Rapid Screening of Anti-OX40 Antibodies for Cancer Immunotherapy
OX40 is a co-stimulatory receptor, and it interacts with its ligand to provide positive signal for T cell activation. Disruption of the OX40 pathway led to defective T cell responses and overexpression of OX40 caused massive immune activation. Due to its importance in keeping immune homeostasis, strategies modulating the OX40 pathway hold great promise in fighting against cancer and autoimmune diseases.
We wanted to develop novel OX40 agonists that would effectively stimulate anti-tumor activity. Dozens of high-affinity candidate antibodies were generated using the classic hybridoma technology. In order to directly screen for antibodies that activate anti-tumor effects in animals, we managed to rank these antibodies in vivo using the drug screening platform based on humanized mouse models. Specifically, we used B-hOX40 mice and implanted syngeneic tumors subcutaneously, followed by treating mice with purified candidate antibodies. Via this approach, we quickly identified several lead antibodies that effectively inhibited tumor growth without prior knowledge of their in vitro activities. Their activity to stimulate T cells was confirmed by an engineered reporter line of T cell in vitro. Furthermore, we showed that one clone works in concert with Keytruda in double humanized model of h-OX40 and h-PD1.