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Article(id=1240710433426960703, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.10.04, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1673280000000, receivedDateStr=2023-01-10, revisedDate=null, revisedDateStr=null, acceptedDate=1721750400000, acceptedDateStr=2024-07-24, onlineDate=1773738018613, onlineDateStr=2026-03-17, pubDate=1729785600000, pubDateStr=2024-10-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773738018613, onlineIssueDateStr=2026-03-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773738018613, creator=13701087609, updateTime=1773738018613, updator=13701087609, issue=Issue{id=1240710432898478399, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='10', pageStart='721', pageEnd='800', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773738018488, creator=13701087609, updateTime=1773738214158, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240711253669237259, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240711253669237260, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=743, endPage=750, ext={EN=ArticleExt(id=1240710433661841729, articleId=1240710433426960703, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Research progress of receptor-biased interleukin-2 analogues in tumor immunotherapy, columnId=1207314219599499390, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

The efficacy of interleukin (IL)-2 in tumor immunotherapy is remarkable, but its adverse reactions greatly limit its further clinical application. In recent years, researchers have tried to improve or regulate the receptor selectivity of IL-2, that is, selectively bias the activation of IL-2Rβγ and reduce or even completely do not bind to IL-2Rα, so as to preferentially activate CD8+ T cells with tumor killing function and maximize the immune activation of IL-2. The main development strategies of receptor biased IL-2 include polyethylene glycol chemical modification and site-specific mutation technology. Currently, the drugs under research include NKTR-214, THOR-707, SHR-1916, TransConIL-2β/γ, 8MW2311,RG7461, FSD13, IBI363, etc. But none of them have been successfully developed yet. Further in-depth research on their mechanisms of action is required, or various drug development strategies need to be used in combination.

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白细胞介素（IL）-2在肿瘤免疫治疗中疗效显著，但不良反应极大地限制了它的临床应用。近年来，研究人员试图通过改善或调控IL-2的受体选择性，即选择性地偏向激动IL-2受体（IL-2R）βγ而减少甚至完全不与IL-2Rα结合，从而偏向性地激活具有肿瘤杀伤功能的CD8+ T细胞，最大限度地发挥IL-2的免疫激活作用。受体偏向性IL-2的主要开发策略包括聚乙二醇化学修饰和定点突变技术等。目前在研的药物包括NKTR-214、THOR-707、SHR-1916、TransConIL-2β/γ、8MW2311、RG7461、FSD13、IBI363等，但都还没有真正研发成功，尚需开展更深入的作用机制研究，或联合运用多种药物开发策略。

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汪熙，男，讲师，博士，主要从事细胞因子类新药临床前研究，E-mail:

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Cell Death Dis, 2018, 9（10）: 989., articleTitle=A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2, refAbstract=null), Reference(id=1240719599260463348, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433426960703, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[36], rfOrder=44, authorNames=康立山, 顾春银, 付凤根, journalName=null, refType=null, unstructuredReference=康立山, 顾春银, 付凤根, 等. 新型白介素2及其用途:CN112105633A[P]. 2020-12-18., articleTitle=新型白介素2及其用途, refAbstract=null), Reference(id=1240719599340155126, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433426960703, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[36], rfOrder=45, authorNames=KANG LS, GU CY, FU FG, journalName=null, refType=null, unstructuredReference=KANG LS, GU CY, FU FG,et al. Novel interleukin 2 and its use: CN112105633A[P]. 