更新于：2024-11-01

IL-2Rβ x IL15R

更新于：2024-11-01

基本信息

关联

项与 IL-2Rβ x IL15R 相关的药物

Neo-5171

靶点

IL-2Rβ x IL15R

作用机制

IL-2Rβ抑制剂 [+1]

在研机构

Neoleukin Therapeutics, Inc.

原研机构

Neoleukin Therapeutics, Inc.

在研适应症

自身免疫性疾病 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IL-2Rβ x IL15R 相关的临床结果

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100 项与 IL-2Rβ x IL15R 相关的转化医学

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0 项与 IL-2Rβ x IL15R 相关的专利（医药）

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项与 IL-2Rβ x IL15R 相关的文献（医药）

2024-05-01·Biomedicine & Pharmacotherapy

Zhen-Wu-Tang ameliorates lupus nephritis by diminishing renal tissue-resident memory CD8+ T cells via suppressing IL-15/STAT3 pathway

Article

作者: Liu, Yuntao ; Yang, Bin ; Qin, Fenglian ; Liang, Chun-Ling ; Chen, Yuchao ; Wei, Yu-Yan ; Luo, Yini ; Chen, Yi ; Qiu, Feifei ; Liu, Huazhen ; Wu, Junbiao ; Dai, Zhenhua

Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (T_RM) cells. Murine LN was induced by a single injection of pristane, while in vitro T_RM cells differentiated with IL-15/TGF-β. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8⁺ T_RM cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited T_RM cell differentiation induced by IL-15/TGF-β in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rβ）expression in CD8⁺ T_RM cells. Importantly, ZWT reduced the number of total F4/80⁺CD11b⁺ and CD86⁺, but not CD206⁺, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8⁺ T_RM cells via inhibition of IL-15/IL-15R /STAT3 signaling.

2023-03-01·Journal of Dermatological Science

Blockade of CD122 on memory T cells in the skin suppresses sclerodermatous graft-versus-host disease

Article

作者: Kubota, Noriko ; Tso, J. Yun ; Tsurushita, Naoya ; Okiyama, Naoko ; Ichimura, Yuki ; Nomura, Toshifumi ; Konishi, Risa ; Tanaka, Ryota

BACKGROUNDAntigen-stimulated naïve T cells differentiate into effector and memory T cells, of which resident memory T (T_RM) cells reside permanently in organ tissues. Involvement of T_RM cells has been indicated in pathological conditions of various skin diseases. CD122, which is the β chain subunit of interleukin (IL)- 2 and IL-15 receptors, is expressed on immune cells including T_RM cells.OBJECTIVETo investigate whether CD122 signaling in skin CD8⁺ T_RM cells mediates the development of mucocutaneous graft-versus-host disease (GVHD).METHODSWe used a genetically modified mouse expressing a membrane-bound form of chicken ovalbumin (OVA) under the control of the keratin 14 promoter, which develops GVHD-like erosive mucocutaneous disease resulting in sclerodermatous disease after transfer of OVA-specific T cell-receptor-transgenic CD8⁺ OT-I cells. Mice with mucocutaneous GVHD were treated with an anti-CD122 blocking antibody.RESULTSAdministration of an anti-CD122 blocking antibody suppresses the development of acute/chronic GVHD-like mucocutaneous disease in our murine model via the reduction of CD122-expressing memory CD8⁺ T cells, including skin, memory autoaggressive CD8⁺ T cells. Moreover, blockade of CD122, even after the establishment of acute GVHD, inhibited the development of chronic GVHD-like sclerodermatous disease via the reduction of epidermal and dermal T_RM autoaggressive CD8⁺ T cells.CONCLUSIONSkin memory CD8⁺ T cells in particular mediate the development of mucocutaneous GVHD, and blockade of CD122 may be an effective treatment strategy, especially for sclerodermatous GVHD.

