CN115697412A - 用clever-1抑制剂与白细胞介素抑制剂联合治疗疾病 - Google Patents
用clever-1抑制剂与白细胞介素抑制剂联合治疗疾病 Download PDFInfo
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Abstract
能够抑制CLEVER‑1表达或结合至CLEVER‑1的药剂与白细胞介素和/或相应受体的抑制剂以及任选地进一步与能够结合至干扰素‑α/β受体(IFNAR)的药剂的组合在疾病治疗中的用途。
Description
技术领域
本发明涉及能够抑制CLEVER-1表达或结合至CLEVER-1的药剂与白细胞介素和/或相应受体的抑制剂的组合在疾病治疗中的用途。本发明还涉及一种用于监测患者对抗CLEVER-1疗法的应答并评估对包含白细胞介素和/或相应受体的抑制剂的组合疗法的需求的方法。
背景技术
在过去的十年中,炎症的概念已经超越了热、肿胀、疼痛和发红,我们已经获得了对炎症中的细胞途径和分子介质的详细理解,现在正在将它们应用于如癌症、心脏病、自身免疫和传染病的研究领域[1]。
炎症是由如损伤的和死亡的细胞、化学刺激物和病原体的多种刺激引起的,这些应答对于病原体入侵期间的有效的免疫应答至关重要。炎性应答的两个关键支柱是先天细胞因子;白细胞介素和1型干扰素[1]。
如肺结核和肝炎的疾病,如流感和冠状病毒的病毒生物体以及癌症,都在疾病部位周围引起炎症,并与促炎细胞因子一起穿过炎症支柱;白细胞介素和1型干扰素是宿主应答的开始[1]。
最近,像新型冠状病毒(SARS-CoV-2)的传染性生物体已经引起了一波巨大的各种开发策略的浪潮,以解决病毒和下游的困扰和并发症。严重的并发症包括败血性休克、急性呼吸窘迫综合征(ARDS)和多器官衰竭(MOF),这些都是威胁生命的病状。ARDS和MOF是危重病状,并且患有这种并发症的患者在ICU中治疗,在ICU中他们对这种病状具有有限的治疗并且没有特异性治疗。患者接受类固醇和机械通气作为疾病的治疗[2]。促炎细胞因子的升高的水平与ARDS的不良预后相关[3]。
目前的治疗选项如类固醇没有显示出临床益处。虽然类固醇加速了呼吸衰竭和循环性休克的消退,但它们也增加了继发感染的风险。败血症、严重COVID-19感染和癌症的常见特征是免疫系统衰竭。最近在SARS-CoV-2疫情中已经观察到,T细胞上的衰竭标志物与癌症和患有慢性感染的患者中观察到的标志物相当[5]-[8]。
癌细胞具有大量的遗传和表观遗传改变,其为宿主免疫系统产生大量的肿瘤相关抗原,从而要求肿瘤对上述炎症的机制产生特异性免疫抗性。
在癌症、ARDS、COVID-19感染和败血症中涉及的重要免疫抗性机制是免疫抑制途径,其中单个分子可以控制免疫系统活性(被称为免疫检查点),并且通常介导免疫耐受以减轻附带组织损伤。最近在控制免疫系统激活方面的大多数突破是由于对细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性细胞死亡蛋白-1(PD-1)及其配体PD-L1的发现、理解和调节。先前的工作已经显示了在癌症诱导的抗肿瘤免疫的小鼠模型中CTLA-4的抗体阻断。此外,免疫检查点受体如PD-1限制了组织内T细胞效应子的功能。通过上调PD-1的配体,肿瘤细胞阻断肿瘤微环境中的抗肿瘤免疫应答[9],[10]。存在许多被批准用于临床的免疫检查点调节剂,从在约10%-20%的患者中具有有效结果的转移性黑色素瘤开始,到已经在其他肿瘤(如前列腺癌、乳腺癌和结肠直肠癌)中进行了测试,但是这些方案对它们仍然是难治的。对检查点抑制良好应答的患者通常具有预先存在的抗肿瘤免疫应答,其特征在于高密度的产生干扰素(IFN)-γ的CD8+T细胞[10],[11]。
为了增加肿瘤对这些可用药物的应答率,理论上肿瘤必须处于发炎的状态,因此开发实现发炎的肿瘤状态的策略是合理的。
在临床上已经尝试了许多实现这一点的方法,然而它们都是基于诱导凋亡细胞死亡的化疗方案,如蒽环类药物,以便增加新抗原的量,从而刺激针对肿瘤的持久免疫[12],[13]。在凋亡细胞死亡期间,白细胞介素表达由于炎性信号而增加,主要是白细胞介素1(IL-1)、白细胞介素6(IL-6)和白细胞介素8(IL-8)及其受体普遍存在,这对于在凋亡信号期间肿瘤生长和抵抗细胞死亡是必需的[1],[10]。IL-1、IL-6和IL-8具有许多下游途径,并且近年来,两者都已成为临床开发的有趣治疗靶点,但原因不同。IL-1激活导致下游肿瘤坏死因子相关因子(TRAF)6激活,进一步导致活化的B细胞的核因子κ-轻链增强子(NF-κB)激活。IL-6被靶向以终止下游Janus激酶(JAK)和信号转导子和转录激活子3(STAT3)的下游磷酸化,而为了解决IL-8,涉及靶向两种G蛋白偶联受体(CXCR1和CXCR2),从而阻止该途径中的下游信号传导。
没有批准的抑制IL-1、IL-6和IL-8或其受体的癌症药物。抗IL-1和抗IL-1受体抑制剂被上市以用于治疗遗传性病症以及肌肉骨骼病症。抗IL-6或抗IL-6受体抗体作为风湿性疾病的抗炎药物上市。
IL-1、IL-6和IL-8是促炎细胞因子,与1型干扰素一起,它们是炎症过程中的主要参与者。这些细胞因子与在肿瘤表面以及与慢性感染相关的组织上大量过量表达的受体结合,所述慢性感染如结核病中的肉芽肿或急性严重疾病状态如败血症和ARDS。
IL-1、IL-6和IL-8受体在肿瘤微环境(TME)中与肿瘤和炎症相关的其他细胞上也很丰富,如肿瘤浸润性嗜中性粒细胞和肿瘤相关巨噬细胞[12]。TME可以与结核病和肝炎中的肉芽肿相比较。
然而,在癌症和慢性感染(如结核病和肝炎)中发现的如巨噬细胞的先天免疫细胞[7]可以抑制T细胞活化并且导致肿瘤进展,尽管在肿瘤细胞中存在高突变负荷。有助于肿瘤相关免疫抑制并提供肿瘤生长支持信号的巨噬细胞可能是靶向疗法的高度合格的候选者,因为这些细胞大量存在于各种肿瘤中,它们是非常可塑性的,并且可以被转化为支持T细胞活化和肿瘤或感染排斥的促炎性巨噬细胞[15,16]。迄今为止,在临床开发中的巨噬细胞靶向策略利用巨噬细胞集落刺激因子受体抑制来耗尽肿瘤中的巨噬细胞群[17]。然而,已经报道了对这些方法的抗性[18]。因此,需要找到利用这些细胞来对抗癌症的新方法。