2020-12-18., articleTitle=Novel interleukin 2 and its use, refAbstract=null), Reference(id=1240719599432429816, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433426960703, doi=null, pmid=null, pmcid=null, year=2018, volume=9, issue=null, pageStart=2905, pageEnd=null, url=null, language=null, rfNumber=[37], rfOrder=46, authorNames=MORTARA L, BALZA E, BRUNO A, journalName=Front Immunol, refType=null, unstructuredReference=MORTARA L, BALZA E, BRUNO A, et al. Anti-cancer therapies employing IL-2 cytokine tumor targeting: contribution of innate,adaptive and immunosuppressive cells in the anti-tumor efficacy[J]. Front Immunol, 2018, 9 : 2905., articleTitle=Anti-cancer therapies employing IL-2 cytokine tumor targeting: contribution of innate,adaptive and immunosuppressive cells in the anti-tumor efficacy, refAbstract=null), Reference(id=1240719599537287419, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433426960703, doi=null, pmid=null, pmcid=null, year=2019, volume=301, issue=null, pageStart=176, pageEnd=189, url=null, language=null, rfNumber=[38], rfOrder=47, authorNames=ZAMAN R, ISLAM RA, IBNAT N, journalName=J Control Release, refType=null, unstructuredReference=ZAMAN R, ISLAM RA, IBNAT N, et al. Current strategies in extending half-lives of therapeutic proteins[J]. 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第58位和第105位Cys之间的黑色线段表示二硫键

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JAK：Janus激酶，STAT5：信号转导和转录活化因子5，PI3K：磷脂酰肌醇3激酶，MAPK：促分裂原活化的蛋白激酶

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药物名称研究机构简称IL-2修饰策略主要适应证临床试验阶段
NKTR-214Nektar Therapeutics缀合6个可降解的PEG链黑色素瘤、肾癌Ⅲ期临床已终止
THOR-707Synthorx非天然氨基酸PEG修饰黑色素瘤、胃癌Ⅱ期临床
SHR-1916恒瑞医药定点突变/ PEG修饰晚期恶性肿瘤Ⅰ期临床
TransConIL-2β-/γAscendis Pharma定点PEG修饰卵巢癌Ⅰ/Ⅱ期临床
8MW2311迈威生物定点PEG修饰晚期恶性肿瘤Ⅰ期临床
RG7461罗氏制药定点突变/蛋白融合实体瘤Ⅰ/Ⅱ期临床
FSD13上海科医联创、马里兰大学、加利福尼亚大学单位点定点突变实体瘤临床前研究
IBI363信达生物定点突变/抗体融合晚期实体瘤或淋巴瘤Ⅰ/Ⅱ期临床
), ArticleFig(id=1240719594801918040, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710433426960703, language=CN, label=表1, caption=

目前在研的受体偏向性IL-2类似药

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药物名称研究机构简称IL-2修饰策略主要适应证临床试验阶段
NKTR-214Nektar Therapeutics缀合6个可降解的PEG链黑色素瘤、肾癌Ⅲ期临床已终止
THOR-707Synthorx非天然氨基酸PEG修饰黑色素瘤、胃癌Ⅱ期临床
SHR-1916恒瑞医药定点突变/ PEG修饰晚期恶性肿瘤Ⅰ期临床
TransConIL-2β-/γAscendis Pharma定点PEG修饰卵巢癌Ⅰ/Ⅱ期临床
8MW2311迈威生物定点PEG修饰晚期恶性肿瘤Ⅰ期临床
RG7461罗氏制药定点突变/蛋白融合实体瘤Ⅰ/Ⅱ期临床
FSD13上海科医联创、马里兰大学、加利福尼亚大学单位点定点突变实体瘤临床前研究
IBI363信达生物定点突变/抗体融合晚期实体瘤或淋巴瘤Ⅰ/Ⅱ期临床
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受体偏向性白细胞介素-2类似药在肿瘤免疫治疗中的研究进展
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汪熙 1 , 张一飞 2 , 滕业方 1 , 吴娟 3
中国新药与临床杂志 | 综述 2024,43(10): 743-750
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中国新药与临床杂志 | 综述 2024, 43(10): 743-750
受体偏向性白细胞介素-2类似药在肿瘤免疫治疗中的研究进展
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汪熙1 , 张一飞2, 滕业方1, 吴娟3
作者信息
  • 1.常州工业职业技术学院材料工程学院，江苏 常州　213164
  • 2.扬子江药业集团江苏紫龙药业有限公司，江苏 常州　213100
  • 3.江苏理工学院化工与环境学院，江苏 常州　213001

    • 汪熙，男，讲师，博士，主要从事细胞因子类新药临床前研究，E-mail:

Research progress of receptor-biased interleukin-2 analogues in tumor immunotherapy
Xi WANG1 , Yi-fei ZHANG2, Ye-fang TENG1, Juan WU3
Affiliations
  • 1.School of Materials Engineering, Changzhou Vocational Institute of Industry Technology, Changzhou JIANGSU 213164, China
  • 2.Yangzijiang Pharmaceutical Group Jiangsu Zilong Pharmaceutical Co., Ltd, Changzhou JIANGSU 213100, China
  • 3.School of Chemical Engineering and Environment, Jiangsu University of Technology, Changzhou JIANGSU 213001, China
出版时间: 2024-10-25 doi: 10.14109/j.cnki.xyylc.2024.10.04
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摘要
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白细胞介素（IL）-2在肿瘤免疫治疗中疗效显著，但不良反应极大地限制了它的临床应用。近年来，研究人员试图通过改善或调控IL-2的受体选择性，即选择性地偏向激动IL-2受体（IL-2R）βγ而减少甚至完全不与IL-2Rα结合，从而偏向性地激活具有肿瘤杀伤功能的CD8+ T细胞，最大限度地发挥IL-2的免疫激活作用。受体偏向性IL-2的主要开发策略包括聚乙二醇化学修饰和定点突变技术等。目前在研的药物包括NKTR-214、THOR-707、SHR-1916、TransConIL-2β/γ、8MW2311、RG7461、FSD13、IBI363等，但都还没有真正研发成功，尚需开展更深入的作用机制研究，或联合运用多种药物开发策略。

白细胞介素-2  /  肿瘤免疫  /  聚乙二醇  /  突变

The efficacy of interleukin (IL)-2 in tumor immunotherapy is remarkable, but its adverse reactions greatly limit its further clinical application. In recent years, researchers have tried to improve or regulate the receptor selectivity of IL-2, that is, selectively bias the activation of IL-2Rβγ and reduce or even completely do not bind to IL-2Rα, so as to preferentially activate CD8+ T cells with tumor killing function and maximize the immune activation of IL-2. The main development strategies of receptor biased IL-2 include polyethylene glycol chemical modification and site-specific mutation technology. Currently, the drugs under research include NKTR-214, THOR-707, SHR-1916, TransConIL-2β/γ, 8MW2311,RG7461, FSD13, IBI363, etc. But none of them have been successfully developed yet. Further in-depth research on their mechanisms of action is required, or various drug development strategies need to be used in combination.