2021-07-07·Cardiovascular Research1区 · 医学

Interleukin-7 and interleukin-15 drive CD4+CD28null T lymphocyte expansion and function in patients with acute coronary syndrome

1区 · 医学

Article

作者: Chhetri, Ismita ; Kaur, Satdip ; Dumitriu, Ingrid E ; Bullenkamp, Jessica ; Mengoni, Veronica ; Dimou, Paraskevi ; Astroulakis, Zoë M J ; Kaski, Juan Carlos

AbstractAimsInflammation has important roles in atherosclerosis. CD4+CD28null (CD28null) T cells are a specialized T lymphocyte subset that produce inflammatory cytokines and cytotoxic molecules. CD28null T cells expand preferentially in patients with acute coronary syndrome (ACS) rather than stable angina and are barely detectable in healthy subjects. Importantly, ACS patients with CD28null T-cell expansion have increased risk for recurrent acute coronary events and poor prognosis, compared to ACS patients in whom this cell subset does not expand. The mechanisms regulating CD28null T-cell expansion in ACS remain elusive. We therefore investigated the role of cytokines in CD28null T-cell expansion in ACS.Methods and resultsHigh-purity sorted CD4+ T cells from ACS patients were treated with a panel of cytokines (TNF-α, IL-1β, IL-6, IL-7, and IL-15), and effects on the number, phenotype, and function of CD28null T cells were analysed and compared to the control counterpart CD28+ T-cell subset. IL-7- and IL-15-induced expansion of CD28null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1β, and IL-6 did not. The mechanisms underlying CD28null T-cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28null T cells compared to control CD28+ T cells. Additionally, IL-7/IL-15 markedly augmented CD28null T-cell cytotoxic function and interferon-γ production. Further mechanistic analyses revealed differences in baseline expression of component chains of IL-7/IL-15 receptors (CD127 and CD122) and increased baseline STAT5 phosphorylation in CD28null T cells from ACS patients compared to the control CD28+ T-cell subset. Notably, we demonstrate that CD28null T-cell expansion was significantly inhibited by Tofacitinib, a selective JAK1/JAK3 inhibitor that blocks IL-7/IL-15 signalling.ConclusionOur novel data show that IL-7 and IL-15 drive the expansion and function of CD28null T cells from ACS patients suggesting that IL-7/IL-15 blockade may prevent expansion of these cells and improve patient outcomes.

