CN114126653A - 用于治疗结节病的方法的ghrh拮抗剂 - Google Patents
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Abstract
本公开内容提供了一种治疗结节病的方法,该方法包括向有相应需要的哺乳动物受试者施用GHRH拮抗剂。
Description
本发明是在由美国退伍军人事务部授予的杰出科学家奖和由美国国立卫生研究院(NIH)授予的拨款号P30CA240139的政府支持下完成的。美国政府在本发明中具有某些权利。
相关申请的交叉引用以及电子方式提交的材料的通过引用并入
本申请在此要求2019年7月18日提交的美国临时专利申请第62/875,703号的优先权,该美国临时专利申请通过引用以其整体并入。
同时随此提交的计算机可读的核苷酸/氨基酸序列表通过引用以其整体并入并且标识如下:54402A_Seqlisting.txt;大小:10,859字节;创建:2020年7月17日。
公开内容的领域
本发明涉及用于治疗结节病的材料和方法。
背景
结节病是一种病因未知的多器官肉芽肿性疾病,在美国与显著的发病率和死亡率相关,并且在全球影响数十万人。Mirsaeidi等人,Chest.2015;147(2):438-449。虽然这种状况的病因尚未清楚了解,但是结节病和其他肉芽肿形成性紊乱(包括分枝杆菌和其他微生物感染)以及环境因素诱导的肉芽肿之间有显著的相似性。Chen等人,Clinics in chestmedicine.2008;29(3):365-377,vii。在受影响的器官中,结节病触发早期炎症反应,其特征在于TH1辅助细胞的细胞募集,随后是巨噬细胞募集导致肉芽肿形成的后期阶段。在某些患者中,包括细胞因子和凋亡的抗炎反应被激活以促进组织愈合和修复。Koh等人,ExpertRev Mol Med.2011;13:e23。几乎50%的结节病患者需要全身类固醇治疗。在高达20%的患者中,尽管使用类固醇,炎症过程仍然持续,并且导致伴有纤维化(受影响组织的永久性疤痕)的组织重塑。Patterson等人,Annals of the American Thoracic Society.2013;10(4):362-370。
鉴于多于50%的患者的结节病有多器官参与,这种疾病的治疗具有挑战性。皮质类固醇是治疗的基石,并且美国食品及药品管理局(FDA)仅批准了两种用于结节病的药物(泼尼松和Acthar-Gel)6,7。Miller等人,Ann Intern Med.1952;37(4):776-784;Baughman等人,Respir Med.2016;110:66-72。然而,这些剂在长期使用后会引起显著的副作用,使得其不适合用于长期治疗。对于有持续症状和复杂表现并累及重要器官的患者,应立即开始治疗并持续数月,这意味着需要毒性更低和可耐受的替代策略。
概述
1.本公开内容提供了一种治疗结节病的方法,该方法包括向有相应需要的哺乳动物受试者施用GHRH拮抗剂。本公开内容还提供了GHRH拮抗剂用于治疗结节病或在制备用于治疗结节病的药物中的用途。本公开内容还提供了用于治疗结节病的GHRH拮抗剂。
2.在各方面,诸如第1段的方法或用途,GHRH拮抗剂包含氨基酸序列(式I):R1-Tyr1-D-Arg2-Asp3-A4-Ile5-A6-Thr7-A8-Har9-A10-A11-A12-Val13-Leu14-A15-Gln16-A17-Ser18-Ala19-A20-A21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-A29-R2-R3-NH2(SEQ ID NO:2),
其中R1是PhAc(苯基乙酰基)、Nac(萘基乙酰基)、Oct(辛酰基)、N-Me-Aib(N-甲基-α-氨基异丁酰基)、Dca(二氯乙酰基)、Ac-Ada(乙酰基-12-氨基十二烷酰基)、Fer(阿魏酰基)、Ac-Amc(乙酰基-8-氨基辛酰基)、Me-NH-Sub(甲基-NH-软木酰基)、PhAc-Ada(苯基乙酰基12-氨基十二烷酰基)、Ac-Ada-D-Phe、Ac-Ada-Phe、Dca-Ada(二氯乙酰基-12-氨基十二烷酰基)、Nac(萘基乙酰基)、Nac-Ada、Ada-Ada或CH3(CH2)10-CO-Ada;
A4是Ala或Me-Ala;
A6是Cpa(对氯苯丙氨酸)或Phe(F)5(五氟-苯丙氨酸,也称为Fpa5);
A8是Ala、Pal(吡啶基丙氨酸)、Dip((3,3-二苯基)丙氨酸)或Me-Ala;
A10是Fpa5、Tyr(Alk),其中Alk是Me或Et;
A11是His或Arg;
A12是Lys、Lys(0-11)(Lys(A0-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-)、Lys(Me)2或Orn(鸟氨酸);
A15是Abu(α-氨基丁酸)或Orn;
A17是Leu或Glu;
A20是Har(高精氨酸)或His;
A21是Lys、Lys(Me)2或Orn;
A29是Har、Arg或Agm(鲱精胺);
R2是β-Ala、Amc(8-氨基辛酰基)、Apa(5-氨基戊酰基)、Ada(12-氨基十二烷酰基)、AE2A(8-氨基-3,6-二氧杂辛酰基)、AE4P(15-氨基-4,7,10,13-四氧杂十五烷酰基)、ε-Lys(α-NH2)(Lys残基,其8-氨基基团被位于N-末端的氨基酸的羰基基团酰化;Lys残基的α-氨基基团是游离的)、Agm(鲱精胺)或不存在;并且
R3是Lys(Oct)、Ahx(6-氨基己酰基)或不存在。
3.在各方面,诸如第1段的方法或用途,GHRH拮抗剂是MIA-602、MIA-604、MIA-606、MIA-610、MIA-640或MIA-690。
4.在各方面,诸如第1段的方法或用途,GHRH拮抗剂是MIA-602。
5.在各方面,诸如第1-4段中任一项的方法或用途,GHRH拮抗剂经由皮内、肌肉内、腹膜内、静脉内、动脉内、皮下、硬膜外、舌下、鼻内、脑内、室内(intraventricular)、鞘内、阴道内、经皮、直肠、吸入、肺内、气道内、支气管内、气管内或表面递送施用。
6.在各方面,诸如第5段的方法或用途,GHRH拮抗剂是皮下施用的。
7.在各方面,诸如第1-5段中任一项的方法或用途,GHRH拮抗剂经由鼻内、吸入、肺内、气道内、支气管内或气管内递送施用。
8.在各方面,诸如第1-7段中任一项的方法或用途,结节病是肺结节病。
附图简述
图1A-1E:说明罹患结节病并用盐水、α-黑皮质素刺激激素(α-MSH,黑皮质素受体激动剂)、MIA-602和Solu-Medrol(甲基泼尼松龙;目前FDA批准的用于结节病的药物)治疗的小鼠中的肺部炎症的百分比的柱状图。肺部炎症由肺病理学家使用苏木精和伊红染色(H&E)染色(图1A)、CD68水平(图1B)、PD-1水平(图1C)、PD-L1水平(图1D)和CD30水平(图1E)确定和评分。
图2A-2T:在从确诊的结节病患者分离的外周血单个核细胞(PBMC)中测试MIA-602在来自人类细胞的结节病样肉芽肿中的抗炎活性。用微粒攻击PBMC导致离体肉芽肿。图2A-2T是说明用MIA-602或Solu-Medrol(甲基泼尼松龙)治疗的肉芽肿样品与未用微粒攻击的PBMC和用盐水治疗的肉芽肿相比的细胞因子产生(x轴,pg/mL)的柱状图。
图3A-3D:说明用MIA-602、甲基泼尼松龙或对照治疗后,体外肉芽肿样品中存活蛋白(图3A)、Mcl-1/Bak二聚体(图3B)、Bcl-xL/Bak二聚体(图3C)和活性胱天蛋白酶-3(图3D)水平的百分比的柱状图。
