Background/Purpose: OX40 (TNFRSF4, CD134) is a costimulatory receptor member of the NGFR/TNFR superfamily expressed predominantly on activated T lymphocytes. Ligation of OX40 by its ligand OX40L (TNFSF4, CD252) leads to enhanced T cell survival, proliferation, and effector function. Blocking the OX40/OX40L pathway is therefore highly attractive to treat a broad range of T cell-mediated autoimmune diseases. While several OX40 agonist antibodies are in clinical development for cancer, generation of a true OX40 antagonist is challenging. The studies presented herein characterize the preclinical profile, mechanism of action, and immunomodulatory capabilities of GBR 830.

Methods: T cell proliferation assay (inhibition or agonism); NFκB reporter cell assay; xenogeneic human graft versus host disease model in SCID mice; cynomolgus monkey T cell‑dependent antigen response (T-DAR) model; and in vitro antigen reactivation model.

Results: GBR 830, a humanized IgG1 anti-OX40 antibody, recognizes the cysteine-rich domain 2 of OX40 that overlaps the binding region to OX40L. Consequently, GBR 830 blocks the binding of OX40L to OX40 and inhibits OX40L-mediated inhibition of T cell proliferation and NFκB signaling. In contrast to all other anti-OX40 antibodies tested, GBR 830 did not reveal any residual agonism even in a sensitive experimental setup. In a xenogeneic graft versus host disease model using immunodeficient mice reconstituted with human peripheral blood mononuclear cells, GBR 830 suppressed T helper cell-mediated responses. In a cynomolgus monkey T-DAR model to keyhole limpet hemocyanin, GBR 830 demonstrated a profound inhibitory effect on memory response but not on primary antibody response. In vitro vaccine (tetanus toxoid) or autoantigen reactivation assays showed that GBR 830 can inhibit memory T cell reactivation.

Conclusion: Overall, these data suggest that GBR 830 has immunomodulatory capabilities in T helper cell-mediated responses, applicable to a broad range of autoimmune pathologies. Accordingly, GBR 830 demonstrated positive results in a phase 2a clinical study in patients with moderate-to-severe atopic dermatitis (NCT02683928) and has the potential to address unmet medical needs in autoimmune and inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gbr830-a-true-ox40-antagonist-antibody-with-potent-suppressive-effects-on-t-cell-mediated-pathological-responses/