近年来,清除剂受体在调节巨噬细胞对不同刺激的应答中的作用越来越受到关注。CLEVER-1(也被称为Stabilin-1)是一种多功能分子,其赋予抗炎巨噬细胞亚群清除能力[19,20]。在这些细胞中,CLEVER-1参与受体介导的内吞和再循环、细胞内分选以及改变的和正常的自身组分的转胞吞作用。最近,已经发现在Stab1-/-(CLEVER-1敲除)小鼠中和在用抗CLEVER-1疗法治疗的小鼠中,癌症生长和转移的进程减弱[20]。
发明内容
现在,已经令人惊讶地发现,在深度免疫抑制的癌症患者的癌症中的抗-CLEVER-1治疗导致免疫系统的激活,这使得宿主免疫系统能够对抗败血症和完全免疫衰竭。还已经令人惊讶地发现,抗CLEVER-1治疗导致抗肿瘤应答,除了当由CLEVER-1抑制或由疾病进展和免疫抗性驱动的免疫应答导致白细胞介素增加时。因此,已经发现抗-CLEVER-1治疗与白细胞介素抑制疗法一起使用和/或通过在尽管抗-CLEVER-1治疗但白细胞介素表达水平如IL-6和/或IL-8增加的患者中施用具有CLEVER-1抑制作用的I型干扰素来进一步诱导由抗-CLEVER-1药剂实现的免疫应答是有益的。抗白细胞介素疗法是抑制白细胞介素和它们相应的受体,如IL-6或IL-6受体(IL-6R)、IL-8或IL-8受体(IL-8R)、和/或IL-1或IL-1受体IL-1Ra和/或IL-1Rb。这种免疫应答也可以由能够结合至干扰素-α/β受体(IFNAR)的药剂引起,如外源性I型干扰素与CLEVER-1抑制剂的组合,用于在其他无应答的病状如急性呼吸窘迫综合征(ARDS)、败血症或癌症中更有效的疾病疗法。
特别地,已经发现能够抑制CLEVER-1表达或结合至CLEVER-1的药剂和白细胞介素和/或其相应受体的抑制剂的组合适合于治疗导致免疫衰竭的肿瘤、慢性感染和急性炎性感染,所述肿瘤、慢性感染和急性炎性感染对能够抑制CLEVER-1表达或结合至CLEVER-1的药剂的单一疗法无应答。此外,能够结合干扰素-α/β受体(IFNAR)的药剂可以用于诱导免疫应答的治疗中。抗IL-1和/或抗IL-6和/或抗IL-8治疗和/或I型干扰素受体(IFNAR)的激活作为单一疗法不是有效的癌症治疗,但在其他适应症中显示出活性。在与抗-CLEVER-1药剂组合时,发现它们具有抗肿瘤和抗感染活性。
因此,本发明的目的是提供一种新的癌症的治疗,特别是提供针对目前无法治疗或不能对抗-CLEVER-1治疗提供所需应答的肿瘤类型的治疗方法。
本发明的另外的目的是提供一种传染病及其致命的急性疾病状态如败血症和ARDS的新的治疗,以支持针对致病生物体或随后的机会性感染的免疫应答,利用对抗第一次严重病状所需的衰竭的免疫系统。
此外,本发明的目的是提供一种方法,用于监测患者对抗-CLEVER-1疗法的应答,并且当已经在患者中施用了能够结合至CLEVER-1的药剂时,评估对包含白细胞介素和/或相应的白细胞介素受体的抑制剂的联合疗法的需求。
为了实现上述目的以及其他目的,本发明的特征在于所附独立权利要求的特征部分中所呈现的内容。本发明的一些优选实施例将在其他权利要求中描述。
在本文中提及的实施例和优点在适用的情况下涉及所述药剂的组合、方法以及根据本发明的用途,尽管并不总是具体提及。
根据本发明的第一方面,本发明涉及一种治疗有效量的以下的组合:
(a)能够抑制CLEVER-1表达或与CLEVER-1结合的药剂,和
(b)白细胞介素和/或相应的白细胞介素受体的抑制剂,
用于治疗选自由以下组成的组的疾病:癌症、传染病、慢性感染、严重流感或冠状病毒感染、败血症和急性呼吸窘迫综合征(ARDS),其中在施用白细胞介素的抑制剂和/或相应的白细胞介素受体的抑制剂之前,向个体施用所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂,并且在开始抗CLEVER-1治疗之后(即,在开始施用所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂之后),将待治疗的个体诊断为白细胞介素IL-1、IL-6和/或IL-8水平升高。
特别地,本发明涉及一种治疗有效量的以下的组合:
(a)能够抑制CLEVER-1表达或与CLEVER-1结合的药剂,和
(b)白细胞介素如IL-1、IL-6和IL-8和/或它们相应的受体IL-1Ra、IL-1Rb、IL-6R和IL-8R的抑制剂,
用于治疗个体中的疾病,所述疾病选自由癌症、传染病、慢性感染、严重流感或冠状病毒感染、败血症和急性呼吸窘迫综合征(ARDS)组成的组,所述个体已被诊断为具有显示促炎性细胞因子(IL-1、IL-6、IL-8)的高表达和/或对单独的抗-CLEVER-1治疗无应答或在抗-CLEVER-1治疗期间显示循环白细胞介素水平增加的适应症。此外,除了能够抑制CLEVER-1表达或与CLEVER-1结合的药剂和白细胞介素如IL-1、IL-6和Il-8和/或它们相应的受体IL-1Ra、IL-1Rb、IL-6R和IL-8R的抑制剂之外,还可以使用能够与干扰素-α/β受体(IFNAR)结合的药剂,如外源性1型干扰素,以用于诱导免疫应答和影响IL-6和/或IL-8表达水平。
根据本发明,白细胞介素和/或相应的白细胞介素受体的抑制剂用于抗-CLEVER-1治疗的组合,或者白细胞介素和/或相应的白细胞介素受体的抑制剂和能够结合至干扰素-α/β受体(IFNAR)的药剂与抗-CLEVER-1治疗组合使用。
对抗CLEVER-1治疗的应答性通常与IL-1、IL-6和IL-8水平的降低有关,而对抗CLEVER-1治疗的无应答性与IL-6和IL-8血浆/血清水平的升高有关。抗-CLEVER-1治疗导致T细胞向肿瘤和肉芽肿中的浸润增加,并以这种方式降低IL-1R和/或IL-6R和/或IL-8R的表达,以用于改善抗-IL-1和/或抗-IL-6和/或IL-8抑制剂和/或IFNAR的激动剂的治疗靶向。因此,本发明提供了抗-IL-1和/或抗-IL-6和/或IL-8治疗和/或1型干扰素(IFN)当与靶向以阻断T细胞在癌症、慢性感染、传染病或其它免疫衰竭状态(例如在败血症和ARDS中)中的负调节的抗-CLEVER-1治疗组合时的改进的功效。最近还在COVID-19感染中观察到的T细胞衰竭标志物与在癌症和患有慢性感染的患者中观察到的标志物相当[5]-[8]。因此,根据本发明的联合治疗也适合于治疗严重的流感和冠状病毒感染,如导致免疫衰竭的新型冠状病毒(Sars-Cov和Sars-Cov2)。本发明为需要激活免疫系统的患者提供了白细胞介素抑制和/或1型干扰素与抗-CLEVER-1药剂的联合治疗。
