FOXP3 regulatory cells ( ) are indispensable for immune homoeostasis and for the prevention of autoimmune diseases. Interleukin-2 (IL-2) signalling is critical in all aspects of biology. Consequences of defective IL-2 signalling are insufficient numbers or dysfunction of and hence autoimmune disorders in human and mouse. The restoration and maintenance of immune homoeostasis remain central therapeutic aims in the field of autoimmunity. Historically, broadly immunosuppressive drugs with serious side-effects have been used for the treatment of autoimmune diseases or prevention of organ-transplant rejection. More recently, ex vivo expanded or in vivo stimulated have been shown to induce effective tolerance in clinical trials supporting the clinical benefit of targeting natural immunosuppressive mechanisms. Given the central role of exogenous IL-2 in homoeostasis, a new and promising focus in drug development are IL-2-based approaches for in vivo targeted expansion of or for enhancement of their suppressive activity. In this review, we summarise the role of IL-2 in biology and consequences of dysfunctional IL-2 signalling pathways. We then examine evidence of efficacy of IL-2-based biological drugs targeting with specific focus on therapeutic candidates in clinical trials and discuss their limitations. FOXP3 调节细胞（ ）是免疫平衡和预防自身免疫性疾病不可或缺的细胞。白细胞介素-2（IL-2）信号在生物学的各个方面都至关重要。IL-2 信号缺陷的后果是免疫细胞数量不足或功能失调，从而导致人类和小鼠的自身免疫性疾病。恢复和维持免疫平衡仍是自身免疫领域的核心治疗目标。一直以来，具有严重副作用的广泛免疫抑制药物被用于治疗自身免疫性疾病或预防器官移植排斥反应。最近，在临床试验中，体外扩增或体内刺激已被证明能诱导有效的耐受，支持了针对天然免疫抑制机制的临床益处。鉴于外源性IL-2在体内平衡中的核心作用，基于IL-2的体内靶向扩增或增强其抑制活性的方法是药物开发中一个新的且前景广阔的重点。在这篇综述中，我们总结了 IL-2 在生物学中的作用以及 IL-2 信号通路功能失调的后果。然后，我们将以临床试验中的候选疗法为重点，研究基于 IL-2 的生物靶向药物的疗效证据，并讨论其局限性。
In 1976, the supernatant of activated T cells was found to contain a potent T cell growth factor, which was cloned in 1983 as interleukin-2 (IL-2) [1-3]. The identification of IL-2 marked the start of substantial efforts to unravel IL-2-dependent immunological processes, to mechanistically understand IL-2 binding to its receptor and to dissect the signalling pathways downstream of receptor activation. Importantly, with the discovery of IL-2 and an increasing knowledge on IL-2 functions, immense research efforts were launched to develop IL-2-based immunotherapies to exploit its properties in cancer and autoimmune diseases. Here, we provide a brief overview on signalling, its relevance in the biology of regulatory cells ( ), and detail recent advances in IL2-based immunotherapeutics for autoimmune and inflammatory diseases predominantly in clinical stages of development. 1976 年，人们发现活化 T 细胞的上清液中含有一种强效 T 细胞生长因子，并于 1983 年将其克隆为白细胞介素-2（IL-2）[1-3]。IL-2 的发现标志着人们开始大力揭示依赖 IL-2 的免疫过程，从机理上理解 IL-2 与其受体的结合，并剖析受体激活下游的信号通路。重要的是，随着IL-2的发现和对IL-2功能认识的加深，人们开始努力开发基于IL-2的免疫疗法，利用其特性治疗癌症和自身免疫性疾病。在此，我们将简要概述信号传导及其在调节细胞生物学中的相关性，并详细介绍基于IL-2的免疫疗法在治疗自身免疫性疾病和炎症性疾病方面的最新进展，这些研究主要处于临床开发阶段。
IL-2 EXPRESSION, CAPTURE AND SIGNALLING il-2的表达、捕获和信号传导
The signalling-competent IL-2 receptor (IL-2R) is expressed either as heterodimer or -trimer [4]. The dimeric IL-2R consists of the IL chain (CD122, shared with IL-15R) and the common chain ( , CD132, shared with the receptors for IL-4/7/9/15/21) [4-10] and displays intermediate affinity for ( ). It can hence signal upon binding of IL-2 as well as IL-15. The trimeric IL2R additionally includes the IL-2Ra chain (CD25) [11]. CD25 can be considered a monomeric IL-2R as it binds IL-2, however, it is not capable of signalling. Although CD25 itself displays only low affinity ( ) and a high on-off rate for , it delivers to the dimeric receptor [11] and its presence increases the affinity of the trimeric receptor for -2 100 -fold ( ), consequently providing the expressing cells with a substantial competitive advantage in IL-2 capture [12-14]. 具有信号能力的 IL-2 受体（IL-2R）以异源二聚体或三聚体形式表达 [4]。二聚体 IL-2R 由 IL 链（CD122，与 IL-15R 共用）和公共链（ⅣCD132，与 IL-4/7/9/15/21 的受体共用）组成[4-10]，并对（）表现出中间亲和力。因此，它可以在 IL-2 和 IL-15 结合时发出信号。三聚体 IL2R 还包括 IL-2Ra 链（CD25）[11]。CD25 可被视为单体 IL-2R，因为它能结合 IL-2，但不能发出信号。虽然 CD25 本身对 IL-2 的亲和力（）较低，且通断率较高，但它能传递给二聚受体[11]，而且它的存在能使三聚受体对 IL-2 的亲和力增加 100 倍（），从而使表达细胞在捕获 IL-2 时具有很大的竞争优势[12-14]。
Various immune and non-immune cell types express the IL-2R. In humans and mice, the dimeric IL-2R is expressed at low levels by CD4 memory cells and naïve cells and at high levels by CD8 memory T cells and CD56 NK cells [17]. In mice, the trimeric on the other hand is expressed highest on and at lower levels on recently activated and effector CD8 T cells, ILC2, and some NKT and CD56 NK cells [17, 20-23]. Similarly, in human peripheral blood mononuclear cells (PBMC), express the highest levels of the trimeric IL-2R whereas other immune cells such as CD45RO CD4 T cells, most CD56 cells, few CD4 and CD8 naïve T cells express it at lower levels [24]. The trimeric IL-2R is also expressed by endothelial cells, with further CD25 upregulation upon IL-2 treatment [25, 26], and signalling can cause the vascular leak syndrome-a known adverse effect of high-dose IL-2 therapy in mice and patients. 各种免疫和非免疫细胞类型都表达 IL-2R。在人类和小鼠中，二聚体 IL-2R 在 CD4 记忆细胞和幼稚细胞中的表达水平较低，而在 CD8 记忆 T 细胞和 CD56 NK 细胞中的表达水平较高 [17]。在小鼠中，三聚体 IL-2R 在最近活化和效应的 CD8 T 细胞、ILC2 以及一些 NKT 和 CD56 NK 细胞中的表达量最高，而在这些细胞中的表达量较低[17, 20-23]。同样，在人类外周血单核细胞（PBMC）中，三聚体 IL-2R 的表达水平最高，而其他免疫细胞，如 CD45RO CD4 T 细胞、大多数 CD56 细胞、少数 CD4 和 CD8 幼稚 T 细胞的表达水平较低 [24]。内皮细胞也表达三聚 IL-2R，IL-2 治疗后 CD25 进一步上调[25, 26]，信号传导可导致血管渗漏综合征--这是已知的大剂量 IL-2 治疗对小鼠和患者的不良反应。
IL-2 is a pleiotropic cytokine that can act in an autocrine and paracrine way, with cell type- and context-dependent positive effects on survival, population expansion or lineage stability [17, 27-29]. The main source of IL-2 are CD4 conventional T cells upon T cell receptor (TCR)/CD28 (co-) stimulation [30, 31]. Other immune cells such as CD8 T cells, NK(T) cells or dendritic cells can produce IL-2 as well albeit at lower quantities [24, 29]. are highly dependent on exogenous IL-2 sources as FOXP3 in cooperation with other transcription factors represses 112 IL-2 是一种多效细胞因子，可通过自分泌和旁分泌方式发挥作用，对细胞的存活、群体扩增或系稳定性产生积极影响[17, 27-29]。在 T 细胞受体（TCR）/CD28（共同）刺激下，IL-2 的主要来源是 CD4 传统 T 细胞[30, 31]。其他免疫细胞如 CD8 T 细胞、NK（T）细胞或树突状细胞也能产生 IL-2，尽管数量较少[24, 29]。
Received: 30 June 2023 Revised: 7 September 2023 Accepted: 8 September 2023 收到：修订：2023 年 6 月 30 日 接受：2023 年 9 月 7 日2023 年 9 月 8 日
Published online: 23 September 2023 在线出版：2023 年 9 月 23 日
Fig. 1 IL-2 expression in mouse and human conventional and FOXP3 CD4 T cells. Mouse splenocytes (wildtype C57Bl6/J, ) and healthy human PBMC were stained for CD3, TCR [mouse], CD4, FOXP3 and IL-2 along with a viability dye. Representative flow plots depicting IL-2 expression in mouse (top) and human (bottom) conventional cells ( , blue) (live [mouse] CD4 FOXP3 ) and (red) (live CD3 TCR [mouse] CD4 FOXP3 ). The frequency of cells of FOXP3 and FOXP3 cells is shown (mean SEM). The geometric mean fluorescence intensities of IL-2 as a measure to compare per cell protein levels between and are (mouse ) vs (mouse ) and (human ) vs (human FOXP3 cells) (mean SEM). Ethical approvals were obtained from the KU Leuven Animal Ethics Committee (150/2019) and the University Clinic Leuven Ethical Committee (S65883). Antibodies were purchased from BD Biosciences (564667, 566405, 624295), Biolegend (100225, 503840, 320214), Miltenyi Biotec (130-111-601), and ebioscience (65-0865-18, 56-0038-80, 48-0048-42). 图 1 IL-2 在小鼠和人类常规及 FOXP3 CD4 T 细胞中的表达。对小鼠脾细胞（野生型 C57Bl6/J，）和健康人 PBMC 进行 CD3、TCR [小鼠]、CD4、FOXP3 和 IL-2 染色，并用活力染料染色。描述小鼠（上）和人类（下）常规细胞中 IL-2 表达的代表性流程图（蓝色）（活[小鼠] CD4 FOXP3）和（红色）（活 CD3 TCR [小鼠] CD4 FOXP3）。图中显示了 FOXP3 和 FOXP3 细胞的频率（平均 SEM）。IL-2 的几何平均荧光强度（平均 SEM）为（小鼠）vs（小鼠）和（人类）vs（人类 FOXP3 细胞）。伦理批准来自鲁汶大学动物伦理委员会（150/2019）和鲁汶大学诊所伦理委员会（S65883）。抗体购自 BD Biosciences (564667, 566405, 624295)、Biolegend (100225, 503840, 320214)、Miltenyi Biotec (130-111-601) 和 ebioscience (65-0865-18, 56-0038-80, 48-0048-42)。
transcription [32-34]. Yet, a sizable population of in mice is capable of producing IL-2, albeit at a lower per cell level compared to Foxp3 CD4 T cells [29]. In contrast, IL-2 expression in human peripheral blood FOXP3 CD4 T cells is limited to a subset of cells with low expression of FOXP3 likely not representing suppressive (Fig. 1) [35]. 转录 [32-34]。然而，与 Foxp3 CD4 T 细胞相比，小鼠中有相当大的群体能够产生 IL-2，尽管单细胞水平较低 [29]。与此相反，人类外周血 FOXP3 CD4 T 细胞中 IL-2 的表达仅限于 FOXP3 低表达的细胞亚群，可能不具有抑制作用（图 1）[35]。
