Interleukin-15 (IL-15) is related to interleukin-2 (IL-2) and is a critical factor for the development, proliferation and activation of effector natural killer (NK) and CD8+ memory T cells. However unlike IL-2, IL-15 does not promote activation-induced cell death and supports long lasting CD8+ T cell memory and effector responses against diseased cells, suggesting that IL-15 may be superior to IL-2 as an immunotherapeutic for the treatment of cancers. A recent National Cancer Institute (NCI) review listed IL-15 as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. IL-15 has a novel mechanism of action in which IL-15 and IL-15 receptor α (IL-15Rα) are coordinately expressed by antigen-presenting cells (monocytes and dendritic cells), and IL-15 bound to IL-15Rα is presented in trans to neighboring NK or CD8+ T cells expressing only the IL-2Rβγ receptor.
Altor has developed a technology to improve the binding ability of IL-15 to its receptor IL-2Rβγ by substituting the amino acid residue asparagine to aspartic acid at the position 72. This amino acid substitution, known as N72D, significantly enhances the binding of IL-15 to its receptor IL-2Rβγ. More importantly, the N72D substitution also increases the biological activity of IL-15 four to five fold. Thus, ALT-803 is a fusion complex of the IL-15N72D mutein with an IL-15Rα-IgG1 Fc.
Altor has demonstrated that ALT-803 treatment can provide durable and protective immune cell-mediated responses in several mouse models of multiple myeloma. Pharmacokinetic and pharmacodynamic studies verified that the ALT-803 complex has a significantly longer half-life and prolonged residence in immune organs as well as increased potency in stimulating NK and T cell responses when compared to IL-15. The enhanced activity of ALT-803 is likely the result of a combination of the increased binding activity of the N72D mutein to the IL-15Rβγ complex, optimized cytokine trans-presentation by the IL-15Rα chain in vivo (through the FcR receptors on dendritic cells and macrophages), the dimeric nature of the cytokine domain (increased avidity to IL-15Rβγ) and its increased in-vivo half-life compared to IL-15 (25 h vs. <40 min).
Altor has also exploited the high-affinity interactions between IL-15 and the extracellular IL-15Rα sushi domain (IL-15RαSu) to create a functional scaffold for the design of multi-specific fusion protein complexes. Using single-chain T cell receptors (scTCRs) and antibody as recognition domains linked to the IL-15:IL-15Rα-Fc scaffold, Altor has generated both bivalent and bispecific complexes. In these fusions, the scTCR and antibody domains retain the antigen binding activity, the IL-15 domain exhibits receptor binding and biological activity and the Fc domain binds to the FcR displayed on the macrophages and NK cells to promote the ADCC function. Extensive characterization of a fusion protein of a therapeutic antibody and this IL-15-based scaffold indicates that such a targeted immunotherapeutic can significantly potentiate the anti-tumor activities of the therapeutic antibody. Together, these properties indicate that the IL-15 and IL-15RαSu-Fc complex can be used as versatile, functional scaffold for generating IL-15-based immunotherapeutic or novel targeted immune molecules.
Novel IL-15 antagonists have also been identified that nonproductively occupy the IL-15βγ receptor that could be useful as immunosuppressive agents for autoimmune disease.
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