图4:示出用微粒攻击的发展出结节病样肉芽肿的小鼠肺在用MIA-602治疗后对比用盐水治疗的肉芽肿的小鼠肺或对照中的GHRHR免疫荧光染色百分比的柱状图。
图5A-5E:示出对照、具有肉芽肿并用盐水治疗和用MIA 602治疗的肉芽肿的小鼠肺中的H&E(图5A)和CD30(图5B)、CD68(图5C)、PD-1(图5D)、PD-L1(图5E)的免疫组织化学(IHC)变化的柱状图。小鼠数量:对照#3,肉芽肿#4,MIA 602#3。
图6A-6C:说明对照小鼠、用MIA 602治疗的小鼠和用甲基泼尼松龙治疗的小鼠的肉芽肿中CD45+CD68+细胞、CD45+CD68+PD-1细胞或CD45+CD68+PD-L1细胞的增加百分比的柱状图。用MIA-602治疗后,与其他细胞类型相比,CD45+CD68+PD-L1细胞的百分比增加更高。
图7:示出对照小鼠肺(无肉芽肿)、用微粒攻击并已发展出肉芽肿的小鼠肺和具有肉芽肿并用MIA-602治疗的小鼠肺中NOS2染色百分比的柱状图。
图8:示出对照小鼠肺(无肉芽肿)、用微粒攻击并发展出肉芽肿的小鼠肺和具有肉芽肿并用MIA-602治疗的小鼠肺中的硝基酪氨酸染色百分比的柱状图。
图9:在用MIA-602治疗结节病小鼠后表现出多于2.5倍差异表达的基因的列表。该列表包括基因稳定标识符(Stable Identifier)(Ensembl数据库参考号)、基因名称和RNA转录物类型。
详细描述
本公开内容提供了治疗结节病(例如,肺结节病)的方法。该方法包括向有相应需要的哺乳动物受试者施用GHRH拮抗剂。本文阐述的数据揭示了GHRH拮抗剂(例如MIA-602)在结节病的体内模型中显著减少炎症。
术语“受试者”包括但不限于人类和非人类哺乳动物,诸如野生动物、家养动物和农场动物。优选地,受试者是人类。受试者可以罹患任何形式的结节病(即,在任何器官诸如肺中的结节病)。
生长激素释放激素(GHRH)由下丘脑分泌并且作用于垂体以刺激生长激素(GH)的释放。通过在GHRH(1-29)的生物活性N末端进行氨基酸取代,已经产生了近2000种合成的GHRH拮抗性类似物。Schally等人,Nat.Clin.Pract.Endocrinol.Metab.4(1),33-43(2008);Zarandi等人,PNAS 91(25),12298-302(1994);Zarandi等人,Peptides 89,60-70(2017)。垂体GHRH受体(pGHRH-R)是与G蛋白偶联的七跨膜结构域受体。Rekasi等人,PNAS97(19),10561-6(2000);Havt等人,PNAS 102(48),17424-9(2005)。pGHRH-R以及其截短的剪接变体(SV)在多种人类组织中表达。SV1与pGHRH-R的差异在于氨基末端胞外结构域。Rekasi,同上。
在各方面,GHRH拮抗剂是肽。GHRH肽的各种修饰赋予了拮抗特性。包含残基1至29的GHRH片段或GHRH(1-29)是对垂体的生物活性所必需的最小序列。该片段保留了50%或更多的天然GHRH的效力。基于hGH-RH(1-29)NH2肽的结构制备的许多GHRH的合成类似物在本文中被设想用于本方法的情况中。hGHRH(1-29)NH2具有以下氨基酸序列:Tyr-Ala-Asp-Ala-Ile5-Phe-Thr-Asn-Ser-Tyr10-Arg-Lys-Val-Leu-Gly15-Gln-Leu-Ser-Ala-Arg20-Lys-Leu-Leu-Gln-Asp25-Ile-Met-Ser-Arg29-NH2(SEQ ID NO:1)。GHRH拮抗剂可以包含进行了氨基酸缺失、插入和/或取代的GHRH肽序列。GHRH拮抗剂也可以是GHRH的片段或修饰片段,所述GHRH的片段或修饰片段具有与GHRH受体结合并抑制生长激素释放的能力。这些拮抗特性被认为是由于在GHRH(1-29)NH2的N-末端处的各种氨基酸的替代和用芳香或非极性酸酰化而产生的。
任选地,GHRH拮抗剂是美国专利公布第20150166617号或美国专利第8,691,942号中描述的拮抗剂(通过引用以其整体并且特别是关于GHRH拮抗剂的描述并入本文)。例如,在各种实施方案中,GHRH拮抗剂包含氨基酸序列(式I/SEQ ID NO:2):R1-Tyr1-D-Arg2-Asp3-A4-Ile5-A6-Thr7-A8-Har9-A10-A11-A12-Val13-Leu14-A15-Gln16-A17-Ser18-Ala19-A20-A21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-A29-R2-R3-NH2,其中R1是PhAc(苯基乙酰基)、Nac(萘基乙酰基)、Oct(辛酰基)、N-Me-Aib(N-甲基-α-氨基异丁酰基)、Dca(二氯乙酰基)、Ac-Ada(乙酰基-12-氨基十二烷酰基)、Fer(阿魏酰基)、Ac-Amc(乙酰基-8-氨基辛酰基)、Me-NH-Sub(甲基-NH-软木酰基)、PhAc-Ada(苯基乙酰基12-氨基十二烷酰基)、Ac-Ada-D-Phe、Ac-Ada-Phe、Dca-Ada(二氯乙酰基-12-氨基十二烷酰基)、Nac(萘基乙酰基)、Nac-Ada、Ada-Ada或CH3(CH2)10-CO-Ada;A4是Ala或Me-Ala;A6是Cpa(对氯苯丙氨酸)或Phe(F)5(也称为Fpa5);A8是Ala、Pal(吡啶基丙氨酸)、Dip((3,3-二苯基)丙氨酸)或Me-Ala;A10是Fpa5、Tyr(Alk),其中Alk是Me或Et;A11是His或Arg;A12是Lys、Lys(0-11)(即Lys(A0-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-),其中每个A是赖氨酸,否则描述为A12位置处的一串赖氨酸残基)、Lys(Me)2或Orn(鸟氨酸);A15是Abu(α-氨基丁酸)或Orn;A17是Leu或Glu;A20是Har(高精氨酸)或His;A21是Lys、Lys(Me)2或Orn;A29是Har、Arg或Agm(鲱精胺);R2是β-Ala、Amc(8-氨基辛酰基)、Apa(5-氨基戊酰基)、Ada(12-氨基十二烷酰基)、AE2A(8-氨基-3,6-二氧杂辛酰基)、AE4P(15-氨基-4,7,10,13-四氧杂十五烷酰基)、ε-Lys(α-NH2)(Lys残基,其8-氨基基团被位于N-末端的氨基酸的羰基基团酰化;Lys残基的α-氨基基团是游离的)、Agm(鲱精胺)或不存在;并且R3是Lys(Oct)、Ahx(6-氨基己酰基)或不存在。