Upon binding of IL-2 to its receptor the quaternary complex is internalised, CD25 is recycled back to the cell surface while CD122 and CD132 are degraded [36, 37]. The IL-2:IL-2R complex can signal via three major pathways, each activating different downstream transcriptional regulators [27, 38, 39]. Depending on the downstream signalling pathway, (PI3K-AKT-mTOR pathway), SHC1 (MAPK pathway) or STAT (signal transducer and activator or transcription) 5 (Janus activating kinase [JAK]1/3-STAT pathway) are triggered. In T cells, and particularly , phosphorylation of the IL-2R chain and common chain by JAK1 and JAK3 and subsequent activation of STAT5 accounts for of IL-2 signalling (Fig. 2)[40, 41]. In , the PI3K-AKT-mTOR pathway is suppressed by PTEN (phosphatase and tensin homologue). This mechanism regulates homoeostasis by negatively regulating proliferation and positively regulating lineage stability likely by increased nuclear translocation of FOXO1/FOXO3a [42-44]. Further, to regulate homoeostasis and maintain IL-2 与其受体结合后，四元复合物被内化，CD25 被回收到细胞表面，而 CD122 和 CD132 则被降解 [36，37]。IL-2：IL-2R 复合物可通过三种主要途径发出信号，每种途径激活不同的下游转录调节因子 [27、38、39]。根据下游信号通路的不同，PI3K-AKT-mTOR 通路、SHC1（MAPK 通路）或 STAT（信号转导和激活或转录）5（Janus 激活激酶 [JAK]1/3-STAT 通路）会被触发。在 T 细胞中，特别是在 IL-2 信号传导过程中，JAK1 和 JAK3 使 IL-2R 链和共同链磷酸化，随后 STAT5 被激活（图 2）[40, 41]。在细胞内，PI3K-AKT-mTOR 通路受到 PTEN（磷酸酶和天丝同源物）的抑制。这一机制可能通过增加 FOXO1/FOXO3a 的核转位来负向调节增殖和正向调节血统稳定性，从而调节体内平衡[42-44]。此外，为了调节体内平衡和维持 lineage fate, STAT5 activation and SOCS1 expression regulate each other in a positive inhibitory loop. IL-2 signalling induces SOCS1 expression and 在细胞系命运中，STAT5 的激活和 SOCS1 的表达通过正向抑制环相互调节。IL-2 信号诱导 SOCS1 的表达和
SOCS1 in turn attenuates IL-2R signalling by blocking JAK proteins, hence interrupting the phosphorylation of STAT5 [45-49]. 反过来，SOCS1 通过阻断 JAK 蛋白，从而中断 STAT5 的磷酸化，从而减弱 IL-2R 信号[45-49]。
homoeostasis is essential to preserve the delicate balance of immune activation. Absence of or decreased function will result in autoimmune diseases, while abundance of will lead to overt immune suppression. These events are balanced by the exclusive IL-2 capture sensitivity of an overall high dependency of on exogenous sources and, hence, reciprocal control between effector cells and . The preferential and high expression of the trimeric IL-2R renders most sensitive to IL-2 capture thereby outcompeting other cell types. This superior efficiency in IL-2 capture is exploited by lowdose IL-2 therapy to specifically target and expand . Further, in the cooperation of the trimeric receptor and the serine/threonine phosphatase PP2A confers increased sensitivity to IL-2 and PP2A deficiency in results in autoimmunity [54]. Consequently, 10-fold lower IL-2 levels are required for STAT5 activation in compared to CD25-expressing non- and optimal IL-2-dependent gene expression in occurs at 100 -fold lower IL-2 concentrations compared to other cell types expressing CD25 [55]. The high sensitivity to IL-2 signalling allows for sufficient signalling when available CD25 surface levels are reduced [56]. If the superior IL-2 capture is strongly compromised such as it is in CD25-deficient mice or in patients with risk alleles for CD25, systemic inflammation and/or autoimmunity are the consequence of the resulting deficiency or disturbed homoeostasis. 平衡对于保持免疫激活的微妙平衡至关重要。缺乏IL-2或IL-2功能降低会导致自身免疫疾病，而IL-2功能增强则会导致明显的免疫抑制。这些事件通过对外源性来源的整体高度依赖性和效应细胞与......细胞之间的相互控制的专属 IL-2 捕获敏感性来平衡。三聚体 IL-2R 的优先高表达使其对 IL-2 捕获最为敏感，从而超越了其他类型的细胞。低剂量 IL-2 疗法可利用这种 IL-2 捕获的卓越效率，特异性地靶向和扩增.IL-2R。此外，三聚体受体和丝氨酸/苏氨酸磷酸酶 PP2A 的合作增加了对 IL-2 的敏感性，PP2A 缺乏会导致自身免疫[54]。因此，与不表达 CD25 的细胞相比，STAT5 激活所需的 IL-2 水平低 10 倍，与表达 CD25 的其他细胞类型相比，IL-2 浓度低 100 倍时，STAT5 才会出现最佳的 IL-2 依赖性基因表达[55]。对 IL-2 信号的高敏感性使其在可用的 CD25 表面水平降低时也能产生足够的信号[56]。如果卓越的IL-2捕获能力受到严重破坏，如在CD25缺陷小鼠或具有CD25风险等位基因的患者中，系统性炎症和/或自身免疫就是由此导致的缺乏或平衡紊乱的后果。
Initially, and with the assumption that the main function of IL-2 was the activation of effector T cells and NK cells, efforts to exploit IL-2 in immunotherapy were focused on promoting anti-tumour immunity [57]. High-dose recombinant IL-2 (aldesleukin; trade name Proleukin) was the first immunotherapy approved by the U.S. Food and Drug Administration (FDA) in 1992 [58, 59]. The activation of effector cells as the main function of IL-2 was contested when ablation of II2, II2ra and II2rb expression in mice caused lethal lymphoproliferation and autoimmunity, rather than immunodeficiency [60]. Ten years later, these observations were explained with the discovery of as an immunosuppressive CD4 cell subset characterised by high levels of CD25 and a non-redundant function for IL-2 in many aspects of biology [18, 61]. The absence or dysfunction of results in fatal multiorgan autoimmunity in mice (scurfy [62]) and human (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, IPEX [63]), and their reduced function has been reported in several systemic (auto-)inflammatory diseases 最初，由于假定 IL-2 的主要功能是激活效应 T 细胞和 NK 细胞，在免疫疗法中利用 IL-2 的努力主要集中在促进抗肿瘤免疫[57]。高剂量重组 IL-2（醛白细胞介素，商品名 Proleukin）是 1992 年美国食品药品管理局（FDA）批准的第一种免疫疗法 [58，59]。激活效应细胞是 IL-2 的主要功能这一观点受到质疑，因为在小鼠体内消减 II2、II2ra 和 II2rb 的表达会导致致命的淋巴细胞增殖和自身免疫，而不是免疫缺陷[60]。十年后，人们发现了一种免疫抑制性 CD4 细胞亚群，其特点是高水平的 CD25 和 IL-2 在生物学许多方面的非冗余功能，从而解释了这些观察结果 [18，61]。在小鼠（scurfy [62]）和人类（免疫调节失调、多内分泌病、肠病、X-连锁综合征、IPEX [63]）中，IL-2 的缺失或功能障碍会导致致命的多器官自身免疫，在一些全身性（自身）炎症性疾病中也有其功能降低的报道。 .
IL-2 signalling (via JAK-STAT5) has been demonstrated to be important for thymic development, peripheral induction, lineage commitment and stability sustainability, and homoeostasis (Fig. 2). development takes place in the thymus (thymic , ) but conventional CD4 cells can convert into upon tolerogenic stimulation in the periphery as well (peripherallyinduced ). IL-2 signalling is important in establishing the identity alongside with TCR and TGF signalling [70, 71]. For development, a two-step model of TCR and cytokine signalling has been proposed in which the main driving cytokine is IL-2 and its induction of the JAK-STAT5 signalling pathway. IL-7 and IL-15 can compensate for the lack of IL-2 but in the presence of IL-2 their receptors are downregulated establishing a dominant role for IL-2 [72-75]. Defective expression of IL-2 or its receptor subunits, caused by single nucleotide polymorphisms in human or via introduced genetic modification in mice, results in a lack of functional and consequently lymphoproliferation, multiorgan infiltration of activated lymphocytes and lethal autoimmunity . Similarly, inappropriate regulation of IL-2 signal IL-2信号（通过JAK-STAT5）已被证明对胸腺发育、外周诱导、血系承诺和稳定性持续以及平衡具有重要作用（图2）。胸腺发育（胸腺发育）发生在胸腺内，但常规CD4细胞在外周耐受刺激后也可转化为CD4细胞（外周诱导）。IL-2信号与TCR和TGF信号一起对建立CD4细胞身份起着重要作用[70, 71]。在发育过程中，有人提出了 TCR 和细胞因子信号的两步模型，其中主要的驱动细胞因子是 IL-2 及其诱导的 JAK-STAT5 信号通路。IL-7和IL-15可弥补IL-2的不足，但在IL-2存在的情况下，它们的受体下调，从而确立了IL-2的主导作用[72-75]。人类单核苷酸多态性或小鼠基因修饰导致的 IL-2 或其受体亚基表达缺陷会导致淋巴细胞增殖、活化淋巴细胞的多器官浸润和致命的自身免疫。同样，IL-2 信号的不适当调节也会导致淋巴细胞增殖的发生。
Fig. 2 Critical roles of IL-2 in T Treg. Upon binding of IL-2 to the trimeric IL-2R, JAK1 and JAK3 phosphorylate the IL-2R or IL-2R common ( ) chain, respectively. STAT5 docks onto the phosphorylated residues and is then phosphorylated by JAK1/3. Phosphorylated STAT5 (pSTAT5) dimerises and translocates to the nucleus to bind its target loci (such as FoxP3/FOXP3). IL-2 signalling is critical in Treg biology. It plays a dominant role in thymic development (bottom, left), during peripheral functional maturation in barrier tissues (bottom, middle), and is indispensable for the survival and functional lineage stability of mature in secondary lymphoid organs (SLO) (bottom, right). 图 2 IL-2 在 T Treg 中的关键作用。IL-2 与三聚体 IL-2R 结合后，JAK1 和 JAK3 分别磷酸化 IL-2R 或 IL-2R 共（ ）链。STAT5 与磷酸化残基对接，然后被 JAK1/3 磷酸化。磷酸化的 STAT5（pSTAT5）会二聚化并转运到细胞核，与其靶基因座（如 FoxP3/FOXP3）结合。IL-2 信号在 Treg 生物学中至关重要。它在胸腺发育（左下图）、屏障组织外周功能成熟（中下图）过程中发挥着主导作用，对于成熟的继发性淋巴器官（SLO）的存活和功能线稳定性也不可或缺（右下图）。
transduction impairs homoeostasis and functional stability [42, 54, 82-86]. Although genetic studies using germline deletion cannot ultimately dissect the requirement for IL-2 during (thymic or peripheral) development from the requirement for IL-2 during peripheral survival and expansion, several lines of evidence support both intrathymic and peripheral roles for IL-2 in 转导会损害平衡和功能稳定性 [42、54、82-86]。虽然利用种系缺失进行的基因研究无法最终将（胸腺或外周）发育过程中对 IL-2 的需求与外周生存和扩展过程中对 IL-2 的需求区分开来，但有几项证据支持 IL-2 在胸腺内和外周发育过程中都能发挥作用。 .