interleukin-2  /  tumor immunotherapy  /  polyethylene glycol  /  mutation
汪熙, 张一飞, 滕业方, 吴娟. 受体偏向性白细胞介素-2类似药在肿瘤免疫治疗中的研究进展. 中国新药与临床杂志, 2024 , 43 (10) : 743 -750 . DOI: 10.14109/j.cnki.xyylc.2024.10.04
Xi WANG, Yi-fei ZHANG, Ye-fang TENG, Juan WU. Research progress of receptor-biased interleukin-2 analogues in tumor immunotherapy[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (10) : 743 -750 . DOI: 10.14109/j.cnki.xyylc.2024.10.04
正文
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世界卫生组织国际癌症研究机构（International Agency for Research on Cancer, IARC）发布的全球最新癌症统计数据显示：2021年全球新发癌症1 929万例，死亡996万例，其中我国新发癌症457万例，占全球的23.7%。癌症已成为严重威胁人类健康的公共卫生问题之一。放疗、化疗以及靶向治疗在提高患者生存质量和延长生存期方面已取得了重大进展，然而，治疗过程中存在的严重副作用和耐药性也限制了上述疗法的深度应用[1,2]。随着学界对肿瘤治疗的深入研究，学者们转而聚焦于人体内的天然“抗癌战士”——免疫系统，并由此诞生了肿瘤免疫疗法[3]。免疫疗法的巨大优势在于其能通过激活人体自身免疫系统，治疗大部分类型的肿瘤甚至是已经转移的晚期恶性肿瘤；同时，还能够利用正常的免疫系统防止肿瘤细胞产生耐药性，从而降低癌症的复发率[4]。免疫治疗药物已成为当前药物研究的热点之一。
白细胞介素（白介素，interleukin，IL）-2是首个被用于肿瘤免疫疗法的药物，美国食品和药物管理局（FDA）基于高剂量IL-2在临床肿瘤免疫治疗中的显著疗效，先后于1992年和1998年批准IL-2类似药阿地白介素（aldesleukin）用于晚期肾癌和恶性黑色素瘤的治疗[5]。然而，随着该药受众面的不断扩大，其在临床应用中存在的问题愈加凸显：一是该药不良反应较多。IL-2类似药不仅可引起发热、呕吐、低血压等一般症状，还可导致水、电解质代谢紊乱等功能异常，严重时可诱发毛细血管渗漏综合征（capillary leakage syndrome，CLS），导致血管内液体积聚在肝、肺等器官中，引发肝细胞损伤和肺水肿，使患者不得不中止治疗。二是该药给药次数多、剂量大。由于IL-2在人体内半衰期较短（<15 min），反复给药不仅增加了副作用的发生几率，还降低了患者对治疗的依从性[6, 7]，这极大地限制了IL-2类似药的临床应用。近年来，免疫疗法的兴起重塑了IL-2在肿瘤治疗方面的巨大潜力，研究者们对IL-2及其受体结合晶体结构的解析，为开发更加安全有效的IL-2类药物提供了重要的结构学信息和新的机遇[8, 9]。本文从IL-2的生物学功能出发，综述了目前在研的受体偏向性IL-2类似药在肿瘤免疫治疗领域的研究进展，以期为开发治疗肿瘤的新型IL-2类似药及疗法提供新的思路。
IL-2的结构与生物学活性
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IL-2是一种由糖蛋白组成的Ⅰ型四α-螺旋束细胞因子，它是细胞因子大家族中的重要一员，在激活与调节免疫细胞，介导T、B细胞活化、增殖与分化以及炎症反应进程中均发挥了重要作用[10-12]。IL-2含有133个氨基酸残基，其结构中的第58、105和125位上含半胱氨酸（Cys）残基，其中第58与105位上的Cys之间形成的二硫键对维持蛋白的空间构造和生物学活性具有十分重要的作用（图1）[13]。若第125位上的Cys残基二硫键发生错配，将会造成该蛋白天然空间构型破坏以及生物学活性显著降低甚至完全丧失。因此，为了避免这种错配的出现以维持IL-2的生物学活性，研究者采用基因工程技术开发IL-2药物时通常选择将第125位的Cys突变为其他氨基酸残基[14]。例如，阿地白介素结构中的第125位Cys就被突变成了丝氨酸（Ser）。另一种已上市药物注射用重组人白介素-2（商品名：欣吉尔）则是将125位的Cys突变为丙氨酸（Ala）。
