NKTR-255 is a polymer-conjugated IL-15 with unique mechanisms of action on T and natural killer cells

J Clin Invest. 2021 Oct 1;131(19):e144365. doi: 10.1172/JCI144365.


NKTR-255 is a PEG conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans or cis presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naive and memory OVA-specific CD8+ T cells (OT-I) and NK cells in mice. NKTR-255 induced a 2.5- and 2.0-fold expansion of CD8+ T and NK cells, respectively, in WT mice. In adoptive transfer studies, proliferation of naive and memory WT OT-I T cells in response to NKTR-255 was not impaired in IL-15Rα-/- mice, suggesting trans presentation was not utilized by NKTR-255. Interestingly, naive IL-15Rα-/- OT-I cells had deficient responses to NKTR-255, while memory IL-15Rα-/- OT-I cell responses were partially impaired, suggesting that naive CD8+ T cells are more dependent on cis presentation of NKTR-255 than memory CD8+ T cells. In bone marrow chimera studies, IL-15Rα-/- and WT NK cells present in WT recipients had similar responses to NKTR-255, suggesting that cis presentation is not utilized by NK cells. NKTR-255 could form soluble complexes with IL-15Rα; binding to murine IL-15Rα generated superagonists that preferentially stimulated NK cells, showing that conversion to IL-15Rβ agonist biases the response toward NK cells. These findings highlight the ability of NKTR-255 to utilize IL-15Rα for cis presentation and act as an IL-15Rαβ agonist on CD8+ T cells.

Keywords: Cancer immunotherapy; NK cells; Oncology; T cells; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Female
  • Immunologic Memory
  • Interleukin-15 / chemistry
  • Interleukin-15 / pharmacology*
  • Interleukin-15 Receptor alpha Subunit / physiology
  • Interleukin-2 Receptor beta Subunit / agonists
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Polyethylene Glycols / chemistry


  • Il2rb protein, mouse
  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Interleukin-2 Receptor beta Subunit
  • Polyethylene Glycols

Grants and funding

This research was supported by the MD Anderson Cancer Center-Cancer Center Prevention Research Institute of Texas (CPRIT) Summer research program (to A.C.).