ID: 99: Identification, function and clinical development of the heterodimeric IL-15 cytokine (hetIL-15)

Abstract

We have shown that the physiologically relevant Interleukin-15 molecule in vivo is a heterodimeric molecule consisting of the IL-15 polypeptide chain and the so-called IL-15 Receptor alpha chain (IL-15Ra), a membrane protein. There are two forms of IL-15 in the body: membrane bound heterodimer of IL-15 and IL-15Ra and soluble heterodimeric IL-15 produced by a specific proteolytic cleavage of the heterodimer at the extracellular domain of IL-15Ra. Our results indicate that IL-15Ra polypeptide is not a receptor but the other half of the heterodimeric IL-15 cytokine. We have characterized the soluble heterodimeric IL-15 (hetIL-15) and developed methods for its efficient production and purification. Injection of hetIL-15 resulted in a significant delay in tumor growth, in preclinical models of tumor-bearing mice. Intratumoral delivery of hetIL-15 induced regression of established tumors. hetIL-15 has the unique property to increase intratumoral CD8 cells and to also increase dramatically the ratio of CD8 to Treg. We dissect the mechanisms leading to tumor control in hetIL-15-treated mice, revealing a novel interplay between IL-15 and the cognate cytokine interleukin-2 (IL-2). Repeated subcutaneous administration of purified hetIL-15 in macaques resulted in sustained plasma IL-15 levels and in dose-dependent expansion of NK and T cells in blood and tissues, demonstrating pharmacokinetics and in vivo bioactivity superior to monomeric IL-15. On the basis of these data, we have produced and characterized a cGMP preparation of hetIL-15 and we have initiated a Phase 1 dose escalation clinical trial in metastatic cancer to assess safety and activity of this cytokine.