Addressing an important driver of autoimmunity with selective targeting
Eliminating highly cytotoxic T cells would offer the potential to treat a range of autoimmune disorders. Broad, non-selective T cell-depleting therapies have shown clinical benefit in many autoimmune diseases, such as multiple sclerosis and psoriasis, but their use has been limited by the adverse effects associated with broad immune-cell depletion.
By targeting the specific immune cell population expressing KLRG1, ABC008 is designed to enable selective targeting of highly cytotoxic T cells while sparing key lymphocyte populations, including naïve, memory and regulatory T cells which are required to maintain normal immune system homeostasis.
Highly cytotoxic T cells are implicated in multiple autoimmune disorders
Highly cytotoxic T cells directed against self-antigens are an important cause of tissue damage in a number of autoimmune disorders. These highly cytotoxic T cells invade target tissues and cause cell death in disease-relevant tissues. Their contribution to disease pathology has been recognized in the literature for many diseases.
Broad, non-specific depletion of all T cells has demonstrated strong efficacy in multiple sclerosis (alemtuzumab, daclizumab), but the use of broadly depleting therapies has been limited due to safety challenges resulting from their broad immune-cell depletion profiles.
In autoimmune disease, we believe the ability to selectively target these KLRG1+ T cells could provide a number of important clinical benefits including:
- Depletion of the most mature, highly cytotoxic T cell populations that drive disease; and
- Sparing of cells that do not express KLRG1 including naïve and central memory T cells that allow the body the ability to continue to fight infections and regulatory T cells that fight and protect against autoimmunity.
In cancer, T cells and NK cells, which are important for anti-tumor activity, are often inhibited by tumors that express proteins that bind co-inhibitory receptors such as KLRG1. The ability to selectively interrupt the interaction of KLRG1 on T and NK cells with immunosuppressive ligands expressed by cancer cells, could potentially activate the most mature, highly cytotoxic T and NK cells to trigger natural anti-tumor activity.
Highly cytotoxic T cells
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