任选地,GHRH拮抗剂是MIA-602:[PhAc-Ada0-Tyr1,D-Arg2,Fpa56,Ala8,Har9,Tyr(Me)10,His11,Orn12,Abu15,His20,Orn21,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2(SEQ ID NO:8),在美国专利公布第20150166617号中进一步描述(通过引用关于MIA-602、MIA-604、MIA-606、MIA-610、MIA-640和MIA-690的结构、活性和制备方法的讨论并入本文)。可选的GHRH拮抗剂包括但不限于Phac-Ada-Tyr1-D-Arg2-Asp3-Ala4-Ile5-Phe(F)5 6-Thr7-Ala8-Har9-Tyr(Me)10-His11-Orn12-Val13-Leu14-Abu15-Gln16-Leu17-Ser18-Ala19-His20-Orn21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-Har29-Agm-NH2(MIA-604/SEQ ID NO:3);Phac-Ada-Tyr1-D-Arg2-Asp3-Ala4-Ile5-Phe(F)5 6-Thr7-Me-Ala8-Har9-Tyr(Me)10-His11-Orn12-Val13-Leu14-Abu15-Gln16-Leu17-Ser18-Ala19-His20-Orn21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-Har29-Agm-NH2(MIA-606/SEQ ID NO:4);Phac-Tyr1-D-Arg2-Asp3-Ala4-Ile5-Cpa6-Thr7-Ala8-Har9-Fpa510-His11-Orn12-Val13-Leu14-Abu15-Gln16-Leu17-Ser18-Ala19-His20-Orn21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-Har29-Ada-NH2(MIA-610/SEQ ID NO:5);Phac-Ada-Tyr1-D-Arg2-Asp3-Ala4-Ile5-Cpa6-Thr7-Ala8-Har9-Fpa510-His11-Orn12-Val13-Leu14-Abu15-Gln16-Glu17-Ser18-Ala19-His20-Orn21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-Har29-Ada-NH2(MIA-640/SEQ ID NO:6);Phac-Ada-Tyr1-D-Arg2-Asp3-Ala4-Ile5-Cpa6-Thr7-Ala8-Har9-Fpa510-His11-Orn12-Val13-Leu14-Abu15-Gln16-Leu17-Ser18-Ala19-His20-Orn21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-Har29-NH2(MIA-690/SEQ ID NO:7)。以上描述的肽的氨基酸序列对应于hGHRH(1-29)(SEQ ID NO:1)的氨基酸残基进行编号。
本公开内容提供了治疗有相应需要的受试者的结节病的方法。“治疗”结节病不需要100%缓解。结节病或结节病症状(例如炎症、肉芽肿形成、肉芽肿尺寸)的任何减少、生活质量的提高构成受试者中有益的生物学效应。治疗结节病的方法的进展可以使用任何合适的方法来确定,诸如生物样品(例如血液)中的生物标志物检测/测量、胸部成像(例如CT扫描)和PET-CT扫描。在某些方面,该方法提供了疾病指标、参数或症状的减少或改善,诸如与治疗前相比,血管紧张素转换酶(ACE)、SIL2R或CRP生物标志物减少至少50%、至少65%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%,或与用泼尼松治疗(在本方法前施用或在匹配患者中施用)所达到的相比,疾病指标、参数或症状减少至少50%。在各方面,“治疗”还包括疾病的稳定化,即疾病的控制或无进一步进展(例如肉芽肿负荷在给定时间范围内不增加,或增加少于10%,优选地少于5%)。
可选地或另外地,如本文描述的治疗任选地改善疾病的分期或降低分期内的严重程度。结节病的常用分期包括:I期,肉芽肿主要位于淋巴结中;II期,肉芽肿位于肺和淋巴结中;III期,肉芽肿主要位于肺中伴随缩小的淋巴结;IV期,肺部纤维化。
结节病疾病进展使用各种临床技术中的任一种来确定,诸如受影响器官的活检以鉴定肉芽肿、血液测试、支气管镜检查、X射线、神经测试(例如肌电图、诱发电位、脊柱叩击或神经传导测试)、高分辨率计算机断层成像术(CT)扫描、磁共振成像(MRI)、正电子断层成像术(PET)扫描、肺功能测试和超声。
用于特定受试者的特定施用方案将部分地取决于施用的拮抗剂的量、施用途径和任何副作用的原因和程度。根据本公开内容向受试者(例如人类)施用的量应该足以在合理的时间范围内实现期望的响应(即减轻、预防或改善患者的不想要的状况、疾病或症状)。GHRH拮抗剂的治疗有效量通常是使得当以生理可耐受的赋形剂组合物施用时,足以达到有效的全身浓度或靶组织中的局部浓度的量。
GHRH拮抗剂的剂量任选地为约0.005mg/kg至约100mg/kg。在各方面,GHRH拮抗剂以约0.05mg/kg至约20mg/kg的剂量施用。在一些实施方案中,GHRH拮抗剂以约0.01mg/kg/剂量至约50mg/kg/剂量、约0.01mg/kg/剂量至约25mg/kg/剂量、约0.1mg/kg至约15mg/kg或约1mg/kg至约10mg/kg的剂量施用。任选地,剂量以每天一次给予或分成2-4次施用/天。当将GHRH拮抗剂静脉内施用于人类患者时,剂量任选地分为1-4次团注(bolus injection)/天或以连续输注给予。
GHRH拮抗剂可以每天一次、至少一周一次、至少一周两次、至少一周三次、至少一周四次、至少一周五次、一周六次、每两周一次、每三周一次、每四周一次、每五周一次或每六周一次施用。治疗期(需要多次施用拮抗剂)将取决于疾病的性质和严重程度,以及任何副作用的存在。治疗期的实例包括但不限于2周、3周、1个月、2个月、3个月、4个月、5个月、6个月、9个月和12个月。
施用方法可以包括但不限于口服施用和肠胃外施用,包括但不限于皮内、肌肉内、腹膜内、静脉内、动脉内、皮下、硬膜外、舌下、鼻内、脑内、室内、鞘内、阴道内、经皮、直肠、吸入、肺内、气道内、支气管内、气管内或表面(例如,向耳、鼻、眼或皮肤)递送。在多方面,拮抗剂被皮下施用。在其他方面,诸如受试者罹患肺结节病的方面,拮抗剂经由鼻内、吸入、肺内、气道内、支气管内或气管内递送施用。
任选地,GHRH拮抗剂被单独施用或与其他药物组合(同时或连续)施用,任选地作为单一的组合制剂或作为单独的组合物。在一些方面,该方法包括施用多于一种GHRH拮抗剂。可选地或另外地,GHRH拮抗剂任选地与其他抗炎剂诸如类固醇组合施用。可选地或另外地,GHRH拮抗剂任选地与一种或更多种改变疾病的抗风湿药物(disease-modifyingantirheumatic drug,DMARD;例如甲氨蝶呤、硫唑嘌呤(azathioprine)或来氟米特)、单克隆抗体(例如英夫利昔单抗、阿达木单抗、利妥昔单抗或戈利木单抗)、秋水仙碱、激素疗法(例如促肾上腺皮质激素)、抗生素和/或己酮可可碱组合施用。
GHRH拮抗剂可以以药学上可接受的无毒盐诸如酸加成盐的形式施用。这样的酸加成盐的示例是盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、延胡索酸盐、葡萄糖酸盐、单宁酸盐、马来酸盐、乙酸盐、三氟乙酸盐、柠檬酸盐、苯甲酸盐、琥珀酸盐、藻酸盐、双羟萘酸盐、苹果酸盐、抗坏血酸盐、酒石酸盐等。特别优选的拮抗剂是低溶解度的盐,例如双羟萘酸盐等。
含有GHRH拮抗剂和合适载体的制剂可以是固体剂型,包括但不限于软凝胶、片剂、胶囊、扁囊剂、粒剂(pellet)、丸剂、粉末和颗粒(granule);表面剂型(topical dosageforms)包括但不限于溶液、粉末、流体乳剂(fluid emulsions)、流体悬浮液(fluidsuspensions)、半固体、软膏、糊剂、乳膏、凝胶和胶冻剂(jelly)以及泡沫;和肠胃外剂型包括但不限于溶液、悬浮液、乳剂和粉末。在一些实施方案中,单剂量可以包括一次或更多次施用(即,多次注射或多个丸剂以达到拮抗剂的单剂量/量)。