IL-2- or IL-2R-deficient mice IL-2 或 IL-2R 缺陷小鼠
Autoimmunity in IL-2- or IL-2R-deficient mice can be prevented by adoptive transfer of demonstrating that proficiency in IL-2signalling in mature is sufficient and necessary for peripheral tolerance even when thymic development is impaired [61, 87-89]. Notably, numbers but not their suppressive activity can be rescued in IL-2- or CD25-deficient mice by depletion of the pro-apoptotic protein Bim [90]. Also in IL-2sufficient mice, Bim has been shown to mediate apoptosis to regulate numbers. A critical role for IL-2 in peripheral survival is to maintain the pro-survival protein Mcl-1 [91]. IL-2或IL-2R缺陷小鼠的自身免疫可通过收养性转移来预防，这表明即使胸腺发育受损，成熟小鼠的IL-2信号转导能力对于外周耐受也是足够和必要的[61, 87-89]。值得注意的是，在IL-2或CD25缺陷小鼠中，可以通过消耗促凋亡蛋白Bim来挽救数量，但不能挽救其抑制活性[90]。在 IL-2 缺乏的小鼠中，Bim 也被证明能介导细胞凋亡，从而调节细胞数量。IL-2 在外周生存中的一个关键作用是维持促生存蛋白 Mcl-1 [91]。
Antibody-mediated neutralisation or preferential delivery of IL-2 抗体介导的中和或 IL-2 的优先输送
Further, antibody-mediated neutralisation of IL-2 and studies utilising IL-2:anti-IL-2 immune complexes have illustrated the indispensable role of IL-2 in peripheral maintenance and functional maturation. Neutralisation of IL-2 induces cellmediated autoimmunity by selectively reducing numbers [92]. Conversely, the application of IL-2:anti-IL-2 immune complexes can prevent the binding of IL-2 to effector cells and preferentially deliver it to to substantially expand these [93]. 此外，抗体介导的 IL-2 中和以及利用 IL-2:anti-IL-2 免疫复合物进行的研究表明，IL-2 在外周维持和功能成熟中发挥着不可或缺的作用。IL-2 中和可选择性地减少细胞数量，从而诱导细胞介导的自身免疫[92]。相反，IL-2：抗 IL-2 免疫复合物的应用可阻止 IL-2 与效应细胞结合，并优先将其输送到效应细胞，从而使这些细胞大幅扩增[93]。
Competitive advantage of IL-2R cells in mixed bone marrow chimeras 混合骨髓嵌合体中 IL-2R 细胞的竞争优势
In IL-2-STAT5 signalling is sensed via the conserved noncoding sequence 2 (CNS2) in the FoxP3 locus sustaining FOXP3 expression and controlling stable FOXP3 expression inheritance [94]. The requirement for IL-2 in development, homoeostasis and competitive fitness has further been studied in mixed bone marrow chimeric mice co-transplanted with IL-2 signallingdeficient bone marrow and wild-type bone marrow. In these mice, wild-type greatly outnumbered mutant FOXP3 CD4 cells in the thymus and in the periphery illustrating the competitive disadvantage conferred by IL-2 signalling deficiency [19, 95]. These experimental designs, however, use bone marrow from IL-2R germline knockout mice and hence, despite analysing thymic as well as peripheral fall short on undoubtedly dissecting the role of IL-2 signalling during development versus its role in homoeostasis of . Indeed, the shared signalling pathway with IL-15 and IL-7 and hence their compensatory potential [74] together with data obtained in TCR-transgenic mice [96], indicate that lineage induction can be IL-2 signalling-independent. 在 IL-2-STAT5 中，信号通过 FoxP3 基因座中的保守非编码序列 2（CNS2）传递，维持 FOXP3 的表达并控制稳定的 FOXP3 表达遗传 [94]。在混合骨髓嵌合体小鼠中，进一步研究了发育、稳态和竞争能力对 IL-2 的需求，这些小鼠共移植了 IL-2 信号缺失骨髓和野生型骨髓。在这些小鼠中，野生型在胸腺和外周的数量大大超过了突变型 FOXP3 CD4 细胞，这说明了 IL-2 信号缺乏所带来的竞争劣势 [19，95]。然而，这些实验设计使用的是 IL-2R 基因敲除小鼠的骨髓，因此，尽管对胸腺和外周进行了分析，但毫无疑问仍无法剖析 IL-2 信号在发育过程中的作用与其在免疫平衡中的作用。 事实上，IL-15 和 IL-7 有着共同的信号通路，因此它们具有代偿潜力[74]，加上在 TCR 转基因小鼠中获得的数据[96]，都表明系诱导可能与 IL-2 信号无关。
-specific rescue of IL-2 signalling -特异性 IL-2 信号救援
Finally, the intrinsic requirement for IL-2 signalling in maintenance and fitness has been demonstrated in mice with lineage-specific deficiency of CD25 or the IL-2R chain presenting with decreased frequencies and reduced per cell FOXP3 protein levels, and developing fatal autoimmune disease [97]. In line with the aforementioned studies, dysfunctional FOXP3 CD25 can be found in mice with germline deficiencies of IL-2 and IL-2R [19, 95, 96]. 最后，在CD25或IL-2R链系特异性缺乏的小鼠中，IL-2信号在维持和健康方面的内在要求得到了证实，这些小鼠出现频率下降和每个细胞FOXP3蛋白水平降低，并发展成致命的自身免疫性疾病[97]。与上述研究一致，在 IL-2 和 IL-2R 基因缺陷的小鼠中也可发现功能失调的 FOXP3 CD25 [19, 95, 96]。
Together, these studies demonstrate the relevance for IL-2 in development, maturation, and survival, and suggest that it serves a direct role in suppressive function. 这些研究共同证明了 IL-2 与发育、成熟和存活的相关性，并表明它在抑制功能中发挥着直接作用。
The role of IL-2 in maturation and function can in part be attributed to a positive feedback loop between FOXP3 and CD25 expression. Upon activation of the IL-2-STAT5 signalling pathway in , phosphorylated STAT5 binds the FoxP3 locus to promote its expression. FOXP3 in turn positively regulates expression of CD25 [33, 85, 98, 99]. CD25 expression constitutes part of the transcriptional signature and upon loss of lineage fate, CD25 gene expression is lost quickly, further illustrating the interdependency of signature genes such as FoxP3 and CD25 [100]. High expression of the high-affinity trimeric IL-2R on however, is not only necessary for to scavenge the low levels of IL-2 for their homoeostasis; the ability to preferentially capture IL-2 also presents an immunosuppressive mechanism by starving effector T cells and NK cells from IL-2 and hence limiting their activation and proliferation. The requirement for the IL-2-STAT5FOXP3 axis in suppressive function was elegantly demonstrated in a study using transgenic mice with -specific -具体
deficiency of the IL-2R with simultaneous expression of constitutively active STAT5 [97]. Early fatal autoimmune disease otherwise observed in mice with IL-2R缺失，同时表达组成性活性 STAT5 [97]。此外，还在小鼠体内观察到了早期致命的自身免疫性疾病。 -specific IL-2R deficiency can be rescued by constitutive STAT5 signalling; however, the mice still succumbed at a later age from uncontrolled CD8 T cell activation and expansion. This demonstrated that IL-2 consumption via the high-affinity trimeric IL-2R expressed by particularly controls the CD8 T cell population size and activity. IL-2 在成熟和功能方面的作用可部分归因于 FOXP3 和 CD25 表达之间的正反馈回路。IL-2-STAT5信号通路激活后，磷酸化的STAT5与FoxP3基因座结合，促进其表达。FOXP3 反过来又正向调节 CD25 的表达 [33、85、98、99]。CD25 的表达构成了转录特征的一部分，而一旦失去细胞系命运，CD25 基因的表达就会迅速消失，这进一步说明了 FoxP3 和 CD25 等特征基因之间的相互依存关系 [100]。然而，高亲和性三聚体 IL-2R 的高表达不仅是清除低水平 IL-2 以维持其平衡的必要条件，其优先捕获 IL-2 的能力还提供了一种免疫抑制机制，使效应 T 细胞和 NK 细胞无法获得 IL-2，从而限制了它们的活化和增殖。一项利用特异性 IL-2R 缺乏的转基因小鼠进行的研究清楚地证明了 IL-2-STAT5FOXP3 轴在抑制功能中的必要性。这表明，IL-2 的消耗通过高亲和性三聚体 IL-2R 表达，特别控制着 CD8 T 细胞群的数量和活性。
Memory )-analogous to their non-regulatory counterparts-are long-lived cells which upon secondary exposure however do not respond with proliferation and proinflammatory cytokine production but instead possess increased suppressive function. The induction of would hence be of therapeutic interest. They are thought to mitigate tissue damage during the rapid and heightened response of effector memory T cells upon secondary antigen exposure or to reinforce foetal tolerance during pregnancy. Accordingly, present as antigen-experienced, CCR7 cells, express high levels of antiapoptotic BCL-2 and proliferate less ( ) compared to activated 记忆细胞（Memory )--类似于非调控细胞--是一种长寿命细胞，但在二次暴露时不会增殖和产生促炎细胞因子，而是具有更强的抑制功能。因此，诱导这种细胞具有治疗意义。据认为，在二次接触抗原时，效应记忆 T 细胞的反应迅速而强烈，它们可减轻组织损伤，或在怀孕期间加强胎儿的耐受性。因此，作为抗原经验丰富的 CCR7 细胞，它们表达高水平的抗凋亡 BCL-2，与活化的 CCR7 细胞相比，增殖较少（）。 .
