NKTR-255 is a polymer-conjugated IL-15 with unique mechanisms of action on T and natural killer cells
Tanya O. Robinson, … , Takahiro Miyazaki, Kimberly S. Schluns
Tanya O. Robinson, … , Takahiro Miyazaki, Kimberly S. Schluns
Published August 10, 2021
Citation Information: J Clin Invest. 2021;131(19):e144365. https://doi.org/10.1172/JCI144365.
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NKTR-255 is a polymer-conjugated IL-15 with unique mechanisms of action on T and natural killer cells

Abstract

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.

Authors

Tanya O. Robinson, Shweta M. Hegde, Allison Chang, Achintyan Gangadharan, Sarai Rivas, Loui Madakamutil, Jonathan Zalevsky, Takahiro Miyazaki, Kimberly S. Schluns

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Figure 5

IL-15Rα−/− CD8+ T cells have impaired responses to NKTR-255.

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IL-15Rα−/− CD8+ T cells have impaired responses to NKTR-255. CFSE-labele...
CFSE-labeled naive WT (CD45.1+) and IL-15Rα−/− (CD45.1/CD45.2+) OT-I T cells (mixed at 1:1 ratio) were transferred into CD45.2+ WT mice (n = 3–4/group). Seven days after transfer, mice were treated with NKTR-255 (0.03 mg/kg, i.p.) or precomplexed rhIL-15/smIL-15Rα-Fc (0.5 μg/3 μg, i.p.). (A) Representative CFSE intensity. (B) Average frequency of dividing WT (CD45.1+) and IL-15Rα−/− (CD45.1/CD45.2+) OT-I T cells ± SD (n = 3-4/group) depicted in A. (C and D) CFSE-labeled CD8+ T cells containing WT or IL-15Rα−/− memory OT-I T cells (CD45.1+) were transferred into CD45.2+ WT or IL-15Rα−/− mice and treated with NKTR-255 (0.03 mg/kg i.p.) 1 day later. Seven days after treatment, CFSE dilution in CD45.1+ memory OT-I T cells in splenocytes was analyzed. (C) CFSE dilution in CD45.1+ donor T cells. (D) Average frequency of dividing cells ± SD (n = 2–3/group). Similar results were observed in at least 2 additional experiments. (E) IL-15Rα−/− memory OT-I T cells were generated in IL-15Rα−/− mice after transfer and infection with VSV-OVA. At least 30 days later, CD8+ T cells were enriched, CFSE labeled, transferred into WT or IL-15Rα−/− recipients (~3–4 × 106 cells/mouse), and treated with NKTR-255 or PBS. Histograms show CFSE dilution in CD45.1+ CD8+ T cells (IL-15Rα−/− memory OT-I T cells) of NKTR-255–treated WT and IL-15Rα−/− recipients. Histogram overlay (dashed line) represents CFSE profile of cells in PBS-treated mice. *P < 0.05, 2-tailed Student’s t test.