CN116819076A - 一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物、应用和方法 - Google Patents
一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物、应用和方法 Download PDFInfo
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Abstract
本发明公开了鼻息肉组织嗜酸性粒细胞浸润和活化的指标作为预测或评估抗IL‑4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物以及应用和方法，具体是使用ECP+细胞数量/HPF作为标志物进行检测，最后预测和评估患者对抗IL‑4Rα单抗治疗应答的ROC曲线显示AUC＝0.824，截断值为33.013，敏感度为100％，特异度为76.5％，本发明的标志物可以快速、准确的预测或评估抗IL‑4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效，填补了现有技术的空白，具有重大的临床价值和经济价值。
Description
技术领域
本发明涉及免疫分析技术领域，具体而言，涉及一种预测抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效生物标志物和应用。
背景技术
目前，全世界有4％的人口患有慢性鼻窦炎伴鼻息肉(chronic rhinosinusitiswith nasal polyps,CRSwNP)，其治疗仍然是一个临床挑战。其中嗜酸型慢性鼻窦炎伴鼻息肉(eosinophilic chronic rhinosinusitis with nasal polyps,ECRSwNP)是难治性CRSwNP中复发率最高的内在型。
IL-4是2型炎性反应的信号转导的关键驱动因素，Th2细胞通过IL-4细胞因子导致嗜酸性粒细胞分化，IL-4细胞因子与IL-4Rα受体，激活细胞内信号转导通路上的转录因子，引起2型炎症反应。作为靶向2型因子的生物制剂，抗IL-4Rα单抗(例如：Dupilumab或CM310)是一种以IL-4Rα为靶点的完全人源化单克隆抗体，通过阻断IL-4Rα与IL-4的结合从而抑制其生物活性，抗IL-4Rα单抗因其优异的疗效和安全性已获得美国食品药品监督管理局和美国药品监督管理总局的批准用于治疗CRSwNP。但临床应用中发现，仍有部分患者经过此类单抗治疗疗效欠佳，且该类药物价格昂贵，并且可作为预测抗IL-4Rα单抗反应的生物标志物较少。在使用抗IL-4Rα单抗(例如：Dupilumab或CM310)治疗的临床研究中，并没有观察到血液中嗜酸性粒细胞具有统计学意义的改变，血液中嗜酸性粒细胞浸润尚不能作为抗IL-4Rα单抗有效的生物标志物。
因此，探究可预测其疗效的指标实现精准治疗至关重要，本研究旨在探索可用于预测抗IL-4Rα单抗疗效的指标。
发明内容
本发明首先提供了一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物，所述标志物为鼻息肉组织嗜酸性粒细胞浸润和活化的指标，所述指标任选地为ECP+细胞数量/HPF。
本发明还提供了一种权利要求1所述的标志物的应用，所述应用为a)制备预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的检测试剂；或b)制备或评估预测抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的检测试剂盒；或c)用于预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的方法，所述方法任选地用于非诊断目的或者非治疗目的。
本发明还提供了鼻息肉组织嗜酸性粒细胞浸润和活化指标的检测试剂在制备用于预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的试剂盒中的应用。
优选的，检测试剂包括样本预处理试剂和用于检测鼻息肉组织中嗜酸性粒细胞浸润和活化指标的试剂；
优选的，所述鼻息肉组织嗜酸性粒细胞浸润和活化指标的检测试剂包括适用于如下至少一种方法的试剂：苏木精和伊红(H&E)染色、多重免疫荧光染色。
所述样本为鼻分泌物、鼻脱落细胞和鼻息肉组织。
