Pegylation Chemistry of NKTR-214 in Melanoma
Adi Diab, MD:The current interleukin-2 [IL-2] in clinical application uses high doses of interleukin-2. That form of administration of interleukin-2 has been traditionally associated with high toxicity and complexity of administration because you need to administer it very frequentlyevery 6 to 8 hours. The patient has to be monitored at the intensive care unit because of cardiac arrhythmias, hypotension that may lead to hypoperfusion of other organs leading to organ dysfunction, as well as a pulmonary edema. High-dose interleukin-2 is associated with another phenomenon called leaky vascular syndrome, which leads to fluid leakage into the lungs and compromises lung function. So we have always wanted the efficacy of the high-dose IL-2 but without the toxicity.
Having a cytokine like NKTR-214, which is a pegylated cytokine with a prodrug design, allows for 2 advantages. One is in terms of toxicity. The slow release of the pegylation allows for activation of the immune system but without the reactive compensatory mechanisms that lead to a spike of proliferation of the immune cells very quickly and…the associated adverse effects that we just described.
But also, the drug designs allow for binding to the beta and gamma subunits of the IL-2 receptor without binding to the alpha subunit. Binding to the alpha subunit leads to activation of endothelial cells and the pulmonary vasculature, and that leads to leaky vascular syndromes and the development of pulmonary edema, which leads to complications. So in terms of toxicity, the pegylated cytokines lead to a slow but sustained release of the cytokines that prevent some of the toxicities. And also, the binding into the beta and gamma subunits of the IL-2 receptor and prevention from the IL-2 alpha subunit of the receptor decreases the risk of pulmonary edema associated with high-dose cytokine IL-2.
In terms of efficacy, the beta-gamma subunit activations without the alpha subunit activations lead to preferential expansions of the effector T cells and the natural killers in the tumor microenvironment without the expansion of the regulatory T cells, which depend a lot on the alpha subunit binding of the IL-2. That’s a clear advantage for the cytokine over traditional high-dose IL-2. It really leads to a higher ratio of CD8 to regulatory T cells in the tumor microenvironment, where the T-cell presence makes the most difference.
Transcript edited for clarity.
