Background/Purpose CGEN-15001 is an Fc-fusion protein consisting of the extracellular domain of a novel B7-like protein, discovered based on shared family characteristics. CGEN-15001 inhibits T cell activation and demonstrates immunomodulatory activity by inhibiting Th1 and Th17 responses while promoting Th2 responses and IL-10 secretion. Potential re-establishment of immune tolerance by CGEN-15001 is suggested by durable long term efficacy observed following short course therapeutic treatment in the EAE model of multiple sclerosis and in the NOD mouse model of type 1 diabetes. Tolerance induction is further supported by prevention of graft rejection in the H-Y minor Ag mismatch bone marrow transplantation model and by enhancement of Tregs. CGEN-15001 is also efficacious in a CIA model of rheumatoid arthritis (RA) and we sought to further study its mode of action in this model. Furthermore, the efficacy of CGEN-15001 was tested in a humanized psoriasis mouse model to elucidate its therapeutic potential for this disease.  

Methods CIA was induced by immunizing DBA/1 mice with type II collagen (CII) in CFA. Efficacy was evaluated following therapeutic treatment starting at onset of arthritis symptoms. On day 10 of arthritis paws and sera were collected for analysis. For mode of action studies, treatment was given from the day of disease induction, and ex-vivorecall responses were tested on draining lymph nodes (dLN) cells harvested on day 10 and re-stimulated with CII or anti-CD3. Proliferation and cytokine secretion were evaluated.

Psoriasis was induced in normal human skin grafted onto SCID mice by intradermal injection of activated PBMCs from psoriatic patients. Treatment began at time of disease induction.

Results

CGEN-15001 demonstrated a potent therapeutic effect in the CIA model with significant reduction of clinical score and joint swelling. Reduced inflammation and joint erosion were observed by histological analysis of the arthritic joints. In addition, CGEN-15001 treatment resulted in increase of the CII-specific IgG1/IgG2a ratio in the serum, which is in line with a Th1/Th17 to Th2 shift observed previously in vitro and in vivo.

Recall responses of dLN cells from CGEN-15001 treated mice results in inhibition of proliferation and secretion of IL-17 and GM-CSF in cultures reactivated with the inducing antigen, CII.

In the psoriasis model, CGEN-15001 treatment resulted in prevention of psoriasiform features in 55% of grafts, and in significant reduction in epidermal thickness. In addition, decrease in hallmark pathologic and inflammatory features of psoriatic skin were shown by IHC.

Conclusion The therapeutic effect of CGEN-15001 in the CIA model of RA and in the humanized mouse model of psoriasis support its therapeutic potential for these diseases. These findings might also indicate a potential clinical value for psoriatic arthritis, a disease which combines both skin and joint pathologies and is underserved by current therapies. Its effect on key pathologic mechanisms of these and other autoimmune diseases, including downregulation of Th1 and Th17 inflammatory responses, induction of regulatory T cells and restoration of immune tolerance suggest a broad therapeutic potential with durable long-term effect.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cgen-15001-a-novel-immunomodulatory-fusion-protein-of-the-b7-family-induces-immune-tolerance-and-shows-efficacy-in-mouse-models-of-rheumatoid-arthritis-and-psoriasis/