项与 IL-2Rβ x IL15R 相关的新闻（医药）

2024-05-01

·佰傲谷BioValley

IL-15获批，当心其促瘤风险

2024年4月22日，ImmunityBio公司宣布，FDA已批准Anktiva（N-803）联合卡介苗（BCG），用于治疗卡介苗不响应的非肌层浸润性膀胱癌 (NMIBC) 伴原位癌 (CIS)，伴或不伴乳头状瘤患者。但是除了抗肿瘤活性，很多研究显示IL-15本身也有促进肿瘤的活性。IL-15及其受体IL-15是一种多效细胞因子，最初被认为是T细胞生长因子，在体内连接先天和适应性免疫反应。IL-15属于四α-螺旋束细胞因子家族，由不同类型的细胞，如单核细胞、巨噬细胞、树突状细胞、基质细胞、基质细胞、上皮细胞等共同产生。IL-15存在四种功能形式可溶性单体形式（soluble IL-15，sIL-15）可溶性复合物sIL-15/ IL-15Rα反式递呈（transpresented IL-15，tp-IL15）跨膜形式（transmembrane IL-15，tmbIL-15）IL-15受体IL-15与IL-2Rβ/γc异源二聚体结合（与IL-2共享，由IL-2Rβ和γc链形成）。IL-2Rβ/γc二聚体受体以中等亲和力结合IL-15 (Kd=0.27 to 2.5 nM)。通过激活Jak/Stat通路（Jak 1和3、Stat3和5）在细胞内转导信号。IL-15Rα链对IL-15具有特异性，并以高亲和力与细胞因子结合（Kd=10-80pM）。IL-15Rα与IL-2Rβ和γc链形成一个高亲和力的三聚体受体，允许细胞对低浓度的IL-15作出反应。IL-15Rα本身也能进行信号转导。IL-15与IL-15R结合Journal for ImmunoTherapy of Cancer 2020sIL-15结合中等亲和二聚体IL-2Rβ/γc受体或高亲和力三聚体IL-15Rα/IL-2Rβ/γc受体。sIL-15/IL-15Rα复合体只结合IL-2Rβ/γc受体tpIL-15与膜IL-15Rα链结合tmb-IL-15通过IL-15Rα非依赖机制锚定在细胞膜上，此二者与IL-2Rβ/γc受体（反式递呈）结合。tp-IL-15要么在出现到细胞膜表面之前就在细胞内组装，要么sIL-15可能结合无细胞因子的膜结合IL15Rα。Journal for ImmunoTherapy of Cancer 2020不可裂解的tp-IL-IL-15/IL15Rα复合物，携带IL-15Rα EX2亚型，介导顺式和反式信号。sIL-IL-15/IL-15Rα复合物携带NPR-IL-15Rα没有生物学活性（NPR, natural proteolytic release）。不可切割的IL-15/IL-15Rα复合物携带IL-15Rα-IC-EX2a-AID亚型，介导反向信号。sIL-15/IL-15Rα复合物携带IL-15Rα-IC3亚型，具有较高的生物活性。IL-15促进肿瘤进展血液肿瘤IL-15可能促进某些表达IL-15受体恶性细胞的生长，如人类T细胞白血病细胞、皮肤T细胞淋巴瘤（CTCL）细胞、大颗粒淋巴细胞（LGL）白血病细胞和多发性骨髓瘤。Front. Oncol.2022sIL-15Rα在健康人的血清中存在的水平很低，在疾病状态下高表达。例如，T细胞大颗粒淋巴细胞白血病（LGL）的特征是血清中sIL-15Rα水平升高，由sIL-15Rα的自然脱落形式以及sIL-15Rα的选择性剪接形式组成，可能来自于不同细胞。此外，IL-15Rα在患者外周血单核细胞中表达上调。IL-15Rα的上调可以保护IL-15免受蛋白水解，降低细胞的IL-15反应阈值，而sIL-15Rα与单体循环IL-15（sIL-15）的复合物可能产生可溶性复合物。这两种事件都可能参与了疾病的进展。此外，LGL细胞表达tp-IL-15，通过顺式和反式信号传导，可以促进白血病细胞的扩增。IL-15可作为淋巴瘤患者恶性T细胞的生长和生存因子。皮肤T细胞淋巴瘤患者的皮肤病变和PB T细胞显示IL-15 mRNA和蛋白均过表达。在这些患者中，恶性CD4+T细胞的存活在早期阶段依赖于微环境提供的IL-15，但在疾病进展过程中，恶性细胞通过自分泌IL-15的产生，可能自主地支持它们的生长和生存。在人类T细胞淋巴细胞病毒白血病中，病毒Tax蛋白诱导IL-15和IL-15Rα的产生，而这种IL-15自分泌环导致白血病的进展。