Deciphering MEDI5752: Unleashing the Potential of Dual Targeting in Cancer Immunotherapy

Research indicates that combining PD-1 inhibitors with αCTLA-4 monoclonal antibodies can enhance clinical outcomes but also raises the risk of severe immune-related side effects. To address this, a new strategy is needed to separate the therapeutic benefits from the toxic effects. MEDI5752 is a novel bispecific antibody that targets both PD-1 and CTLA-4 with a modified Fc domain to minimize side effects. It is designed to specifically bind to these two T cell regulators, aiming to maximize anti-tumor activity while minimizing peripheral toxicity.

The study shows that MEDI5752 can effectively saturate CTLA-4 on PD-1 positive cells at much lower concentrations than on PD-1 negative cells. It also demonstrates that the monovalent targeting of CTLA-4 by MEDI5752 is less potent than bivalent targeting with traditional αCTLA-4 antibodies. However, the potency of targeting PD-1 is only moderately affected when switching from a bivalent to a monovalent approach.

MEDI5752 exhibits similar activity to a combined treatment of PD-1 and CTLA-4 antibodies in primary T cell activation assays. It is rapidly internalized upon binding to its targets, similar to the kinetics of traditional αCTLA-4 antibodies. Notably, MEDI5752's unique mechanism involves tethering CTLA-4 to PD-1, leading to the internalization and degradation of PD-1, which is a distinct advantage over the use of separate antibodies targeting these receptors.

This innovative bispecific antibody may offer a better therapeutic profile compared to the combined use of bivalent αPD-1 and αCTLA-4 antibodies, potentially providing significant benefits in various cancer treatments. The research was presented at the American Association for Cancer Research Annual Meeting in 2018.