本发明还提供了一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的方法，所述方法任选地用于非诊断目的或者非治疗目的，其包含检测鼻息肉组织嗜酸性粒细胞浸润和活化指标的步骤，所述指标任选地为ECP+细胞数量/HPF，并且以鼻息肉组织嗜酸性粒细胞浸润和活化指标结果来预测或评估抗IL-4Rα单抗疗效。
优选的，所述检测鼻息肉组织嗜酸性粒细胞浸润和活化指标的步骤包括适用于如下至少一种方法：苏木精和伊红(H&E)染色、多重免疫荧光染色。
优选的，所述苏木精和伊红(H&E)染色包括：将息肉组织在含有1％青霉素、1％链霉素和1％两性霉素的PBS中冲洗，称量后切成重量约0.1g的小切片，将工作浓度10μg/μL，体积10μL的IL-4或PBS分别注射至每个所述的小切片，与获得息肉的同一受试者分离的白细胞共培养96小时(每孔106个细胞)，在苏木精和伊红(H&E)染色后评估组织中嗜酸性粒细胞浸润程度。
优选的，通过多重免疫荧光染色方法评估鼻息肉基线组织中每高倍镜视野(perhighpower field,HPF)下ECP+细胞、ECP+CD63+细胞和ECP+CD69+细胞的数量。从福尔马林固定的石蜡包埋组织中切下厚度为4μm的切片，在二甲苯中去石蜡化，并通过分级醇系列再水化。使用乙二胺四乙酸(EDTA，Dako，S2367)或AR6缓冲液(AR600125ML，AkoyaBiosciences)进行抗原回收(微波炉，120℃，20分钟)。使用Opal 6-plex手动检测试剂盒(NEL811001KT，Akoya Biosciences)进行多重免疫荧光染色。蛋白质阻断(ARD1001EA，Akoya Biosciences)后，在37℃下依次应用一级抗体孵育40分钟，然后二级抗体孵育10分钟，随后通过酪胺信号放大技术和Opal荧光检测10分钟。嗜酸性粒细胞的多重免疫荧光标记物的评估包括：嗜酸性阳离子蛋白(ECP，ab207429，1:4000)、CD63(ZA-0694，未稀释)、CD69(ab233396，1:1000)。在每一轮检测之后，使用抗原回收缓冲液进行热诱导的表位回收。在最后一轮免疫荧光染色后，使用4',6-二脒基-2-苯基吲哚(DAPI，AkoyaBiosciences，FP1490)孵育5分钟。使用ProLong GoldAntifade(ThermoFisherScientific，P36935)安装盖玻片。使用VectraPolaris多光谱成像系统(AkoyaBiosciences)获得40倍镜下多光谱图像的代表性区域。用单色和未染色切片作对照生成光谱库后使用inForm软件包(Akoya Biosciences，v2.6)进行多光谱解混。
优选的，采用NPS评分将抗IL-4Rα单抗治疗后NPS较基线NPS变化是否大于等于2分将受试者分为应答组和无应答组。0分：无息肉；1分：中鼻道可见小息肉，大小未超过中鼻甲下缘；2分：息肉达到中鼻甲下缘；3分：息肉至下鼻甲下缘，或评分为2的息肉同时伴有中鼻甲内侧的大息肉；4分：息肉完全或者接近完全堵塞鼻腔，即至鼻底。两侧NPS评分之和即为最终得分。
本发明与现有技术相比，至少具有如下有益效果：
本发明发现了鼻息肉组织嗜酸性粒细胞浸润和活化的指标作为预测抗IL-4Rα单抗疗效生物标志物的应用，具体是使用ECP+细胞数量/HPF预测患者对抗IL-4Rα单抗治疗应答的ROC曲线显示AUC＝0.824，截断值为33.013，敏感度为100％，特异度为76.5％，本发明的标志物可以快速、准确的预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效，填补了现有技术的空白，具有重大的临床价值和经济价值。
附图说明
图1.IL-4促进嗜酸性粒细胞浸润与活化；0.1g鼻息肉切片组织中注射浓度10μg/μL，体积10μL的IL-4或PBS，与获得息肉组织的受试者分离的白细胞共同孵育96小时后，收集鼻息肉切片，在苏木精和伊红(H&E)染色后评估嗜酸性粒细胞的数量；
图2区分应答组和无应答组的潜在生物标记物；(A)应答组嗜酸性粒细胞组：CD63、CD69、ECP；(B)非应答组嗜酸性粒细胞组：CD63、CD69、ECP；(C)潜在生物标记物预测应答组和无应答组的ROC曲线。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚，下面将结合附图及具体实施例进行详细描述。
实施例1获得样本