根据一个方面,本发明提供了一种用于治疗或延缓个体的癌症进展的方法,所述方法包含向所述个体施用治疗有效量的能够抑制CLEVER-1表达或结合CLEVER-1的药剂与白细胞介素和/或其相应受体的抑制剂的组合,以及任选地进一步与能够结合至干扰素-α/β受体(IFNAR)如1型干扰素的药剂的组合。
根据另一方面,本发明提供了一种用于治疗或预防个体的慢性感染、传染病或其他免疫衰竭状态例如败血症和ARDS的方法,所述方法包含向所述个体施用治疗有效量的能够抑制CLEVER-1表达或结合CLEVER-1的药剂与白细胞介素和/或其相应受体的抑制剂的组合,以及任选地进一步与能够结合至干扰素-α/β受体(IFNAR)如1型干扰素的药剂的组合。
此外,根据本发明的一个方面,本发明提供了一种方法,用于监测患者对抗-CLEVER-1疗法的应答,并且评估当在患者中已经施用了能够结合至CLEVER-1的药剂时,对包含白细胞介素和/或相应的白细胞介素受体的抑制剂的联合疗法的需求,所述方法包含
-在向患者施用能够结合至CLEVER-1的药剂之前的第一时间点从患者获得样品,
-在向患者施用能够结合至CLEVER-1的药剂之后的稍后时间点从患者获得样品,
-从所获得的样品中测量白细胞介素IL-1、IL-6和/或IL-8的水平,
-将从在稍后的时间点获得的样品中测量的IL-1、IL-6和/或IL-8的水平与从在第一时间点获得的样品中测量的IL-1、IL-6和/或IL-8的表达水平进行比较,其中白细胞介素IL-1、IL-6和/或IL-8水平的升高是开始伴随施用IL-1抑制剂和/或相应受体的抑制剂、IL-6抑制剂和/或相应受体的抑制剂、IL-8抑制剂和/或相应受体的抑制剂或其任何组合的指征。
此外,已经发现,对于使用人源化的抗-CLEVER-1抗体如贝马瑞利单抗(bexmarilimab)以用于提供免疫刺激以治疗根据本发明的所述疾病,根据患者的体重,优选的剂量范围是0.3-10mg/kg,优选地0.3mg/kg至3mg/kg。与以最大耐受剂量使用的常规药理学疾病治疗不同,抗-CLEVER-1抗体治疗产生免疫应答。在低剂量下,不发生免疫应答,而在高剂量下,免疫系统产生新的方式来平衡所实现的免疫激活,例如通过增加CLEVER-1表达或IL-8的分泌。
附图说明
图1.抗-CLEVER-1治疗期间患者的血清中IFNγ、IL-6和IL-8的变化,以及具有抗肿瘤应答(即,稳定的疾病或部分应答(SD/PR))的患者与患有进行性疾病(PD)的患者之间的比较。IFNγ的上调,但IL-6和IL-8的下调与抗肿瘤应答相关。
图2.IFNγ、IL-6和IL-8在抗-CLEVER-1治疗期间根据不同剂量的变化。在0.3mg/kg、1mg/kg和3mg/kg的剂量下观察到最有利的免疫应答。
图3.用抗-CLEVER-1抗体(FP-1305)使深度免疫抑制的癌症患者的免疫恢复。这使得患者1能够在败血症中存活。在抗-CLEVER-1治疗之前,患者的外周血细胞对LPS刺激没有任何应答。LPS由细菌片段组成。在给药人源化的抗CLEVER-1抗体后,患者的血细胞对LPS刺激产生“正常”反应,并且产生反击感染所需的细胞因子。免疫衰竭转化为免疫激活得以实现。C=治疗周期,D=天数
具体实施方式
CLEVER-1是在专利出版物WO 03/057130“普通淋巴管内皮和血管内皮受体-1(Common Lymphatic Endothelial and Vascular Endothelial Receptor-1)”中公开的蛋白质。CLEVER-1(也被称为Stabilin-1)是一种多功能分子,其赋予抗炎巨噬细胞亚群清除能力[19,20]。
术语“能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂”、“CLEVER-1抑制剂”和“抗CLEVER-1药剂”可以互换,并且是指能够抑制CLEVER-1表达或结合至CLEVER-1以用于阻断CLEVER-1的功能或阻断CLEVER-1与涉及疾病病因学的细胞的相互作用的药剂,包括抗体及其片段、肽等。该药剂也可以是任何其他抑制剂,如RNA疗法、小分子抑制剂或具有足够亲和力以结合至CLEVER-1受体或具有降低其表达和/或抑制蛋白质活性的能力的大分子。术语“抗体、其片段或分子”以最广泛的意义使用,以涵盖任何治疗药剂,无论是能够抑制个体中的CLEVER-1表达或结合CLEVER-1分子的抗体、其片段或小分子。特别是,它应被理解为包括嵌合的、人源化的或灵长类化的抗体,以及抗体片段和单链抗体(例如,Fab、Fv),只要它们表现出所需的生物活性。特别有用的药剂是抗CLEVER-1抗体及其片段。因此,根据本发明的实施例,能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂,即CLEVER-1抑制剂或抗CLEVER-1药剂,选自由抗体或其片段、肽、RNA、小分子或大分子及其任意组合组成的组。抗CLEVER-1治疗或抗CLEVER-1疗法是指包含施用能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂的治疗或疗法。
在根据本发明的实施例中,能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂包含人源化的单克隆抗CLEVER-1抗体。在本发明的实施例中,抗CLEVER-1抗体是人源化的单克隆免疫球蛋白G4κ抗体贝马瑞利单抗(国际非专利名称(INN),如在《WHO药物信息(WHODrug Information)》,第33卷,第4期(2019)中作为建议的INN和在《WHO药物信息》,第34卷,第3期(2020),第699-700页中作为建议的INN)公开的,或贝马瑞利单抗变体或贝马瑞利单抗生物仿制药中的抗体。