While memory may be less dependent on IL-2 for long-term maintenance, they express high levels of CD25 and expand in response to low-dose IL-2 therapy [55, 101, 103-105]. However, long-lived (local) tolerance induced by IL-2-based therapy relies on the pre-existence of antigen-specific or (local) induction of . Antigen therapy to induce hyposensitivity to allergens might be explained by the induction of . However, e.g. isletspecific antigen therapy alone has been disappointing in trials with type 1 diabetes patients and it has been suggested that antigen therapy must be combined with a such as low-dose IL-2. While this presents a promising strategy for type 1 diabetes and other autoimmune diseases, clinical trials are needed to establish antigen dosing and boosting regimens, longterm efficacy and its correlation with induction and persistence. 虽然记忆可能不太依赖 IL-2 的长期维持，但它们表达高水平的 CD25，并对低剂量 IL-2 治疗做出反应 [55、101、103-105]。然而，IL-2疗法诱导的长效（局部）耐受依赖于预先存在的抗原特异性或（局部）诱导.抗原疗法诱导的对过敏原的低敏感性可能是通过诱导.抗原疗法诱导的对过敏原的低敏感性来解释的。 然而，在对1型糖尿病患者进行的试验中，例如单独的胰岛特异性抗原疗法令人失望，有人建议抗原疗法必须与低剂量IL-2等药物相结合。虽然这是治疗 1 型糖尿病和其他自身免疫性疾病的一种有前途的策略，但还需要进行临床试验，以确定抗原剂量和增强方案、长期疗效及其与诱导和持续性的相关性。
The roles of IL-2 in biology and suppressive function make IL-2 a highly attractive immunotherapeutic molecule in the context of autoimmunity and transplantation. However, its activities on different (immune) cell types also demand caution in clinical trial design and close monitoring of adverse effects. In the below chapters, we will discuss recent pre-clinical and clinical efforts to develop IL-2-based immunotherapeutic strategies that target to treat autoimmune conditions characterised by low numbers or reduced suppressive activity of as well as to prevent transplant rejection. IL-2 在生物学中的作用和抑制功能使 IL-2 成为自身免疫和移植方面极具吸引力的免疫治疗分子。然而，IL-2 对不同（免疫）细胞类型的作用也要求临床试验设计谨慎，并密切监测不良反应。在下面的章节中，我们将讨论最近在开发基于 IL-2 的免疫治疗策略方面所做的临床前和临床努力，这些策略的目标是治疗自身免疫性疾病，这些疾病的特点是自身免疫细胞数量少或抑制活性降低，以及预防移植排斥反应。
IL-2-BASED IMMUNOTHERAPIES 基于IL-2的免疫疗法
IL-2 was the first cytokine therapy approved by the U.S. FDA [58]. The initial indications were in metastatic cancers where IL-2 had to be administered at very high doses (HD IL-2) to achieve clinical benefit. The high doses were necessary because of a very short half-life of IL-2 in vivo and for stimulation the cytotoxic effector T cells and NK cells, presumably, once the high-affinity receptor on has been saturated. The approval was based on the overall objective response rates in up to of patients and durable complete responses for up to 91 months [59]. However, the treatment also induced severe treatment-associated toxicities including vascular leak syndrome and clinical manifestations of a cytokine storm. Efforts to reduce toxicities by lowering the dose led to a considerable loss of therapeutic efficacy due to the expansion of immunosuppressive that contain a high-affinity IL-2 receptor and thereby outcompete other cells for IL-2 [106]. HD IL-2 remains an important treatment in selected patients, either as a first-line option or in combination with new targeted and immunological therapies [107]. IL-2 是美国 FDA 批准的第一种细胞因子疗法[58]。最初的适应症是转移性癌症，IL-2 必须以极高的剂量（HD IL-2）给药才能取得临床疗效。之所以需要大剂量，是因为 IL-2 在体内的半衰期很短，而且一旦高亲和力受体达到饱和，就可能刺激细胞毒性效应 T 细胞和 NK 细胞。批准该疗法的依据是多达 91 个月的患者总体客观反应率和持久的完全反应[59]。然而，该疗法也诱发了严重的治疗相关毒性，包括血管渗漏综合征和细胞因子风暴的临床表现。由于含有高亲和性 IL-2 受体的免疫抑制细胞扩增，从而使其他细胞无法竞争 IL-2，因此通过降低剂量来减少毒性的努力导致疗效大打折扣[106]。HD IL-2 仍是特定患者的重要治疗手段，既可作为一线选择，也可与新的靶向疗法和免疫疗法联合使用[107]。
The preferential capture of natural IL-2 via the high-affinity IL-2R expressed by is exploited in low-dose (LD) IL-2 therapy. The short half-life of IL-2 (<10 min [108]) requires daily injections of 0.5-3 million international units (MIU) in repetitive treatment courses with effects on lasting days to weeks, but at the same time its quick clearance allows for fast and flexible dose adjustment to ameliorate possible adverse effects. Overall, LD IL2 treatment is well-tolerated as documented in animal studies and clinical trials (reviewed in [50, 51]). Long-term administration in mice showed no impairment of immune responses or vaccination, nor did it increase cancer occurrence [109]. Similarly, a long-term study in children with early onset type 1 diabetes mellitus (T1D) concluded that the treatment was safe and well-tolerated [110]. However, inherent to the pleiotropic nature of IL-2, dosedependent mild-to-moderate adverse effects are associated with LD IL-2 treatment. While high-dose IL-2 treatment can induce vascular leak syndrome, LD IL-2 may result in transient influenzalike symptoms, or in eosinophilia driven by ILC2-produced IL-5 [24, 51]. Overall, data obtained in murine disease models and clinical studies are promising with partial or complete response to treatment. Completed and ongoing clinical trials with LD IL-2 in autoimmune and rheumatic diseases are summarised elsewhere [111]. 低剂量（LD）IL-2疗法利用了天然IL-2通过高亲和性IL-2R表达的优先捕获性。IL-2 的半衰期短（<10 分钟[108]），需要每天注射 0.5-3 百万国际单位（MIU），重复治疗疗程，疗效可持续数天至数周，但与此同时，IL-2 的快速清除允许快速灵活地调整剂量，以改善可能出现的不良反应。总体而言，动物研究和临床试验（见文献[50, 51]）表明，LD IL2 治疗的耐受性良好。对小鼠的长期用药表明，免疫反应或疫苗接种没有受到影响，也没有增加癌症发生率[109]。同样，一项针对早发 1 型糖尿病（T1D）儿童的长期研究也得出结论，这种治疗方法安全且耐受性良好 [110]。然而，IL-2 本身具有多效应性，低剂量 IL-2 治疗会产生轻度至中度的不良反应。大剂量 IL-2 治疗可诱发血管渗漏综合征，而低剂量 IL-2 则可能导致一过性流感样症状，或由 ILC2 产生的 IL-5 导致嗜酸性粒细胞增多 [24，51]。总之，在小鼠疾病模型和临床研究中获得的数据很有希望，对治疗有部分或完全的反应。关于 LD IL-2 治疗自身免疫性疾病和风湿性疾病的已完成和正在进行的临床试验，请参见其他文献 [111]。
Fuelled by the therapeutic benefit of LD IL-2 and to overcome its limitations, further efforts have focused on the development of second-generation versions of IL-2 with superior pharmacokinetics and selectivity. Aims of these efforts beyond target cell selectivity and reduced off-target effects are to increase the halflife of the novel molecules (at the expense of fast adjustment of dosing in case of adverse effects), less frequent administration, and increased therapeutic dose range. Several groups and pharmaceutical companies have developed PEGylated IL-2 variants [112, 113], IL-2 muteins [114-116], fusion proteins of IL-2 linked to CD25 [117, 118], and IL-2:anti-IL-2 antibody complexes [93, 119-121] that promote cell expansion in vivo. 在 LD IL-2 治疗效果的推动下，为了克服其局限性，人们进一步致力于开发具有更佳药代动力学和选择性的第二代 IL-2。除了靶细胞选择性和减少脱靶效应外，这些努力的目标还包括延长新型分子的半衰期（代价是在出现不良反应时快速调整剂量）、减少给药次数和扩大治疗剂量范围。一些研究小组和制药公司已开发出促进体内细胞扩增的 PEG 化 IL-2 变体 [112，113]、IL-2 静音素 [114-116]、IL-2 与 CD25 连接的融合蛋白 [117，118]，以及 IL-2：抗 IL-2 抗体复合物 [93，119-121]。
Here, we will present promising IL-2-based molecules and clinical translation thereof with focus on selected therapeutic IL-2 molecules with post-translational modifications, IL-2 muteins, fusion proteins of IL-2 with other molecules, alternative delivery methods of IL-2, and IL-2:anti-IL-2 antibody complexes (Table 1). 在此，我们将介绍有前景的基于 IL-2 的分子及其临床转化，重点是经过翻译后修饰的特定治疗性 IL-2 分子、IL-2 静音素、IL-2 与其他分子的融合蛋白、IL-2 的替代给药方法以及 IL-2 与抗 IL-2 抗体复合物（表 1）。
PEGylated IL-2 variants 聚乙二醇化 IL-2 变体
PEGylation is a covalent conjugation of proteins to inert polyethylene glycol (PEG) moieties. PEGylation extends the halflife of protein therapeutics by increasing the effective molecular weight of the molecule, while the PEG moieties can also shield the proteins from digestion by proteolytic enzymes via increased steric hindrance. For example, a PEG-modified murine IL-2 increased IL-2 retention in vivo by protection from enzymatic digestion and renal clearance [122]. Although PEG is known as a safe, inert and non-immunogenic synthetic polymer, some FDAapproved drugs are associated with the development of antibodies against PEG moieties that accelerate drug clearance and loss of clinical efficacy PEG 化是将蛋白质与惰性聚乙二醇 (PEG) 分子共价结合。PEG 化通过增加分子的有效分子量来延长蛋白质疗法的半衰期，同时 PEG 分子还能通过增加立体阻碍来保护蛋白质不被蛋白水解酶消化。例如，PEG 改性的小鼠 IL-2 可防止酶消化和肾脏清除，从而提高 IL-2 在体内的存留率 [122]。尽管 PEG 是众所周知的安全、惰性和非免疫原性合成聚合物，但美国食品及药物管理局批准的一些药物会产生针对 PEG 分子的抗体，从而加速药物的清除和临床疗效的丧失。 .
NKTR-358/LY3471851/rezpegaldesleukin (Nektar/Lilly) is recombinant human IL-2 (aldesleukin sequence) chemically conjugated with stable PEG moieties, which has an attenuated affinity for IL NKTR-358/LY3471851/rezpegaldesleukin（Nektar/Lilly）是重组人 IL-2（醛白细胞介素序列），与稳定的 PEG 分子化学共轭，对 IL-2 的亲和力减弱。 compared with recombinant human IL-2. NKTR-358 promoted selective 与重组人 IL-2 相比，NKTR-358NKTR-358 促进了选择性 activation and increased 激活和增加 suppressive function in mice. The durability and specificity of the response was greater following a single subcutaneous administration of NKTR-358 compared to five daily administrations of IL-2, and led to disease suppression in a mouse delayed-type hypersensitivity (DTH) model [125]. Further, biweekly dosing induced preferential and sustained 对小鼠的抑制功能。与每天注射五次IL-2相比，单次皮下注射NKTR-358后反应的持久性和特异性更强，并能在小鼠迟发型超敏反应（DTH）模型中抑制疾病[125]。此外，双周给药可诱导优先和持续的 expansion in mice and non-human primates (NHP) resulting in ameliorated disease progression in a mouse model of systemic lupus erythematosus (SLE), and in a non-human primate cutaneous hypersensitivity model [112]. The single ascending dose study in healthy volunteers (NCT04133116) and the multiple ascending dose study with three biweekly subcutaneous doses of 在小鼠和非人灵长类动物（NHP）中进行扩增，结果改善了系统性红斑狼疮（SLE）小鼠模型和非人灵长类动物皮肤超敏模型的疾病进展[112]。在健康志愿者中进行的单次递增剂量研究（NCT04133116）和每两周三次皮下注射多剂量的