IL-2的信号转导及调控
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IL-2可通过多种途径调节免疫激活和免疫抑制之间的平衡：一方面，IL-2可诱导CD4+ T细胞增殖、分化为辅助性T细胞（包括Th1和Th2细胞），增加CD8+ T细胞和自然杀伤（natural killer，NK）细胞的数量，并提高其活性，从而促进免疫应答；另一方面，IL-2也可通过信号转导和转录活化因子5（STAT5）的磷酸化及其他途径，促进CD4+、叉头框蛋白3（FOXP3）、调节性T细胞（Treg）等的生成和稳定，从而抑制免疫反应[15]。IL-2的上述信号转导与调控作用是通过与效应细胞膜上的IL-2受体结合来实现的。IL-2受体含有3个亚单位——P55、P70、P64，分别由较短的α链、具有传递信号的β链和普通γ链组成，即IL-2Rα（CD25）、IL-2Rβ（CD122）和IL-2Rγ（CD132）[16]。其中，IL-2与低亲和力的IL-2Rα（解离常数Kd值约为10-8 mol·L-1）结合后，通常不具备信号传递功能；IL-2Rβ和IL-2Rγ分别负责与Janus激酶（JAK）1和JAK3结合，JAK经磷酸化后被激活，活化后的JAK可启动磷脂酰肌醇3激酶（PI3K）、STAT5和促分裂原活化的蛋白激酶（MAPK）等信号通路进行信号转导[17]，见图2。
同时，IL-2受体还存在异二聚体（IL-2Rβγ）或异三聚体（IL-2Rαβγ）这两种变体。其中，效应T细胞 （Teff）和NK细胞可表达中等亲和力的IL-2Rβγ（Kd值约10-9 mol·L-1）并且对高浓度的IL-2敏感[18]。因此，高剂量的IL-2与异二聚体IL-2Rβγ结合，能够促进具有肿瘤杀伤功能的Teff扩增；而Treg可表达高亲和力的IL-2Rαβγ（Kd值约为10-11 mol·L-1），由于IL-2Rα可在Treg表面持续表达，因此Treg在机体无外来抗原刺激的情况下，对IL-2的敏感性大于NK、Teff等细胞。低剂量的IL-2会优先与异三聚体IL-2Rαβγ结合，激活具有免疫抑制性的CD4+和CD25+ T细胞表达，从而发挥免疫调节的作用[19]。在传统肿瘤免疫治疗过程中，为了发挥更有效的肿瘤免疫杀伤作用，需要激活更多NK、Teff等细胞，就往往需要使用高剂量IL-2，但同时也产生了大量抑制性的Treg，部分抵消了高剂量IL-2的肿瘤免疫治疗效果，也带来了CLS等毒副作用。
受体偏向性IL-2的免疫疗法药物
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在传统的肿瘤免疫治疗中，IL-2的辅助性治疗效果因伴随着严重的副作用（如CLS），遭遇了难以突破的瓶颈。基于对IL-2的生物学功能及信号调控的深入研究，研究人员试图通过改善或调控IL-2的受体选择性，即选择性地偏向激动IL-2Rβγ而减少甚至完全不与IL-2Rα结合，从而偏向性地激活具有肿瘤杀伤功能的CD8+ T细胞，最大限度地发挥IL-2的免疫激活作用。IL-2作为下一代肿瘤免疫疗法的基石，可与多种药物［如程序性死亡受体1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）等］联用起到协同增效的作用，广泛适用于各种类型的肿瘤。因此，免疫疗法的兴起，重塑了IL-2在肿瘤治疗方面的巨大潜力[20, 21]。下文主要介绍以聚乙二醇（polyethylene glycol，PEG）化学修饰和定点突变体策略为代表的IL-2Rβγ受体偏向性IL-2类似药的开发（表1）及其在肿瘤免疫治疗中的应用进展。
1　PEG修饰
PEG修饰是将PEG通过化学方法偶联到蛋白质或多肽分子上，从而提升多肽活性的一种方法。自1977年DAVIES用PEG修饰牛血清白蛋白以来，PEG修饰技术广泛应用于多种蛋白质和多肽的化学修饰。PEG修饰具有延长半衰期、降低免疫原性、减少毒副作用以及增强化学和生物稳定性等优势[22]。早在20世纪80年代就有学者对IL-2进行了PEG修饰的研究，然而临床研究表明，修饰后的IL-2在黑色素瘤患者中的有效应答率低于未修饰的IL-2，因此这一研究宣告失败[23]。其根本原因在于该研究选用的PEG修饰剂类型为不可降解的甲氧基聚乙二醇琥珀酰亚胺乙酸酯，且采用的是随机饱和修饰策略，导致PEG对IL-2的修饰程度较高，几乎完全掩蔽了蛋白结构中与IL-2受体结合的活性区域，因而无法激活CD8+ T细胞发挥肿瘤杀伤活性。