贝马瑞利单抗生物仿制药是指被任何国家的监管机构批准作为贝马瑞利单抗生物仿制药上市的生物制品。在实施例中,贝马瑞利单抗生物仿制药包含贝马瑞利单抗变体作为药物物质。在实施例中,贝马瑞利单抗生物仿制药具有与贝马瑞利单抗基本上相同的重链和轻链的氨基酸序列。如本文所使用的,“贝马瑞利单抗变体”是指包含重链和轻链的序列的抗体,所述重链和轻链的序列与贝马瑞利单抗中的重链和轻链的序列相同,除了在位于轻链CDR之外的位置处具有一个或多个保守氨基酸取代和/或在位于重链CDR之外的位置处具有一个或多个保守氨基酸取代,例如变体位置位于框架区或恒定区。换句话说,贝马瑞利单抗和贝马瑞利单抗变体包含相同的CDR序列,但是由于在它们的全长轻链和重链序列的其它位置处具有保守的氨基酸取代而彼此不同。就与CLEVER-1的结合亲和力而言,贝马瑞利单抗变体与贝马瑞利单抗基本上相同。
根据本发明的实施例,产生治疗性抗CLEVER-1抗体贝马瑞利单抗(FP-1305)的细胞系已于2020年5月27日根据《关于为专利程序的目的国际承认微生物保藏的布达佩斯条约(Budapest Treaty on the International Recognition of the Deposit of Micro-organisms for the Purposes of Patent Procedure)》的条款被保藏在德国布伦瑞克D-38124号Inhoffenstrasse 7B的DSM德国微生物和细胞培养物保藏中心GmbH(DSMZ-GermanCollection of Microorganisms and Cell Cultures GmbH,Inhoffenstrasse 7B,D-38124Braunschweig,Germany),并且具有保藏号DSM ACC3361。本发明的范围不受保藏的培养物的限制,因为保藏的实施例旨在作为本发明的一个方面的单一说明,并且任何功能等同的培养物都在本发明的范围内。本文中材料的保藏并不构成承认本文含有的书面描述不足以实现本发明的任何方面,包括其最佳模式,也不应被解释为将权利要求的范围限制于其所代表的具体说明。
根据本发明,在免疫系统的激活中,将能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂与白细胞介素和/或相应的白细胞介素受体的抑制剂组合使用。此外,能够结合至干扰素-α/β受体IFNAR的药剂可以与能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂以及白细胞介素和/或相应的白细胞介素受体的抑制剂一起使用。特别地,所述组合用于治疗已被诊断患有显示促炎细胞因子(IL-1、IL-6、IL-8)的高表达和/或对单独的抗CLEVER-1治疗无应答或在抗CLEVER-1治疗期间显示循环白细胞介素水平增加的适应症的个体。根据本发明,所述联合治疗用于治疗或预防选自由癌症、传染病、慢性感染、严重流感或冠状病毒感染、败血症、严重流感或冠状病毒感染、急性呼吸窘迫综合征(ARDS)和多器官衰竭(MOF)组成的组的疾病。
术语“治疗(treatment)”或“治疗(treating)”应被理解为包括疾病或病症的完全治愈,以及所述疾病或病症的改善或减轻。术语“治疗有效量”是指包括足以产生所需的治疗结果的根据本发明的药剂的任何量。
在本发明的实施例中,白细胞介素和/或相应的白细胞介素受体的抑制剂选自由IL-1抑制剂和/或相应受体的抑制剂、IL-6抑制剂和/或相应受体的抑制剂、IL-8抑制剂和/或相应受体的抑制剂或其任意组合组成的组。在本发明中,抗IL-1和/或抗IL-6和/或抗IL-8疗法是指能够阻断作为CXCR1或CXCR2信号传导途径的IL-1/IL-1R或IL-6/IL-6R或IL-8/IL-8R的抑制剂。
IL-1和IL-1R抑制剂起抑制IL-1及其受体IL-1R的缔合的作用。当IL-1结合下游肿瘤坏死因子相关因子(TRAF)TRAF6时。
IL-6和IL-6R抑制剂起抑制IL-6及其受体IL-6R的缔合的作用。IL-6与下游Janus激酶(JAK)结合时被激活,并且信号转导子和转录激活子3(STAT3)的下游磷酸化。
IL-8和IL-8R抑制剂起抑制IL-8与其受体CXCR1和/或CXCR2(IL-8R)的缔合的作用。当IL-8与任一受体结合时,它触发多种途径的下游信号传导。IL-8信号传导促进其主要效应子磷脂酰-肌醇3-激酶(PI3K)或磷脂酶C的激活,从而促进Akt、PKC、钙动员和/或MAPK信号传导级联的下游激活。
根据本发明的实施例,白细胞介素或相应受体的抑制剂包含能够阻断所述白细胞介素和相应受体之间的相互作用的抗体或其片段、肽、RNA、小分子或大分子以及它们的任意组合。在本发明的实施例中,IL-1/IL-1R抑制剂是IL-1/IL-1R结合拮抗剂,其可以是阻断IL-1与其受体IL-1R之间的相互作用的抗体或其片段、肽或分子。抗体或其片段、肽或分子可以特异性结合至IL-1或IL-1R,以用于破坏IL-1和IL-1R之间的相互作用并抑制下游信号传导。抗IL1/IL-1R抗体可以是嵌合的、人源化的或单克隆抗体或其任何片段或任何分子。根据本发明,IL-1/IL-1R抑制剂可以是任何合适的IL-1/IL-1R抑制剂,并且基于所需的治疗进行选择。在根据本发明的示例性实施例中,抗IL-1/IL-1R抗体或其片段、肽或分子可以选自任何当前的开发资产,例如Anakinra(Swedish Orphan Biovitrium)及其任何组合。这些开发中的的抗IL-1/IL-1R抗体或其片段、肽或分子只是目前公开的和已知的本领域正在开发的开发抗体、片段、肽和分子的实例,本发明不限于这些。
