A New Cancer Therapy based on Superantagonist Interleukin 15

Interleukin 15 (IL-15) is a major target for cancer therapies.

A new drug SO-C101 has been able to overcome and lower the challenges presented by IL-15 and IL-2 targeted therapies. Expression of the cytokine produced by IL-15 within human tumors is an essential criteria for successful antitumor immune responses. This is because IL-15 signalling is known to activate cytotoxic CD8+ T cells and natural killer (NK) cells. Stimulation of IL-15 receptor on CD8+ T cells causes a potent immune response that compliments a number of existing therapies including PD-1

IL-2 signal targeting has acted as proof-of-concept for IL-15 targeting. This is because they both posses common subunits and functions. IL-2 is known to activate cytotoxic T cells and Natural killer (NK) cells but results in adverse events (vascular leakage) when administered to patients suffering from renal cell carcinoma and melanoma. The adverse events are due to regimens binding with IL-2 receptors that are expressed in the lung epithelia and vascular endothelium, in this way IL-2 holds a disadvantage that IL-15 does not come with as it is not present in these locations.

SO-C101 is administered through the subcutaneous route as an IL-15 superantagonist that demonstrates maximum specificity for the IL-2 and IL-15 receptors on cytotoxic T cells and NK cells. As a superantagonist (an analogue of a natural ligand for a receptor) it is capable of producing significant response which is higher than the natural ligand can produce resulting in 100 percent effectiveness.

The receptors expressed by IL-2 and IL-15 are of the same subunits beta and gamma and expressed on NK and cytotoxic T cells. Although the IL-15 receptor alpha chains are presented on dendritic cells, for successful binding to occur, NK cells, cytotoxic T cells and dendritic cells must be in close proximity. PD-1 has surmounted the challenge of alpha subunit presentation by dendritic cells. This was achieved by designing the drug as a human fusion protein of IL-15 and the IL-15 receptor alpha chain.

The half-life of SO-C101 allows for stimulation of T cells and NK cells physiologically by enabling pulses in cytokine concentration. Exhaustion results from extended half-lives of T cells and NK cells due to tonic stimulation. The shorter half-life of this new agent prevents this outcome and improves its efficacy by enabling pulsatory stimulation. Its inability to bind to IL-2 receptors on the epithelial cells of the lung and the vascular endothelium negate the adverse events mentioned previously so much so not binding to regulatory T cells (Tregs) prevents activation and resultant weakening of the immune response and consequently reducing the therapeutic efficacy of the drug.

SO-C101 is undergoing clinical trials and is yielding positive effects. Its effectiveness on NK and T-cell activation and expansion in metastatic solid tumor patients is remarkable.

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