近年来，PEG修饰IL-2的代表药物NKTR-214和THOR-707与PD-1/程序性死亡受体配体1（PD-L1）联合疗法先后在多个临床试验中取得了积极的研究结果，使得PEG修饰策略在改善IL-2药物受体选择性方面的潜力被重新审视。其联合用药方案设计的基础在于NKTR-214、THOR-707等偏向性IL-2受体激动剂负责在肿瘤微环境中让CD8+ T细胞和NK细胞获得扩增和增殖，PD-1/PD-L1等免疫检查点抑制剂则负责通过抑制T细胞表面的负性免疫调节分子的功能，增强T细胞的抗肿瘤免疫应答，进而产生抗肿瘤的免疫效应。因此，理论上偏向性IL-2受体激动剂与免疫检查点抑制剂联合治疗具有协同作用，可产生“1+1>2”的效果。
1.1　NKTR-214
Nektar Therapeutics成立于1990年，是一家以PEG修饰和先进的聚合物共轭技术平台开发候选药物的生物制药公司。NKTR-214是由Nektar Therapeutics开发的新一代PEG化的IL-2药物。NKTR-214是由IL-2缀合6个可降解的PEG链得到的一种前体药[24]，其PEG修饰剂为相对分子量20 000的含有刚性芴环结构的两臂聚乙二醇琥珀酰亚胺碳酸酯。芴及其衍生物是一类重要的具有刚性平面联苯结构的化合物[25]，该PEG可在弱碱和强碱性条件下发生β消除反应，进而降解、脱落。NKTR-214在体外因PEG过度修饰而不具有生物活性，在注射进体内后，随着PEG的脱落可转变为活性相对较强的1-PEG-IL-2和2-PEG-IL-2（平均修饰1个和2个PEG链的活性形式）。同时，NKTR-214上6个修饰位点的选择也生动地体现了药物分子的设计理念——通过对PEG结构和偶联反应类型进行优化，促进定点修饰选择性发生在IL-2/IL-2Rα界面处聚集的赖氨酸（Lys）残基（K31、K34、K42、K47、K48、K75）上，使PEG恰好位于IL-2/IL-2Rα相互作用的关键疏水性结合位点附近，可用于掩蔽与IL-2Rα亚基相互作用的IL-2区域（该区域负责激活Treg），从而偏向性地激活CD8+ T细胞的活性。PEG的修饰一方面可以降低IL-2的肾清除率和蛋白水解速度以延长半衰期，同时也可以增加IL-2的水溶性并降低免疫原性；另一方面，PEG在体内的“程序式”降解脱落使得IL-2得以与IL-2Rβγ结合而提供持续的信号传导，驱动CD8+ T细胞和NK细胞的增殖和激活，而不会在肿瘤微环境中不必要地扩增Treg[24, 26]。
NKTR-214单药治疗实体瘤的Ⅰ期临床试验结果显示：患者接受NKTR-214治疗后，肿瘤内的CD8+ T细胞和NK细胞相比治疗前增加10倍，PD-1的表达在肿瘤浸润淋巴细胞中也增加了2倍，与此同时，Treg数量则无明显变化[27]。2017年11月，肿瘤免疫治疗学会（Society for Immunotherapy of Cancer，SITC）披露了NKTR-214联合纳武利尤单抗治疗黑色素瘤的早期数据，结果显示其有效应答率高达64%。2018年2月，百时美施贵宝（BMS）花费36亿美元购买了NKTR-214的部分权益，拟同时开展以NKTR-214和PD-1抑制剂为基础的针对20种癌症的大规模临床试验。SITC在2018年发布的数据显示，NKTR-214联合纳武利尤单抗的有效率稳定维持在50%左右，尽管这一数据相比之前有所下滑，但是基于其在前期临床试验中的优异表现，美国FDA仍在2019年8月授予了NKTR-214联合纳武利尤单抗突破性疗法的认定，批准其用于治疗初治无法手术切除或转移性黑色素瘤患者。然而，在随后开展的Ⅲ期临床试验中，相对于纳武利尤单抗单药治疗，NKTR-214联合纳武利尤单抗并未表现出额外的临床获益，且毒性反应的发生率有所增加，未达到预期的无进展生存期和总生存期，该临床试验研究宣告失败。2022年4月，对NKTR-214联合纳武利尤单抗治疗肾癌（Ⅲ期临床）、膀胱癌（Ⅱ期临床）的研究数据进行提前分析后，BMS与Nektar Therapeutics宣布终止NKTR-214和纳武利尤单抗联合治疗的所有临床研究。NKTR-214的失利可能在于IL-2理论上有11个可进行化学修饰的Lys残基，尽管能通过药物的化学计量和反应条件控制来获得修饰均匀的IL-2（平均修饰6个PEG链），但是药物的结合位点通常很难控制。这就导致进入体内后NKTR-214的活性药物形式不能完全靶向肿瘤微环境，从而引起不良反应的发生。另一方面，免疫治疗的相互作用机制仍未被完全揭示，机体中存在大量表达IL-2Rβγ二聚体受体的T细胞，而这些细胞没有抗肿瘤作用，因此NKTR-214虽然可以特异性促进这些细胞的增殖，但是并不能发挥抗肿瘤疗效，因而无法实现与纳武利尤单抗联用的协同效应。