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rezpegaldesleukin versus placebo in patients with SLE (NCT03556007) yielded promising results [126]. Dose-dependent, selective, and sustained increases in percentages and absolute numbers of total CD4 and CD25 were observed, with no significant changes in conventional CD4 and CD8 T cells, and low-level increases in NK cells. At the highest dose tested, a 12-17-fold increase in CD25 bright over baseline was sustained for 20-30 days. Most adverse events were grade 1-2 injection-site reactions. Immunogenicity was not observed. SLE disease score was not evaluated due to study limitations, however, data for the follow-up phase randomised studies in psoriasis (NCT04119557) and atopic dermatitis (NCTO4081350) have been recently presented [127]. Treatment of patients with psoriasis with rezpegaldesleukin resulted in increased numbers, and improved disease score (PASI, psoriasis area and severity index) versus placebo, which was maintained up to week 19 posttreatment [128]. In atopic dermatitis, biweekly subcutaneous injections of rezpegaldesleukin increased total and CD25 bright during treatment period ( 12 weeks), while a dose-dependent improvement was observed in disease-relevant scores (EASI, eczema area and severity index) versus placebo up to 36 weeks following end of treatment [129]. Together with a favourable safety profile these data further support clinical development of rezpegaldesleukin in patients with atopic dermatitis [130]. Less encouraging data were reported for phase 2 ISLAND study (NCT04433585) that enroled adults with moderate-to-severe SLE. Although respegaldesleukin led to dose-dependent proliferation of , the primary endpoint of the study-a four-point reduction in the SLE disease activity index (SLEDAl-2K)—-was not met [131]. 在系统性红斑狼疮患者中使用雷贝格白细胞介素与安慰剂（NCT03556007）的研究结果令人鼓舞[126]。研究观察到总 CD4 和 CD25 的百分比和绝对数量出现了剂量依赖性、选择性和持续性的增加，常规 CD4 和 CD8 T 细胞无明显变化，NK 细胞出现了低水平的增加。在测试的最高剂量下，CD25亮度比基线增加了12-17倍，并持续了20-30天。大多数不良反应为 1-2 级注射部位反应。未观察到免疫原性。由于研究的局限性，没有对系统性红斑狼疮的疾病评分进行评估，但最近公布了银屑病（NCT04119557）和特应性皮炎（NCTO4081350）的随访阶段随机研究数据[127]。与安慰剂相比，使用雷贝格白细胞介素治疗银屑病患者的人数有所增加，疾病评分（PASI，银屑病面积和严重程度指数）也有所改善，而且这种改善一直维持到治疗后第 19 周[128]。在特应性皮炎中，每两周皮下注射一次雷贝格白细胞介素可在治疗期间（12 周）增加总亮度和 CD25 亮度，而在治疗结束后 36 周内，与安慰剂相比，疾病相关评分（EASI、湿疹面积和严重程度指数）的改善呈剂量依赖性[129]。这些数据以及良好的安全性进一步支持了雷贝格列白蛋白在特应性皮炎患者中的临床开发[130]。ISLAND 2 期研究（NCT04433585）的数据不太令人鼓舞，该研究招募了中重度系统性红斑狼疮成人患者。尽管复方地塞米松可导致中度至重度系统性红斑狼疮患者的血小板剂量依赖性增殖，但该研究的主要终点--系统性红斑狼疮疾病活动指数（SLEDAl-2K）降低四点--并未达到[131]。
THOR-809/SAR444336 (Synthorx/Sanofi) is a site-specific PEGylated IL-2 variant with a PEG moiety attached to an unnatural amino acid at the interface designed to increase half-life and enhance selectivity for the trimeric IL-2R. The modified IL-2 has a reduced affinity to the IL-2R chain so that the potency of trimeric engagement relies on the chain binding [132]. In mice and NHP, THOR-809 preferentially stimulated proliferation of peripheral relative to effector cells and NK cells. Expanded had sustained pSTAT5 signalling and upregulated suppression markers FOXP3, CD25, ICOS and HELIOS. Furthermore, THOR-809 administration in mice led to dosedependent expansion of highly suppressive and control of skin inflammation in the DTH mouse model [133]. A phase 1 trial in healthy subjects (NCT05876767) is currently ongoing [134]. THOR-809/SAR444336（Synthorx/Sanofi）是一种位点特异性 PEG 化 IL-2 变体，其界面上的一个非天然氨基酸上附有 PEG 分子，旨在延长半衰期并提高对三聚体 IL-2R 的选择性。改良后的 IL-2 与 IL-2R 链的亲和力降低，因此三聚体参与的效力依赖于链的结合 [132]。在小鼠和 NHP 中，相对于效应细胞和 NK 细胞，THOR-809 能优先刺激外周细胞的增殖。增殖的细胞具有持续的 pSTAT5 信号，并上调抑制标记物 FOXP3、CD25、ICOS 和 HELIOS。此外，在 DTH 小鼠模型中，给小鼠服用 THOR-809 会导致高度抑制性皮肤炎症的剂量依赖性扩增和控制 [133]。目前正在进行健康受试者的 1 期试验（NCT05876767）[134]。
Another promising IL-2 variant with site-specific PEGylation, designated dual 31/51-20 K, similarly displayed substantially increased clearance half-life, preferentially stimulated over effector T cells compared with unmodified IL-2 by selectively reducing the binding affinity for the subunit of IL-2R, and significantly reduced disease activity and severity in mouse models of xenogeneic graft-versus-host disease (GvHD), SLE and collagen-induced arthritis. Moreover, a single subcutaneous injection of this PEGylated IL-2 did not induce anti-drug antibody formation, nor did it compromise the host defence against viral infection [113]. 另一种很有前景的 IL-2 变体是经特定位点 PEG 化的 IL-2，被命名为 dual 31/51-20 K，与未修饰的 IL-2 相比，它通过选择性降低与 IL-2R 亚基的结合亲和力，大大延长了清除半衰期，优先刺激效应 T 细胞，并在异种移植物抗宿主病（GvHD）、系统性红斑狼疮和胶原诱发关节炎的小鼠模型中显著降低了疾病的活动性和严重程度。此外，单次皮下注射这种 PEG 化 IL-2 不会诱导抗药抗体的形成，也不会损害宿主对病毒感染的防御能力 [113]。
IL-2 muteins IL-2 静音素
The elucidation of the crystal structure of IL-2 bound to its trimeric receptor [11, 135, 136] facilitated the informed introduction of mutations into IL-2 with the aim to increase its affinity or direct its binding. Such targeted mutagenesis allows to uncouple the pleiotropic effects of IL-2 on different immune cells and to target IL-2 activity toward specific cell populations that express either the dimeric IL-2R to boost tumour immunity or the trimeric IL-2R expressed by to increase tolerance in autoimmunity and to transplanted grafts. IL-2 variants with increased binding to CD25 and/or decreased binding to CD122 and/or CD132 preferentially activate and expand . These cytokines are further fused to either the fragment crystalisable ( ) domain of immunoglobulin IL-2与其三聚体受体结合的晶体结构的阐明[11, 135, 136]有助于在知情的情况下将突变引入IL-2，以增加其亲和力或引导其结合。这种有针对性的诱变可以解除 IL-2 对不同免疫细胞的多效作用，使 IL-2 的活性针对表达二聚体 IL-2R 的特定细胞群，以增强肿瘤免疫力，或针对表达三聚体 IL-2R 的特定细胞群，以增强自身免疫和移植移植物的耐受性。与 CD25 结合增加和/或与 CD122 和/或 CD132 结合减少的 IL-2 变体可优先激活和扩增.IL-2。这些细胞因子进一步与免疫球蛋白的片段可结晶（ ）结构域融合。
( ) or the full , which results in significantly extended half-life due to increased hydrodynamic radius and hence decreased renal clearance but also due to the recycling of the protein via the neonatal Fc receptor. In the following paragraphs, we discuss a selection of promising mutein molecules, each designed for selectivity and application in autoimmune or inflammatory disease, that are currently in clinical development. ()或全价，由于增加了流体力学半径，从而降低了肾脏清除率，但也由于蛋白质通过新生儿 Fc 受体的再循环，导致半衰期显著延长。在下面的段落中，我们将讨论一些有前景的静音蛋白分子，它们都具有选择性，可用于自身免疫性或炎症性疾病，目前正处于临床开发阶段。
AMG592 or efavaleukin alpha (Amgen) is an IL-2 mutein with V91K/C125A mutations that confers high CD25-binding affinity, and that is expressed as a fusion to the C-terminus of an Fc homodimer [137]. In a first-in-human study, efavaleukin alpha single subcutaneous administration resulted in dose-dependent expansion, which was highly selective relative to conventional cells ( ) and NK cells. -to- ratio peaked at day 8 (4fold vs baseline) and remained elevated up to day 29, while no increases in serum proinflammatory cytokines IL-6, TNFa or IFNY were detected. The expanded displayed increased CD25 and FOXP3 levels and were enriched for CD31 recent thymic emigrants. Treatment was well tolerated [138] and several earlyphase studies were initiated to further evaluate safety and efficacy in subjects with rheumatoid arthritis (RA) (NCT03410056), steroidrefractory chronic GvHD (NCT03422627), and SLE (NCT03451422). Amgen ended the trials in RA due to insufficient therapeutic benefit for the use of efavaleukin alpha plus standard of care therapy in the assessed study population (NCTO3410056); and chronic GvHD [139]. Data from a multiple ascending dose phase 1b study in patients with SLE demonstrated that efavaleukin alpha was well tolerated and induced a robust and prolonged dosedependent expansion, with minimal changes in CD4 and CD8 NK cells or serum levels of pro-inflammatory cytokines [140]. The biweekly administration resulted in a 50 -fold increase in CD25 bright above baseline, and the numbers remained above baseline for an average of 42 days after the last dose. Despite these promising results, a phase study of efavaleukin alpha in patients with SLE (NCT04680637) has been discontinued as it met pre-defined criteria for futility, i.e., it was unlikely to achieve its objectives [141]. However, a phase 2 study in ulcerative colitis (NCT04987307) is still ongoing. AMG592或efavaleukin alpha（安进公司）是一种具有V91K/C125A突变的IL-2静默素，具有很高的CD25结合亲和力，并以融合到Fc同源二聚体C端的形式表达[137]。在首次人体研究中，efavaleukin alpha 单次皮下注射可导致剂量依赖性扩增，相对于常规细胞（）和 NK 细胞具有高度选择性。-to-比率在第8天达到峰值（与基线相比增加了4倍），并在第29天保持升高，而血清中的促炎细胞因子IL-6、TNFa或IFNY没有增加。扩增的胸腺细胞显示 CD25 和 FOXP3 水平升高，并富含 CD31 近期胸腺移植物。治疗耐受性良好[138]，并启动了几项早期研究，以进一步评估类风湿性关节炎（RA）（NCT03410056）、类固醇难治性慢性GvHD（NCT03422627）和系统性红斑狼疮（NCT03451422）受试者的安全性和有效性。由于在接受评估的研究人群（NCTO3410056）中使用依伐白蛋白α加标准护理疗法的治疗效果不佳，安进公司终止了在RA和慢性GvHD[139]的试验。一项针对系统性红斑狼疮患者的多剂量递增 1b 期研究数据显示，依法白细胞介素α的耐受性良好，并能诱导强效、长时间的剂量依赖性扩增，CD4 和 CD8 NK 细胞或血清中促炎细胞因子水平的变化极小[140]。每两周一次的给药使 CD25 亮度比基线增加了 50 倍，在最后一次给药后的平均 42 天内，CD25 亮度仍高于基线。尽管取得了这些令人鼓舞的结果，但一项针对系统性红斑狼疮患者的依伐白细胞介素α的阶段性研究（NCT04680637）已经终止，因为它达到了预先设定的徒劳标准，即不可能实现其目标[141]。不过，一项针对溃疡性结肠炎的 2 期研究（NCT04987307）仍在进行中。
RG7835 (Roche) is a bivalent conjugate of human IL-2 mutein (T3A, N88D, C125A) and a human IgG1 with abolished binding to Fcy receptors. Due to its reduced affinity to IL-2R , IgG-(IL2N88D) 2 has a 6-9-fold reduced ability to stimulate in human whole blood pSTAT5 activation assays compared to a wild-type IL-2 dimer but had no effect on other cell types except some activity on CD56 NK cells. Treatment of cynomolgus monkeys and humanised NSG mice (engrafted with human foetal liver CD34 cells) with a single dose of -(IL-2N88D) induced sustained 10 14-fold expansion of CD4 and CD8 CD25 FOXP3 with no effect on other cell types. The in vivo activated and expanded cynomolgus and human had demethylated epigenetic signatures for FOXP3 and CTLA4 characteristic of functionally suppressive cells. However, neither mouse disease models nor multiple-dose studies in NHP could be performed due to the immunogenicity of the molecule in both species [115]. Phase 1 b study initiated to assess safety, efficacy, pharmacokinetics, and pharmacodynamics of RG7835 in patients with ulcerative colitis (NCT03943550) was terminated after 8 weeks based on the lack of robust clinical improvement in the underlying condition, according to ClinicalTrials.gov. Following the failure in ulcerative colitis, a phase 2 clinical trial designed to evaluate the effect of RG7835 on time to relapse following forced corticosteroid tapering in patients with autoimmune hepatitis (NCT04790916) was also terminated. RG7835（罗氏）是人 IL-2 mutein（T3A、N88D、C125A）和人 IgG1 的二价共轭物，其与 Fcy 受体的结合被取消。由于与 IL-2R 的亲和力降低，IgG-(IL2N88D) 2 在人全血 pSTAT5 活化试验中的刺激能力比野生型 IL-2 二聚体降低了 6-9 倍，但除了对 CD56 NK 细胞有一些活性外，对其他类型的细胞没有影响。用单剂量的-（IL-2N88D）处理野猴和人源化 NSG 小鼠（接种人胎肝 CD34 细胞），可诱导 CD4 和 CD8 CD25 FOXP3 持续扩增 10 14 倍，但对其他细胞类型没有影响。体内活化和扩增的犬科动物和人类的 FOXP3 和 CTLA4 表观遗传学特征为去甲基化，具有功能抑制细胞的特征。然而，由于该分子在两种动物中的免疫原性，小鼠疾病模型和 NHP 多剂量研究都无法进行 [115]。.NCT03943550》称，为评估 RG7835 在溃疡性结肠炎患者中的安全性、有效性、药代动力学和药效学而启动的 1 b 期研究（NCT03943550）在 8 周后终止，原因是基础病症缺乏有力的临床改善。继溃疡性结肠炎试验失败后，一项旨在评估 RG7835 对自身免疫性肝炎患者强制减量皮质类固醇后复发时间的影响的 2 期临床试验（NCT04790916）也被终止。
