Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.
Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.
复制标题
DOI：
10.1371/journal.pone.0179431
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Zalevsky J
中科院分区：
文献类型：
--
作者：
Charych D;Khalili S;Dixit V;Kirk P;Chang T;Langowski J;Rubas W;Doberstein SK;Eldon M;Hoch U;Zalevsky J
细胞因子是有效的免疫调节剂，但由于其半衰期短和多效性全身效应，其天然形式并不是理想的药物。 NKTR-214 是一种临床阶段的生物制剂，包含由多个可释放的聚乙二醇 (PEG) 链结合的白细胞介素 2 (IL2) 蛋白。在这种高度 PEG 结合的形式中，IL2 没有活性；因此，NKTR-214是一种生物前药。当体内给药时，PEG 链缓慢释放，产生由较少 PEG 链结合的活性逐渐增强的 IL2 蛋白缀合物的级联。源自 NKTR-214 的 1-PEG-IL2 和 2-PEG-IL2 种类是最活跃的缀合 IL2 种类。游离 IL2 蛋白在体内无法检测到，因为它的消除速度比形成速度快。 NKTR-214 上的 PEG 链位于 IL2 区域，该区域与异源三聚体 IL2 受体复合物 IL2Rαβγ 的 α (α) 亚基接触，从而降低其结合和激活异源三聚体的能力。 IL2Rαβγ 复合物在调节性 T 细胞 (Treg) 上组成型表达。因此，在不使用突变的情况下，聚乙二醇化会比 IL2Rβγ（CD8 T 细胞上主要的受体复合物）更大程度地降低对 IL2Rαβγ 的亲和力。 NKTR-214 体内治疗有利于肿瘤微环境中 CD8 T 细胞而非 Tregs 的激活，从而在多种同基因模型中提供抗肿瘤功效。基于体外和体内动力学数据的机制模型提供了对 NKTR-214 药理学机制的深入了解。该模型表明，与游离 IL2 蛋白相比，源自 NKTR-214 的缀合 IL2 蛋白更大程度地占据 IL-2Rβγ。该模型准确地描述了单剂量 NKTR-214 后观察到的持续体内信号传导，并解释了 NKTR-214 的特性如何赋予独特的动力学控制的免疫学作用机制。
Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.