Built with Precision
Given the complexity of the immune system, elimination or modulation of effector cytotoxic T or NK cells to treat a range of diseases requires precise targeting of the specific immune cell type driving the pathology. If other protective immune cell types, such as regulatory T cells, are unintentionally impacted by a drug,efficacy can be limited, and safety compromised. Therefore, in a range of autoimmune and oncology indications, highly precise targeting of effector cytotoxic T and NK cells can improve treatment-limiting safety concerns and maximize the potential for efficacy.
Targeting KLRG1+ Cytotoxic T Cells for Autoimmunity and Immuno-oncology
In autoimmune disease tissues, KLRG1 expression is restricted to pathogenic, late-differentiated effector memory (TEM) and effector (TEMRA) T cells that are highly cytotoxic. In the tumor microenvironment of cancer, these T cells, as well as some natural killer (NK) cells, have potential cytotoxicity that is being inhibited by tumor expression of E- and N-cadherin. The ability to precisely target effector cytotoxic T and NK cells while avoiding engagement of other immune cell type allows:
- Highly selective depletion of the specific pathogenic cell population driving autoimmune disease
- Unleashing of anti-tumor T and NK cells in the tumor microenvironment
Targeting KLRG1+ Cells is Different from Existing T Cell Targeting Approaches
- Tissue damaging effector cytotoxic T cells express KLRG1, but tissue protective regulatory T cells and infection protective long-term central memory T cells do not express KLRG1
- For cytotoxic T cell driven autoimmune disease therapeutic approaches, targeting KLRG1 is advantageous over other T cell depletion targets such as CD25, CD2, CD52 and ICOS because these targets are expressed on helpful regulatory T cells and central memory T cells
- For cancer therapeutic approaches involving immune cell activation via checkpoint receptors (i.e., immuno-oncology), KLRG1 targeting activates the most potent cytotoxic T and NK cells, while CTLA-4 and PD-1 targeting does not activate these cells
The Role of KLRG1+ T cells in Inclusion Body Myositis (IBM)
IBM is an autoimmune disease characterized by T cell infiltration and attack of muscle fibers. A chronic disease with no therapeutic options, the long-term effect of this autoimmune disease is loss of hand function and ability to walk, difficulty swallowing, and a significant impact on quality of life. Based on gene expression data, muscle biopsies and blood samples, this study identified a significant increase in the percentage of KLRG1+ CD8 T cells in IBM muscle biopsies as opposed to other muscle diseases. It also highlighted the favorable safety expectations of targeting KLRG1, demonstrating its absence from helpful regulatory T cells and lymph node central memory T cells.
KLRG1: Human Cancer Expression and Efficacy of Neutralization in Murine Cancer Models
This study reported on translational studies of human KLRG1 expression and the in vivo activity of an anti-mouse KLRG1 neutralizing antibody in murine cancer models. Results provided the first evidence that inhibition of the KLRG1 pathway enhances immune control of cancer in murine models and provided target validation for KLRG1 targeting of human cancer.