Using a structure-guided approach, several mutations in IL-2 were introduced that significantly decreased CD122 binding affinity in addition to other mutations that increased CD25 binding affinity (L118I, N88D, V69A, Q74P, C125S) [142]. The resulting Fc-fusion molecules, PT101/MK-6194 (Pandion/Merck), selectively activated and expanded in preclinical studies in humanised NSG mice and NHP without significant effects on other immune cell types, and without eliciting proinflammatory cytokine production [143]. These expanded had increased expression of FOXP3 and CD25, suggesting enhanced function and stability. In a phase 1a single ascending dose clinical trial in healthy volunteers, PT101 was safe and well-tolerated, and a dosedependent expansion of CD25 cells was observed with mean maximum increase of 72.5 -fold for CD25 bright by day 8-10 (and an overall 3.6-fold increase in total ) [144]. and NK cells were not increased while increases in eosinophil counts were transient. A phase 1 clinical trial in ulcerative colitis (NCT04924114) was initiated by Merck & Co. in 2021 to further evaluate PT101/MK-6194. 利用结构引导方法，在 IL-2 中引入了几个突变，这些突变除了增加 CD25 结合亲和力（L118I、N88D、V69A、Q74P、C125S）外，还显著降低了 CD122 结合亲和力 [142]。由此产生的 Fc 融合分子 PT101/MK-6194（Pandion/Merck）在人源化 NSG 小鼠和 NHP 的临床前研究中选择性激活和扩增，对其他免疫细胞类型无明显影响，也不会引起促炎细胞因子的产生 [143]。这些扩增的 FOXP3 和 CD25 表达增加，表明功能和稳定性增强。在一项针对健康志愿者的 1a 期单次递增剂量临床试验中，PT101 安全且耐受性良好，观察到 CD25 细胞的剂量依赖性扩增，到第 8-10 天，CD25 亮细胞的平均最大增幅为 72.5 倍（总增幅为 3.6 倍）[144]。默克公司于 2021 年启动了一项针对溃疡性结肠炎的 1 期临床试验（NCT04924114），以进一步评估 PT101/MK-6194。
A similar molecule, an IL-2 mutein (T3A, N88R, C125S) fused to a human IgG Fc domain, DEL106/CC-92252 (Delinia/Celgene/BMS) also preferentially binds to IL-2Ra. A single intravenous dose of the compound in cynomolgus monkeys resulted in dose-dependent and selective expansion and activation, which was better 一种类似的分子，即与人 IgG Fc 结构域融合的 IL-2 mutein（T3A、N88R、C125S），DEL106/CC-92252（Delinia/Celgene/BMS）也能优先与 IL-2Ra 结合。在绒猴体内单次静脉注射该化合物可导致剂量依赖性和选择性的扩增和激活，其效果更佳。
was 15 -fold on day 5 , while no change in the number of circulating or CD8 cells was detected. The compound also stimulated expression of suppression and proliferation markers CD25, FOXP3 and Ki67 on IL-2 induced selective STAT5 phosphorylation of over a narrow dose range, also activating CD8 T, NK and B cells; in contrast, DEL106 demonstrated over 1000 -fold-greater selectivity for over other immune cells. In addition, subcutaneous administration showed that DEL106 exhibited a lower serum clearance and had a longer circulating half-life than IL-2. A phase 1 first-in-human study with this molecule was conducted in three parts: as a single ascending dose or multiple ascending dose study in healthy volunteers and a multiple ascending dose study in psoriasis patients (NCT03971825). CC-92252 was found safe and well-tolerated across studies with adverse effects of mild to moderate intensity. The treatment resulted in a selective but modest (maximum 2fold) expansion in circulation of healthy participants and in skin lesions of participants with psoriasis. However, as for RG7835 (Roche), no apparent trend of clinical improvement compared to placebo was observed in patients, indicating that the achieved expansion may be insufficient for robust efficacy in active disease. Mechanistic studies revealed that although highly selective, CC-92252 is a weak partial agonist with only a subset of responding to this IL-2 mutein [146]. Given limited evidence for clinical efficacy, the CC-92252 programme has been discontinued, although BMS is pursuing alternative approaches to selectivity with IL-2 constructs (see below, with IL-2/CD25 fusion). 在第 5 天，CD8 细胞的数量增加了 15 倍，而循环细胞或 CD8 细胞的数量没有变化。该化合物还能刺激抑制和增殖标志物 CD25、FOXP3 和 Ki67 的表达，IL-2 诱导的选择性 STAT5 磷酸化剂量范围较窄，也能激活 CD8 T、NK 和 B 细胞；相比之下，DEL106 对其他免疫细胞的选择性超过 1000 倍。此外，皮下注射显示，与 IL-2 相比，DEL106 的血清清除率更低，循环半衰期更长。对该分子的 1 期首次人体试验分三部分进行：在健康志愿者中进行的单剂量或多剂量递增试验，以及在银屑病患者中进行的多剂量递增试验（NCT03971825）。在各项研究中，CC-92252的安全性和耐受性良好，不良反应程度为轻度至中度。在健康参与者的血液循环和银屑病参与者的皮损中，该疗法导致了选择性但适度（最多 2 倍）的扩增。然而，与 RG7835（罗氏）一样，与安慰剂相比，在患者中没有观察到明显的临床改善趋势，这表明所实现的扩张可能不足以在活动性疾病中产生强大的疗效。机制研究显示，CC-92252 虽然具有高度选择性，但却是一种弱的部分激动剂，只有一部分患者对这种 IL-2 静音素有反应[146]。鉴于临床疗效证据有限，CC-92252 项目已经终止，不过 BMS 仍在寻找 IL-2 构建物（见下文，IL-2/CD25 融合）选择性的替代方法。
The therapeutic molecule CUG252 (Cugene/Abbvie) is an IL-2 mutein (L19H, C125I, Q126E) Fc-fusion protein designed for biased binding activity to IL-2Ra but attenuated binding to the IL-2R complex [147]. In mice and cynomolgus monkeys, administration of CUG252 resulted in dose-dependent increases in expansion by 10 - to 30 -fold, with largely abolished activities in effector T cells and NK cells [148]. had enhanced expression of functional and inhibitory markers (CD25, FOXP3, PD-1, CTLA-4, TIM3 and ICOS) and increased suppressive capacity in DTH. In T cell-dependent antibody response models, CUG252 strongly inhibited antigendriven inflammation, B cell maturation, and antibody production. The molecule is currently in phase 1 study, which aims to evaluate the safety and tolerability of single escalating subcutaneous doses of CUG252 in healthy adult subjects, and multiple escalating subcutaneous doses of CUG252 in patients with mild to moderate SLE (NCT05328557). 治疗分子 CUG252（Cugene/Abbvie）是一种 IL-2 mutein（L19H、C125I、Q126E）Fc 融合蛋白，设计用于偏向结合 IL-2Ra 的活性，但减弱与 IL-2R 复合物的结合 [147]。在小鼠和猕猴体内，给药 CUG252 可导致剂量依赖性扩增 10 至 30 倍，但效应 T 细胞和 NK 细胞的活性基本消失 [148]。在 T 细胞依赖性抗体反应模型中，CUG252 能强烈抑制抗原驱动的炎症、B 细胞成熟和抗体产生。该分子目前正在进行 1 期研究，目的是评估单次递增皮下注射 CUG252 对健康成人受试者的安全性和耐受性，以及多次递增皮下注射 CUG252 对轻中度系统性红斑狼疮患者的安全性和耐受性（NCT05328557）。
MDNA209 (Medicenna) is an IL-2 mutein (L18R, Q22E, Q126T, S130R) with increased affinity to the IL-2R and greatly decreased affinity for IL-2RY, resulting in attenuated IL-2R heterodimerization and reduced signalling. The design of MDNA209 is based on 异二聚化并减少信号传导。MDNA209 的设计基于
the scaffold of IL-2 'superkine' variants that had an increased affinity for the IL-2 "超级激酶 "变体的支架，这些变体对IL-2的亲和力更强。 chain of the IL-2 receptor [114]. Rather than triggering IL-2 signalling, however, MDNA209 acts as an antagonist, blocking the receptor and preventing it from transmitting the signal. When targeted to T cell subsets, this IL-2 variant could be clinically translated in the context of controlling T-cell mediated (auto)immune disorders where it is essential to prevent effector T cell activation and expansion resulting in effector cell-mediated tissue damage, such as during acute GvHD. The mutein and its Fcfusion version have been characterised ex vivo and in vivo. MDNA209 prevented IL-2- and IL-15-induced signalling via STAT5 and blocked proliferation of cells and cells, while inhibiting helper cell type ( ) and cells but promoting cell differentiation. Mice treated with an Fc-fusion version of MDNA209 for 10 days showed prolonged survival in a full MHC-mismatched acute GvHD model compared to control IgG [149]. MDNA209（Medicenna）是一种IL-2静音素（L18R、Q22E、Q126T、S130R），对IL-2R的亲和力增强，而对IL-2RY的亲和力大大降低，导致IL-2受体的IL-2R链减弱[114]。然而，MDNA209 并不触发 IL-2 信号，而是作为一种拮抗剂，阻断受体并阻止其传递信号。当针对 T 细胞亚群时，这种 IL-2 变体可在临床上用于控制 T 细胞介导的（自身）免疫性疾病，在这种情况下，防止效应 T 细胞活化和扩增导致效应细胞介导的组织损伤至关重要，例如在急性 GvHD 期间。已对静音素及其 Fcfusion 版本进行了体内外表征。MDNA209 通过 STAT5 阻止了 IL-2 和 IL-15 诱导的信号传导，并阻断了细胞和细胞的增殖，同时抑制了辅助细胞类型（ ）和细胞，但促进了细胞分化。与对照 IgG 相比，用 Fc 融合型 MDNA209 治疗 10 天的小鼠在完全 MHC 不匹配的急性 GvHD 模型中存活时间更长 [149]。
Other IL-2 fusion proteins 其他 IL-2 融合蛋白
An alternative approach to increase the selectivity of IL-2 for is through fusion with CD25. The mouse IL-2/CD25 fusion protein forms a tight inactive dimer that slowly releases the active monomer to stimulate the high-affinity IL-2R [117]. The longacting biologic expands in vivo more potently than IL-2, but also increases their activation and migration into lymphoid tissues as well as non-lymphoid tissues as shown for the pancreas and its inhibition of anti-insulin autoantibodies. Moreover, the IL-2/CD25 fusion protein was effective in treating diabetes and inhibiting lupus nephritis in mouse models [118, 150]. The human version of the compound is a full agonist, which maintains high selectivity on over other cell types in whole blood pSTAT5 assays [151]. The human IL-2/CD25 had a prolonged half-life and induced a dosedependent selective increase in in cynomolgus monkeys compared to IL-2 or IL-2 mutein Fc-fusion molecules [146]. The first-in-human study is still ongoing, but preliminary single-dose pharmacodynamics data confirm robust and prolonged induction in humans with no expansion of inflammatory CD8 or cells 另一种提高 IL-2 选择性的方法是与 CD25 融合。小鼠的 IL-2/CD25 融合蛋白会形成一个紧密的非活性二聚体，并缓慢释放出活性单体以刺激高亲和力的 IL-2R [117]。这种长效生物制剂在体内的扩增作用比 IL-2 更强，而且还能增加它们的活化和向淋巴组织及非淋巴组织的迁移，如在胰腺及其对抗胰岛素自身抗体的抑制作用所示。此外，在小鼠模型中，IL-2/CD25 融合蛋白还能有效治疗糖尿病和抑制狼疮肾炎 [118，150]。该化合物的人类版本是一种完全激动剂，在全血 pSTAT5 检测中对其他类型的细胞保持较高的选择性 [151]。与 IL-2 或 IL-2 mutein Fc 融合分子相比，人 IL-2/CD25 的半衰期较长，能诱导犬科猴体内剂量依赖性选择性增加 [146]。首次用于人体的研究仍在进行中，但初步的单剂量药效学数据证实，该药物在人体中的诱导作用强劲且持续时间长，不会导致炎性 CD8 或细胞的扩增[147]。 .