在多发性骨髓瘤中，恶性浆细胞显示功能性IL-15受体，IL-15Rα链的表达增加和IL-15的自分泌产生，这些现象有利于恶性细胞的生存和增殖，独立于它们的微环境。实体瘤头颈部麟癌患者血清中sIL-15Rα水平升高和瘤内IL-15浓度较高，与临床预后较差高度相关。临床研究报告了肿瘤内IL-15浓度与肺癌患者不良的临床预后之间的相关性。Journal for ImmunoTherapy of Cancer 2020原代黑色素瘤细胞培养产生的IL-15，参与了肿瘤逃逸机制和促炎信号的激活。类似地，在裸鼠体内注射低浓度的人重组IL-15（rhIL-15），会导致在皮下植入人黑色素瘤细胞时产生更具侵袭性的肿瘤。在转移性黑色素瘤患者的血清中检测到高水平的sIL-15/IL-15Rα，提示肿瘤内和/或循环的sIL-15/IL-15Rα复合物，可能有助于有利于肿瘤进展和免疫逃逸的肿瘤微环境的发展。肾内IL-15由管状细胞和皮质细胞产生，在维持上皮细胞内稳态中起着重要作用。相比之下，肾透明癌细胞（RCCs）不分泌IL-15，但表达tmb-IL-15，在RCCs中，重组IL-15（rhIL-15）和tmb-IL-IL5都能转导一种不平衡的信号，促进上皮间充质转化，从而作为致瘤因子。相比之下，肾癌干细胞表达IL-15Rα/IL-2Rβ/γc异三聚体受体。当该受体受到rhIL-15的刺激时，促进极化、非致瘤性和分泌IL-15的上皮细胞的产生，这些细胞像“正常细胞”一样能够自分泌IL-15。因此，IL-15可能同时显示促肿瘤和抗肿瘤作用，这取决于所涉及的肾癌细胞亚群。对70例结肠癌活检样本进行免疫染色，将人结肠癌细胞植入裸鼠，结果显示，IL-15是由转移性结肠癌细胞产生的，可诱导结肠癌附近粘膜增生，从而促进血管生成和肿瘤进展。此外，IL-15在体外促进人结肠癌细胞的增殖、运动性和侵袭性，并增加其对凋亡的抵抗力。相比之下，在人类患者中，约30%的转移性患者中IL-15表达的缺失与较低的T细胞密度、T细胞增殖的减少、复发的高风险和生存率的降低相关。参考文献ANKTIVA获批：https://ir.immunitybio.com/news-releases/news-release-details/immunitybio-announces-fda-approval-anktivar-first-class-il-15?field_nir_news_date_value[min]=Azzi S, Gallerne C, Romei C, et al. Human renal normal, tumoral, and cancer stem cells express membrane-bound interleukin-15 isoforms displaying different functions. Neoplasia 2015;17:509–17.Yuan H, Meng X, Guo W, et al. Transmembrane-Bound IL-15- Promoted epithelial-mesenchymal transition in renal cancer cells requires the Src-dependent Akt/GSK-3β/β-catenin pathway. Neoplasia 2015;17:410–20.Fiore PF, Di Matteo S, Tumino N, et al. Interleukin-15 and cancer: some solved and many unsolved questions. Journal for ImmunoTherapy of Cancer 2020;8:e001428. doi:10.1136/jitc-2020-001428Isabelle C, Boles A, Chakravarti N, Porcu P, Brammer J and Mishra A (2022) Cytokines in the Pathogenesis of Large Granular Lymphocytic Leukemia. Front. Oncol. 12:849917. doi: 10.3389/fonc.2022.849917

