Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15R beta. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8(+) T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8(+) T cell responses.

Automated summary

IL-15, when structured into a chimeric protein, shows a significant improvement in half-life and bioavailability, enhancing its therapeutic potential. The chimeric protein, covalently linked with IgG2 base, displays a stable dimeric structure, providing greater stability and resistance to proteolytic cleavage. With a longer half-life and enhanced transpresentation by APCs to T cells, the chimeric IL-15 becomes a super-agonist for memory CD8(+) T cell responses.