Enhancing Cancer Immunotherapy with the PD-L1 and OX40 Bispecific Antibody IBI327

PD-L1, a B7 family member, is frequently expressed on tumors and can be upregulated by INF-γ, acting as a negative regulator of T cell function and suppressing anti-tumor immunity. On the other hand, OX40, a TNFR superfamily member, is primarily expressed on activated T cells and can initiate T cell activation, reinvigorate T cell effector functions, and block Treg suppressive functions. The combination of a PD-L1 blockade antibody and an OX40 activating antibody has demonstrated synergistic effects in tumor regression.

To enhance tumor growth inhibition, a bispecific antibody, IBI327, has been developed. This novel antibody fuses the PD-L1 VHH antibody at the C terminal of the OX40 antibody IgG2 Fc, potentially increasing localization to the tumor area and reducing the risk of systemic T-cell activation. The study designed IBI327 to bridge hOX40 positive cells with hPD-L1 positive cells, and it was tested in mixed lymphocyte reaction (MLR) assays and T cell activation assays. The impact of IBI327 on tumor growth was evaluated using Lovo (colon), H292 (lung), and MJ (colon) cell lines.

Results indicate that IBI327 has high affinity for both human PD-L1 and OX40, with a higher affinity for PD-L1. The bispecific antibody retains the functions of both PD-L1 and OX40 independently, bridging PD-L1-expressing tumors or DCs to T cells and activating T effector immune function. In vivo studies demonstrated significant tumor regression in a humanized model and induced more CD8 T cell infiltration.

The study concludes that the PD-L1 and OX40 bispecific antibody, IBI327, induces enhanced immune activation and improves cancer immunotherapy. It suggests that this bispecific antibody could offer a new therapeutic option for patients with PD-L1 positive or weakly positive tumors in the clinic.