Assignees

US Department of Health and Human Services

Abstract

Regulatory B cells (tBreg) are disclosed herein. These regulatory B cells express CD25 (CD25+) a pan B cell marker such as B220 (B220+), and also express CD19 (CD19+). These regulatory B cells suppress resting and activated T cells in cell contact-dependent manner. Methods for generating these regulatory B cells are also disclosed herein, as are methods for using these regulatory B cells to produce regulatory T cells (Treg). In some embodiments, methods for treating an immune-mediated disorder, such as an autoimmune disease, transplant rejection, graft-versus-host disease or inflammation, are disclosed. These methods include increasing regulatory B cell number or activity and/or by administering autologous regulatory B cells. Methods for treating cancer are also disclosed herein. These methods include decreasing regulatory B cell activity and/or number.

Core Innovation

Regulatory B cells (tBreg) are disclosed herein that express CD25 (CD25+) and CD19 (CD19+), and can also express pan B cell markers such as B220 (B220+). These tBreg cells suppress resting and activated T cells in a cell contact-dependent manner, and in some embodiments, also in a contact-independent manner. The tBreg cells can express additional surface markers including CD40, CD69, CD80, CD86, BAFF-R, CCR6, CXCR5, MHC class I and II molecules, TSLPR, Fas, FasL, and PD-1, while not expressing CD5 and/or CD27. They can also express phosphorylated STAT3 and demonstrate a phenotype such as pStat3+CD25HighB7-H1HighCD86HighCCR6High and CD62LLowIgMInt/Low B cells. Methods for generating these regulatory B cells, including by culturing B cells in tumor-conditioned media, are disclosed. The tBreg cells are capable of inducing the generation of FoxP3+ regulatory T cells (Tregs) from CD8+ and/or CD4+ T cells.

The problem being addressed is that while regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are known to play roles in cancer immune escape and in suppressing immune responses, the contribution of other regulatory immune cells, especially certain B cell populations, was not well-defined. There was a need to identify other regulatory immune cells such as tBregs and to use these cells for the treatment of immune-mediated disease. Additionally, there was a need for methods to inhibit regulatory immune cells that suppress immune-mediated therapy, including cancer treatments.

The invention also includes methods for treating immune-mediated disorders such as autoimmune diseases, transplant rejection, graft-versus-host disease, or inflammation by increasing regulatory B cell number or activity and/or administering autologous regulatory B cells. Conversely, methods for treating cancer include decreasing regulatory B cell activity and/or number, for example through administration of antibodies targeting CD25 or CD19 expressed on the tBregs. It also provides methods for monitoring the efficacy of therapy by measuring tBreg cell number or activity in biological samples.

Claims Coverage

This patent includes one independent claim detailing a method of producing regulatory T cells using a defined population of regulatory B cells with specific phenotypic characteristics.

The claims cover methods for producing regulatory T cells using a specific subset of regulatory B cells characterized by CD25High-CD19+ expression and other selective markers, their phenotypic features including phosphorylated STAT3, and their use in the context of immune-mediated disorders.

Stated Advantages

Documented Applications