Research Biology: Pharmacology, Nektar Therapeutics, San Francisco, California, USA.
Protein Chemistry, Nektar Therapeutics, San Francisco, California, USA.
J Immunother Cancer. 2021 May;9(5). doi: 10.1136/jitc-2020-002024.
BACKGROUND: NKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and pharmacologic differences between endogenous IL-15 receptor α (IL-15Rα)-dependent (NKTR-255 and rhIL-15) and IL-15Rα-independent (precomplexed rhIL-15/IL-15Rα) cytokines. METHODS: In vitro pharmacological properties of rhIL-15, NKTR-255 and precomplex cytokines (rhIL-15/IL-15Rα and rhIL-15 N72D/IL-15Rα Fc) were investigated in receptor binding, signaling and cell function. In vivo pharmacokinetic (PK) and pharmacodynamic profile of the cytokines were evaluated in normal mice. Finally, immunomodulatory effect and antitumor activity were assessed in a Daudi lymphoma model. RESULTS: NKTR-255 and rhIL-15 exhibited similar in vitro properties in receptor affinity, signaling and leukocyte degranulation, which collectively differed from precomplexed cytokines. Notably, NKTR-255 and rhIL-15 stimulated greater granzyme B secretion in human peripheral blood mononuclear cells versus precomplexed cytokines. In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R engagement in lymphocytes compared with only transient engagement observed for rhIL-15 and precomplexed rhIL-15 N72D/IL-15Rα Fc. As a consequent, NKTR-255 provided a durable and sustained proliferation and activation of natural killer (NK) and CD8 T cells. Importantly, NKTR-255 is more effective than the precomplexed cytokine at inducing functionally competent, cytotoxic NK cells in the tumor microenvironment and the properties of NKTR-255 translated into superior antitumor activity in a B-cell lymphoma model versus the precomplexed cytokine. CONCLUSIONS: Our results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial (NCT04136756) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer.
背景：NKTR-255 是一种新型的聚乙二醇缀合物，由重组人白细胞介素-15（rhIL-15）组成，旨在保留 IL-15 分子的所有已知受体结合相互作用。我们探索了内源性白细胞介素-15 受体 α（IL-15Rα）依赖性（NKTR-255 和 rhIL-15）和 IL-15Rα 非依赖性（预复合 rhIL-15/IL-15Rα 和 rhIL-15 N72D/IL-15Rα Fc）细胞因子之间的生物学和药理学差异。
方法：在受体结合、信号转导和细胞功能方面，研究了 rhIL-15、NKTR-255 和预复合细胞因子（rhIL-15/IL-15Rα 和 rhIL-15 N72D/IL-15Rα Fc）的体外药理学特性。在正常小鼠中评估细胞因子的体内药代动力学（PK）和药效学特征。最后，在 Daudi 淋巴瘤模型中评估免疫调节作用和抗肿瘤活性。
结果：NKTR-255 和 rhIL-15 在受体亲和力、信号转导和白细胞脱颗粒方面表现出相似的体外特性，与预复合细胞因子不同。值得注意的是，NKTR-255 和 rhIL-15 比预复合细胞因子刺激人外周血单核细胞中更多的颗粒酶 B 分泌。体内，NKTR-255 表现出与 rhIL-15 相比清除率降低和半衰期延长的 PK 特征，并在淋巴细胞中与仅观察到短暂的 IL-15R 结合相比，表现出延长的 IL-15R 结合。结果，NKTR-255 提供了自然杀伤（NK）和 CD8 T 细胞的持久和持续增殖和激活。重要的是，与预复合细胞因子相比，NKTR-255 在肿瘤微环境中诱导功能成熟、细胞毒性 NK 细胞的效果更好，并且 NKTR-255 的特性转化为优于预复合细胞因子的 B 细胞淋巴瘤模型中的抗肿瘤活性。
结论：我们的研究结果表明，新型免疫疗法 NKTR-255 保留了 rhIL-15 的全部 IL-15 生物学特性，但具有改善的 PK 特性。这些发现支持正在进行的复发性或难治性血液恶性肿瘤患者首次人体试验（NCT04136756）的 NKTR-255，有可能推进基于 rhIL-15 的免疫疗法用于癌症治疗。
J Immunother Cancer. 2021-5
J Immunother Cancer. 2024-9-12
Signal Transduct Target Ther. 2024-7-22
Immune Netw. 2024-2-16
Expert Opin Biol Ther. 2020-7
Proc Natl Acad Sci U S A. 2019-12-23
Immunol Lett. 2017-8-16
Cancer Immunol Res. 2015-10-28
Clin Cancer Res. 2014-4-15
Zotero 插件
