OX40, also known as Tnfrsf4 (Tumor necrosis factor receptor superfamily, member 4), is mainly expressed on activated CD4+ and CD8+ T cells. YH002 demonstrated excellent in vivo efficacy as well as great potential for co-medication in the Biocytogen OX40 humanized mouse pharmacodynamic animal model. In preclinical studies, the combination potential of YH002 with antibodies against multiple tumor immune checkpoint targets in different animal models was extensively evaluated by a robust in vivo antibody efficacy screening evaluation model. Eucure Biopharma discovered a first-in-class combination value of YH002 with another immune checkpoint (non-PD-1/L1) antibody in animal models.
Anti-OX40 mAb is an ongoing study for treatment of multiple solid tumors as a single agent or in combination with other therapies; it is independently developed by Eucure Biopharma, and is currently under Phase I clinical study in Australia.
Mechanism of Action
OX40, also known as tumor necrosis factor receptor superfamily (TNFRSF) 4 or CD134, is a key costimulator of T cell response. OX40L is a membrane-bound trimer that further activates OX40 by causing OX40 to develop a trimer. High expression of OX40L in antigen-presenting cells promotes high aggregation of OX40 receptors, and strong mediating signals enable activation of T cells. OX40 initiates downstream signals tumor necrosis factors (TNF) (TRAF) 2 and TRAF5 to activates downstream transcription factors and kinases including NF-κB, PI3K, and AKT. Activation of these signaling pathways leads to upregulation of antiapoptotic genes and prolongation of T cell survival.
OX40 is not expressed on the inactive T cells. Upon T cell receptor involvement, OX40 is transiently expressed in CD4+ T cells and CD8+ T cells to promote proliferation and survival of effector cytokine, and prevent tolerance of T cell. In addition, OX40 plays an important role in the formation of memory T cells. OX40 is highly expressed in effector and memory T cells as well as regulatory T cells (Tregs). In addition, activation of the OX40 signaling pathway can inhibit the production and secretion of immunosuppressive cytokines. Inhibition of these immunosuppressive signals can significantly enhance anti-tumor immune responses, particularly in the tumor microenvironment.
YH002 is a recombinant human IgG1 antibody against the human OX40 receptor (TNFRSF4). Nonclinical studies have demonstrated the specificity and anti-tumor effect of YH002. YH002 has excellent immune activation and good safety for its unique antigen-binding epitope as demonstrated in PK and toxicology studies in cynomolgus monkeys. In addition, YH002 can reverse the immunosuppressive effect of intratumoral regulatory T cells (Treg cells), including directly inhibiting Tregs activation and mediating ADCC-dependent cell clearance, to further amplify the T cell activation effect for treatment of multiple tumors. YH002 demonstrated excellent in vivo efficacy as well as great potential for co-medication in the Biocytogen OX40 humanized mouse pharmacodynamic animal model.
Clinical Study for OX40
In June 2020, the first patient screening was completed for Phase I clinical study of YH002 in Australia.