CN115227824A - 免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤机制相关疾病药物中的应用 - Google Patents
免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤机制相关疾病药物中的应用 Download PDFInfo
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Abstract
本发明提供了免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤机制相关疾病药物中的应用,属于眼部药物技术领域,为了直接而精准的控制青光眼患者眼内免疫细胞的活性及免疫反应强度,本发明提出以针对免疫检查点蛋白的抑制剂作为药物,可调控T细胞的异常激活。从根本上控制眼部免疫炎症反应的水平,避免视神经的持续损伤。本发明所述应用与目前临床上仅针对眼压的青光眼治疗方案不同,在青光眼治疗领域属于开拓新的创新。试验表明,免疫检查点的抑制剂可有效保护视网膜及视神经,有效调节眼部T细胞的比例及异常激活,对于青光眼以及其他眼部免疫损伤病理机制相关疾病有显著疗效,作为其治疗药物应用。
Description
本申请为申请日为2018年11月12日,申请号为201811338646.5,发明名称为“免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤机制相关疾病药物中的应用”的分案申请。
技术领域
本发明涉及眼部药物技术领域,尤其涉及免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤病理机制相关疾病的药物中的应用。
背景技术
青光眼是指患者特征性的视神经持续损伤的一种眼病。如不及时治疗,患者视网膜神经纤维层将持续死亡,同时视野可以全部丧失而至失明。青光眼是导致人类失明的三大致盲的眼病之一,总人群发病率为1%,并随年龄增长而增加。长期以来,眼压增高被认为是青光眼发病的主要风险因素,青光眼治疗目前多集中在降低眼压目标上,但许多患者在眼压恢复正常后,其病情依然会恶化,而部分眼压升高的患者可较长时期不出现视神经损伤。因此,引起青光眼视神经变性的高眼压假说目前尚缺乏定论,临床上同时缺乏有效的预防干预手段。临床中应用最广泛的小梁切除术,其原理是通过人为造瘘的方式实现房水的外引流,从而降低眼压。但这种术式不符合人体正常的生理状态,且术后出现各种类型的并发症几率高,如眼压波动幅度大、并发性白内障、和术后滤过泡疤痕化导致手术失败等。
本发明的前期研究中发现,青光眼患者体内大量抑制性免疫检查点蛋白呈现表达显著下调,患眼免疫细胞的大量异常激活。这种失衡的免疫反应可持续不断的攻击视神经细胞,从而导致临床可见的视野持续损伤和视神经纤维层的丢失(Chen H,Cho K S,Vu T HK,et al.Commensal microflora-induced T cell responses mediate progressiveneurodegeneration in glaucoma[J].Nature Communications,2018,9.)。
免疫检查点机制是对机体调控免疫稳态最重要的机制之一。免疫检查点蛋白在免疫治疗研究领域占有及其重要的地位,这是一系列在免疫反应中的产生共刺激或抑制信号的分子。病理环境下免疫检查点信号异常可加强或者削弱免疫反应,进而是免疫稳态遭到破坏。免疫检查点蛋白分为两大类,一类是以PD1,CTLA-4和VISTA为代表的抑制性蛋白,一类是以CD28,CD86 和CD80为代表的激动性蛋白。近年来,阻断这些免疫检查点的抗体药,例如程序性死亡-1(PD-1)途径(Francisco等,2010)已显示出显著的抗肿瘤功效,突出显示了释放免疫系统在对抗各种恶性肿瘤中的能力的潜力。最近,显示 (WO2015/136541;Baruch等,2016)向阿尔茨海默病的动物模型施用抗-PD-1 抗体导致Aβ的清除、认知衰退的逆转,并且与神经炎性应答的消退相关。
发明内容
本发明的目的在于提供一种免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤病理机制相关疾病的药物中的应用,通过解除由一个或多个免疫检查点施加到免疫细胞的限制来调节眼部免疫失衡状态,从而免除免疫细胞对视神经细胞的特异性攻击。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了免疫检查点的抑制剂在制备治疗视网膜和/或视神经损伤相关疾病的药物中的应用;
所述免疫检查点的抑制剂为抗-CD27的抗体和抗-CD28的抗体的组合。
优选的,所述免疫检查点的抑制剂能够有效调节眼部T细胞的比例及异常激活,从而降低视网膜节细胞和/或视神经轴索的持续性损伤,进而治疗视网膜和/或视神经损伤相关疾病。
