Background/Purpose: T-cells are important in the pathogenesis of rheumatoid arthritis (RA). T-cell activation depends on at least two signals. Next to the first signal that is provided by the binding of the T-cell receptor (TCR) to a peptide bound by an MHC molecule it requires a second signal provided by one or more co-stimulatory pathways. If only the first signal is present without co-stimulation T cells become anergic. One of the most important pathways, which is of therapeutic interest is that between CD80/86 on antigen-presenting cells and CD28 on naïve T-cells. This interaction is necessary for T-cell activation. Intervention in this pathway has resulted in clinical success in the treatment of RA as demonstrated by treatment with the CD80/86 antagonist CTLA4-Ig (Abatacept). Here we present the beneficial result of treatment with a novel CD28 antagonist, which blocks CD28 instead of CD80/86, in a nonhuman primate model of inflammatory arthritis.

Methods: FR104, is a monovalent and pegylated humanized Fab’ antibody fragment directed against CD28. FR104 functions as a CD28 antagonist that prevents the interaction between CD28-CD80/86 without inhibiting the interaction with CTLA-4 and PDL-1, thereby promoting immune regulation. FR104 is a primate specific antibody and safety and efficacy was tested in a collagen-induced arthritis (CIA) model in the rhesus monkey. The rhesus CIA model is an autoimmune-mediated model of polyarthritis with inflammation and erosion of joints that shares several important cellular and histopathological features with (RA). Treatment with either Vehicle (N=5) or FR104 (N=7) started at the day of induction and continued weekly until day 42 (7 administrations)

Results: Treatment with FR104 prevented the development of clinical arthritis leading to a significant disease free survival compared to placebo treated animals. This was supported by unchanged production of cartilage breakdown products and minimal histological changes. This was associated with a suppressed production of CRP and IL-6. Treatment with FR104 also resulted in a robust suppression of collagen type II-specific proliferation and antibody (IgM/IgG) production and prevented the development of joint swelling and the subsequent destruction of cartilage and bone.

Conclusion: FR104 was well tolerated after the multiple dosing in this nonhuman primate model of arthritis. Treatment resulted in a robust suppression of collagen specific immune responses and inhibited the development clinical arthritis. In addition it prevented the development of neutralizing antibodies, a phenomenon that is regularly observed in the model with treatments targeting inflammatory cytokines like IL-6. The current study demonstrated the strong potential of CD28 as a therapeutic target of antagonist antibodies in a range of inflammatory disorders, including RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluation-of-selective-manipulation-of-the-cd28-co-stimulation-pathway-in-the-rhesus-monkey-model-of-collagen-induced-arthritis/