Unlocking the Potential of MEDI7526: Enhancing Tumor Immunotherapy through CD40 Pathway Activation and PD-L1 Inhibition

Stimulation of the CD40 receptor on antigen-presenting cells (APCs) has been shown to enhance the activation of CD8+ cytotoxic T cells, and CD40 agonistic antibodies have displayed anti-tumor potential in early clinical studies. Nonetheless, this stimulation can also result in an increase in PD-L1 levels on APCs, which may counteract the immune response against tumors. The combination of PD-L1 blocking agents with CD40 agonists is theorized to produce a more potent anti-tumor effect than CD40 agonists alone.

A new bispecific antibody, MEDI7526, has been developed. It is comprised of an anti-PD-L1 antibody, two forms of a CD40 ligand fusion protein, and a human IgG4 Fc domain. MEDI7526 is engineered to activate the CD40 pathway while inhibiting PD-L1, which is intended to boost T cell activation and address the limitations of traditional CD40 agonists.

The in vitro analysis of MEDI7526 included flow cytometry and cell-based assays to examine its binding properties and functional activity. The antibody's internalization along with that of CD40 and PD-L1 was studied using flow cytometry and immunofluorescence microscopy. The impact of MEDI7526 on cytokine production by human peripheral blood mononuclear cells (PBMCs) was assessed using a multiplex assay. Its anti-tumor efficacy was evaluated using a murine model of MEDI7526 in a B16F10 syngeneic tumor model.

The results confirmed that MEDI7526 is capable of binding to both CD40 and PD-L1 at the same time. It induced a strong activation of CD40 signaling and led to rapid internalization of CD40. Notably, MEDI7526 also caused a swift and significant reduction in PD-L1 levels on the surface of various CD40-expressing cells, including specific cell lines and human monocytes. This effect was not observed with treatments using either anti-PD-L1 antibodies or CD40L fusion protein alone. Prolonged exposure to MEDI7526 resulted in a sustained decrease in PD-L1 expression for several days. MEDI7526 also induced a robust production of interferon-gamma (IFNγ) in antigen recall assays, and the murine version of MEDI7526 effectively reduced tumor growth in the B16F10 model.

These findings suggest that MEDI7526 not only promotes the internalization and degradation of PD-L1 but also shows potent in vitro and in vivo activity. The creation of this innovative bispecific molecule combines two distinct mechanisms of action that differ from the parent compounds. MEDI7526, by simultaneously activating the CD40 pathway and reducing PD-L1 expression, presents itself as a promising new therapeutic strategy for cancer treatment.

The study was presented by Yaya Wang et al. at the Annual Meeting of the American Association for Cancer Research in 2020.