Peter Rhode, Ph.D., R&D vp at Altor Bioscience, spoke on maximizing production of interleukin-15. Touted as a possible curative treatment for cancer and viral diseases, IL-15 is poorly expressed in bacterial and animal cells. Production in mammalian cells, explained Dr. Rhode, is controlled at the levels of gene expression, translation, and secretion.
“Researchers have tried optimizing codons and altering genetic elements, as well as fusing with albumin, but those approaches have not improved expression that much.” The National Cancer Institute has produced GMP-scale quantities of IL-15 in bacterial systems. The protein is excreted in inclusion bodies, which requires re-folding. But issues with protein deamination and amino acid additions have complicated large-scale production.
Altor scientists found that co-expressing an IL-15 superagonist variant with a soluble IL-15 receptor alpha-IgG1 Fc (IL-15Rα) fusion molecule leads to fully active IL-15:IL-15Rα complex in high yield from CHO cells.
Compared with the “bare” cytokine, the IL-15:IL-15Rα complex is far more active. “It is the substance that immune cells produce,” noted Dr. Rhode, “and how IL-15 is presented in the body.” The superagonist IL-15 variant alone is as much as 10 times as active as the native cytokine. When combined with IL-15Rα, potency and pharmacokinetics improve over 20-fold.
The receptor also acts as a molecular chaperone vital to proper expression and secretion of IL-15. “The limitations we’ve observed with IL-15 are likely due to the lack of this ‘partner’ molecule in animal expression cell lines. We recognized early in our development plans that co-expressing IL-15Rα could assist both in expression and efficacy.”
The IL-15 complex is a potent molecule dosed at microgram/kg compared with multiple mg/kg for monoclonal antibodies. According to Dr. Rhode a “modest-scale GMP run will provide enough material to treat several hundred patients.”