Induction of immune tolerance by CGEN-15001, a novel immunomodulatory Fc fusion protein of the B7 family (THER5P.823)
2014
We discovered a novel immune checkpoint protein based on characteristics of the B7/CD28 family. CGEN-15001 is a fusion protein composed of the extracellular domain of this protein fused to IgG Fc. CGEN-15001 inhibits T cell activation, demonstrates immunomodulation by inhibiting pro-inflammatory Th1 and Th17 responses while promoting anti-inflammatory IL-10 and Th2 responses, and enhances iTreg differentiation. CGEN-15001 is efficacious in animal models of autoimmunity such as multiple sclerosis (MS), rheumatoid arthritis, type1 diabetes (T1D) and psoriasis. In the EAE model of MS and in the NOD model of T1D, short 2-week treatment with CGEN-15001 resulted in long term inhibition of disease. In the T1D model, mice treated with CGEN-15001 retained normal blood glucose levels18 weeks after cessation of treatment. To further study tolerance induction, the H-Y minor Ag mismatch bone marrow transplantation model was used. CGEN-15001 treatment resulted in graft survival and increase in Tregs, indicating donor specific tolerance induction. The prolonged therapeutic responses in models of autoimmunity and the prevention of graft rejection, imply establishment of immune tolerance by CGEN-15001. Taken together, the mode of action of CGEN-15001 that combines inhibition of autoreactive cells, immunomodulation and restoration of immune tolerance, suggests it should provide long standing and safe therapy for autoimmune diseases.
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