在根据本发明的实施例中,IL-6/IL-6R抑制剂是IL-6/IL-6R结合拮抗剂,其可以是阻断IL-6与其受体IL-6R之间的相互作用的抗体或其片段、肽或分子。抗体或其片段、肽或其分子可以特异性结合至IL-6或IL-6R,以用于破坏IL-6和IL-6R之间的相互作用并抑制下游信号传导。抗IL-6/IL-6R抗体可以是嵌合的、人源化的或单克隆抗体或其任何片段或任何分子。根据本发明,IL-6/IL-6R抑制剂可以是任何合适的IL-6/IL-6R抑制剂,并基于所需的治疗进行选择。在根据本发明的示例性实施例中,抗IL-6/IL-6R抗体或其片段、肽或分子可以选自任何当前的开发资产,例如托珠单抗(Tocilizumab)(Hoffmann-La Roche SA)和塞妥昔单抗(Siltuximab)(EUSA制药有限公司(EUSA Pharmaceuticals Ltd))及其任何组合。这些开发中的的抗IL-6/IL-6R抗体或其片段、肽或分子只是目前公开的和已知的本领域正在开发的开发抗体、片段和分子的实例,本发明不限于这些。
在根据本发明的实施例中,IL-8/IL-8R抑制剂是IL-8/IL-8R结合拮抗剂,其可以是阻断IL-8及其受体IL-8R之间的相互作用的抗体或其片段、肽或其分子。抗体或其片段、肽或分子可以特异性地结合至IL-8或IL-8R,以用于破坏IL-8和IL-8R之间的相互作用并抑制下游信号传导。抗IL-8/IL-8R抗体可以是嵌合的、人源化的或单克隆抗体或其任何片段或任何分子。根据本发明,IL-8/IL-8R抑制剂可以是任何合适的IL-8/IL-8R抑制剂,并且基于所需的治疗进行选择。在根据本发明的示例性实施例中,抗IL-8/IL-8R抗体、片段或分子可以选自任何当前的开发资产,例如瑞帕利辛(Reparixin)(Dompe Farmaceutici SpA)、AZD-5069(AstraZeneca Plc)、BMS-986253(Bristol-Myers Squibb Co)和纳瓦利辛(Navarixin)(Merck&Co Inc)或其任何组合。这些开发中的抗IL-8/IL-8R抗体、片段或分子仅是目前公开和已知的本领域正在开发的开发抗体或其片段、肽和分子的实例,本发明不限于这些。
能够结合至干扰素-α/β受体(IFNAR)的药剂是能够结合至受体并诱导Tyk2和Jak1的药剂,这产生信号转导子和转录激活子(STAT)。
根据本发明的实施例,能够结合至IFNAR的药剂可以是任何1型干扰素(I型IFN)结合激动剂,其可以是结合至诱导下游途径的受体IFNAR的抗体或其片段、肽或其分子。抗体、其片段或分子特异性地结合至I型干扰素受体IFNAR并诱导下游信号传导。1型IFN抗体可以是嵌合的、人源化的或单克隆抗体或其任何片段或任何分子。根据本发明的实施例,能够结合至干扰素-α/β受体(IFNAR)的药剂是外源性1型干扰素或能够诱导类似作用的药剂。外源性1型干扰素包括干扰素-α和干扰素-β的亚型。在本发明的实施例中,能够结合至干扰素α/β受体(IFNAR)的药剂包含干扰素α或干扰素β。根据本发明的实施例,外源性I型干扰素可以是干扰素β-1a或干扰素β-1b。根据本发明,能够结合至干扰素-α/β受体(IFNAR)的药剂是基于所需的治疗来选择的。在根据本发明的示例性实施例中,能够结合至IFNAR的药剂可以选自任何当前的开发资产,例如包含干扰素β-1a的Rebif(Merck和Co)、包含干扰素β-1a的Avonex(Biogen)、包含干扰素β-1b的Betaseron(Bayer)和包含干扰素β-1a的Traumakine(Faron Pharmaceuticals)或其任何组合。这些1型IFN药物产品只是目前公开和已知开发的1型IFN激动剂的实例,本发明不限于这些。
根据本发明的实施例,一种用于治疗或预防选自由癌症、传染病、慢性感染、败血症、严重流感或冠状病毒感染和急性呼吸窘迫综合征(ARDS)组成的组的疾病的方法,包含向个体施用治疗有效量的:
-能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂,如抗CLEVER-1抗体或其片段、肽、RNA、小分子或大分子及其任意组合,以及
以下抑制剂/药剂中的至少一者:
-抗IL-1和/或IL-1R抑制剂,如特异性地结合至IL-1或IL-1Rα或IL-1Rβ受体并通过这些手段抑制IL-1的活性的抗IL-1/IL-1R抗体、其片段或分子,
-抗IL-6和/或IL-6R抑制剂,如特异性地结合至IL-6或受体(IL-6R)并通过这些手段抑制IL-6的活性的抗IL-6/IL-6R抗体、其片段或分子,和
-抗IL-8和/或IL-8R抑制剂,如特异性地结合至白细胞介素8(IL-8)或受体CXCR1或CXCR2并通过这些手段抑制IL-8的活性的抗IL-8/IL-8R抗体、其片段或分子,和
任选地,能够结合至干扰素-α/β受体(IFNAR)的另外的药剂,如外源性1型干扰素。
本发明可用于治疗具有衰竭的免疫应答的疾病状态,所述疾病状态对作为单一药剂的抗CLEVER-1药剂或白细胞介素抑制剂和/或它们相应的受体或1型干扰素无应答。根据本发明的实施例,抗CLEVER-1药剂与白细胞介素抑制剂和/或它们相应的受体的组合以及任选地与1型干扰素的组合用于治疗已被诊断患有与癌症、感染、败血症和ARDS相关的免疫衰竭的疾病状态的个体。根据本发明,抗CLEVER-1药剂与白细胞介素抑制剂的组合以及任选地与1型干扰素的组合可以用于治疗或预防选自由癌症、传染病、慢性感染、败血症、严重流感或冠状病毒感染、急性呼吸窘迫综合征(ARDS)组成的组的疾病。传染病是由病原微生物(如细菌、病毒、寄生虫或真菌)引起的;这些疾病可以直接或间接地从一个人传播到另一个人。传染病可能是由如流感和冠状病毒的病毒生物体引起的。具有免疫衰竭的发炎的或感染的组织的特征可以是高巨噬细胞浸润和/或低T细胞浸润,或者是通过血液样品获得的T细胞群体上检查点抑制剂的表达升高。
根据本发明的实施例,抗CLEVER-1药剂与白细胞介素抑制剂和/或它们相应的受体的组合以及任选地与1型干扰素的组合用于通过减少恶性肿瘤生长和/或通过抑制转移形成来治疗癌症,其适用于所有形式的癌症。因此,可以治疗任何良性或恶性肿瘤或恶性肿瘤的转移。根据本发明的实施例,抗CLEVER-1药剂与白细胞介素抑制剂的组合以及任选地与它们相应的受体和/或1型干扰素的组合用于产生对传染性病原体的免疫应答。