临床结果上市批准

2023-07-19

·佰傲谷BioValley

聊聊“ENFJ人格型”免疫调节因子——IL-15

主人公型人格（ENFJ）是16型人格中的一种人格类型。他们浑身散发着天然的自信，潜移默化地影响着周围的人，能够指导他人团结协作，帮助别人提升自己并促进集体的共同进步。ENFJ的精神世界永远散发着利他主义者的光芒。在免疫系统中就存在着这样一种人格类型的角色，它积极帮助其他细胞的成长和功能发挥，进而促进整个免疫系统的高效运行。本期我们就一起去认识这个免疫系统中的多面手——IL-15。背景介绍白细胞介素是由多种细胞产生并作用于多种细胞的一类细胞因子。由于最初是由白细胞产生又在白细胞间发挥作用，所以由此得名，现仍一直沿用。现是指一类分子结构和生物学功能已基本明确，具有重要调节作用而统一命名的细胞因子。白细胞介素在传递信息，激活与调节免疫细胞，介导T、B细胞活化、增殖与分化及在炎症反应中起重要作用。1994 年，Grabstein 等首先在猴肾表皮细胞系上清中发现一种能维持T细胞增殖的细胞因子，随后基因克隆获得成功并命名IL-15(interleukin-15，白介素-15)，其具有与IL-2类似的结构和功能。虽然基因工程使IL-2应用于肝炎以及某些癌症的治疗已经取得了令人瞩目的成果，但是大剂量长时间的用药对患者仍然存在一定的不良反应( 如发热、头晕、水盐代谢紊乱) ，导致肾、肝、心、肺等功能异常，其中最常见、最严重的是毛细血管渗漏综合征。IL-15具备一些IL-2所不具备的优势而受到广泛重视。近些年， IL-15在抗肿瘤免疫治疗方面的应用也得到了研究者的关注。图1、2：IL-15在细胞间的传递与结合靶点结构IL-15是分子量为14～15 kDa 的糖蛋白，由169 个氨基酸构成。人IL-15 基因位于染色体4q31，跨度约34 kb，有7 个内含子和9 个外显子，其mRNA 长1.5～1.8kb。IL-15 的等电点约为4.35，在pH 值为2～10时较为稳定。IL-15由不同细胞产生，如单核细胞、巨噬细胞、树突状细胞、基质细胞、上皮细胞等，属于四个α- 螺旋束细胞因子家族。IL-15受体(IL-15R) 与IL-2 受体(IL-2R) 一样，包含3条链，分别命名为IL-15Rα、IL-15Rβ( 也称为CD122) 、RIL-15Rγ(也称CD132) 。其中β 和γ亚单位相同，但IL-15R本身有特异的IL-15Rα，是IL-15 的高亲和力受体。当IL-2Rα亚基( 也称为CD25) 与其β、γ 亚基结合后， IL-2Rαβγ成为IL-2的高亲和力受体，但IL-15Rαβγ对IL-15的亲和力没有改变，这有可能是两者具有不同生物学效应的基础之一。图3：IL-2和IL-15与细胞表面受体结合的比较信号通路IL-15 的生物学作用范围非常广泛，是机体免疫调节网络中的重要物质，与其他细胞因子有协同或拮抗作用，共同完成机体免疫功能的平衡调节作用。IL-15在NK细胞、T细胞及某些内皮细胞的发育中起重要作用，并且是记忆性CD8+T细胞的生长因子和调节因子，而其能诱导细胞毒性T细胞和淋巴因子激活的杀伤细胞的活化和增殖。图4：IL-15的多功能作用下面介绍IL-15的两种信号通路：1️⃣ IL-15与其在抗原呈递细胞上表达的高亲和力IL-15Rα结合，并反向呈递给IL-2 /15Rβγ异二聚体，随后，效应细胞的激活可以通过三种不同的途径进行：涉及JAK / STAT激活，磷酸化的STAT蛋白形成异二聚体，然后转运至细胞核进行转录激活；将Shc募集到IL-2 /15Rβ链上的磷酸化位点，然后激活Grb2；Grb2可以沿着PI3K途径继续磷酸化Akt，或者可以结合鸟嘌呤核苷酸交换因子SOS激活RAS–RAF，最终激活MAPK。2️⃣在肥大细胞中，IL-15通过独特的受体链IL-15RX发出信号，从而激活JAK2/STAT5途径。IL-15还可以与常见的γ链结合，以通过Tyk2/STAT6传递其信号，从而启动生存（Bcl-XL）和Th2免疫应答。图5：IL-15的信号通路但是硬币总是有两面，过多的IL-15可能会引发强烈的免疫应答，引发炎症。在排斥反应和多种自身免疫性疾病中IL-15 表达增加的现象很明显。所以对于炎症性疾病，需要阻断IL-15的活性，抑制免疫反应，以改善临床症状。使用抗IL-15R抗体，可防止IL-15通过其受体结合和发出信号。靶向JAK/STAT途径的抑制剂可防止STAT异二聚体活化和转运至细胞核。蛋白酶体抑制剂如硼替佐米可防止NF-κB和Myc的活化。值得注意的是，这些疗法都靶向恶性细胞中的IL-15信号传导，但这可能对依赖IL-15的正常细胞产生影响。研究现状临床前的动物试验研究中，IL-15在研究中的疗效已得到证实，包括前列腺癌、黑色素瘤、结肠癌模型等，表明IL-15可能比IL-2在癌症治疗中的作用更为有效。IL-15的具体给药方案可分为单药治疗和联合用药治疗。IL-15的首次人体临床研究是通过静脉推注，在转移性肾细胞癌和黑色素瘤患者中开展的，研究者在患者的外周血中观察到NK细胞和CD8＋记忆性T细胞显著增加，但同时伴有剂量限制毒性。