尽管NKTR-214在开发联合免疫疗法上未能成功，但该药物的研发思路值得借鉴。NKTR-214的设计充分利用了第三代PEG修饰技术，使其在体内逐步降解，进而解决了传统IL-2半衰期短、给药频繁、剂量高和不良反应等缺陷，是PEG修饰技术运用的一大进步。
1.2　THOR-707
THOR-707是由Synthorx公司开发的新一代PEG定点修饰的IL-2类似药，2019年12月被赛诺菲公司以25亿美元收购。THOR-707利用工程细菌在IL-2与IL-2Rα结合的界面上引入了非天然氨基酸，从而可将一种不可“切割”的PEG链精准连接在IL-2表面。这种PEG定点修饰，不仅延长了IL-2的半衰期，还阻止了IL-2和IL-2Rα亚基结合，从而偏向激动IL-2Rβ，有效增加了CD8+ T细胞和NK细胞的数量，同时避免了IL-2类似药的毒副作用[28]，是继NKTR-214之后又一个极具应用潜力的偏向性IL-2激动剂。
临床前研究显示，在CT26小鼠结肠癌模型中，THOR-707可将Teff在所有CD8+ T细胞中的比例提高到60%以上，抗肿瘤有效应答率为36%；其与PD-1免疫检查点抑制剂联用可协同增强 CD8+ T细胞的免疫反应，同时安全性良好[29]。2021年4月，赛诺菲公布了THOR-707（SAR444245）的中期临床数据：患者在首次服用THOR-707后体内CD8+ T细胞和NK细胞数量有所增加，并且在整个给药周期内持续增加，具有剂量递增效应；与帕博利珠单抗联合使用时，这种效应更加明显。与此同时，在该项研究中未观察到CD4+ Treg或嗜酸性粒细胞的显著增加，表明THOR-707对IL-2Rα受体不具有选择性，与最初的分子结构设计理念相符。在安全性方面，THOR-707未观察到剂量限制性毒性，单药剂量高达24 μg·kg-1，联合用药剂量高达16 μg·kg-1。第一次给药后最常见的不良事件包括流感样症状、发热、呕吐/恶心和寒战等，良好的安全性表现也拓展了其在后续临床试验中的剂量爬坡空间，赛诺菲计划将THOR-707单药的Ⅱ期临床试验推荐剂量上调至每3周给药24~32 μg·kg-1。2022年8月，我国信达生物与赛诺菲达成多项战略合作及许可协议，双方将就THOR-707在中国的临床开发及商业化展开合作，并探索与信达生物的信迪利单抗联合给药的一系列临床研究。目前，THOR-707正在皮肤癌、胃肠癌、非小细胞肺癌/间皮瘤、头颈癌和淋巴瘤等多个适应证上开展全球性Ⅱ期临床试验。
THOR-707的修饰策略与NKTR-214相似，但也有所改进，通过在IL-2/IL-2Rα的结合界面上引入非天然氨基酸，再将PEG链“精准连接”在IL-2表面，能够更好地阻断IL-2与IL-2Rα的结合。
1.3　SHR-1916
SHR-1916为恒瑞医药自主研发的全新PEG修饰和位点突变的IL-2分子，也是国内首个递交新药临床试验申请的国产IL-2类似药。除了采用与NKTR-214、THOR-707类似的PEG修饰策略外，恒瑞医药还对其中若干个氨基酸位点进行突变设计，通过亲和力和细胞增殖活性筛选获得能够消除或减少与IL-2Rαβγ结合，同时不影响与IL-2Rβγ结合的偏向性IL-2突变体类似药。SHR-1916选用的PEG修饰剂为相对分子量20 000的非降解释放型PEG，一方面可延长药物半衰期，另一方面加入的PEG基团能够减弱或阻止IL-2与IL-2Rαβγ的相互作用，进而通过激活JAK1/JAK3/STAT5信号通路，促进CD8+ T细胞和NK细胞增殖，发挥抗肿瘤作用。相较于IL-2本身，SHR-1916可降低对Treg的激活，而不影响甚至还可增加对免疫效应细胞的激活。临床前研究结果显示，在人源肿瘤小鼠动物模型中，SHR-1916在给药27 d内表现出显著的抗肿瘤活性，对黑色素瘤细胞的生长抑制率高达96%，同时未显示出明显的免疫原性[30]。SHR-1916治疗晚期或转移性恶性肿瘤的Ⅰ期临床试验已于2021年3月开展，恒瑞医药预计未来会将其与自主研发的卡瑞利珠单抗作为肿瘤免疫联合疗法进行开发。相对于完全依靠PEG修饰技术的NKTR-214，SHR-1916首先采用定点突变技术筛选获得IL-2Rβγ偏向性突变体，然后通过PEG定点修饰赋予其蛋白长效性和低免疫原性，该药物的设计是多种药物开发策略联合运用的又一体现。