CUE-401 (Cue Biopharma) is a tolerogenic IL-2/TGF Fc-fusion protein designed to activate and induce FOXP3 expression in CD4 T cells ( ). In mouse CD4 T cells, it induces FOXP3 expression in vitro ( ). Also, in human CD4 T cells from healthy donors, inflammatory bowel disease and RA patients, it results in increased number of FOXP3-expressing cells, however, induction of FOXP3 expression versus preferential expansion of containing has not been dissected. The in vitro induced/expanded suppress polyclonal T cell proliferation and express comparable phenotypic CUE-401（Cue Biopharma）是一种可耐受的 IL-2/TGF Fc 融合蛋白，旨在激活和诱导 CD4 T 细胞中 FOXP3 的表达（）。在小鼠 CD4 T 细胞中，它能在体外诱导 FOXP3 的表达（）。此外，在来自健康供体、炎症性肠病和 RA 患者的人类 CD4 T 细胞中，它也会导致表达 FOXP3 的细胞数量增加，然而，诱导 FOXP3 表达与优先扩增包含的问题尚未得到研究。体外诱导/扩增可抑制多克隆 T 细胞的增殖，并表达相似的表型。
CTLA-4, PD-1, GITR, CD38, CD73, GARP). A single dose of CUE-401 administered to TXA23 mice with ongoing autoimmune gastritis increased FOXP3 CD4 T cells in blood and lymph nodes and inhibited autoreactive cell proliferation in gastric lymph nodes CTLA-4、PD-1、GITR、CD38、CD73、GARP）。给患有持续性自身免疫性胃炎的 TXA23 小鼠注射单剂量 CUE-401 可增加血液和淋巴结中的 FOXP3 CD4 T 细胞，并抑制胃淋巴结中的自反应细胞增殖。 .
TNF signalling via TNFR2 enhances expansion, function and stability of [156]. A dual-acting fusion protein, with IL-2 fused to a TNFR2-selective TNF mutein (IL2-EHD2-sc-mTNFR2) promoted TNF 信号通过 TNFR2 增强[156]的扩增、功能和稳定性。IL-2 与 TNFR2 选择性 TNF 缄默蛋白（IL2-EHD2-sc-mTNFR2）的双重作用融合蛋白促进了
compared to either IL-2 or TNFR2 stimulation alone, with both components necessary for superior biological activity [157]. The combination of IL-2 and a TNFR2 agonist is therefore a promising approach for selective expansion in vivo [158]. 与 IL-2 或 TNFR2 单独刺激相比，IL-2 和 TNFR2 共同作用可产生更强的生物活性 [157]。因此，IL-2 和 TNFR2 激动剂的结合是在体内进行选择性扩增的一种很有前景的方法 [158]。
Alternative IL-2 delivery methods 其他 IL-2 给药方法
The therapeutic IL-2 molecules described above are expressed in living cells and are administered as formulations of recombinant protein. Novel technologies are instead based on the in situ expression of encoded proteins and include lipid nanoparticle (LNP)-mediated mRNA delivery, DNA vaccines and gene transfer using viral vectors. Nucleic acid therapeutics are considered safe, well-tolerated and efficacious with major advantages over proteinbased therapeutics including simple and cost-effective production processes and opportunities to improve the drug characteristics [159, 160]. However, several challenges remain. The greatest challenge for mRNA nanomedicine is immunogenicity both against the LNP itself as well as against the mRNA-encoded proteins. With gene therapies, which are designed for permanent integration of the viral vector into genome, the uncertainty about delayed adverse events remains the greatest risk factor [160]. 上述治疗性 IL-2 分子在活细胞中表达，并作为重组蛋白制剂给药。新技术则以编码蛋白质的原位表达为基础，包括脂质纳米粒子（LNP）介导的 mRNA 给药、DNA 疫苗和使用病毒载体的基因转移。核酸疗法被认为是安全、耐受性好、疗效显著的疗法，与基于蛋白质的疗法相比，其主要优势包括生产工艺简单、成本效益高，并有机会改善药物特性 [159，160]。然而，仍存在一些挑战。mRNA 纳米药物面临的最大挑战是针对 LNP 本身和 mRNA 编码蛋白质的免疫原性。基因疗法旨在将病毒载体永久整合到基因组中，因此延迟不良事件的不确定性仍是最大的风险因素 [160]。
mRNA-6231 (Moderna) is a lipid nanoparticle (LNP)-encapsulated mRNA encoding a -specific IL-2 mutein fused to human serum albumin (HSA). Two triple-mutant molecules (V69A/Q74P/N88D or V69A/Q74P/V91K) showed the highest difference in pSTAT5 signal between and other cell subsets in human PBMC in vitro and selectively activated and expanded in mice. LNP-formulated mRNA encoding HSA fused to wild-type IL-2 elevated the percentage of in cynomolgus monkeys and was also effective in preclinical models of murine acute GvHD and collagen-induced rat arthritis [161, 162]. The first-in-human trial of mRNA-6231 in healthy adult participants (NCTO4916431) was stopped after early clinical data became available [163]. mRNA-6231（Moderna）是一种脂质纳米粒子（LNP）封装的 mRNA，编码与人血清白蛋白（HSA）融合的特异性 IL-2 mutein。两个三重突变分子（V69A/Q74P/N88D 或 V69A/Q74P/V91K）在体外人 PBMC 中显示出与其他细胞亚群之间最大的 pSTAT5 信号差异，并在小鼠体内选择性激活和扩增。与野生型 IL-2 融合的编码 HSA 的 LNP 制剂 mRNA 提高了野生猴中 HSA 的比例，在小鼠急性 GvHD 和胶原诱导的大鼠关节炎的临床前模型中也很有效 [161，162]。mRNA-6231 在健康成人参与者中的首次人体试验（NCTO4916431）在获得早期临床数据后停止了[163]。
A tolerogenic immunotherapy NNC0361-0041 (Novo Nordisk) involves a DNA plasmid which encodes for pre-proinsulin (PPI), TGF , IL-10, and IL-2 [164]. The combination of antigen (PPI) with the three immune response modifiers (TGF , and ) is intended to induce antigen-specific accumulating in the pancreas, and to preserve beta cell function in type 1 diabetes (T1D). The safety and efficacy of treatment was demonstrated in NOD mice as assessed by delayed disease progression, necessity of both antigen and IL-2 for increased efficacy and robustness, and tolerability of chronic dosing [165]. However, no pharmacodynamicrelated measurements such as activity or cytokine expression were performed. The phase 1 trial in adults with recent-onset T1D is currently recruiting and will evaluate safety, tolerability, and pharmacokinetics of the therapy (NCT04279613). 耐受性免疫疗法NNC0361-0041（诺和诺德公司）涉及一种DNA质粒，该质粒编码前胰岛素（PPI）、TGF、IL-10和IL-2[164]。抗原（PPI）与三种免疫反应调节剂（TGF、IL-10 和 IL-2）的结合旨在诱导抗原特异性在胰腺中蓄积，并保护 1 型糖尿病（T1D）患者的 beta 细胞功能。治疗的安全性和有效性已在 NOD 小鼠中得到证实，其评估指标包括疾病进展延迟、抗原和 IL-2 对提高疗效和稳健性的必要性以及长期用药的耐受性 [165]。不过，没有进行药效学相关测量，如活性或细胞因子表达。针对新发 T1D 成人的 1 期试验目前正在招募，将评估该疗法的安全性、耐受性和药代动力学（NCT04279613）。
Adeno-associated viral (AAV) vector-mediated gene transfer for systemic and continuous IL-2 production has been investigated using a single administration of an AAV-IL-2 vector in mice. The treatment enabled sustained stimulation and expansion of without inducing effector cell activation while preventing diabetes in NOD mice [109] or alleviating Alzheimer's disease in APP/PS1 E9 mice with established pathology [166]. Moreover, the long-term IL-2 expression did not impair immune responses to infections, vaccination or cancer [109]. However, this approach does not allow to interrupt or stop the treatment in case of adverse events. A tissue-specific gene-delivery approach of IL-2 for the treatment of neuroinflammatory pathologies has been developed by Yshii et al. constitute a small resident cell population in the brain, where low levels of IL-2 are thought to limit the natural anti-inflammatory processes. Tissue-specific IL-2 expression targeted to astrocytes via an AAV vector induced a local and transient expansion of the cell population in the mouse brain, which led to beneficial effects in mouse models of traumatic brain injury, multiple sclerosis and stroke [167]. Both the tissue-specific IL-2 delivery system as well as the ability to control the encoded protein expression are promising approaches to improve the clinical translation of gene therapy. 研究人员利用单次给小鼠注射 AAV-IL-2 载体的方法，研究了腺相关病毒（AAV）载体介导的基因转移对全身性和持续性 IL-2 生产的影响。这种治疗方法能在不诱导效应细胞活化的情况下实现持续刺激和扩增，同时还能预防 NOD 小鼠的糖尿病 [109]，或缓解已确诊病理的 APP/PS1 E9 小鼠的阿尔茨海默病 [166]。此外，长期表达 IL-2 不会损害对感染、疫苗接种或癌症的免疫反应 [109]。不过，这种方法无法在出现不良反应时中断或停止治疗。Yshii 等人开发了一种组织特异性 IL-2 基因递送方法，用于治疗神经炎症病症。通过 AAV 载体针对星形胶质细胞的组织特异性 IL-2 表达诱导了小鼠大脑中细胞群的局部和短暂扩张，从而对小鼠脑外伤、多发性硬化和中风模型产生了有益的影响 [167]。组织特异性 IL-2 递送系统以及控制编码蛋白表达的能力都是改善基因疗法临床转化的有前途的方法。
Coupling of IL-2 to specific monoclonal antibodies can modify the interaction of IL-2 with its receptor leading to a targeted and longer-lasting in vivo biological activity compared with soluble IL2 [93, 119]. Depending on the antibody-binding site on IL-2, the IL2:antibody complex (IL-2c) can preferentially activate either the cells expressing high levels of CD122, such as memory CD8 T cells and NK cells, or CD25-expressing cells such as . A prominent and well-studied example is the complex of mouse IL-2 bound to .一个突出的、研究得很透彻的例子是小鼠 IL-2 与钙离子结合的复合物。
the anti-mouse IL-2 antibody JES6-1. JES6-1 binding sterically obstructs mouse IL-2 interaction with the IL-2R 抗小鼠 IL-2 抗体 JES6-1。JES6-1 与小鼠 IL-2 的结合会固态地阻碍 IL-2 与 IL-2R 的相互作用 heterodimer to block the signalling on IL-2Ra effector cells. Thereupon, IL-2 is preferentially delivered to the trimeric receptor via a unique allosteric exchange mechanism, where the IL-2Ra subunit displaces the JES6-1 antibody allowing IL-2 to initiate signalling via the subunits. This complex prolonged the in vivo halflife of IL-2 and led to selective expansion of murine in a murine dextran sodium sulphate colitis model [119, 168]. The efficacy of this approach has been further demonstrated in various experimental models of autoimmune diseases or other inflammatory settings as exemplified below: 将 IL-2 与特异性单克隆抗体偶联可改变 IL-2 与其受体的相互作用，与可溶性 IL2 相比，IL-2 在体内的生物活性更有针对性且更持久[93, 119]。根据 IL-2 上的抗体结合位点，IL2：抗体复合物（IL-2c）可优先激活表达高水平 CD122 的细胞，如记忆 CD8 T 细胞和 NK 细胞，或表达 CD25 的细胞，如异源二聚体，以阻断 IL-2Ra 效应细胞上的信号传导。随后，IL-2 通过一种独特的异位交换机制优先传递给三聚受体，其中 IL-2Ra 亚基置换 JES6-1 抗体，使 IL-2 通过亚基启动信号传导。这种复合物延长了 IL-2 在体内的半衰期，并在小鼠右旋糖酐硫酸钠结肠炎模型中导致小鼠选择性扩增 [119，168]。这种方法的功效已在各种自身免疫性疾病或其他炎症实验模型中得到进一步证实，举例如下：
enhanced allograft survival in a murine model of islet transplantation and experimental autoimmune encephalomyelitis (EAE) prevention in combination with rapamycin [169], 在小鼠胰岛移植模型中提高了异体移植物存活率，与雷帕霉素联合使用可预防实验性自身免疫性脑脊髓炎（EAE）[169]、
markedly attenuated acute GvHD while preserving graftversus-leukaemia activity after allo-hematopoietic cell transplantation at higher efficacy than tacrolimus treatment [170], 与他克莫司疗法相比，该疗法能明显减轻异体造血细胞移植后的急性并发症，同时保留移植物抗白血病活性，疗效更高[170]、
survival of fully MHC-mismatched skin allograft: IL-2c failed to augment the survival of skin allografts as monotherapy but initial treatment with anti-IL-6 monoclonal antibody followed by supplementation with rapamycin led to graft survival and elevated intra-graft levels [171], 完全 MHC 不匹配的皮肤异体移植的存活率：IL-2c作为单一疗法无法提高皮肤异体移植的存活率，但使用抗IL-6单克隆抗体进行初始治疗并辅以雷帕霉素可提高移植存活率和移植体内水平[171]、
attenuation of CNS inflammation and neurological deficits in EAE [172], 减轻 EAE 中的中枢神经系统炎症和神经功能缺损 [172]、
suppression of experimental myasthenia gravis [173], 抑制实验性肌无力症 [173]、
inhibition of collagen-induced arthritis [174], 抑制胶原诱导的关节炎 [174]、
attenuation of atherosclerosis in apolipoprotein E-deficient mice [175], 减弱脂蛋白 E 缺乏小鼠的动脉粥样硬化 [175]、
decreased myofiber injury in murine muscular dystrophy model 减少小鼠肌肉萎缩症模型中的肌纤维损伤 .