本研究共纳入22名患者，所有患者需满足以下入组标准：1)年龄为18-70岁；2)在导入期前2年内接受过系统性糖皮质激素(systemic corticosteroids,SCS)治疗，或对SCS治疗有禁忌症或不耐受，或在导入期前6个月前接受过鼻息肉手术；3)鼻息肉评分(nasalpolyp score,NPS)至少为5分(每个鼻孔至少2分)；4)有中度或重度鼻塞(0＝无症状，1＝轻度，2＝中度，3＝重度)，每周平均鼻塞评分(nasal congestion score,NCS)为2或3分，以及任何其他症状，如嗅觉丧失或流涕；5)患者在筛选前至少4周内需要稳定持续使用鼻喷激素，在整个研究过程中，患者接受糠酸莫米松鼻喷雾剂(MFNS)作为背景治疗；6)所有患者的外周血嗜酸性粒细胞百分比≥6.9％(无哮喘)或≥3.7％(有哮喘)(4)；2)通过鼻息肉活检，组织嗜酸性细胞绝对计数≥55个/高倍镜视野或嗜酸性细胞百分比≥27％(2,3)。
如果患者有以下情况则会被排除：1)在随机分组前10周或5个半衰期(以较长者为准)内使用过IL-4Rα拮抗剂，或在8周或5半衰期(以较长者为准的)内使用生物治疗/全身免疫抑制剂，或在130天内使用抗IgE单克隆抗体；2)在筛选/导入期之前的6个月内经历过鼻息肉手术；3)在筛选前4周内接受中效和短效SCS治疗，或在6周内接受长效SCS治疗；4)患有严重肝或肾损伤；5)在随机分组前12周内接种活疫苗或减毒疫苗，或在研究期间计划接种活疫苗和减毒疫苗；6)已知或疑似免疫抑制的患者，包括但不限于有侵袭性机会性感染史(如肺结核、组织胞浆菌病、李斯特菌病、球虫病、肺囊肿、曲霉菌病)，即使感染已解决；7)怀孕或哺乳的妇女，或计划在研究期间怀孕的妇女；8)研究人员认为存在不适合参与研究的任何其他医疗或非医疗状况。本研究经首都医科大学北京同仁医院伦理委员会批准(TREC2022-KY053.R1)。在患者参与之前进行书面知情同意。
实施例2样本检测
患者签署知情同意书后进入4周的筛选/导入期(V1)，期间，所有患者接受MFNS喷鼻，每天每侧鼻腔100μg(每日总剂量为200μg)；之后患者接受抗IL-4Rα单抗治疗16周(首次600mg皮下注射，之后每2周300mg皮下注射，V2-V10)。患者在V1时进行息肉采集用于组织嗜酸性粒细胞计数计免疫荧光染色，在V2、V10进行NPS评分。
通过苏木精和伊红(H&E)染色评估息肉组织中嗜酸性粒细胞浸润程度。将息肉组织在含有1％青霉素、1％链霉素和1％两性霉素的PBS中冲洗，称量后切成重量约0.1g的小切片。将工作浓度10μg/μL，体积10μL的IL-4或PBS分别注射至每个小切片，与获得息肉的同一受试者分离的白细胞共培养96小时(每孔106个细胞)，在苏木精和伊红(H&E)染色后评估组织中嗜酸性粒细胞浸润程度。
通过多重免疫荧光染色方法评估鼻息肉基线组织中每高倍镜视野(perhighpower field,HPF)下ECP+细胞、ECP+CD63+细胞和ECP+CD69+细胞的数量。从福尔马林固定的石蜡包埋组织中切下厚度为4μm的切片，在二甲苯中去石蜡化，并通过分级醇系列再水化。使用乙二胺四乙酸(EDTA，Dako，S2367)或AR6缓冲液(AR600125ML，Akoya Biosciences)进行抗原回收(微波炉，120℃，20分钟)。使用Opal 6-plex手动检测试剂盒(NEL811001KT，Akoya Biosciences)进行多重免疫荧光染色。蛋白质阻断(ARD1001EA，AkoyaBiosciences)后，在37℃下依次应用一级抗体孵育40分钟，然后二级抗体孵育10分钟，随后通过酪胺信号放大技术和Opal荧光检测10分钟。嗜酸性粒细胞的多重免疫荧光标记物的评估包括：嗜酸性阳离子蛋白(ECP，ab207429，1:4000)、CD63(ZA-0694，未稀释)、CD69(ab233396，1:1000)。在每一轮检测之后，使用抗原回收缓冲液进行热诱导的表位回收。在最后一轮免疫荧光染色后，使用4',6-二脒基-2-苯基吲哚(DAPI，Akoya Biosciences，FP1490)孵育5分钟。使用ProLong GoldAntifade(ThermoFisher Scientific，P36935)安装盖玻片。使用VectraPolaris多光谱成像系统(Akoya Biosciences)获得40倍镜下多光谱图像的代表性区域。用单色和未染色切片作对照生成光谱库后使用inForm软件包(AkoyaBiosciences，v2.6)进行多光谱解混。