1.4　TransConIL-2β/γ
TransConIL-2β/γ是Ascendis Pharma借助瞬时连接（transient conjugation）技术自主研发的一款可实现药物全身持续释放以及局部（肿瘤内）释放的IL-2类似药。TransConIL-2β/γ的结构特点为在IL-2的IL-2Rα结合区域偶联一个稳定的分子量为5 000的直链PEG，用以降低药物与IL-2Rα的亲和力；而在其IL-2Rβ结合区域，则偶联一个可释放的分子量为40 000的直链PEG作为载体，用以抑制原型药物的活性并保护其免于被机体清除。当药物注射到体内时，在生理pH和温度条件下，未修饰的、具有活性的原型药物会以预定的速率和方式进行释放，进而发挥抗肿瘤作用。在灵长类动物模型中，TransConIL-2β/γ表现出较低的血药峰浓度和较长的有效半衰期（> 30 h）。相对于CD4+ T细胞、Treg和嗜酸性粒细胞，TransConIL-2β/γ更倾向于诱导CD8+ T细胞和NK细胞的激活和扩增，同时没有引起细胞因子风暴或CLS的迹象[31]。目前，TransConIL-2β/γ单药或与帕博利珠单抗联合使用治疗局部晚期或转移性实体瘤的Ⅰ/Ⅱ期临床试验正在进行中。
1.5　8MW2311
8MW2311为迈威生物自主研发的一款PEG修饰的IL-2类似药。2022年2月，8MW2311治疗晚期恶性肿瘤的临床试验申请获得国家药品监督管理局受理。该药注入体内后，可刺激下游转录因子STAT5的磷酸化，有效激发CD8+ T细胞的增殖，从而发挥药效。临床前研究结果显示，8MW2311能在肿瘤组织中富集并可偏向性地激活CD8+ T细胞，在多种肿瘤模型中显示出持续有效的生长抑制作用，并且与免疫检查点抑制剂联用能表现出显著增强的协同抑瘤效果。
2　定点突变
IL-2与IL-2R结合晶体结构的解析，为激发细胞类型特异性IL-2候选疗法的开发提供了重要的结构学信息，IL-2对Teff和Treg的激活机制得以被进一步揭示。构建IL-2突变体并筛选受体偏向性IL-2类似药成为研究的热点之一。前文介绍的SHR-1916也是此类药物。
2.1　RG7461
RG7461是罗氏制药研发的一种靶向性的免疫细胞因子，其含有一种工程化改造的IL-2突变体和成纤维细胞活化蛋白（fibroblast activation protein,FAP）。FAP可在多种肿瘤细胞中表达[32]。罗氏制药通过对多个IL-2Rα结合区域的氨基酸进行突变筛选获得了能够显著降低与IL-2Rα结合的关键氨基酸位点，如将42位苯丙氨酸（Phe）和45位酪氨酸（Tyr）突变成Ala，72位亮氨酸（Leu）突变成甘氨酸（Gly），研发制成了RG7461。该突变体对IL-2Rα的亲和力较低，但能够维持与IL-2Rβ的正常结合[33]。目前，正在开展RG7461与罗氏制药的阿替利珠单抗联合使用治疗晚期或转移性头颈癌、食道癌和宫颈癌的Ⅱ期临床试验。
2.2　FSD13
基于IL-2R的三维空间结构，上海科医联创联合美国马里兰大学和加利福尼亚大学洛杉矶分校通过氨基酸定点突变研发了一款高效、低毒的IL-2突变体FSD13——其将IL-2上的65位脯氨酸（Pro）突变成Lys，以最小的构象变化基本消除了IL-2与IL-2Rα的结合[34]。临床前研究结果显示，相对于野生型IL-2，FSD13对CD4+、CD8+ T细胞和NK细胞具有高效的激活和促增殖功能，可显著增强CD69等的表达，在体外具有强大的肿瘤杀伤效力。在黑色素瘤模型小鼠中，FSD13表现出抑制肿瘤生长和转移的能力，且能降低Treg的比例，同时对肝脏和肺组织没有造成严重的毒副作用[35]。上海科医联创目前正联合免疫检查点抑制剂开展进一步的临床前研究。
2.3　IBI363