优选的,所述视网膜和/或视神经损伤相关疾病包括青光眼、眼部炎症性疾病、眼增生性疾病、视网膜变性病症、眼缺血性疾病和眼占位性病变中的至少一种。
本发明提供了免疫检查点的抑制剂在制备治疗青光眼及其他眼部免疫损伤病理机制相关疾病的药物中的应用;
所述其他眼部免疫损伤病理机制相关疾病包括眼部炎症性疾病、眼增生性疾病、视网膜变性病症以及眼缺血性疾病。
优选的,免疫检查点包括下述中的一种或多种:
(1)CD27;
(2)CD28;
(3)CD40;
(4)CD48;
(5)CD70;
(6)CD80;
(7)CD86;
(8)CD122;
(9)CD134;
(10)CD137;
(11)CD137L;
(12)CD152;
(13)CD154;
(14)CD244;
(15)CD252;
(16)CD273;
(17)CD274;
(18)CD275;
(19)CD278;
(20)CD279;
(21)CD357;
(22)GITRL;
(23)BTN2A1;
(24)DC-SIGN;
(25)TL1A;
(26)DR3。
优选的,所述免疫检查点的抑制剂的类型包括抗体或抗体模拟物。
优选的,所述抗体包括人源化抗体、鼠源化抗体、抗体功能片段、单结构域抗体、重组抗体或CsFv;
所述抗体模拟物包括亲合体分子、affilin、粘合素、affitin、avimer、DARPin 或Kunitz结构域肽。
优选的,所述免疫检查点的抑制剂的类型为抗体时,包括以下抗体中的一种或多种:
(a)抗-CD27的抗体;
(b)抗-CD28的抗体;
(c)抗-CD40的抗体;
(d)抗-CD48的抗体;
(e)抗-CD70的抗体;
(f)抗-CD80的抗体;
(g)抗-CD86的抗体;
(h)抗-CD122的抗体;
(i)抗-CD134的抗体;
(j)抗-CD137的抗体;
(k)抗-CD137L的抗体;
(l)抗-CD152的抗体;
(m)抗-CD154的抗体;
(n)抗-CD244的抗体;
(o)抗-CD252的抗体;
(p)抗-CD273的抗体;
(q)抗-CD274的抗体;
(r)抗-CD275的抗体;
(s)抗-CD278的抗体;
(t)抗-CD279的抗体;
(u)抗-CD357的抗体;
(v)抗-GITRL的抗体;
(w)抗-BTN2A1的抗体;
(x)抗-DC-SIGN的抗体;
(y)抗-TL1A的抗体;
(z)抗-DR3的抗体。
优选的,所述免疫检查点的抑制剂对人的施用剂量为0.1mg/kg~20mg/kg。
优选的,所述眼部炎症性疾病包括葡萄膜炎、角膜炎、巩膜炎、视神经炎、视神经脊髓炎、眼内炎或眶蜂窝织炎;
所述眼增生性疾病包括复发性视网膜脱落或增殖性糖尿病视网膜;
所述视网膜变性病症包括年龄相关性黄斑变性或视网膜色素变性;
所述眼缺血性疾病包括急性视神经缺血、视网膜中央静脉阻塞、视网膜中央动脉阻塞或前部缺血性视神经病变;
所述眼占位性病变包括甲状腺相关性眼病、视神经母细胞瘤或脉络膜恶性黑色素瘤。
优选的,所述药物中还包括腺苷、腺苷A1受体激动剂、腺苷A2a受体激动剂和腺苷A3受体激动剂中的一种或多种。
本发明的有益的技术效果:
本发明提供了免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤病理机制相关疾病的药物中的应用;所述其他眼部免疫损伤病理机制相关疾病包括眼部炎症性疾病、眼增生性疾病、视网膜变性病症以及眼缺血性疾病。本发明研究显示,T细胞的免疫失活状态是青光眼视神经持续损伤的病理机制,为了直接而精准的控制青光眼患者眼内免疫细胞的活性及免疫反应强度,本发明提出以针对免疫检查点蛋白的抑制剂作为药物,可调控T细胞的异常激活。从根本上控制眼部免疫炎症反应的水平,避免视神经的持续损伤。本发明所述应用与目前临床上仅针对眼压的青光眼治疗方案不同,在青光眼治疗领域属于开拓新的创新。
本发明实施例显示,对高眼压模型小鼠施用免疫检查点的抑制剂后,可有效调节高眼压模型小鼠眼内免疫反应水平,制造的免疫耐受状态可使高眼压小鼠的节细胞及视神经轴索损伤显著下;同时,给予免疫检查点的抑制剂后,高眼压小鼠体内的CD4+T细胞比例较未注射免疫检查点的抑制剂的对照组小鼠有显著降低。表明免疫检查点的抑制剂可有效保护视神经,对于青光眼以及其他眼部免疫损伤病理机制相关疾病有显著疗效,作为其治疗药物应用。
本发明的实施例还显示,采用免疫检查点的抑制剂对急性视神经缺血模型动物、葡萄膜炎模型动物、糖尿病视网膜病变模型动物均有显著疗效,即免疫检查点的抑制剂对于青光眼外的其他眼部免疫损伤病理机制相关疾病也有显著的治疗作用。
附图说明
图1为实施例1、2中各组小鼠的视网膜节细胞损伤率以及视神经轴索损伤率情况;其中,A、B、C为实施例1中各组小鼠的节细胞损伤率以及轴索损伤率,D、E、F为实施例2中各组小鼠的节细胞损伤率以及CD4+T细胞比例;