具体的，采用NPS评分将抗IL-4Rα单抗治疗后NPS较基线NPS变化是否大于等于2分将受试者分为应答组和无应答组。0分：无息肉；1分：中鼻道可见小息肉，大小未超过中鼻甲下缘；2分：息肉达到中鼻甲下缘；3分：息肉至下鼻甲下缘，或评分为2的息肉同时伴有中鼻甲内侧的大息肉；4分：息肉完全或者接近完全堵塞鼻腔，即至鼻底。两侧NPS评分之和即为最终得分。
具体的，采用SAS版本9.4进行统计分析。一般来说，连续变量通过受试者数量、平均值、标准差、中位数、25％分位数、75％分位数、最小值和最大值进行描述性总结，分类变量通过频率和百分比进行总结。在所有统计分析中，除非另有规定，否则所有统计测试均采用双侧α＝0.05。组间比较通过Mann-Whitney U检验进行。生成受试者工作特性曲线(receiver operating characteristic,ROC)，并计算ROC曲线下的面积(AUC)以评估其预测价值。AUC的>0.9预测价值较高；0.7<AUC≤0.9预测价值中等；0.5<AUC≤0.7时预测价值弱。
实施例3样本检测结果
在苏木精和伊红(H&E)染色后评估鼻息肉组织中嗜酸性粒细胞的数量，研究发现，将IL-4注入鼻息肉并与获得息肉的同一受试者分离的白细胞共培养96小时后，与注射PBS组相比，IL-4处理的鼻息肉组织切片中存在大量嗜酸性粒细胞，可促进局部组织中嗜酸性粒细胞的浸润和活化(图1)。
依据抗IL-4Rα单抗治疗后NPS较基线NPS变化是否大于等于2分将22位患者分为应答组(n＝17)和无应答组(n＝5)，患者基本特征见表1。
表1应答组和无应答组患者特征
并对其石蜡包埋的鼻息肉组织嗜酸性粒细胞进行多重免疫荧光染色(ECP Opal520、CD69 Opal 690和CD63 Opal 620)，并评估每高倍镜视野(perhigh power field,HPF)下ECP+细胞、ECP+CD63+细胞和ECP+CD69+细胞的数量。结果显示无应答组患者的ECP阳性细胞数较应答组少(表2)。
表2.区分应答组和无应答组的潜在生物标记物
使用ECP+细胞数量/HPF预测患者对抗IL-4Rα单抗治疗应答的ROC曲线显示AUC＝0.824，截断值为33.013，敏感度为100％，特异度为76.5％(图2)。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物，其特征在于所述标志物为鼻息肉组织嗜酸性粒细胞浸润和活化的指标，所述指标任选地为ECP+细胞数量/HPF。
2.一种权利要求1所述的标志物的应用，其特征在于，所述应用为a)制备预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的检测试剂；或b)制备或评估预测抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的检测试剂盒；或c)用于预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的方法，所述方法任选地用于非诊断目的或者非治疗目的。
3.一种权利要求1所述的标志物的检测试剂在制备用于预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的试剂盒中的应用。
4.根据权利要求3所述的检测试剂在制备用于预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的试剂盒中的应用，其特征在于，所述检测试剂包括样本预处理试剂和用于检测鼻息肉组织中嗜酸性粒细胞浸润和活化指标的试剂；所述样本为鼻分泌物、鼻脱落细胞和鼻息肉组织。
5.一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的方法，其特征在于，所述方法任选地用于非诊断目的或者非治疗目的，其包含检测鼻息肉组织嗜酸性粒细胞浸润和活化的指标的步骤，所述指标任选地为ECP+细胞数量/HPF，并且以鼻息肉组织嗜酸性粒细胞浸润和活化的指标结果来预测或评估抗IL-4Rα单抗疗效。
6.根据权利要求2-4所述的应用，其特征在于，所述鼻息肉组织嗜酸性粒细胞浸润和活化指标的检测试剂包括适用于如下至少一种方法的试剂：苏木精和伊红(H&E)染色、多重免疫荧光染色。
