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Abstract Number: 133

GBR830, a True OX40 Antagonist Antibody with Potent Suppressive Effects on T Cell-Mediated Pathological Responses

Julie Macoin1, Stanislas Blein1, Thierry Monney1, Pavankumar Sancheti2, Venkateshwar Reddy3 and Jonathan Back1, 1Glenmark Pharmaceuticals SA, La Chaux-de-Fonds, Switzerland, 2Glenmark Pharmaceuticals Ltd, Mumbai, India, 3Glenmark Pharmaceuticals SA, Paramus, NJ

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: autoimmune diseases and inflammation, T cells

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Session Information

Date: Sunday, October 21, 2018

Session Title: T Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

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.


Disclosure: J. Macoin, Glenmark Pharmaceuticals SA, 3; S. Blein, Glenmark Pharmaceuticals SA, 3; T. Monney, Glenmark Pharmaceuticals SA, 3; P. Sancheti, Glenmark Pharmaceuticals Ltd, 3; V. Reddy, Glenmark Pharmaceuticals SA, 3; J. Back, Glenmark Pharmaceuticals SA, 3.

To cite this abstract in AMA style:

Macoin J, Blein S, Monney T, Sancheti P, Reddy V, Back J. GBR830, a True OX40 Antagonist Antibody with Potent Suppressive Effects on T Cell-Mediated Pathological Responses [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/gbr830-a-true-ox40-antagonist-antibody-with-potent-suppressive-effects-on-t-cell-mediated-pathological-responses/. Accessed April 13, 2021.
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