An improved approach for de novo design of therapeutic proteins

The natural immune cytokine interleukin-2 (IL-2), although very promising for cancer treatment, has several drawbacks, such as poor thermostability and undesirable cross-reactivity with several receptors, which are difficult to address using classical mutagenesis. David Baker and colleagues have used a computational approach to design Neoleukin-2/15, a mimic of IL-2 and IL-15, keeping only the interface with the βγ_c heterodimer of the IL-2 receptor—and not the interface with alpha subunits of the IL-2 or IL-15 receptors—and based on a different topology and amino acid sequence. Neoleukin-2/15 shows good therapeutic efficacy compared to IL-2 in mouse models of melanoma and colon cancer, with increased thermostability, reduced toxicity and no signs of immunogenicity. The strategy for building such stable de novo mimetics can be readily extended to numerous cytokines or other signalling proteins.