相关研究表明，静脉推注IL-15 对CD8＋T细胞和NK细胞有显著作用。上述研究提示IL-15单药治疗方案疗效有限，需考虑其单药治疗疗效受限机制及进一步的改进方案。IL-15的单药治疗效果可能受到体内IL-15Rα表达的限制，而后者是IL-15发挥生物活性所必需的。其次，由于IL-15分子量小，给药后半衰期相对较短。为解决上述问题，相关研究者研发出由IL-15蛋白N72D突变后结合IL-15Rα及IgG1Fc共同表达的融合蛋白，该融合蛋白是一种独特的新型IL-15超级激动剂。相关研究显示，此IL-15衍生物具有良好的分布和持久性，其治疗潜力优于天然IL-15。图6：突变体IL-15与IL-15Rα受体融合蛋白 (IL-15Rα-Fc) 非共价相互结合，可增强更久的半衰期和生物活性IL-15 还可与ICIs（免疫检查点抑制剂）联合应用，实验证明IL-15 与PD-1/PD-L1单抗联合应用比单独用药更有效。此外IL-15还可与治疗性单克隆抗体、单倍体相合NK细胞、卡介苗等联合应用，在癌症治疗领域表现出不俗的实力。活性检测细胞株甲贝医药构建的Jurkat-IL15-Luc的细胞表面高表达IL-15受体，下游具有报告基因Luciferase。当IL-15蛋白与细胞表面IL-15受体结合后，会诱导下游Luciferase信号的表达，该信号值高低和IL-15蛋白活性或浓度成正比，形成剂量依赖型曲线。图7：报告基因法检测IL15的作用机制图构建的报告基因法优势如下：方法稳定、变动小；实验窗口大、响应值高；利用转基因构建的细胞可稳定传代；该细胞株可以作为以IL-15为靶点的药物活性检测细胞株；适合放行、长期稳定性检测，方便方法验证；报告基因法Jurkat-IL15-Luc测试活性数据展示：图8：Jurkat-IL15-Luc的活性结果图报告基因法Jurkat-IL15-Luc的专属性数据展示：图9：Jurkat-IL15-Luc的专属性结果图细胞增殖法与报告基因法检测对比：图10：细胞增殖法检测IL-15生物学活性图11：报告基因法检测IL-15生物学活性表1:报告基因法与细胞增殖法检测IL-15生物学活性的比较报告基因法（Jurkat-IL15-Luc）与细胞增殖法检测同一IL-15蛋白样品的EC50趋于相似。但相比细胞增殖法，报告基因法的优势在于：该方法窗口更高，重复率佳，方法变异低，更容易操作，同时检测时间较短，所以该方法更加适合方法验证，QC放行，稳定性检测等需求。而细胞增殖法因为药物因子干扰多,如:GM-CSF、IFN-α、IFN-β、IFN-γ、IL-2、IL-3、IL-4、IL-6、IL-15、NGF、SCF、TNF-α、TPO等都可促进细胞增殖，所以导致专属性较差。另外细胞增殖法所需检测时间更长,和报告基因法相比，该方法中IL-15和细胞作用时间长可达24，48，72小时，甚至更长。文献引用：【1】Anjali Mishra, Laura Sullivan and Michael A. Caligiuri. Molecular Pathways: Interleukin-15 Signaling in Health and in Cancer, Clinical Cancer Research, 2014, 20(8). 【2】Marek Jakobisiak, Jakub Golab, Witold Lasek, Interleukin 15 as a promising candidate for tumor immunotherapy, Cytokine & Growth Factor Reviews, 22(2), 2011. 【3】Jason C. Steel, Thomas A. Waldmann, John C. Morris, Interleukin-15 biology and its therapeutic implications in cancer, Trends in Pharmacological Sciences, 33(1), 2012. 【4】Jakobisiak M, Golab J, Lasek W. Interleukin 15 as a promising candidate for tumor immunotherapy. Cytokine Growth Factor Rev. 2011 Apr;22(2):99-108. 【5】Patidar M, Yadav N, Dalai SK. Interleukin 15: A key cytokine for immunotherapy. Cytokine Growth Factor Rev. 2016 Oct;31:49-59.【6】丁子文,汪璐,任燕,郑岩,李渊,张婧妍,倪娜.白介素15在肿瘤免疫治疗中的临床研究进展[J].世界临床药物,2022,43(01):87-90+104.【7】赵煜,张涛,谭勇.白细胞介素15的研究进展[J].医述,2013,19(03):414-416.【近期活动】

