1099 GBR 830: An OX40 antagonist antibody with a favorable toxicity profile in non-human primates

OX40 is a costimulatory receptor member of the NGFR/TNFR superfamily expressed predominantly on activated T cells. Ligation of OX40 by its ligand OX40L leads to enhanced T cell survival, proliferation, and effector functions. 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 under development in oncology, generating an OX40 antagonist devoid of agonist activity remains a challenge. GBR 830 is a humanized IgG1 targeting OX40 with a monovalent affinity for human OX40 (∼90 nM as measured by surface plasmon resonance) and cross-reactivity to macaque OX40 albeit with a lower affinity. However, its apparent affinity drastically increases when GBR 830 binds bivalently. GBR 830 blocks OX40L binding and inhibits OX40L-mediated T cell proliferation at a low nM concentration. It also mediates low levels of antibody dependent cellular cytotoxicity and complement dependent cytotoxicity. Importantly, GBR 830 was evaluated for residual agonism by assessing its costimulatory effect on the proliferation of purified T cells from multiple donors. Compared to OX40L or anti-CD28 positive controls, GBR 830 did not stimulate T cells with or without addition of a crosslinking antibody. In a more sensitive experimental setup in which anti-OX40 antibodies were co-coated with an anti-CD3 antibody, no agonism was detected with GBR 830, whereas all other anti-OX40 antibodies tested showed agonism. When administered to cynomolgus monkeys in the repeat-dose intravenous/subcutaneous toxicity studies (6-weeks or 6-months duration), GBR 830 was well tolerated without any adverse findings. The no-observed-adverse-effect-level was 100 mg/kg/week. These data show that GBR 830 is able to block OX40L-induced proliferation without inducing receptor agonism, in contrast to other anti-OX40 antibodies.