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.

中文翻译：

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NKTR-255 是一种聚合物偶联的 IL-15，对 T 细胞和自然杀伤细胞具有独特的作用机制

NKTR-255 是一种重组人 IL-15 (rhIL-15) 的 PEG 缀合物，被研究为一种潜在的癌症免疫治疗剂。由于 IL-15 反应可以通过 IL-15Rα 或可溶性 IL-15/IL-15Rα 复合物的反式或顺式呈递介导，我们使用定义的初始和记忆 OVA 特异性研究了 IL-15Rα 在驱动 NKTR-255 反应中的作用小鼠中的 CD8 ⁺ T 细胞 (OT-I) 和 NK 细胞。NKTR-255在 WT 小鼠中分别诱导 CD8 ⁺ T 和 NK 细胞扩增 2.5 倍和 2.0 倍。在过继转移研究中，响应 NKTR-255 的幼稚和记忆 WT-I T 细胞的增殖在 IL-15Rα ^-/-小鼠中未受损，表明 NKTR-255 未利用反式呈递。有趣的是，幼稚的 IL-15Rα ^-/-OT-I 细胞对 NKTR-255 的反应不足，而记忆 IL-15Rα ^-/- OT-I 细胞反应部分受损，表明幼稚 CD8 ⁺ T 细胞比记忆 CD8 ⁺更依赖于 NKTR-255 的顺式呈递T细胞。在骨髓嵌合体研究中，IL-15Rα ^-/-WT 受体中存在的 WT NK 细胞对 NKTR-255 具有相似的反应，表明 NK 细胞不利用顺式呈递。NKTR-255 可与 IL-15Rα 形成可溶性复合物；与鼠 IL-15Rα 结合产生优先刺激 NK 细胞的超激动剂，表明转化为 IL-15Rβ 激动剂会使反应偏向于 NK 细胞。这些发现强调了 NKTR-255 利用 IL-15Rα 进行顺式呈递并作为 CD8 ⁺ T 细胞上的 IL-15Rαβ 激动剂的能力。