These results motivate the investigation of IL-2-based therapies in inflammatory diseases or conditions that are not caused by autoimmune or alloimmune reactions. 这些结果推动了对非自身免疫或同种免疫反应引起的炎症性疾病或病症进行基于 IL-2 疗法的研究。
A fully human anti-IL-2 antibody F5111.2 that resembles the exchange mechanism observed for the anti-mouse IL-2 antibody JES6-1, was developed by Trotta et al. [120]. Comparison of the crystal structure of IL-2c with the IL-2/IL-2R quaternary structure revealed that F5111.2 sterically obstructs the binding of human IL2 to IL-2R and allosterically reduces the affinity of the cytokine to IL-2Ra. Administration of F5111.2-hIL-2 complex results in the preferential STAT5 phosphorylation of in vitro and selective expansion of in vivo. When complexed with human IL-2, F5111.2 induced remission of T1D in the NOD mouse model, reduced disease severity in a model of EAE and protected mice against xenogeneic GvHD [120]. Trotta 等人[120]开发了一种全人源抗 IL-2 抗体 F5111.2，它与抗小鼠 IL-2 抗体 JES6-1 的交换机制相似。将 IL-2c 的晶体结构与 IL-2/IL-2R 的四元结构进行比较后发现，F5111.2 在立体上阻碍了人 IL2 与 IL-2R 的结合，并在异构上降低了细胞因子与 IL-2Ra 的亲和力。服用 F5111.2-hIL-2 复合物会导致体外 STAT5 优先磷酸化和体内选择性扩增。当 F5111.2 与人 IL-2 复合物复配时，可诱导 NOD 小鼠模型中 T1D 的缓解，降低 EAE 模型中疾病的严重程度，并保护小鼠免受异种 GvHD 的影响 [120]。
Another anti-human IL-2Ra-biased IL-2 antibody, UFKA-20, uses a similar mechanism to selectively target [121]. The IL-2 bound to UFKA-20 fails to induce cell activation via the dimeric IL-2R unless the cells also express CD25. Once the IL-2/UFKA-20 complex is bound to CD25, the antibody dissociates from IL-2 and allows the formation of high affinity quaternary IL-2/LL-2R structure that leads to intracellular signalling. Consequently, the IL-2/UFKA-20 complexes efficiently and preferentially stimulated in freshly isolated human cells ex vivo and in mice and rhesus macaques in vivo [121]. 另一种抗人IL-2Ra-biased IL-2抗体UFKA-20也采用了类似的选择性靶向机制[121]。与 UFKA-20 结合的 IL-2 无法通过二聚 IL-2R 诱导细胞活化，除非细胞也表达 CD25。一旦 IL-2/UFKA-20 复合物与 CD25 结合，抗体就会与 IL-2 分离，形成高亲和力的 IL-2/LL-2R 四元结构，导致细胞内信号传导。因此，IL-2/UFKA-20 复合物能有效并优先刺激体内新鲜分离的人体细胞以及小鼠和猕猴 [121]。
The clinical translation of the IL-2/antibody complex approach is complicated by the instability of the cytokine/antibody complex and the need to optimise dosing ratios, as dissociation would lead to off-target effects and rapid clearance. Genetically fusing IL-2 and the antibody should circumvent these drawbacks [168, 177]. A single-chain hIL-2/F5111 antibody-fusion protein has been engineered that demonstrated selective bias and showed efficacy in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus [178]. 由于细胞因子/抗体复合物的不稳定性以及优化剂量比例的需要，IL-2/抗体复合物方法的临床转化变得复杂起来，因为细胞因子/抗体复合物的分离会导致脱靶效应和快速清除。基因融合 IL-2 和抗体可以避免这些缺点 [168，177]。已设计出一种单链 hIL-2/F5111 抗体融合蛋白，它在小鼠结肠炎模型和检查点抑制剂诱导的糖尿病模型中表现出选择性偏倚和疗效 [178]。
CONCLUSIONS 结 论
IL-2 is central in the biology of during development, functional maturation, lineage stability, peripheral homoeostasis, and function. The consequence of the dependency of on IL-2 is the development of autoimmunity in the absence of IL-2 signalling. compensate for the dependency with an exceptional IL-2 capture sensitivity that outcompetes that of other cell types. The necessity for signalling and the high expression of the high-affinity trimeric IL-2R make the IL-2 signalling pathway a prime-candidate for -targeting therapeutic approaches in autoimmune and inflammatory diseases as well as in the prevention of transplant rejection. IL-2 在发育、功能成熟、血统稳定、外周稳态和功能等生物学过程中起着核心作用。IL-2依赖性的后果是，在缺乏IL-2信号的情况下会发展成自身免疫。信号传导的必要性和高亲和性三聚体 IL-2R 的高表达使 IL-2 信号传导途径成为自身免疫和炎症疾病以及预防移植排斥反应的靶向治疗方法的主要候选途径。
Despite its high efficacy, given the limitations of low-dose IL-2, numerous approaches have been developed to increase the targeting specificity of IL-2 and hence to avoid binding of the new IL-2-based biologicals to non-T cells. Informed by structural and empirical studies, modified IL-2-based molecules are being tested in pre-clinical studies as well as in clinical trials. Yet, informed design may not entirely predict therapeutic success as illustrated by insufficient efficacy and incomplete translation of pre-clinical data in clinical trials for some candidates. However, despite the requirement for thorough clinical assessment of therapeutic benefit in each disease, recent successes in clinical trials for several modified IL-2-based molecules in various autoimmune contexts are representative of the promising therapeutic perspective of IL-2-based immunotherapeutics. 尽管 IL-2 具有很高的疗效，但鉴于低剂量 IL-2 的局限性，人们开发了许多方法来提高 IL-2 的靶向特异性，从而避免基于 IL-2 的新型生物制剂与非 T 细胞结合。在结构和经验研究的指导下，改良的基于 IL-2 的分子正在临床前研究和临床试验中进行测试。然而，知情设计可能并不能完全预测治疗的成功，一些候选药物临床前数据在临床试验中的疗效不足和转化不完全就说明了这一点。不过，尽管需要对每种疾病的治疗效果进行全面的临床评估，但最近几种改良的 IL-2 分子在各种自身免疫性疾病的临床试验中取得的成功，代表了以 IL-2 为基础的免疫疗法前景广阔的治疗前景。
The further possibility to target (modified) IL-2 to subsets of particular prevalence in a disease context by the use of additional moieties may expand the drug development toolbox in the future. Similarly, combinatorial therapy, such as with rapamycin, may prove beneficial but will require assessment in clinical trials. Finally, and undoubtedly, an increasing understanding of structural modifications and their functional consequences will further the design of IL-2-based molecules to increase targeting efficiency as well as to minimise risk for off-target activity and hence maximise safety and efficacy. 通过使用额外的分子，还可以将（改良的）IL-2 靶向疾病中特别流行的亚群，这可能会扩大未来的药物开发工具箱。同样，雷帕霉素等组合疗法也可能被证明是有益的，但需要在临床试验中进行评估。最后，毋庸置疑的是，对结构修饰及其功能性后果的理解不断加深，将进一步推动基于 IL-2 的分子设计，以提高靶向效率，最大限度地降低脱靶风险，从而最大限度地提高安全性和有效性。
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Nektar therapeutics presents data for Rezpegaldesleukin (LY3471851) in patients with atopic dermatitis and psoriasis from two separate clinical studies at 2022 European Academy of Dermatology (EADV) Congress. 2022. https:// ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-presentsdata-rezpegaldesleukin-ly3471851 Nektar therapeutics在2022年欧洲皮肤病学会（EADV）大会上展示了Rezpegaldesleukin（LY3471851）在特应性皮炎和银屑病患者中的两项独立临床研究数据。2022. https:// ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-presentsdata-rezpegaldesleukin-ly3471851
Forman S, Schmitz C, Budelsky A, Benschop R, Jackson K, Zou H, et al. Efficacy and safety of a selective regulatory T-cell inducing IL-2 conjugate (LY3471851) in the treatment of psoriasis: a phase 1 randomised study. EADV Congress 2022. Forman S、Schmitz C、Budelsky A、Benschop R、Jackson K、Zou H 等. 选择性调节性 T 细胞诱导 IL-2 结合物 (LY3471851) 治疗银屑病的疗效和安全性：1 期随机研究。2022年EADV大会。
Schleicher S, Schmitz C, Budelsky A, Benschop R, Jackson K, Zou H, et al. in the Treatment of atopic dermatitis: a phase 1 randomised study. EADV Congress 2022 Schleicher S、Schmitz C、Budelsky A、Benschop R、Jackson K、Zou H 等人在 "特应性皮炎的治疗：1 期随机研究 "中的研究结果。2022 年欧洲特应性皮炎大会
Nektar Announces Promising New and Corrected Rezpegaldesleukin Efficacy Data Which Were Previously Reported in 2022 and Incorrectly Calculated by Former Collaborator Eli Lilly & Company. 2023. https://ir.nektar.com/news releases/news-release-details/nektar-announces-promising-new-and-correctedrezpegaldesleukin Nektar宣布新的和经更正的Rezpegaldesleukin疗效数据很有希望，这些数据以前曾在2022年报告过，但被前合作者礼来公司错误地计算了。2023. https://ir.nektar.com/news releases/news-release-details/nektar-announces-promising-new-and-correctedrezpegaldesleukin
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AUTHOR CONTRIBUTIONS 作者贡献
SMS and VL conceived and wrote the manuscript. VL and VM prepared figures and tables. SHB contributed to the writing and revision of the manuscript. SMS 和 VL 构思并撰写了手稿。VL 和 VM 准备了图表。SHB 参与了手稿的撰写和修改。
FUNDING 资金
VL is funded by a Baekeland mandate from the Flanders Innovation & Entrepreneurship Agency (VLAIO) (HBC.2019.2214). VM is supported by the Research Foundation Flanders (FWO) (Fundamental Research PhD fellowship, 1117523N). Research in the SMS lab is supported by Research Foundation Flanders (FWO) (Fundamental Research Grant, G054722N), KU Leuven (C1 grant, C14/20/106), and Flanders Innovation & Entrepreneurship Agency (VLAIO) (HBC.2021.0529). Research in the SHB lab is supported by the KU Leuven (STG/19/032). VL 由佛兰德斯创新与创业局 (VLAIO) 的 Baekeland 任务（HBC.2019.2214）资助。VM 由佛兰德斯研究基金会（FWO）资助（基础研究博士奖学金，1117523N）。SMS 实验室的研究工作得到了法兰德斯研究基金会 (FWO) (基础研究基金，G054722N)、鲁汶大学 (C1 基金，C14/20/106) 和法兰德斯创新与创业局 (VLAIO) (HBC.2021.0529) 的支持。SHB 实验室的研究得到了鲁汶大学（STG/19/032）的支持。
COMPETING INTERESTS 利益冲突
The authors declare no competing interests. 作者声明不存在利益冲突。
ADDITIONAL INFORMATION 其他信息
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