7.根据权利要求5所述的方法，其特征在于，所述检测鼻息肉组织嗜酸性粒细胞浸润和活化的指标的步骤包括适用于如下至少一种方法：苏木精和伊红(H&E)染色、多重免疫荧光染色。
8.根据权利要求7所述的方法，其特征在于，所述苏木精和伊红(H&E)染色包括：将息肉组织在含有1％青霉素、1％链霉素和1％两性霉素的PBS中冲洗，称量后切成重量约0.1g的小切片，将工作浓度10μg/μL，体积10μL的IL-4或PBS分别注射至每个所述的小切片，与获得息肉的同一受试者分离的白细胞共培养96小时(每孔106个细胞)，在苏木精和伊红(H&E)染色后评估组织中嗜酸性粒细胞浸润程度。
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| CN117949666A (zh) * | 2024-01-12 | 2024-04-30 | 首都医科大学附属北京同仁医院 | 一种预测或评估抗IL-4Rα单抗在治疗鼻黏膜2型炎症相关鼻病疗效的标志物、方法和应用 |
| CN118501447A (zh) * | 2023-05-26 | 2024-08-16 | 首都医科大学附属北京同仁医院 | 一种预测或评估抗IL-4 Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物、应用和方法 |
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| FR2783326B1 (fr) * | 1998-09-10 | 2000-12-01 | Immunotech Sa | Procede de detection ou de quantification des basophiles et des eosinophiles |
| LT3010539T (lt) * | 2013-06-21 | 2019-10-10 | Sanofi Biotechnology | Nazalinės polipozės gydymo būdai, skiriant il-4r antagonistą |
| MX2017006286A (es) * | 2014-11-14 | 2018-01-23 | Sanofi Biotechnology | Metodos para tratar sinusitis cronica con polipos nasales por administracion de un antagonista de il-4r. |
| US20180092894A1 (en) * | 2016-09-07 | 2018-04-05 | Northwestern University | Treatment of eosinophilic inflammatory disease |
| KR101974504B1 (ko) * | 2017-04-10 | 2019-05-03 | 재단법인 아산사회복지재단 | 호산구성 비용종 동물모델 |
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| CN116819076A (zh) * | 2023-05-26 | 2023-09-29 | 首都医科大学附属北京同仁医院 | 一种预测或评估抗IL-4Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物、应用和方法 |
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| CN118501447A (zh) * | 2023-05-26 | 2024-08-16 | 首都医科大学附属北京同仁医院 | 一种预测或评估抗IL-4 Rα单抗在治疗慢性鼻窦炎伴鼻息肉中疗效的生物标志物、应用和方法 |
| CN117949666A (zh) * | 2024-01-12 | 2024-04-30 | 首都医科大学附属北京同仁医院 | 一种预测或评估抗IL-4Rα单抗在治疗鼻黏膜2型炎症相关鼻病疗效的标志物、方法和应用 |
| WO2025087446A1 (zh) * | 2024-01-12 | 2025-05-01 | 首都医科大学附属北京同仁医院 | 一种预测或评估抗IL-4Rα单抗在治疗鼻黏膜2型炎症相关鼻病疗效的标志物、方法和应用 |
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