IBI363是信达生物研发的一款PD-1/IL-2抗体融合蛋白，该药将突变的IL-2蛋白与抗PD-1抗体融合，进而同时起到刺激IL-2通路与阻断PD-1免疫检查点的作用，可用于晚期恶性实体瘤和淋巴瘤的治疗。信达生物采用其特有的酵母展示平台构建了突变文库，通过对多个IL-2Rα和IL-2Rβ结合区域的氨基酸进行突变，筛选获得了能够显著降低与IL-2Rα的结合能力、提高与IL-2Rβ的结合能力的关键突变位点，同时引入糖基化位点进一步降低了该药与IL-2Rα的结合能力[36]。IBI363不仅在多种荷瘤药理学模型中展现出了良好的抗肿瘤活性，在PD-1耐药和转移模型中也表现出了突出的抑瘤效力；同时，IBI363作用于肿瘤模型食蟹猴的研究显示，该药具有良好的耐受性，并且在低至0.03 mg·kg-1的剂量下仍能诱导肿瘤消退，显示出了强大的抗肿瘤作用[37]。目前正在中国和澳大利亚开展IBI363的Ⅰ/Ⅱ期临床试验。
结语与展望
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细胞因子IL-2在30多年前获得美国FDA批准成为首个肿瘤免疫疗法制剂。近年来，PD-1和CTLA-4负性免疫调节机制的发现和应用重塑了IL-2在肿瘤治疗方面的巨大潜力，为开发更加安全有效的肿瘤免疫疗法提供了新机遇。随着多种化学生物学新技术的引入，肿瘤免疫疗法已成为当下最引人瞩目的研究领域之一。如今，多款IL-2生物制品已经进入临床开发阶段，以PEG化学修饰和定点突变技术为代表开发的偏向性IL-2受体激动剂展现出良好的临床应用潜力。然而单一的开发策略存在一定的局限性。例如，PEG修饰策略可能因不同的修饰位点而不完全一致，导致部分IL-2不能选择性地激活CD8+ T细胞和NK细胞，从而影响候选疗法的效果；同时，PEG修饰蛋白进入体内后难以有效控制PEG链降解的释放位点和释放速率，可能会导致Teff激活不足或激活过度等；此外，PEG因其不可生物降解的特性，会在体内慢慢蓄积而表现出潜在的免疫原性[38]。IL-2突变技术通过改变IL-2表面的氨基酸，可有效赋予IL-2蛋白与特定IL-2R结合的选择性，然而它的一个潜在隐患是引入的基因变异可能引发针对IL-2突变体的免疫反应，从而降低潜在疗法的疗效。
当前，IL-2肿瘤免疫治疗药物的开发还没有真正成功的先例，BMS、Nektar Therapeutics等头部企业的临床研究接连失利也给IL-2药物的研发增加了不确定性。然而，IL-2这个“老”靶点对免疫细胞激活呈现的“双面性”仍将使其在未来竞争中占据一个重要位置。目前，国内在研的IL-2类似药有10余款，建议我国研发者一方面进一步深入研究和揭示肿瘤免疫的相互作用机制，在充分理解IL-2的免疫激活与抑制“双面性”的基础上，更加科学合理地选择开发策略；另一方面，考虑到单一开发策略存在的局限性，布局IL-2疗法的企业可选择联合运用多种开发策略，如PEG修饰/定点突变、定点突变/抗体融合等，通过不同策略之间的互补，实现更精准的IL-2Rβγ受体偏向性和循环长效性，为临床应对恶性肿瘤提供有力武器。
基金
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  • 中国博士后科学基金面上资助项目(2020M681533)
  • 常州市应用基础研究计划项目(CJ20235004)
  • 常州工业职业技术学院博士基金项目(J022001)
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2024年第43卷第10期
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doi: 10.14109/j.cnki.xyylc.2024.10.04
  • 接收时间：2023-01-10
  • 首发时间：2026-03-17
  • 出版时间：2024-10-25
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  • 收稿日期：2023-01-10
  • 录用日期：2024-07-24
基金
中国博士后科学基金面上资助项目(2020M681533)
常州市应用基础研究计划项目(CJ20235004)
常州工业职业技术学院博士基金项目(J022001)
作者信息
    1.常州工业职业技术学院材料工程学院，江苏 常州　213164
    2.扬子江药业集团江苏紫龙药业有限公司，江苏 常州　213100
    3.江苏理工学院化工与环境学院，江苏 常州　213001
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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