图2为实施例3中各组小鼠的体内免疫反应水平;其中,A为外周血中阳性表达细胞比例,B、C和D分别为使用CD45RO及CD45RA标记小鼠外周血CD4+FoxP3+T细胞,E为流式细胞仪分选CD4+T细胞中记忆性Treg细胞比例,F为外周血中ki67阳性细胞比例,G为Elispots实验检测抗体药物注射后T细胞分反应强度;
图3为实施例4中各组小鼠的视网膜节细胞损伤率以及视神经轴索损伤率情况;其中,A为注射各抗体药物后各组小鼠的节细胞损伤率,B为注射腺苷及其受体后各组小鼠的节细胞损伤率;
图4为实施例5中各组小鼠的视网膜节细胞损伤率以及视神经轴索损伤率情况;其中,A为各组小鼠的节细胞损伤率,B为各组小鼠的轴索损伤率; C为HE染色显示视网膜节细胞数目及视神经纤维层厚度;
图5为实施例6中各组小鼠的节细胞损伤率以及轴索损伤率情况;其中, A为临床体征评分标准,B为各组小鼠的临床体征评分结果,C为分选CD4+ 细胞群散点分布图,D为流式细胞仪显示IFN-γ+T细胞比例;
图6为实施例7中各组小鼠的视功能损伤情况;其中,A、B为各组小鼠视网膜电图结果,C为流式细胞仪显示IFN-γ+T细胞比例,D为HE染色显示视网膜新生血管。
具体实施方式
本发明提供了免疫检查点的抑制剂在制备治疗青光眼和其他眼部免疫损伤病理机制相关疾病的药物中的应用;
所述其他眼部免疫损伤病理机制相关疾病包括眼部炎症性疾病、眼增生性疾病、视网膜变性病症以及眼缺血性疾病。
在本发明中,所述眼部炎症性疾病包括葡萄膜炎、角膜炎、巩膜炎、视神经炎、视神经脊髓炎、眼内炎或眶蜂窝织炎;所述眼增生性疾病包括复发性视网膜脱落或增殖性糖尿病视网膜;所述视网膜变性病症包括年龄相关性黄斑变性或视网膜色素变性;所述眼缺血性疾病包括视网膜中央静脉阻塞、视网膜中央动脉阻塞或前部缺血性视神经病变。本发明所述其他眼部免疫损伤病理机制相关疾病基于与青光眼同样的自身免疫失衡原理,也能够通过免疫检查点的抑制剂制备的药物进行治疗。
本发明以免疫检查点的抑制剂应用于制备治疗青光眼其他眼部免疫损伤病理机制相关疾病是为了调节青光眼等相关疾病患者眼部的T细胞免疫反应失衡,通过免疫检查点的抑制剂解除由一个或多个免疫检查点施加到患者免疫系统的限制来恢复患者体内的免疫稳态,有效调节眼部T细胞的比例及异常激活,从而有效的降低失衡免疫系统对视神经的损伤。同时,选择免疫检查点的抑制剂可精准的调控患者自身免疫耐受以及对异体抗原的免疫攻击,作用更精准,更易恢复患者体内的免疫平衡。
在本发明中,所述免疫检查点优选的包括以下中的一种或多种:
(1)CD27,又名S152、S152、LPFS2、T14、TNFRSF7、Tp55等;
(2)CD28,又名Tp44等;
(3)CD40,又名Bp50、CDW40、TNFRSF5、p50等;
(4)CD48,又名BCM1、BLAST、BLAST1、MEM-102、SLAMF2等;
(5)CD70,又名CD27LG、TNFSF7等;
(6)CD80,又名B7、B7-1、B7.1、BB1、CD28LG、CD28LG1、LAB7 等;
(7)CD86,又名B7-2、B7.2、B70、CD28LG2、LAB72等;
(8)CD122,又名IL2RB、IL15RB、P70-75等;
(9)CD134,又名TNFRSF4、ACT35、IMD16、OX40、TXGP1L等;
(10)CD137,又名TNFRSF9、4-1BB、CDw137、ILA等;
(11)CD137L,又名4-1BBL,TNFSF9等;
(12)CD152,又名CTLA4、ALPS5、CELIAC3、CTLA-4、GRD4、GSE、 IDDM12等;
(13)CD154,又名CD40LG,CD40L、HIGM1、IGM、IMD3、T-BAM、 TNFSF5、TRAP、gp39等;
(14)CD244,又名2B4、NAIL、NKR2B4、Nmrk、SLAMF4等;
(15)CD252,又名TXGP1、OX-40L、gp34等;
(16)CD273,又名PDCD1LG2、B7DC、PD-L2、PDCD1L2、PDL2等;
(17)CD274,又名CD274、B7-H、B7H1、PD-L1、PDCD1L1、PDCD1LG1、 PDL1等;
(18)CD275,又名ICOSLG、B7-H2、B7H2、B7RP-1、B7RP1、CD275、 GL50、ICOS-L、ICOSL、LICOS等;
(19)CD278,又名ICOS、AILIM、CD278、CVID1等;
(20)CD279,又名PDCD1、CD279、PD-1、PD1、SLEB2、hPD-1、hSLE1 等;
(21)CD357,又名TNFRSF18、AITR、CD357、GITR、GITR-D等;
(22)GITRL;
(23)BTN2A1;
(24)DC-SIGN,又名CD209、CDSIGN、CLEC4L、DC-SIGN、DC-SIGN1 等;
(25)TL1A,又名TNFSF15、TL1、TL1A、VEGI、VEGI192A等;
(26)DR3,又名TNFRSF25等。
更优选的,本发明选择下述组合中的一种或多种免疫检查点:
(A)CD28-CD80;
(B)CD28-CD86;