GHRH拮抗剂可以被包含在具有药学上可接受的稀释剂、填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、疏水媒介物、水溶性媒介物、乳化剂、缓冲剂、湿润剂、保湿剂、增溶剂、防腐剂等的制剂中。施用的手段和方法是本领域已知的并且技术人员可以参考各种药理学参考文献用于指导。例如,可参考Modern Pharmaceutics,Banker&Rhodes,Marcel Dekker,Inc.(1979);和Goodman&Gilman’s The Pharmaceutical Basis of Therapeutics,第6版,MacMillan Publishing Co.,New York(1980)。药物组合物可以包含合适的固相或凝胶相载体或赋形剂。这样的载体或赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶和聚合物,诸如例如聚乙二醇。
通过参考以下实施例,将更容易理解所概括描述的本发明,所述实施例是以举例说明的方式提供的,并不意图限制本发明。
实施例
一般方法
MIA-602制备
MIA-602的化学结构为[PhAc-Ada0,D-Arg2,Fpa56,Ala8,Har9,Tyr(Me)10,His11,Orn12,Abu15,His20,Orn21,Nle27,D-Arg28,Har29]hGH-RH(1–29)NH2。将化合物溶解于100%二甲基亚砜(DMSO,ACS级,Sigma)中作为储备液,并且在相应的培养基中以1:1000稀释至1μM的最终浓度。体外和体内对照组接受有相同体积和浓度DMSO的安慰剂。
微粒开发
微粒如先前展示的产生(Zhang等人,Sci Rep 2020;10:7277)。微粒从脓肿分枝杆菌(Mycobacterium abscessus MAB)的临床菌株的粗糙菌落通过超声和加热活杆菌产生。通过扫描电子显微镜(SEM)获得了非传染性MAB颗粒的高质量图像。
人体血液样品
从迈阿密大学结节病生物库(University of Miami Sarcoidosis Biobanking)随机选择并且按年龄、性别和种族与当时健康的对照匹配的九名确诊肺结节病患者采集血液样品。为了避免额外的静脉穿刺术相关的不便和风险,采集了10ml血液样本。当时具有hgb<7mg/dL的患者被排除参与本研究。
成熟的体外肉芽肿样形成
如先前描述的(Zhang等人,Sci Rep 2020;10:7277)通过用微粒攻击PBMC来发展体外肉芽肿。
暴露于MAB微粒的小鼠模型
如先前描述的(Zhang等人,Front Immunol 2019;10:2888)发展小鼠肺中的肉芽肿反应。
ELISA
(Zhang等人,Sci Rep 2020;10:7277),在含有蛋白酶抑制剂混合物(CellSignaling Technology,Beverly,MA)的裂解缓冲液(Cell Signaling Technology,Beverly,MA)中裂解PBMC,并超声3次,每次2秒,每2s脉冲之间至少在冰上停留1min。样品在4℃以10,000×g离心5min,并且收集上清液。蛋白浓度通过来自Cell SignalingTechnology的BCA蛋白测定试剂盒确定。方法在Zhang等人,Sci Rep 2020;10:7277中进一步描述。
将30微克的总蛋白混合在还原性样品缓冲液中,并根据试剂盒说明书用于线粒体凋亡测定。该测定使用Bio-Rad试剂盒(171-WAR3CK)进行。
为了测量培养基中的细胞因子,分析上清液等分试样样品,将样品解冻,并以12,000rpm旋转10min以分离底部的颗粒物质。根据预定图谱,通过手动移液,将来自每个样品的50μl未稀释培养基置于96孔V形底板(源板)上。在整个过程期间,等分试样被包裹在封口膜中,并保持在4℃的潮湿室中,但不超过72hr。生长因子及其受体捕获抗体按照生产商说明书进行重构和稀释,并将50μl置于各96孔高结合半孔板(high-binding half-wellplate)的每个孔中,然后将其密封并在4℃孵育过夜。细胞因子水平使用来自Invitrogen的procartaplex人th1/th2细胞因子组11plex(epx 110-10810-901)测量。
免疫荧光共聚焦显微术
用于共聚焦显微术的方法的细节在Zhang等人,Front Immunol 2019;10:2888)中讨论。总之,在第14天处死小鼠,并且收获左肺。将肺用10%缓冲福尔马林填充,并且在福尔马林中固定至少72h,然后进行IHC染色。H&E染色用于确定炎症病理。
对于免疫荧光,石蜡包埋的系列切片(5μm)首先经历标准的脱蜡和再水合程序。然后用GHRHR(Origene,cat#TA311715)作为一抗并用来自Sigma的抗兔抗体(cat#F-9887)作为二抗探测切片。细胞核用DAPI复染。所有试剂均来自Sigma-Aldrich。组织切片使用荧光显微术和ImageJ软件(6.0版;NIH)来分析以定量荧光强度。在三色染色的载玻片上,还使用ImageJ定量分析了蓝色染色(胶原含量)。
共聚焦免疫荧光图像在迈阿密大学McKnight Analytical Imaging CoreFacility使用Leica DM6000显微镜用SP5共聚焦模块获得。捕获的图像使用VelocitySoftware 6.1.1软件(Perkin-Elmer,Waltham,MA)处理。
对于免疫组织化学,将5-μm石蜡切片通过脱蜡和再水合,随后内源性过氧化物酶封闭(甲醇中的1%H2O2持续20分钟)和抗原修复(antigen retrieval)(在10mM柠檬酸盐缓冲液中煮沸30分钟)进行处理。将组织切片用2%山羊或马血清(Vector Laboratories)封闭,并与抗体CD68(Proteintech,Cat#25747-1-AP)、PD-1(Cell Signaling,cat#84651)、PD-L1(Proteintech,Cat#17952-1-AP)、CD30(Lsbio,cat#LS-c162069)、CD3(CellSignaling,cat#99940)、iNOS(Invitrogen,cat#PAI-036)或硝基酪氨酸(Novus,NBP2-54606)一起在4℃孵育过夜,用TBST洗涤5次,然后暴露于二抗(Vector Laboratories,cat#PI-2000)。免疫反应使用ABC Elite试剂盒(Vector Laboratories)来检测。DAB用作最终发色体并且苏木精用作核复染。所有抗体的阴性对照通过用非免疫原性IgG替代一抗来进行。
如先前描述的(Zhang等人,Front Immunol 2019;10:2888),使用在100X放大倍率具有最高浸润强度(infiltrate's intensity)的3个视场对肺部炎症进行评分。测量炎症的面积,并对3个检查的高倍率视场计算平均值。
RNA分离和分析
使用RNA Miniprep Plus试剂盒(Zymo Research)从小鼠肺提取RNA。简言之,将整个肺在TRI试剂中匀浆,并按照生产商提供的说明书进行总RNA提取,伴随额外的DNA酶处理。样品的量和质量分别通过NanoDrop分光光度计和Agilent Bioanalyzer 2100确定(Zhang等人,Front Immunol 2019;10:2888)。