本发明基于这样的发现,即尽管实现了免疫激活,但血浆/血清白细胞介素(如具有CLEVER-1抑制作用的IL-6和IL-8)的增加与抗肿瘤应答无关,这已经通过CD8+T细胞、NK细胞和血浆IFNγ的增加而观察到。血浆中白细胞介素的减少与肿瘤缩小有关。本发明对于已被诊断患有与IL-6和/或IL-8的高表达相关的肿瘤的患者是最有价值的,因为那时对CLEVER-1的抑制可以将冷肿瘤转化为热肿瘤并增加患者中免疫疗法的功效,所述患者通常不会对这种疗法产生应答。
根据本发明的实施例,在开始抗CLEVER-1治疗后,待治疗的个体被诊断为白细胞介素水平,通常是血浆/血清白细胞介素水平,如IL-1、IL-6和/或IL-8的表达水平的升高。
在本发明的实施例中,测量患者的IL-1、IL-6和/或IL-8的表达水平,以便决定对伴随的白细胞介素抑制剂和/或它们相应的受体治疗的需要,并且还决定对伴随的1型干扰素治疗的需要。在本发明的实施例中,一种用于监测患者对抗CLEVER-1疗法的应答并评估当在患者中已经施用能够结合至CLEVER-1的药剂时对联合疗法的需要的方法,所述方法包含:
-在向患者施用能够结合至CLEVER-1的药剂之前的第一时间点从患者获得样品,
-在向患者施用[3能够结合至CLEVER-1的药剂之后的稍后时间点从患者获得样品,
-从获得的样品中测量白细胞介素IL-1、白细胞介素IL-6和/或IL-8的水平,
-将从在稍后的时间点获得的样品中测量的IL-1、IL-6和/或IL-8的水平与从在第一时间点获得的样品中测量的IL-1、IL-6和/或IL-8的表达水平进行比较,其中白细胞介素IL-1、IL-6和/或IL-8水平的升高是开始伴随施用IL-1抑制剂和/或相应受体的抑制剂、IL-6抑制剂和/或相应受体的抑制剂、IL-8抑制剂和/或相应受体的抑制剂或其任何组合的指征。在根据本发明的实施例中,从血液样品,优选地从血清样品中测量白细胞介素IL-1、IL-6和/或IL-8的水平。
根据本发明的实施例,所述方法进一步包含测量IFNγ应答,其中从在向患者施用能够结合至CLEVER-1的药剂之前的第一时间点获得的样品和在将向患者施用够结合至CLEVER-1的药剂之后的稍后时间点获得的样品中测量IFNγ,并将测量的水平进行比较。在本发明的实施例中,在观察到IFNγ的升高和白细胞介素IL-1,IL-6和/或IL-8的水平升高之后,决定开始伴随的白细胞介素抑制剂和/或它们相应的受体治疗,并且还决定对伴随的1型干扰素治疗的需求。
本发明还涉及一种治疗方法,其包含当患者患有选自由癌症、传染病、慢性感染、败血症、严重流感或冠状病毒感染和急性呼吸窘迫综合征(ARDS)并伴有免疫衰竭组成的组的疾病时,向患者施用能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂,与施用白细胞介素如IL-1、IL-6和IL-8和/或它们相应的受体IL-1Ra、IL-1Rb、IL-6R和IL-8R的抑制剂组合,以及任选地进一步与施用能够结合至干扰-α/β受体(IFNAR)的药剂组合。特别地,当患者首次用单独的抗-CLEVER-1治疗且患者显示促炎细胞因子(IL-1、IL-6、IL-8)的高表达和/或在抗CLEVER-1治疗期间显示循环白细胞介素水平的增加时,根据本发明的实施例的所述组合的治疗方法是有价值的。
在根据本发明的实施例中,一种治疗的方法包含向患者施用抗CLEVER-1药剂,并且在此之后测量干扰素-γ和/或白细胞介素,如IL-1、IL-6和/或IL-8的水平。如果未观察到所需的应答,则通过施用抗CLEVER-1药剂与白细胞介素如IL-1、IL-6和IL-8和/或它们相应的受体IL-1Ra、IL-1Rb、IL-6R和IL-8R的抑制剂组合来继续治疗。将测量的干扰素-γ和白细胞介素值如IL-1、IL-6和IL-8与在开始抗CLEVER-1治疗前从所述患者测得的值或在抗CLEVER-1治疗期间的先前测量值进行比较。如果不需要IL-1、IL-6和/或IL-8应答,则可以通过施用白细胞介素如IL-1、IL-6和IL-8和/或它们相应的受体IL-1Ra、IL-1Rb、IL-6R和IL-8R的抑制剂来改善抗CLEVER-1治疗的功效。此外,可以通过施用能够结合至干扰素-α/β受体(IFNAR)的药剂来改善应答。
根据本发明的实施例,在施用白细胞介素的抑制剂和/或相应的白细胞介素受体的抑制剂之前,向个体施用能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂。根据本发明的实施例,在施用能够结合至IFNAR的药剂之前,向个体施用能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂。根据本发明的另一个实施例,将能够结合至CLEVER-1的药剂与白细胞介素的抑制剂和/或相应的白细胞介素受体的抑制剂同时施用于个体,其中它们可以作为单一组合物混合或同时施用。在本发明的实施例中,能够结合至IFNAR的药剂也与能够结合至CLEVER-1的药剂和/或白细胞介素的抑制剂和/或相应的白细胞介素受体的抑制剂同时施用,其中它们可以作为单一组合物混合或同时施用。在根据本发明的实施例中,可以顺序施用能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂和白细胞介素的抑制剂和/或相应的白细胞介素受体的抑制剂,以及任选地还有能够结合至IFNAR的药剂,其中至少部分抗CLEVER-1药剂在白细胞介素抑制剂和/或相应的白细胞介素受体的抑制剂和/或能够结合至IFNAR的药剂之前被施用。施用可以例如进行一次、多次和/或在一个或多个延长的时间段内进行。
根据本发明的实施例,在施用白细胞介素的抑制剂和/或相应受体的抑制剂之后,和/或在施用能够结合至干扰素-α/β受体(IFNAR)的药剂之后,对个体持续施用能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂。在本发明的实施例中,可以首先用白细胞介素抑制剂和/或相应的白细胞介素受体的抑制剂与1型IFN组合来治疗患者,并且在告知没有达到所需的治疗应答后,可以通过施用抗CLEVER-1药剂与白细胞介素抑制剂和/或相应的白细胞介素受体的抑制剂和/或1型IFN抑制剂的组合来继续治疗。