(C)ICOS-B7RP1;
(D)CD40L-CD40;
(E)CD137-CD137L;
(F)OX40L;
(G)CD27-CD70:
(H)CD122;
(I)GITR-GITRL;
(J)CD48-2B4;
(K)BTN2A1-DC-SIGN;
(L)TL1A-DR3和A2aR-腺苷;
(M)PD1-PDL1;
(N)PD1-PDL2。
在本发明中,所述免疫检查点的抑制剂的类型优选的包括抗体或抗体模拟物。在本发明中,所述抗体优选的包括人源化抗体、鼠源化抗体、抗体功能片段、单结构域抗体、重组抗体或CsFv;所述抗体模拟物优选的包括亲合体分子、affilin、粘合素、affitin、avimer、DARPin或Kunitz结构域肽。本发明对所述免疫检查点的抑制剂如何制成上述形式无特殊限定,采用本领域已知方式即可。
在本发明中,所述免疫检查点的抑制剂更优选为封闭抗体。
在本发明中,所述免疫检查点的抑制剂更优选的包括以下组合中的一种或多种:
(a)抗-CD27的抗体;
(b)抗-CD28的抗体;
(c)抗-CD40的抗体;
(d)抗-CD48的抗体;
(e)抗-CD70的抗体;
(f)抗-CD80的抗体;
(g)抗-CD86的抗体;
(h)抗-CD122的抗体;
(i)抗-CD134的抗体;
(j)抗-CD137的抗体;
(k)抗-CD137L的抗体;
(l)抗-CD152的抗体;
(m)抗-CD154的抗体;
(n)抗-CD244的抗体;
(o)抗-CD252的抗体;
(p)抗-CD273的抗体;
(q)抗-CD274的抗体;
(r)抗-CD275的抗体;
(s)抗-CD278的抗体;
(t)抗-CD279的抗体;
(u)抗-CD357的抗体;
(v)抗-GITRL的抗体;
(w)抗-BTN2A1的抗体;
(x)抗-DC-SIGN的抗体;
(y)抗-TL1A的抗体;
(z)抗-DR3的抗体。
本发明可以选择上述任意一种免疫检查点的抑制剂作为有效成分进行治疗,更优选的选择多种免疫检查点的抑制剂联用以增强效果。本发明更优选的采用CD28-CD86/CD80抑制剂的组合应用于制备治疗青光眼及其他眼部免疫损伤病理机制相关疾病的药物中;CD28-CD86/CD80抑制剂的组合保护视神经作用更为显著。
在本发明中,所述免疫检查点的抑制剂在制备治疗青光眼及其他眼部免疫损伤病理机制相关疾病的药物中的应用中,所述药物除了包括免疫检查点的抑制剂外还可以包括腺苷、腺苷A1受体激动剂、腺苷A2a受体激动剂和腺苷A3受体激动剂中的一种或多种,通过免疫检查点的抑制剂与腺苷及其受体激动剂联用来进一步提高药物治疗效果。
在本发明中,应用所述免疫检查点的抑制剂而制备的药物适用于显示系统性以及眼部免疫反应失衡的患者(青光眼及其他眼部免疫损伤病理机制相关疾病),所述系统性以及眼部免疫反应失衡反映为患者的外周血和/或眼前房穿刺液中效应性T细胞的数量上升和/或活性增强;同时分离外周血T细胞的Elispots反应显著增强。例如根据本发明已发现,与野生型小鼠相比,青光眼的动物模型外周血及眼部效应性T细胞的标志性分泌因子谱(IFN-γ、 IL-17、IL21),及其他促分化的重要因子谱(IL-12、IL-6、IL-2、IL-23)均显著上升。而系统性以及眼部免疫反应失衡的患者应用含有本发明所述免疫检查点的抑制剂的药物后,系统性及眼部免疫病理的水平或活性降低,治疗过程中可出现各效应性T细胞比例回落以及功能细胞因子的减少,从而使患者的免疫系统恢复稳态,有效降低自身免疫系统对视神经的损伤。
在本发明中,适用于应用免疫检查点的抑制剂制备的药物的患者在用药前可通过检测患者的免疫反应水平来确定。例如,可通过外周血单核细胞或T 淋巴细胞的流式细胞术分析来测量,所述淋巴细胞针对CD45、TCR-β或CD4 标记物进行免疫染色,并测量特异性结合所述细胞的抗体的量。T细胞的功能活性可通过分离外周血T细胞并使用Elispots试剂盒来测量;本领域技术人员可使用本领域已知的方法容易地评估产生效应性T细胞的数量或它们的活性或它们的增殖能力;例如,产生IFNγ的T细胞的水平可通过对外周血单核细胞分离培养以及流式细胞术分析,收集这些细胞的条件培养基并使用 ELISA对所分泌的细胞因子的水平进行定量,或比较条件培养基中不同细胞因子(例如IL2/IL10、IL2/IL4、INFγ/TGFβ等)的比率。
当所述免疫反应水平检测显示,循环中效应性T细胞的总数比健康对照群体中升高10%~100%或更高,总T细胞百分比比健康对照群体中升高了 10%~100%或更高,或者T细胞的功能活性比健康对照群体中升高了10%~100%或更高时,外周/系统性免疫水平可被认为改变。或者,当眼部IFN-γ、 IL-17、IL21等炎性细胞因子的水平相对于健康对照群体的水平上升10%~100%;或T细胞响应于刺激的增殖相对于健康对照群体的增殖上升了10%~100%时,眼部的免疫活性可被认为升高。