进行RNA文库的制备和测序。简言之,使用Agilent Bioanalyzer确定总RNA的量和质量。根据生产商的方案,至少300ng的总RNA被用作KAPA RNA HyperPrep Kit withRiboErase(HMR)的输入,以创建核糖体RNA耗尽的测序文库。测序在Illumina NextSeq 500上进行,每个样品产生~4000万单端75个碱基的读段。测序数据通过生物信息学流程(bioinformatics pipeline)进行处理,包括质量控制、与hg19人类参考基因组比对和基因定量。将计数数据输入edgeR软件进行差异表达分析。使用M值的截尾均值(trimmed meanof M-values,TMM)方法对计数进行归一化,以说明文库之间的组成差异,并以样品作为组块因子(blocking factor)使用广义线性模型进行配对差异表达分析。并且错误发现率p值(FDR)≤0.05的基因被认为统计学上有差异。
流式细胞术
在第14天处死小鼠,并用10ml的PBS灌注右心室,然后收获左肺用于病理学。
去除左肺组织的上半部分(无气管、主支气管和分支),并用PBS冲洗以清除血液。用剪刀将组织切碎并分散以增加总表面积。为了产生单细胞悬液,使用5ml塑料注射器的橡胶端使细胞过滤(mesh)通过100μm细胞过滤器,并且用冰冷的RPMI 1640连续冲洗细胞。将细胞悬浮液再次过滤通过70μm细胞过滤器,并用3ml含有DNA酶的洗涤缓冲液彻底冲洗,然后用15ml不含DNA酶的洗涤缓冲液彻底冲洗。样品在286×g和18℃离心5min,并弃去上清液(Posel等人J Vis Exp 2016:53658)。
将细胞(106个细胞/ml)重悬于100μl蛋白封闭溶液中,其中含有5μl荧光缀合抗体、CD8(Biolegend Cat#100714)、CD45(Biolegend Cat#103130)、CD68(Biolegend Cat#137004)、PD-1(Biolegend Cat#135219)、PD-L1(Biolegend Cat#124308)、CD4(BiolegendCat#100510)、CD11b(Biolegend Cat#101243)、CD11c(Biolegend Cat#117318)、F4/80(Biolegend Cat#123146)或IFNg(Biolegend Cat#505836)。样品在BD LSR II流式细胞仪上使用BD FACSDiva软件进行分析,并且数据分析使用Flowjo软件(TreeStar,Ashland,OR)进行。使用顺序门控策略(sequential gating strategy)鉴定细胞群体;激活标志物的表达以中值荧光强度呈现。基于FC标志物表达对肺免疫细胞进行分类,如先前描述的(Misharin等人,Am J Respir Cell Mol Biol 2013;49:503-510)。
实施例1
以下实施例展示了使用本公开的GHRH拮抗剂体内对结节病的治疗。
肺结节病的小鼠模型通过气管内施用微粒在C57Bl/6小鼠中建立。用小压舌板拉出舌头,并在喉部张开时将20G血管导管(angio-catheter tube)插入气管,并使该导管前进到主支气管直到达到受阻。放置管后,施用微粒:50μL中5×108CFU的脓肿分枝杆菌(M.abscessus)的第一剂量和3次20μL中2×108CFU的脓肿分枝杆菌的后续剂量。对照组气管内接受仅20μL PBS。接受微粒的小鼠的肺中发展出非干酪样肉芽肿(noncaseatinggranuloma),如使用H&E染色和CD68巨噬细胞标志物、CD4标志物和PD-L1的免疫组织化学染色观察到的。
建立了4组表现出肺结节病的小鼠,连同第5未处理组作为未表现出结节病的对照。第1结节病组接受MIA-602(5μg/天),经由腹膜内注射施用。第2结节病组接受α-黑素细胞刺激素(α-MSH),第3结节病组接受类固醇治疗(甲基泼尼松,目前用于结节病的一线治疗),并且第4组接受仅盐水。两周后处死小鼠,并对肺样品中的炎症进行分级。如图1A-1E所示,未治疗的结节病组的肺中表现出显著的炎症。用MIA-602和a-MSH治疗的结节病组具有较低的炎症评分。类固醇治疗不影响炎症。
以上描述的结果首次展示了生长激素释放激素受体拮抗剂(此处为MIA-602)在治疗结节病中是有效的。
实施例2
以下实施例展示了本公开内容的肽积极影响治疗的肉芽肿的细胞因子谱。
肉芽肿和PBMC采集自5名结节病受试者。将样品分组为对照(未攻击)、用微粒以10:1处理攻击但保持未治疗的肉芽肿组、用1μM MIA-602体外治疗的受攻击的肉芽肿组和用甲基泼尼松龙体外治疗的受攻击的肉芽肿组。治疗后48h去除培养基。细胞因子使用多重ELISA仪器测量。
与PBMC相比,肉芽肿中几种细胞因子的表达有显著差异。MIA-602显著降低肉芽肿中IL2、IL7、IL10、IL12、IL15、IL17A、CCL2、CCL5、IFNα和CXCL9的细胞因子产生。参见图2A-2T。
实施例3
检查了本公开的肽MIA-602影响肉芽肿细胞的呼吸作用和凋亡的能力。肉芽肿中凋亡和线粒体动力学的具体过程尚未被完全阐明。为了测试MIA-602是否具有促凋亡或抗凋亡作用,在体外肉芽肿模型中测量促凋亡因子(活性胱天蛋白酶-3)和抗凋亡因子(存活蛋白、Bcl-xL/Bak二聚体和Mcl-1/Bak二聚体)的蛋白水平。将来自5名确诊结节病受试者的PBMC分组为对照(未攻击)、用从脓肿分枝杆菌细胞壁产生的微粒以10∶1处理攻击的肉芽肿组、用1μM的MIA-602治疗的肉芽肿组和用甲基泼尼松龙(138μM)治疗的肉芽肿组。治疗后48h去除培养基。
如图3A所示,在各组之间存活蛋白水平没有显示出统计学差异。在未治疗的肉芽肿中,Mcl-1/Bak二聚体的水平显著降低,但用MIA-602治疗恢复(图3B)。与用盐水治疗的肉芽肿相比,用MIA-602治疗的肉芽肿中BclxL/Bak二聚体水平增加(图3C)。与PBMC相比,肉芽肿中活性胱天蛋白酶3水平显著增加,可能是由于淋巴细胞早期激活(Zhang C等人,SciRep 2020;10:7277)。MIA-602进一步增加了活性胱天蛋白酶3(图3D)。这些数据表明,用GHRHR拮抗剂治疗没有增加肉芽肿中的凋亡。
实施例4
建立小鼠肺肉芽肿模型用于研究暴露于脓肿分枝杆菌细胞壁后的I型IFN途径。由于该模型的非传染性肺肉芽肿模型的特点,其适于肺结节病研究。使用C57Bl/6小鼠建立模型(Zhang等人,Front Immunol 2019;10:2888)。
小鼠每天经由腹膜内注射5μg本公开内容的肽MIA-602进行治疗。两周后,处死小鼠,并且由肺病理学家对肺部炎症进行分级。肺样品用H&E、CD68、PD1、PD-L1和CD30染色,并根据表达每种标志物的细胞的百分比评分。
如图4所示,肉芽肿组在肺中具有显著的炎症,但用MIA-602治疗的小鼠具有较低的炎症评分。图4示出了小鼠肺肉芽肿反应中MIA-602治疗后GHRHR免疫荧光染色的定量。
肉芽肿组中肺的炎症评分显著更高。如图5A-5E中所示,接受MIA-602治疗的小鼠中肺部炎症几乎正常化。具有肉芽肿的肺中CD30细胞在统计学上显著增加,并且在MIA-602治疗的小鼠中有不显著的降低。肺中CD68+细胞的百分比在罹患肉芽肿的受试者中增加并且在MIA-602治疗的受试者中减少,但这些变化不是统计学上显著的。该模式可见于肉芽肿组和MIA-602治疗组中的PD-1+细胞和PD-L1+细胞。