根据本发明的实施例,在能够结合至IFNAR的药剂之前,向个体施用白细胞介素抑制剂或相应受体的抑制剂,或者在能够结合至IFNAR的药剂之后,向个体施用白细胞介素抑制剂和/或相应受体的抑制剂,其中在第一次治疗后没有观察到应答。在本发明的实施例中,将白细胞介素抑制剂和/或相应受体的抑制剂与能够结合至IFNAR的药剂同时施用于个体。
“施用”是指使用本领域技术人员已知的任何各种方法和递送系统和递送系统将包含所述治疗药剂的组合物物理引入到个体。待用于本发明的药剂可以通过实现其预期目的的任何手段施用。例如,施用可以是口服、吸入、静脉内、肌内、腹膜内、肿瘤内、皮下或其它肠胃外施用途径,例如通过注射。除了药理活性化合物之外,所述药剂的药物制剂优选地含有合适的药学上可接受的载体,所述载体包含赋形剂和助剂,所述赋形剂和助剂有助于将活性药剂加工成可以在药学上使用的制剂。选择的剂量应当足以减少恶性肿瘤生长和/或抑制转移形成和/或阻断癌症、慢性感染、传染病或其他免疫衰竭状态中(例如在败血症和ARDS中)T细胞的负调节。
在根据本发明的治疗方法中,除了白细胞介素抑制剂和/或1型干扰素和抗CLEVER-1药剂之外,也可以使用任何其它抗癌药剂。
根据本发明的实施例,根据患者的体重,以0.3-10mg/kg,优选地0.3mg/kg至3mg/kg的范围施用人源化的单克隆抗CLEVER-1抗体。在根据本发明的实施例中,人源化的单克隆抗CLEVER-1抗体包含治疗性抗CLEVER-1抗体贝马瑞利单抗(FP-1305),并且根据患者的体重,其以0.3-10mg/kg,优选地0.3mg/kg至3mg/kg的范围施用。所述剂量范围在本发明的用于提供对所述疾病的免疫刺激的联合治疗中也是优选的。在根据本发明的实施例中,将根据患者的体重的0.3-10mg/kg,优选地0.3-3mg/kg的人源化的单克隆抗CLEVER-1抗体如贝马瑞利单抗(FP-1305)与白细胞介素和/或相应的白细胞介素受体的抑制剂组合使用,以及任选地还与能够结合至干扰素-α/β受体(IFNAR)的药剂组合使用。通常,待治疗的患者对抗CLEVER-1治疗(如单独的治疗性抗CLEVER-1抗体贝马瑞利单抗(FP-1305)治疗)未显示出所需的应答,和/或在开始抗CLEVER-1治疗后诊断出白细胞介素水平(如IL-1、IL-6和IL-8)升高,尽管IFN-γ水平增加并显示出应答。
实验部分
以下研究仅仅是对本发明的原理的说明,并且不旨在限制本发明的范围。
用于治疗癌症的Clever-1抑制的人类研究
CLEVER-1抑制剂(一种抗CLEVER-1抗体FP-1305)目前正在患有晚期实体瘤的患者中的I/II期研究中测试其安全性和初步功效(clinicaltrials.gov NCT03733990:一项评估FP-1305在癌症患者中的安全性、耐受性和初步功效的研究(MATINS)))。
抗CLEVER-1抗体FP-1305是一种人源化的单克隆CLEVER-1抗体,其先前在专利公开WO2017/182705中提出。更准确地说,FP-1305(DSM ACC3361)是一种人源化的单克隆免疫球蛋白G4κ抗体贝马瑞利单抗(国际非专利名称(INN)),如在《WHO药物信息》,第33卷,第4期(2019年)中作为建议的INN和《药物信息》,第34卷,第3期(2020年)第699-700页中作为建议的INN所公开的)。
在本研究中,在开始FP-1305之前采集第一份(给药前)血清样品。在开始FP-1305治疗后7天以及在从开始抗CLEVER-1治疗起第14天、第21天、第42天和第63天后采集第二份血清样品(给药后)。此后,重复CT扫描来评估肿瘤的进展或消退,并与开始抗Clever-1治疗前进行的现有扫描进行比较(图1)。进行性疾病(PD)是指癌症正在生长。肿瘤大小没有显著变化(这在侵袭性的否则不可治疗的癌症中是积极的效果,如在MATINS试验中)被标记为稳定的疾病(SD),并且被认为是良好的应答。根据用于评估治疗应答的RECIST标准,肿瘤缩小被称为部分应答(PR)。
血浆/血清IL6和IL8的增加与用抗CLEVER-1抗体(FP-1305)治疗的癌症患者的无应答相关
抗CLEVER-1抗体FP-1305已经开始在上述环境中进行临床开发。在这项首次人类试验(clinicaltrials.gov NCT03733990)中,对任何可用疗法均无应答的转移性结肠直肠癌、黑色素瘤和卵巢癌患者已经表现出抗肿瘤应答。到目前为止,这些都与治疗期间血清IFNγ水平的升高有关(图1)。IFNγ、IL-6和IL-8血清水平使用多重细胞因子面板进行测量。出人意料的是,与IFNγ应答相反,IL-6和IL-8水平的升高与无应答(即进行性疾病)相关。因此,抗CLEVER-1抗体FP-1305的治疗可以通过向患者施用白细胞介素和/或相应的白细胞介素受体的抑制剂,以及任选地还施用能够结合至干扰素-α/β受体(IFNAR)的药剂以用于降低IL-6和/或IL-8水平来改善。
此外,当比较不同的剂量时,根据患者的体重,使用0.3mg/kg至3mg/kg范围的FP-1305的剂量来实现通过IFNγ升高测量的最佳免疫激活。以类似的方式,根据患者的体重,在0.3mg/kg至3mg/kg的范围内的FP-1305的剂量内观察到IL-6和IL-8的最有利变化。最小剂量0.1mg/kg的FP-1305没有显著的免疫变化,而最高剂量10mg/kg与IL-6和IL-8的最大升高相关(图2)。因此,根据患者的体重,0.3–10mg/kg,优选地0.3mg/kg至3mg/kg的剂量范围的人源化的单克隆抗CLEVER-1抗体FP-1305可以与白细胞介素和/或相应的白细胞介素受体的抑制剂组合使用,以及任选地还与能够结合至干扰素-α/β受体(IFNAR)的药剂组合使用。
抗CLEVER-1使衰竭的免疫系统重新焕发活力并且有助于对抗败血症