当向个体施用药物后,该个体的循环中效应性T细胞的总数与施用该药剂之前的水平相比降低了10%~100%或更多,总CD4+细胞百分比相对于施用该药剂之前下降了10%~100%或更多,或者效应性T细胞的功能活性与施用该药剂之前的水平相比降低了10%~100%或更多时,该药剂可被认为是引起系统性免疫反应水平的降低的药剂。或者,当在眼部施用药剂后,产生的IFN- γ、IL-17、IL21等炎性细胞因子的水平较施用该药剂之前降低了10%-100%或更多;或T细胞响应于刺激的增殖相对于施用该药剂之前降低了10%-100%或更多时,该药剂可被认为是引起眼部免疫反应水平降低的药剂。
如本发明实施例的试验显示,对高眼压模型动物施用应用免疫检查点的抑制剂制备的药物后,其外周血中的Th1、Th2、Th17型CD4+T细胞的比例均有显著降低;青光眼模型动物体内记忆性Treg细胞比例显著降低,对再次免疫反应的诱发有抑制作用;Elispots实验也正是施用药物后T细胞的反应显著降低。可以显示,本发明提供的免疫检查点的抑制剂可用于制备治疗青光眼及其他眼部免疫损伤病理机制相关疾病的药物中,并且治疗效果显著。
在本发明中,所述免疫检查点的抑制剂对人体的施用剂量优选为 0.1mg/kg-20mg/kg;更优选为0.2mg/kg-15mg/kg;进一步优选为 0.3mg/kg-10mg/kg;更进一步优选为1mg/kg-6mg/kg;最优选为 1.5mg/kg-5mg/kg。
在本发明中,所述免疫检查点的抑制剂应用于制备治疗青光眼及其他眼部免疫损伤病理机制相关疾病的药物时,所述药物的治疗期和间隔期的长度可由医生在针对某一患者群体的临床试验中确定,然后一致地应用于该患者群体,而无需基于个人监测免疫抑制的水平。
在本发明中,所述治疗期可以是单次施用,或者其可包括在1天到4周之间(例如1天、2天或3天或1周到4周之间)的过程中给予的多次施用。也可以根据外周血或眼部检测炎性因子水平的变化决定非治疗的间隔期。非治疗的间隔期可以是1到2个月长、1到3个月长或2到3个月长。
在本发明的一些实施例中,所述治疗期中,应用免疫检查点的抑制剂制备的药物的施用可以是单次施用或重复施用,例如所述药物可仅被施用一次,然后间隔紧随其后,或者可每天一次、或每两天一次、每三天一次、每四天一次、每五天一次或每六天一次、或每周一次、每两周一次、每三周一次或每四周一次施用。这些频率适用于任何所述的药物,可基于本领域常用的实践,并且最终可由医师在临床试验中确定。或者,可根据所述药物的性质调整治疗期中重复施用的频率,其中例如小分子可每天一次施用,并且抗体可每3天一次施用。应当理解的是,当在治疗期的期间以相对较低的频率(例如在一个月的治疗期的期间每周一次或在六个月的治疗期的期间每月一次)施用药剂时,该治疗期之后是非治疗间隔期,该非治疗间隔期的长度长于在该治疗期的期间重复施用之间的时期(即,在该实施例中分别长于一周或一个月)。在该实施例中在治疗期的期间,施用之间的一周或一个月的暂停不被认为是间隔期。
在本发明中,所述药物的施用方法包括但不限于胃肠外,例如静脉内、腹膜内、肌内、皮下、粘膜(例如口服、鼻内、口含、阴道、直肠、眼内)、鞘内、局部和真皮内途径。施用可以是系统的或局部的。用于口服施用的制剂可被适当地配制以给予所述药物的受控释放。口含施用,所述药物可呈以常规方式配制的片剂或锭剂的形式。所述药物可被配制用于通过注射,例如通过快速或连续输注进行肠胃外施用。用于注射的制剂可以单位剂量形式(例如在安瓿中或在多剂量容器中)与添加的防腐剂一起呈现。所述药物可在油性或水性媒介物中的悬浮液、溶液或乳液的形式,并且可含有配制剂,例如悬浮剂、稳定剂和/或分散剂。或者,所述药物可呈粉末形式,以供在使用前用适合的媒介物(例如无菌的无热原水)重构。所述药物还可被配制成直肠组合物,例如栓剂或保留灌肠剂,例如含有常规栓剂基质,例如可可脂或其他甘油酯。对于吸入施用,根据本发明所述药物以来自加压包装或喷雾器的气雾形式,使用适合的推进剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他适合的气体,被方便地递送。在加压气雾剂的情况下,剂量单位可通过提供递送计量量的阀来确定。用于吸入器或吹入器中的例如明胶的胶囊和药筒可配制为容纳免疫检查点的抑制剂和适合的粉末基质(例如乳糖或淀粉)的粉末混合物。
在本发明中,所述药物用于人使用的活性成分的剂量的确定基于本领域中常用的实践,并且将由医师在临床试验中最终确定。可基于下文所公开的体内实验证据,使用已知的规则(例如Reagan-Show等(2007)重新审视的从动物到人研究的剂量转换(Dosetranslation from animal to human studies revisited).The FASEB Journal 22:659-661)计算向人施用的预期近似当量剂量。根据该范例,成人当量剂量(mg/kg体重)等于给予小鼠的剂量(mg/kg体重)乘以0.081。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