本动物模型研究证实了结节病肺中GHRHR显著增加。MIA-602具有显著减少肺组织中的炎症细胞数量的抗炎特性。
实施例5
流式细胞术显示,在结节病小鼠模型中MIA-602治疗后CD68+细胞减少。将小鼠分组为对照,用微粒攻击并用盐水治疗,受攻击并用MIA-602(5μg)治疗,和受攻击并用甲基泼尼松龙(100μg)治疗。两周后,从所有组中收获肺,并产生肺单细胞用于流式细胞术分析。如图6A中所示,在受攻击的小鼠中CD45+CD68细胞的群体显著增加,并且该群体被MIA-602治疗显著降低。
假设MIA-602将恢复表达PD-1的CD68+细胞的数量。图6B显示,在肺中有肉芽肿反应的受攻击的小鼠中,表达PD-1的CD45+CD68+细胞的数量显著降低。在MIA-602治疗后,这些细胞的百分比显著增加。
为了证实具有肉芽肿的小鼠肺显示出表达PD-L1的CD45+CD68+的更高的百分比,在所有实验组中对肺单细胞染色。如图6C中所示,CD45+CD68+PD-L1细胞的群体在肉芽肿中显著增加,并且用MIA-602治疗后检测到更高的百分比。MIA-602的抗炎作用主要是通过降低CD68+细胞,并且PD-1和PD-L1在此过程中发挥作用。
实施例6
诱导型一氧化氮合酶(iNOS)产生一氧化氮,并且在肉芽肿发展中具有关键作用。在暴露于细菌脂多糖和IFNγ后,巨噬细胞中表达iNOS(Facchetti等人,Am J Pathol1999;154:145-152)。为了解MIA-602对一氧化氮响应的影响,iNOS和硝基酪氨酸(作为NO功能的指标)通过对微粒攻击(结节病模型)并每天注射盐水的小鼠肺、每天腹膜内注射MIA-602(5μg)的小鼠肺以及未受攻击且未接受MIA-602的对照组进行染色来检测。3周后收获肺组织,并对NOS2和硝基酪氨酸进行组织染色。如图7中所示,在结节病样肉芽肿中NOS2表达增加,并且然后在MIA-602治疗后降低。该发现不是统计学上显著的。
如图8中所示,在具有结节病样肉芽肿的小鼠的肺中,硝基酪氨酸表达统计学上显著地增加。用MIA-602治疗降低了硝基酪氨酸水平,但该降低不是统计学上显著的。
用微粒攻击在肺中激活了iNOS并且增加了硝基酪氨酸。在这些实验中,MIA-602降低了两者,但不是以统计学上显著的方式。这些实验表明了在结节病小鼠模型中MIA-602的抗亚硝基化作用。
实施例7
检查结节病小鼠模型中的转录组学变化。从用微粒攻击(结节病模型)并每天注射盐水或每天腹膜内注射MIA-602(5μg)治疗的小鼠的肺中提取RNA,或从从未受攻击且未接受MIA-602的对照组中提取RNA。在3周的过程中从肺组织分离RNA,并进行RNASeq。相比于用盐水治疗的具有肉芽肿的小鼠,每天用MIA-602治疗的具有肉芽肿的小鼠中778个基因上调并且293个基因下调(508个蛋白编码,或TEC基因,并且其余的为非编码基因)。图9提供了在用MIA-602治疗后表现出多于2.5倍差异表达的基因。在各方面,本公开内容提供了表征受试者对结节病治疗的响应的方法,其中该方法包括测量图9中列出的一个或更多个基因中的表达。在各方面,相比于治疗前的表达水平,2.5倍差异表达指示对治疗的治疗性响应(即,紊乱被治疗,紊乱的一种或更多种症状被缓解等)。
整个文件旨在作为统一的公开内容进行关联,并且应当理解,本文描述的特征的所有组合都被设想,即使特征的组合没有一起出现在本文件的同一句子、段落或部分中。此外,作为另外的方面,本发明包括比以上特别提到的变化以任何方式在范围上更窄的本发明的所有实施方案。关于用“一(a)”或“一(an)”描述或要求保护的本发明的方面,应当理解,这些术语意指“一个或更多个”,除非上下文明确要求更严格的含义。关于被描述为一个集合中的一个或更多个要素,应当理解,该集合内的所有组合都被设想。如果本发明的方面被描述为“包含/包括(comprising)”一个特征,则实施方案也被设想为“由该特征组成”或“基本上由该特征组成”。
尽管本申请人发明了在此所附的权利要求书的完整范围,但是在此所附的权利要求书并不旨在将其他人的现有技术工作包含在其范围内。因此,在权利要求范围内的法定现有技术被专利局或其他实体或个人提请本申请人注意的情况下,本申请人保留根据适用专利法行使修改权的权利,以重新定义这样的权利要求的主题,从而将这样的法定现有技术或法定现有技术的明显变化明确排除在这样的权利要求的范围之外。由这样的修改的权利要求限定的本发明的变化也旨在作为本发明的方面。根据本申请的整体,本发明的另外的特征和变化对于本领域技术人员将是明显的,并且所有这样的特征都旨在作为本发明的方面。
本说明书中引用的所有出版物、专利和专利申请通过引用并入本文,如同每个单独出版物或专利申请被具体和单独地指明通过引用并入。虽然为了清楚理解的目的通过说明和实例的方式相当详细地描述了以上发明,但对本领域普通技术人员将容易地明显的是,根据本发明的教导,可以对其进行某些改变和修改,而不偏离所附权利要求书的精神或范围。
序列表
<110> 迈阿密大学
<120> 用于治疗结节病的方法
<130> 32286/54402A/PC
<150> US 62/875,703
<151> 2019-07-18
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 29
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> MISC_FEATURE
<223> hGHRH (1-29)HN2
<400> 1
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 2
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是PhAc(苯基乙酰基)、Nac(萘基乙酰基)、Oct(辛酰基)、N-Me-Aib(N-甲基-α-氨基异丁酰基)、Dca(二氯乙酰基)、Ac-Ada(乙酰基-12-氨基十二烷酰基)、Fer(阿魏酰基)、Ac-Amc(乙酰基-8-氨基辛酰基)、Me-NH-Sub(甲基-NH-软木酰基)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa是Ala或Me-Ala
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是Cpa(对氯苯丙氨酸)或Phe(F)
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa是Ala、Pal(吡啶基丙氨酸)、Dip((3,3-二苯基)丙氨酸)或Me-Ala
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是FPa5、Tyr(Alk),其中Alk是Me或Et
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是His或Arg
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa是Lys、Lys(0-11)(Lys(A0-A1-A2-A3-A4-A5-A6-A7-A8-A9
A10-A11-)、Lys(Me)2或Orn(鸟氨酸)
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa是Abu(α-氨基丁酸)或Orn
<220>
<221> MISC_FEATURE
<222> (18)..(18)
<223> Xaa是Leu或Glu
