MDNA11—An Immune Activation Switch
MDNA11, our second lead candidate, is a long-acting IL-2 Superkine that has been fused with human recombinant albumin, which increases its half-life and minimizes dosing requirements without sacrificing efficacy and safety.
This Superkine has been designed to preferentially bind the IL-2 beta receptor (IL-2Rβ) on immune cells and to become a powerful switch for activating and proliferating the immune cells needed to fight cancer. It is being developed specifically as a therapeutic for various solid tumors, potentially in combination with other immunotherapies.
Basics of MDNA11
MDNA11 has the ability to preferentially stimulate cancer-fighting NK cells and naive CD8 cells instead of immuno-suppressive regulatory T cells, by 80 and 200 fold, respectively, when compared to native IL-2. It does so by specifically binding to IL-2Rβ. and begins a cascade of events that overcomes the immune-suppressing effects of cancer and activates the cancer-killing immune cells – including cytotoxic T cells, naive T cells, and natural killer cells.
In preclinical studies, MDNA11 has shown synergy with checkpoint inhibitors, demonstrating the additional potential for combination therapies. a 200 fold higher affinity for IL-2Rβ over natural IL-2. It specifically binds IL-2Rβ and begins a cascade of events that overcomes the immune-suppressing effects of cancer and activates the cancer-killing immune cells – including cytotoxic T cells, naive T cells, and natural killer cells.
Importance of IL-2Rβ
IL-2 was one of the first immunotherapies developed against cancer because of its ability to drive the generation of activated immune cells, immune memory cells and immune tolerance. However, overstimulating immune cells with IL-2 can imbalance the ratio of pathogen killing effector T cells to immune suppressing regulatory T cells. Part of the reason for this is the nature of the IL-2 receptor, which is composed of three subunits – IL-2Rα, IL-2Rβ and IL-2Rγ.
The arrangement of these subunits in a receptor determines the response to IL-2 signaling. When all three components are together, the receptor binds IL-2 with a much higher affinity. This three-piece receptor is usually found on regulatory T cells, which suppress an ongoing immune response. A different form of the receptor, made up of just the β and γ subunits, exists on naive T cells and NK cells, which are awaiting an IL-2 signal to begin seeking out cancer.
MDNA11 was engineered to possess an increased affinity for the receptor variant that includes IL-2Rβ, but not IL-2Rα. In doing so, it only activates immune responses that attack cancer over those that turn the immune system off.