1、试验对象
抗CD28抗体、抗CD86抗体、抗CD80抗体和IgG,并分别将上述抗体制成封闭抗体。
2、建立青光眼小鼠模型:
通过腹腔注射氯胺酮(120mg/kg)及二甲苯胺噻嗪(12mg/kg)混合液麻醉小鼠。通过在成年C57BL/6J小鼠右侧眼前房注射直径为15μm的聚苯乙烯微粒(Invitrogen,Oregon,USA)诱导短期眼压升高。微粒注射浓度为5.0×106/ml。首先用30G针头(BD,USA)在小鼠右眼角膜中央作一细小穿刺口,然后换以玻璃微型注射器注射3~4微升微粒至前房。正常对照组以同样的操作方式注射同样体积的PBS至前房。
按照上述方法共构建20只青光眼小鼠模型,随机分为4组。上述建立青光眼小鼠模型术毕,随即向各组模型小鼠的玻璃体腔分别注射抗CD28抗体、抗CD86抗体、抗CD80抗体或IgG,给药浓度为1μg/ml,给药剂量为2μ L/只。
3、检测
4或8周后处死小鼠,并取视神经电镜及视网膜铺片以评估视神经损伤。结果如图1所示。
视神经及视网膜损伤检测:
采用Karnovsky solution固定视神经过夜。取眼球后2mm处视神经横断面切片并电镜照相(EM410,Philips)。使4%多聚甲醛固定眼球过夜。取视网膜铺片及冰冻切片。使用beta-III-tubulin(invitrogen)标记RGCs,并使用共聚焦激光显微镜(Olympus FV1000)读片记录。
4、检测结果
如图1的A、B所示,可以看出,青光眼模型小鼠分别注射抗CD28抗体、抗CD86抗体后抗CD80抗体后,视网膜节细胞损伤率和视神经轴索损伤相对于注射了IgG的模型组小鼠有显著降低。如图1的C所示,可以看出,联合 2种或3种抗体药物可更进一步加强这种保护效果。表明免疫检查点的抑制剂可有效降低青光眼视网膜节细胞及视神经轴索的持续性损伤,是一种具有临床应用前景的新靶点药物。
实施例2
1、试验对象
抗CD28抗体、抗CD86抗体、抗CD80抗体和IgG,并分别将上述抗体制成封闭抗体。
2、动物模型:
购买自发性高眼压转基因小鼠DBA/2J(赛柏诺生物科技有限公司),该小鼠的自发性视神经损伤从6个月开始显现,将DBA/2J小鼠作为试验组,随机分为4组,每组5只,并以3月龄的各组DBA/2J小鼠的检测数据作为对照。
DBA/2J小鼠6月龄起,每周分别对各试验组小鼠的玻璃体腔注射一次抗 CD28抗体、抗CD86抗体、抗CD80抗体或IgG,每次的给药浓度为0.1μg/ml、给药剂量为2μL/只。当试验组小鼠长至8月龄时各组处死一半,12月龄时处死另一半。
3、检测
分别在各组DBA/2J小鼠的3月龄、8月龄和12月龄的节细胞损伤率;在各组DBA/2J小鼠8月龄时对其CD4+T细胞比例进行检测,结果如图1所示。
(1)视网膜节细胞损伤情况的检测与实施例1相同;
(2)流式细胞仪检测细胞因子谱:
分别采用消化酶及抗体标记取视网膜单细胞匀浆、淋巴细胞单细胞匀浆,并使用PBS重悬。固定及穿透包膜后分别使用抗体标记表面抗原(CD25, Foxp3,CTLA4,Nrp1,CD73,CD45等)胞内分泌因子(IFN-γ、IL-17、IL21、 TGF-β),及其他促分化细胞因子谱(IL-12、IL-6、IL-2、IL-23、IL-10)等。使用流式细胞仪检测。
4、检测结果
如图1的D所示,DBA/2J小鼠分别注射抗CD28抗体、抗CD86抗体以及抗CD80抗体后,节细胞损伤率在8月龄和12月龄时,相对于注射了IgG 的DBA/2J小鼠均有显著降低;如图1的E、F所示,DBA/2J小鼠分别注射抗CD28抗体、抗CD86抗体以及抗CD80抗体后,CD4+IFN-γ+T细胞比例相对于注射了IgG的DBA/2J小鼠有显著降低。这表明,免疫检查点的抑制剂可有效降低青光眼小鼠眼内的免疫反应水平,调节T细胞的异常激活,从而有效保护视网膜及视神经,逆转青光眼损害。
实施例3
1、试验对象
抗CD28抗体IgG,并分别将上述抗体制成封闭抗体。
2、建立青光眼小鼠模型:
按照实施例1所示的方法构建青光眼小鼠模型。
按照上述方法共构建15只青光眼小鼠模型,随机分为3组。上述建立青光眼小鼠模型术毕,随即向各组模型小鼠的玻璃体腔分别注射抗CD28抗体或 IgG,给药浓度为1μg/ml,给药剂量为2μl/只。
3、检测
(1)注射后1周后,取各组青光眼模型小鼠的外周血,按照实施例2所示方法,以流式细胞术检测CD4+IFNγ+/IL-4+/IL-17+细胞;
(2)使用CD45RO及CD45RA标记小鼠外周血CD4+FoxP3+T细胞,并检测CD4+FoxP3+T细胞在其外周血中的含量;
RT-PCR检测转录因子:
使用超生乳化小鼠视网膜或视神经匀浆、离心、分离RNA。使用Trizol 步法提取总mRNA,并检测其纯度及计算其浓度。使用invitrogen的逆转录kit合成cDNA,并将其产物置于-20℃保存。根据Genebank序列设计的转录因子谱(T-bet、RORγt、BCL6、FOXP3、LAG3等)的引物序列并合成引物。使用Premix Ex TaqTM和Light CyclerPCR扩增仪(Roche)进行荧光扩增。