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa是Har(高精氨酸)或His
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> Xaa是Lys、Lys(Me)2或Orn
<220>
<221> MISC_FEATURE
<222> (28)..(28)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是Har、Arg或Agm(鲱精胺)
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Ala、Amc、Apa、Ada、AE2A、AE4P、E-Lys(α-NH2)、Agm或不存在
<220>
<221> MISC_FEATURE
<222> (32)..(32)
<223> Xaa是Lys(Oct)、Ahx (6-氨基己酰基)或不存在
<220>
<221> MOD_RES
<222> (32)..(32)
<223> 酰胺化
<400> 2
Xaa Tyr Xaa Asp Xaa Ile Xaa Thr Xaa Xaa Xaa Xaa Xaa Val Leu Xaa
1 5 10 15
Gln Xaa Ser Ala Xaa Xaa Leu Leu Gln Asp Ile Xaa Xaa Xaa Xaa Xaa
20 25 30
<210> 3
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是Phac
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa是Ada
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是Phe(F)5
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是Tyr(Me)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa是Abu
<220>
<221> MISC_FEATURE
<222> (23)..(23)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (32)..(32)
<223> Xaa是Agm
<220>
<221> MOD_RES
<222> (32)..(32)
<223> 酰胺化
<400> 3
Xaa Xaa Tyr Xaa Asp Ala Ile Xaa Thr Ala Xaa Xaa His Xaa Val Leu
1 5 10 15
Xaa Gln Leu Ser Ala His Xaa Leu Leu Gln Asp Ile Xaa Xaa Xaa Xaa
20 25 30
<210> 4
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是Phac
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa是Ada
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是Phe(F)5
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa是Thr(Me)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是Tyr(Me)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa是Abu
<220>
<221> MISC_FEATURE
<222> (23)..(23)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (32)..(32)
<223> Xaa是Agm
<220>
<221> MOD_RES
<222> (32)..(32)
<223> 酰胺化
<400> 4
Xaa Xaa Tyr Xaa Asp Ala Ile Xaa Xaa Ala Xaa Xaa His Xaa Val Leu
1 5 10 15
Xaa Gln Leu Ser Ala His Xaa Leu Leu Gln Asp Ile Xaa Xaa Xaa Xaa
20 25 30
<210> 5
<211> 31
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是Phac
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa是D-Ala
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是Cpa
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是Fpa
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa是Abu
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (28)..(28)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Ada
<220>
<221> MOD_RES
<222> (31)..(31)
<223> 酰胺化
<400> 5
Xaa Tyr Xaa Asp Ala Ile Xaa Thr Ala Xaa Xaa His Xaa Val Leu Xaa
1 5 10 15
Gln Leu Ser Ala His Xaa Leu Leu Gly Ala Ile Xaa Xaa Xaa Xaa
20 25 30
<210> 6
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是Phac
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa是Ada
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是Cpa
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是Fpa
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa是Abu
<220>
<221> MISC_FEATURE
<222> (23)..(23)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (32)..(32)
<223> Xaa是Ada
<220>
<221> MISC_FEATURE
<222> (32)..(32)
<223> C-末端NH2
<220>
<221> MOD_RES
<222> (32)..(32)
<223> 酰胺化
<400> 6
Xaa Xaa Tyr Xaa Asp Ala Ile Xaa Thr Ala Xaa Xaa His Xaa Val Leu
1 5 10 15
Xaa Gln Gln Ser Ala His Xaa Leu Leu Gln Asp Ile Xaa Xaa Xaa Xaa
