Application of TABO8 for the treatment of rheumatoid arthritis (RA)
RA is an autoimmune disease characterized by a chronic CD4+ T-cell response that has escaped normal control mechanisms.Activated CD4+ T-cells play a central role in the disease process by mechanisms that include stimulation of pro-inflammatory cytokines.
T-cell responses to self-antigens and foreign antigens are tightly controlled by immune system. Dysfunction of mechanisms controlling T-cells or of ‘immune tolerance’ is thus considered to be of critical importance in the development of autoimmune diseases.
Accumulating scientific data demonstrate that regulatory T-cells (Treg), a subpopulation of CD4+ T-cells, play an important role in dampening the immune response. Treg cells appear to suppress the action of other T-cell subsets by a number of mechanisms. Suppression by Treg is thought to involve the anti-inflammatory cytokines IL 10 and transforming growth factor beta (TGF-β). Reduced expression of both molecules as well as decreased proliferation of the regulatory CD4+ T-cell subsets producing IL-10 has been demonstrated in RA patients. Thus strategy for the treatment of RA is to maintain T-cell homeostasis mediated via expansion of regulatory T-cells.
The goal of TheraMAB is to achieve well-tolerated and effective control of autoimmunity by activation and expansion of functional regulatory T-cells, by control of “pathogenic” T-cells, and by induction of anti-inflammatory cytokines.
It could be demonstrated in a number of in-vivo experiments that superagonistic anti-CD28 antibodies orthologous to TAB08 have anti-inflammatory properties. TAB08 orthologues were effective in the prophylaxis and/or treatment of RA in relevant animal models for the disease, e.g. the rat adjuvant arthritis model or the rhesus monkey collagen-induced arthritis model.
Indeed, JJ316 (rat ortholog of TAB08) efficiently inhibited arthritis-related clinical symptoms in the treated animals. Moreover, it could be shown that antibody were sufficient to substantially reduce the arthritis score as compared to control animals. As expected, histopathology data revealed protection of joint destruction exclusively in treated animals. The prophylactic effect of an IgG1 variant of TAB08 was evaluated in a non-human primate model of collagen-induced arthritis which shares relevant features with human RA. All monkeys tolerated the antibody injections well without any overt side-effects. Prophylactic treatment of animals with antibody resulted in a delayed onset and improvement of clinical symptoms of arthritis in four out of six animals. In agreement with these clinical results, increase in acute phase serum proteins and bone/ cartilage degradation products were reduced in treated animals. Prophylactic and curative effects of TAB08 in all in-vivo models were mediated by expansion and activation of regulatory T-cells.
Thus, TAB08, its orthologues and variants exhibit pronounced protection in animal models for RA whereby it affects T-cells involved in the disease pathogenesis. Treg cellshave great potential for immunotherapy since they control secretion of anti-inflammatory cytokines and regulate other protective mechanisms involved in the pathogenesis of RA. Considering unique mechanism of action of TAB08 in the cascade process of RA, TAB08 offers an exciting opportunity for the effective treatment of rheumatoid arthritis compared to other drugs and represent perspective approach for treatment of the diseasein patients unresponsive to standard therapy.