临床结果免疫疗法信使RNA

2021-01-06

·Endpoints

After an up-and-down year, Nektar watches development head Wei Lin walk away as it pursues pipeline rebound

More than any other year in recent memory, 2020 was a rollercoaster of highs and lows —mostly lows. Just ask San Francisco’s Nektar: Despite ditching its opioid program in January and offloading royalties to its two US-marketed meds, the biotech still has hopes for its pipeline to hit a rebound this year. But that rebound won’t happen under the watch of senior VP and head of development Wei Lin, who is stepping down and leaving immunology head Brian Kotzin to step in. Lin is “leaving the company to pursue another opportunity,” Nektar announced on Wednesday. It’s unclear where the Genentech vet is headed next. Nektar poached Lin from Genentech in 2018, where he held roles such as global development leader for cancer immunotherapy and senior medical director over a seven-year stint. The Harvard Medical School grad joined Nektar as senior VP and head of oncology before getting promoted to head of development. “Over the past two years, Wei has played a leadership role in recruiting an experienced clinical development organization and executing a late-stage clinical development strategy for BEMPEG, positioning it for future success,” chief R&D officer Jonathan Zalevsky said in a statement. “I would like to thank him for his contributions to Nektar, and wish him the best in his next opportunity.” With big shoes to fill, Kotzin is stepping up as interim CMO and head of development. The Amgen vet joined Nektar in 2017 and helped lead early development of NKTR-255, the company’s IL-15 receptor agonist currently in two Phase II studies: one for non-Hodgkin’s lymphoma and multiple myeloma in combo with Rituxan or Darzalex, and another in head, neck and colorectal cancer paired with Erbitux. He also spearheaded the Eli Lilly-partnered NKTR-358 program, which is in Phase II for systemic lupus erythematosus and Phase Ib studies for psoriasis and atopic dermatitis. At Amgen, Kotzin served as VP of global clinical development and head of inflammation therapeutics, as well as VP of translational sciences and head of medical sciences/early development. “This is an exciting time for the company with multiple registrational studies underway in a range of tumor types for BEMPEG, a broadening clinical program for NKTR-358 in a number of auto-immune disorders, and an emerging opportunity for NKTR-255 in both hematological malignancies and solid tumors,” Kotzin said. Last month, Nektar sold the royalties to Adynovate and Movantik off to Healthcare Royalty Management for $150 million in cash. The biotech said it would funnel most of the money into two programs: bempegaldesleukin (or NKTR-214) and NKTR-255. Bempegaldesleukin, Nektar’s lead program, is being studied in several Phase III trials in combination with Bristol Myers Squibb’s Opdivo. The CD122-preferential IL-2 agonist is being evaluated in several indications, including metastatic melanoma, renal cell carcinoma and muscle-invasive bladder cancer. That news came just less than a year after Nektar dropped its opioid program, NKTR-181, which was rebuffed by an FDA adcomm last January. The panel voted 27-0 against approving the drug, citing concerns that patients could abuse it and causing their stock $NKTR to fall 15%. On Wednesday morning, the company’s stock was down 0.61%, at $17.97 a share.

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