Background/Purpose:

CGEN-15001 is an Fc fusion protein composed of the extracellular domain of a novel B7-like protein. Therapeutic CGEN-15001 treatment is effective in collagen induced arthritis and potentially re-establishes immune tolerance. This is supported by long lasting efficacy in autoimmune disease models, and by establishment of tolerance to donor graft in a bone marrow transplantation model. CGEN-15001 inhibits T cell activation and induces Th1/Th17 to Th2 shift, IL-10 secretion and regulatory T cell (Treg) differentiation.

As Tregs have key role in tolerance, their involvement in the effects of CGEN-15001 was studied in the EAE (experimental autoimmune encephalomyelitis) model of multiple sclerosis by blocking IL-10 or TGFβ which play critical roles in Treg differentiation, or upon transient Treg inactivation by anti-CD25.

The therapeutic potential of CGEN-15001 for RA was studied in co-cultures of cytokine activated T cells (TcK) and macrophages (Mϕ) from RA patients and healthy donors. Such co-cultures mimic the interaction of cells in RA synovium that lead to aberrant cytokine production and provide a translational tool to evaluate potential therapies.

Methods:

CD4+ T cells and monocytes were isolated from healthy donors or RA patients’ blood and cultured for 6 days with TNFα, IL-6 and IL-15 to induce TcK or with M-CSF to induce Mϕ differentiation, respectively. Autologous TcK and Mϕ were co-cultured in the presence of CGEN-15001 or controls for 24hrs. Cytokines were evaluated by luminex.

EAE was induced in SJL mice primed with PLP_139-151in CFA. Mice were treated from onset of remission, 3 times/week for 2 weeks. Anti-IL-10 or anti-TGFβ were injected concomitantly with CGEN-15001. Alternatively, 2 injections of anti-CD25 were given 2 days before treatment with CGEN-15001 or 2 weeks after last treatment. Disease severity was followed.

Results:

In synovial-like Mϕ: TcK co-cultures, CGEN-15001 abrogated secretion of pro-inflammatory cytokines including TNFα, IL-17, IFNγ, GM-CSF, RANTES and MIP-1α. Similarly, inhibition in TNFα secretion was observed in co-cultures from RA patients’ cells.

In EAE, durable remission was induced by a short course of therapeutic treatment. This effect was abrogated by concomitant treatment with anti-TGFb or anti-IL-10, demonstrating a central role for Treg supporting pathways in the therapeutic effects of CGEN-15001. Transient inactivation of Tregs by anti-CD25 before CGEN-15001 treatment did not affect the durable remission achieved by CGEN-15001, however, administration of anti-CD25 2 weeks after the last treatment resulted in transient disease relapse, suggesting that Treg functionality is crucial for the durable effects of CGEN-15001, while at early stages Th1/Th17 to Th2 skew may control the disease.

Conclusion:

The anti-inflammatory activity of CGEN-15001 in a translational assay mimicking RA synovium supports its therapeutic potential in RA. The long remission maintained by active Tregs in the EAE model supports a novel mechanism of re-establishing tolerance to autoantigens. Therefore, these results support the therapeutic potential of CGEN-15001 to reduce inflammation and maintain long-term remission in autoimmune diseases and RA in particular.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cgen-15001-a-novel-b7-like-protein-controls-inflammation-in-a-translational-rheumatoid-arthritis-ra-assay-and-induces-treg-driven-long-term-remission-in-an-autoimmune-disease-model/