Background/Purpose: CGEN-15001 is a recombinant Fc fusion protein consisting of the extracellular domain of CGEN-15001T, a protein predicted to be a member of the B7/CD28 costimulatory family. CGEN-15001T was identified using a proprietary discovery platform based on shared bioinformatic characteristics with known members of this family. The immunomodulatory effect of CGEN-15001 on T cell activity and its efficacy in the murine collagen-induced arthritis (CIA) model were evaluated.

Methods: Murine naïve CD4+ T cells were activated with plate bound anti-CD3 and either CGEN-15001 or control proteins. The effect of CGEN-15001 on activation marker expression and cytokine secretion was evaluated after 48hrs of incubation, while effects on cell division and apoptosis were evaluated after 96hrs. The effect of CGEN-15001T was studied using a similar experimental system utilizing HEK-293 transfected cells expressing CGEN-15001T or empty vector.  

To study the effects of CGEN-15001 on T cell proliferation and differentiation, CD4+ T cells from DO11.10 mice were activated with OVA_323-339  plus irradiated APCs in the presence of Th driving conditions and either CGEN-15001 or control Ig. Proliferation was evaluated after 72hrs and cytokine secretion after 96hrs.

To study the effect of CGEN-15001 in the CIA model, DBA/1 mice (n=7-10/group) were immunized with type II bovine collagen in complete Freund’s adjuvant.  Mice were injected intraperitoneally with CGEN-15001, TNFR-Ig, CTLA4-Ig or Ig control at 100ug/mouse, three times/ week for 10 days. Treatment started at onset of clinical arthritis and mice were scored daily for arthritis severity. On day 10 of arthritis, mice were sacrificed and paws were removed for histological analysis.

Results: CGEN-15001 as well as stably expressed CGEN-15001T, inhibited T cell activation demonstrated by inhibition of proliferation, inflammatory cytokine secretion and expression of early activation markers. CGEN-15001 elicited its immunomodulatory activity by skewing immune response from Th1/Th17 to Th2.

In the CIA model, CGEN-15001 demonstrated potent therapeutic efficacy when administered to mice with existing disease. Treatment with CGEN-15001 resulted in significant inhibition of clinical symptoms including joint swelling, erythema, and stiffness compared to mice treated with Ig control. Histological analysis of the diseased joints showed reduced inflammation and joint erosion compared to the control.

Conclusion: These results as well as data showing long term efficacy of CGEN-15001 in murine models of multiple sclerosis, support the therapeutic potential of CGEN-15001 in the treatment of rheumatoid arthritis and other autoimmune diseases. The therapeutic use of negative co-stimulators to keep the immune system in check promises to provide an efficacious and safe approach to the treatment of autoimmune diseases.