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.
AUTOIMMUNE DISEASE
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.
CANCER
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.
REFERENCES:
Highly cytotoxic T cells
- Jilek et al., CSF enrichment of highly differentiated CD8+ T cells in early multiple sclerosis, Clin Immunol 2007 Apr;123(1):105-13
- Kronenberg et al., Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill β-cells, Diabetes 2012 Jul;61(7):1752-9
- Dolff et al., Urinary T cells in active lupus nephritis show an effector memory phenotype, Ann Rheum Dis 2010 Nov;69(11):2034-41
- Coles et al., Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial, Lancet 2012 Nov 24;380(9856):1829-39
- Gold et al., Long-term safety and efficacy of daclizumab beta in relapsing-remitting multiple sclerosis: 6-year results from the SELECTED open-label extension study, J Neurol 2020 Oct;267(10):2851-2864
- Dalakas et al., Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis, Brain 2009 Jun;132(Pt 6):1536-44
KLRG1
- Goyal et al., Immunophenotyping of Inclusion Body Myositis Blood T and NK Cells, Neurology 2022 Mar 29;98(13):e1374-e1383, ACR 2020 Poster
- Knauss et al., PD1 pathway in immune-mediated myopathies: Pathogenesis of dysfunctional T cells revisited, Neurol Neuroimmunol Neuroinflamm 2019 Apr 10;6(3):e558
- Akbar & Henson, Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?, Nat Rev Immunol 2011 Apr;11(4):289-95