在正在进行的抗Clever-1抗体FP-1305首次人类试验(clinicaltrials.govNCT03733990)中,免疫系统极度衰竭的结肠直肠癌患者(图3中的患者1)被招募以接受根据患者的体重的1mg/kg的剂量的抗Clever-1抗体FP-1395治疗。通过给予患者外周血细胞细菌片段,即脂多糖(LPS),观察到在接受抗CLEVER-1抗体FP-1305疗法前的完全免疫衰竭。她的血细胞无法对给定的LPS产生反应,这意味着在重大感染的情况下,她的免疫系统无法产生所需的免疫应答,并且感染很可能导致她的死亡。在接受第一剂FP-1305后二十四小时,重复LPS实验。现在,患者的外周正常地对LPS刺激起作用,并产生细胞因子和炎性信号,这些信号需要引起对抗外来病原体的免疫应答。随后,患者因胆汁淤积导致败血症,但由于她已经接受了FP-1305,因此她能够在败血症中存活。如果没有治疗,她将无法对败血症做出适当的应答。
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Claims (15)
1.一种治疗有效量的以下的组合:
(a)能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂,和
(b)白细胞介素和/或相应的白细胞介素受体的抑制剂,
用于治疗或预防选自由以下组成的组的疾病:癌症、传染病、慢性感染、严重流感或冠状病毒感染、败血症和急性呼吸窘迫综合征(ARDS),其中在施用白细胞介素的抑制剂和/或相应的白细胞介素受体的抑制剂之前,向个体施用所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂,并且在开始施用所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂之后,将待治疗的个体诊断为白细胞介素IL-1、IL-6和/或IL-8水平升高。
2.根据权利要求1所述的用于使用的组合,其中所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂选自由抗体或其片段、肽、RNA、小分子或大分子及其任意组合组成的组。
3.根据权利要求1或2所述的用于使用的组合,其中所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂包含人源化的单克隆抗CLEVER-1抗体,优选地贝马瑞利单抗(bexmarilimab,DSMACC3361)或贝马瑞利单抗变体或贝马瑞利单抗生物仿制药中的抗体。
4.根据前述权利要求中任一项所述的用于使用的组合,其中白细胞介素和/或相应的白细胞介素受体的抑制剂选自由IL-1抑制剂和/或相应受体的抑制剂、IL-6抑制剂和/或相应受体的抑制剂、IL-8抑制剂和/或相应受体的抑制剂或其任何组合组成的组。
5.根据前述权利要求中任一项所述的用于使用的组合,其中白细胞介素或相应的白细胞介素受体的抑制剂包含能够阻断所述白细胞介素与相应受体之间的相互作用的抗体或其片段、肽、RNA、小分子或大分子及其任何组合。
6.根据前述权利要求中任一项所述的用于使用的组合,其中所述组合进一步包含能够结合至干扰素-α/β受体(IFNAR)的药剂。
7.根据权利要求6所述的用于使用的组合,其中所述能够结合至干扰素-α/β受体(IFNAR)的药剂是外源性1型干扰素。
8.根据前述权利要求中任一项所述的用于使用的组合,其中所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂与白细胞介素的抑制剂和/或相应受体的抑制剂同时施用于个体,和/或与能够结合至干扰素-α/β受体(IFNAR)的药剂同时施用于个体。
9.根据前述权利要求中任一项所述的用于使用的组合,其中在施用白细胞介素的抑制剂和/或相应受体的抑制剂之后,和/或在施用能够结合至干扰素-α/β受体(IFNAR)的药剂之后,向个体持续施用所述能够抑制CLEVER-1表达或能够结合至CLEVER-1的药剂。
10.根据前述权利要求6至9中任一项所述的用于使用的组合,其中将白细胞介素的抑制剂和/或相应受体的抑制剂与能够结合至干扰素-α/β受体(IFNAR)的药剂同时施用于个体。
11.根据前述权利要求6至10中任一项所述的用于使用的组合,其中在施用能够结合至干扰素-α/β受体(IFNAR)的药剂之后,向个体施用白细胞介素的抑制剂和/或相应受体的抑制剂。
12.根据前述权利要求3至11中任一项所述的用于使用的组合,其中所述人源化的抗CLEVER-1抗体贝马瑞利单抗根据患者的体重以0.3-10mg/kg、优选地0.3mg/kg至3mg/kg的范围施用。
13.一种方法,用于监测患者对抗CLEVER-1疗法的应答并且评估当在患者中已经施用了能够结合至CLEVER-1的药剂时,对包含白细胞介素和/或相应的白细胞介素受体的抑制剂的联合疗法的需求,所述方法包含:
-在向患者施用能够结合至CLEVER-1的药剂之前的第一时间点从所述患者获得样品,
-在向患者施用能够结合至CLEVER-1的药剂之后的稍后时间点从所述患者获得样品,
-从所获得的样品中测量白细胞介素IL-1、IL-6和/或IL-8的水平,
-将从在稍后的时间点获得的所述样品中测量的IL-1、IL-6和/或IL-8的水平与从在第一时间点获得的所述样品中测量的IL-1、IL-6和/或IL-8的表达水平进行比较,其中白细胞介素IL-1、IL-6和/或IL-8水平的升高是开始伴随施用IL-1抑制剂和/或相应受体的抑制剂、IL-6抑制剂和/或相应受体的抑制剂、IL-8抑制剂和/或相应受体的抑制剂或其任何组合的指征。
14.根据权利要求13所述的方法,其中所述方法进一步包含测量IFNγ应答,其中从在向患者施用能够结合至CLEVER-1的药剂之前的第一时间点获得的所述样品和在向患者施用能够结合至CLEVER-1的药剂之后的稍后时间点获得的所述样品测量IFNγ,并且比较所测量的水平。
15.根据权利要求13或14所述的方法,其中所述样品是血液样品,优选地血清样品。
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