(3)以Elispots实验检测各组青光眼模型小鼠的T细胞反应强度。
Elisa检测外周血细胞因子滴度:
处死小鼠后,剪开腹部皮肤,暴露出腹腔血管,用5ml空针自腹主静脉采血2ml,放于未抗凝的生化管中,按2000r/min离心5min,移取上清液10μl入预置抗原ELISA试剂盒(invitrogen,USA)。酶标板自动读数仪410nm处读数。
4、检测结果
检测结果如图2所示:
由图2中A可以看出,Th1、Th2、Th17型CD4+T细胞在注射抗CD28 抗体后比例均下降,表明免疫检查点的抑制剂能够使青光眼模型小鼠的免疫反应水平显著下降;
由图2中B~F可以看出,为给药前青光眼模型小鼠体内记忆性Treg细胞比例大幅上升,而在注射抗CD28抗体之后mTreg细胞比例下降,表明免疫检查点的抑制剂对再次免疫反应的诱发具有抑制作用。
有图2中G可以看出,向青光眼模型小鼠注射抗CD28抗体药物后T细胞反应显著下降。
综上所述,免疫检查点的抑制剂可持续有效降低青光眼模型小鼠体内的免疫反应水平。
实施例4
1、试验对象
抗CD40抗体、抗CD154抗体、抗CD137抗体、抗CD137L抗体、抗 CD27抗体、抗CD70抗体、抗CD122抗体、抗CD48抗体、抗CD278抗体、抗CD275抗体、抗CD357抗体、抗CD279抗体、抗CD134抗体、抗CD255 抗体、抗CD244抗体以及IgG,并分别将上述抗体制成封闭抗体。
2、建立青光眼小鼠模型:
按照实施例1所示的方法构建青光眼小鼠模型。
按照上述方法共构建48只青光眼小鼠模型,随机分为16组。上述建立青光眼小鼠模型术毕,随即向各组模型小鼠的玻璃体腔分别注射抗CD40抗体、抗CD154抗体、抗CD137抗体、抗CD137L抗体、抗CD27抗体、抗 CD70抗体、抗CD122抗体、抗CD48抗体、抗CD278抗体、抗CD275抗体、抗CD357抗体、抗CD279抗体、抗CD134抗体、抗CD255抗体、抗CD244 抗体以及IgG;给药浓度为0.2μg/ml,给药剂量为2μl/只。
3、检测
8周后处死小鼠,并取视网膜铺片以评估视网膜节细胞损伤。结果如图3 所示。视网膜损伤检测方法如实施例1所示。
4、检测结果
检测结果如图3的A、B所示:发现各封闭抗体药物的注射可有效调节眼内免疫反应水平,这种免疫耐受状态可以使高眼压小鼠的视神经损伤显著下降。这表明免疫检查点CD40、CD154、CD137、CD137L、CD27、CD70、CD122、 CD48、CD278、CD275、CD357、CD279、CD134、CD255、CD244的封闭抗体可有效的保护视神经。
综合实施例1~4可以看出,免疫检查点的抑制剂对青光眼模型动物具有显著的视神经保护作用,给药后可有效降低青光眼模型动物的免疫紊乱状态,疗效显著,能够应用于青光眼治疗药物的制备中。
实施例5
1、试验对象
抗CD28抗体、抗CD86抗体、抗CD80抗体、抗CD27抗体、抗CD70 抗体和IgG,并分别将上述抗体制成封闭抗体。
2、建立急性视神经缺血小鼠模型:
应用生理盐水前房灌注的方法建立小鼠急性高眼压模型,使用30G静脉输液针头在鼻下方角巩膜缘进行前房穿刺,针尖避免扎伤虹膜和晶状体,固定针头,拧开连接有生理盐水的三通管,使动物眼压迅速达到80mmHg(即114cmH2O,1mmHg=0.133kPa),开始计时1小时。
按照上述方法共构建18只急性视神经缺血小鼠模型,随机分为6组。上述建立急性视神经缺血小鼠模型术毕,随即向各组模型小鼠的玻璃体腔分别注射抗CD28抗体、抗CD86抗体、抗CD80抗体抗CD27抗体、抗CD70抗体或IgG,给药浓度为1μg/ml,给药剂量为2μL/只。
3、检测
4周后处死小鼠,并取视神经电镜及视网膜铺片以评估视神经及视网膜损伤。结果如图4所示。视神经及视网膜损伤检测方法如实施例1所示。
4、检测结果
如图4的A、B所示,可以看出,急性视神经缺血小鼠模型小鼠分别注射抗CD28抗体、抗CD86抗体、抗CD80抗体、抗CD27抗体以及抗CD70抗体后,节细胞损伤率和轴索损伤相对于注射了IgG的模型组小鼠有显著降低。而联合注射抗CD27抗体和抗CD28抗体,或者联合注射抗CD70抗体和抗 CD86抗体可进一步降低青光眼视神经损伤。表明免疫检查点的抑制剂可有效降低急性视神经缺血小鼠模型的视神经及视网膜损伤,而联合用药可更为有效的实现这一目标。
实施例6
1、试验对象
抗CD28抗体、抗CD86抗体、抗CD80抗体、抗CD278抗体、抗70抗体、抗CD40抗体、抗CD154抗体、抗CD122抗体和IgG,并分别将上述抗体制成封闭抗体。
2、建立葡萄膜炎小鼠模型:
