AACR 2020: Rapid screening of novel OX40 agonistic antibodies for cancer immunotherapy
OX40, also known as TNFRSF4 or CD134, is a member of the tumor necrosis factor receptor superfamily and is an important co-stimulator of T cell responses. OX40L expressed at high levels on activated antigen presenting cells (APCs) can result in higher order multimerization of OX40 receptors, leading to stronger activation in T cells. OX40 plays an important role in memory T cell formation. The highest levels of OX40 are found on effector and central memory CD4+ T cells and regulatory T cells (Treg). Given the duality of OX40 agonism in both stimulating effector T cell activity and suppressing Treg activity, OX40 agonists have been widely explored in the setting of cancer immunotherapy.
We hoped to develop novel OX40 agonists that can effectively inhibit tumor growth. YH002 is a recombinant, humanized IgG1 monoclonal antibody that specifically targets OX40. In vitro studies demonstrated that YH002 bound specifically and potently to human and monkey OX40 proteins. YH002 was able to dose-dependently potentiate the activation of human OX40 on reporter cells in the presence of FcγRIIB-expressing accessory cells. YH002 mediated ADCC activity in vitro. YH002 demonstrated robust anti-tumor efficacy with a bell-shaped dose response relationship against established MC38 syngeneic tumors in human OX40 transgenic mice (B-hOX40 mice) and Treg depletion were noted in tumor-infiltrating lymphocyte analysis using the same murine model. In conclusion, YH002 enhances anti-tumor activities by stimulating effector T cells and overcoming immune suppressions via suppressing or depleting regulatory T cells. Furthermore, we showed that YH002 works in concert with Pembrolizumab in double humanized model of h-OX40 and h-PD1. The combination of YH002 and ipilimumab is synergistic in double humanized model of h-OX40 and h-CTLA4. In the GLP-compliant single-dose toxicology study, the MTD of a single i.v. dose of YH002 in cynomolgus monkeys was considered to be 200 mg/kg/day. Repeated i.v. infusions of YH002 to male and female cynomolgus monkeys at 10, 30, or 90 mg/kg for 29 days (QW×5) were tolerated, the HNSTD was considered to be 90 mg/kg.