将HS-AgP35冻干粉配制为4mg/mL的抗原溶液,取HS-AgP35与等量 CFA混合,充分乳化至膏状乳剂,水合氯醛腹腔注射麻醉小鼠,取0.1mL HS-Ag 乳化剂注射Lewis小鼠双后足垫、双后腿及背部皮下,同时腹腔注射百白破三联疫苗0.1mL。1w后,同法2次免疫。于HS-Ag 2次免疫后次日,以450 μg/mL的伤寒杆菌内毒素0.5μL于小鼠睫状体平坦部进针行玻璃体腔注射。
按照上述方法共构建27只葡萄膜炎小鼠模型,随机分为9组。上述建立葡萄膜炎小鼠模型术毕,随即向各组模型小鼠的玻璃体腔分别注射抗CD28 抗体、抗CD86抗体、抗CD80抗体、抗CD278抗体、抗70抗体、抗CD40 抗体、抗CD154抗体、抗CD122抗体或IgG,给药浓度为1μg/ml,给药剂量为2μL/只。
3、检测
(1)4周后处死小鼠,并取视神经电镜及视网膜铺片以评估视神经损伤。结果如图5所示。视神经及视网膜损伤检测方法如实施例1所示。
(2)取疾病组及对照组小鼠视网膜通过流式细胞检测,方法如实施例2 所示的流式细胞检测法。
4、检测结果
如图5的A所示,葡萄膜炎小鼠模型的临床体征评分标准,每只小鼠对照该标准进行评分,以评定葡萄膜炎严重程度。如图5的B所示,小鼠分别注射抗CD28抗体、抗CD86抗体后抗CD80抗体、抗CD278抗体、抗70抗体、抗CD40抗体、抗CD154抗体和抗CD122抗体后,其临床体征评分相对于注射了IgG的模型组小鼠有显著降低,表明免疫检查点的抑制剂可有效降低葡萄膜炎小鼠模型的眼内免疫反应水平,使免疫系统恢复较为稳定的免疫耐受状态,从而降低疾病损伤。
如图5的C、D所示,模型小鼠视网膜大量炎性细胞聚集及炎性因子释放,但在免疫检查点的抑制剂注射后,炎性细胞的增殖得到有效抑制。
综合实施例1、5和6可以看出,免疫检查点的抑制剂对于青光眼及其他眼部免疫损伤病理机制相关疾病均具有有效的治疗作用。
实施例7
1、试验对象
抗CD27抗体、抗CD28抗体和IgG,并分别将上述抗体制成封闭抗体。
2、建立糖尿病视网膜小鼠模型:
取6周龄C57BL/6小鼠,实验组按照小鼠体重60mg/kg连续3d腹腔注射STZ,对照组按照小鼠体重腹腔注射等量PBS缓冲液。术闭随即玻璃体腔注射抗体药物。注射1周后取小鼠尾部静脉血液测量血糖值。血糖值>250 mg/dl或13.9mmol/L,表示造模成功。造模成功后持续饲养3个月。期间每周注射抗体药物2次。通过ERG检测其视觉功能。
按照上述方法共构建9只葡萄膜炎小鼠模型,随机分为3组。上述建立葡萄膜炎小鼠模型术毕,随即向各组模型小鼠的玻璃体腔分别注射抗CD27 抗体、抗CD28抗体或IgG,给药浓度为1μg/ml,给药剂量为2μL/只。
3、检测
(1)3月后麻醉小鼠,并通过视网膜电图(ERG)以评估视觉功能损伤。结果如图6所示。
(2)取疾病组及对照组小鼠视网膜通过流式细胞检测,方法如实施例2 所示的流式细胞检测法。
4、检测结果
如图6的A、B所示,注射抗CD27抗体或抗CD28抗体可使糖尿病小鼠 ERG的a波或b波波幅较IgG注射组显著上升,这表明免疫检查点的抑制剂可有效提高其视觉功能。
如图6的C所示,模型小鼠视网膜大量炎性细胞聚集及炎性因子释放,但在免疫检查点的抑制剂注射后,CD4+/IFN-γ+T细胞得到有效抑制。表面其眼内的免疫反应水平到抑制。
如图6的D所示,糖尿病视网膜病变的中晚期常伴随大量新生血管(箭头所示)的生长,但抗体药物注射可有效逆转该病理进程。
综合实施例1、5、6和7可以看出,免疫检查点的抑制剂对于青光眼及其他眼部免疫损伤病理机制相关疾病均具有有效的治疗作用。
以上仅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 (6)
1.免疫检查点的抑制剂在制备治疗视网膜和/或视神经损伤相关疾病的药物中的应用;
所述免疫检查点的抑制剂为抗-CD27的抗体和抗-CD28的抗体的组合。
2.根据权利要求1所述的应用,其特征在于,所述治疗为:降低视网膜节细胞和/或视神经轴索的持续性损伤。
3.根据权利要求1所述的应用,其特征在于,所述视网膜和/或视神经损伤相关疾病包括青光眼、眼部炎症性疾病、眼增生性疾病、视网膜变性病症、眼缺血性疾病和眼占位性病变中的至少一种。
4.根据权利要求1所述的应用,其特征在于,所述眼部炎症性疾病包括葡萄膜炎、角膜炎、巩膜炎、视神经炎、视神经脊髓炎、眼内炎或眶蜂窝织炎;
所述眼增生性疾病包括增殖性玻璃体视网膜病变或增殖性糖尿病视网膜病变;
所述视网膜变性病症包括年龄相关性黄斑变性或视网膜色素变性;
所述眼缺血性疾病包括急性视神经缺血、视网膜中央静脉阻塞、视网膜中央动脉阻塞或前部缺血性视神经病变;
所述眼占位性病变包括甲状腺相关性眼病、视神经母细胞瘤或脉络膜恶性黑色素瘤。
5.根据权利要求1~4任意一项所述的应用,其特征在于,所述免疫检查点的抑制剂对人的施用剂量为0.1mg/kg~20mg/kg。
6.根据权利要求1所述的应用,其特征在于,所述药物中还包括腺苷、腺苷A1受体激动剂、腺苷A2a受体激动剂和腺苷A3受体激动剂中的一种或多种。
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