20 25 30
<210> 7
<211> 31
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是Phac
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa是Ada
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是Cpa
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是Fpa
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa是Abu
<220>
<221> MISC_FEATURE
<222> (23)..(23)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Har
<220>
<221> MOD_RES
<222> (31)..(31)
<223> 酰胺化
<400> 7
Xaa Xaa Tyr Xaa Asp Ala Ile Xaa Thr Ala Xaa Xaa His Xaa Val Leu
1 5 10 15
Xaa Gln Leu Ser Ala His Xaa Leu Leu Gln Asp Ile Xaa Xaa Xaa
20 25 30
<210> 8
<211> 31
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是PhAc
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa是Ada
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是D-ARg
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是Fpa
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是Har
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是Tyr(Me)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa是Abu
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> Xaa是Orn
<220>
<221> MISC_FEATURE
<222> (29)..(29)
<223> Xaa是Nle
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa是D-Arg
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa是Har
<400> 8
Xaa Xaa Tyr Xaa Asp Ala Ile Xaa Thr Ala Xaa Xaa His Xaa Val Leu
1 5 10 15
Xaa Gln Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Xaa Xaa Xaa
20 25 30
Claims (16)
1.一种治疗结节病的方法,所述方法包括向有相应需要的哺乳动物受试者施用GHRH拮抗剂。
2.根据权利要求1所述的方法,其中GHRH拮抗剂包含氨基酸序列(式I/SEQ ID NO:2):R1-Tyr1-D-Arg2-Asp3-A4-Ile5-A6-Thr7-A8-Har9-A10-A11-A12-Val13-Leu14-A15-Gln16-A17-Ser18-Ala19-A20-A21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-D-Arg28-A29-R2-R3-NH2,
其中R1是PhAc(苯基乙酰基)、Nac(萘基乙酰基)、Oct(辛酰基)、N-Me-Aib(N-甲基-α-氨基异丁酰基)、Dca(二氯乙酰基)、Ac-Ada(乙酰基-12-氨基十二烷酰基)、Fer(阿魏酰基)、Ac-Amc(乙酰基-8-氨基辛酰基)、Me-NH-Sub(甲基-NH-软木酰基)、PhAc-Ada(苯基乙酰基12-氨基十二烷酰基)、Ac-Ada-D-Phe、Ac-Ada-Phe、Dca-Ada(二氯乙酰基-12-氨基十二烷酰基)、Nac(萘基乙酰基)、Nac-Ada、Ada-Ada或CH3(CH2)10-CO-Ada;
A4是Ala或Me-Ala;
A6是Cpa(对氯苯丙氨酸)或Phe(F)5;
A8是Ala、Pal(吡啶基丙氨酸)、Dip((3,3-二苯基)丙氨酸)或Me-Ala;
A10是Fpa5、Tyr(Alk),其中Alk是Me或Et;
A11是His或Arg;A12是Lys、Lys(0-11)(Lys(A0-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-)、Lys(Me)2或Orn(鸟氨酸);
A15是Abu(α-氨基丁酸)或Orn;
A17为Leu或Glu;
A20是Har(高精氨酸)或His;
A21是Lys、Lys(Me)2或Orn;
A29是Har、Arg或Agm(鲱精胺);
R2是β-Ala、Amc(8-氨基辛酰基)、Apa(5-氨基戊酰基)、Ada(12-氨基十二烷酰基)、AE2A(8-氨基-3,6-二氧杂辛酰基)、AE4P(15-氨基-4,7,10,13-四氧杂十五烷酰基)、ε-Lys(α-NH2)(Lys残基,其8-氨基基团被位于N-末端的氨基酸的羰基基团酰化;Lys残基的α-氨基基团是游离的)、Agm(鲱精胺)或不存在;并且
R3是Lys(Oct)、Ahx(6-氨基己酰基)或不存在。
3.根据权利要求1所述的方法,其中所述GHRH拮抗剂是MIA-602、MIA-604、MIA-606、MIA-610、MIA-640或MIA-690。
4.根据权利要求1所述的方法,其中所述GHRH拮抗剂是MIA-602。
5.根据权利要求1所述的方法,其中所述GHRH拮抗剂经由皮内、肌肉内、腹膜内、静脉内、动脉内、皮下、硬膜外、舌下、鼻内、脑内、室内、鞘内、阴道内、经皮、直肠、吸入、肺内、气道内、支气管内、气管内或表面递送施用。
6.根据权利要求5所述的方法,其中所述GHRH拮抗剂经由鼻内、吸入、肺内、气道内、支气管内或气管内递送施用。
7.根据权利要求3所述的方法,其中所述GHRH拮抗剂经由皮内、肌肉内、腹膜内、静脉内、动脉内、皮下、硬膜外、舌下、鼻内、脑内、室内、鞘内、阴道内、经皮、直肠、吸入、肺内、气道内、支气管内、气管内或表面递送施用。
8.根据权利要求7所述的方法,其中所述GHRH拮抗剂经由鼻内、吸入、肺内、气道内、支气管内或气管内递送施用。
9.根据权利要求4所述的方法,其中所述GHRH拮抗剂经由皮内、肌肉内、腹膜内、静脉内、动脉内、皮下、硬膜外、舌下、鼻内、脑内、室内、鞘内、阴道内、经皮、直肠、吸入、肺内、气道内、支气管内、气管内或表面递送施用。
10.根据权利要求9所述的方法,其中所述GHRH拮抗剂经由鼻内、吸入、肺内、气道内、支气管内或气管内递送施用。
11.根据权利要求1所述的方法,其中所述结节病是肺结节病。
12.根据权利要求3所述的方法,其中所述结节病是肺结节病。
13.根据权利要求4所述的方法,其中所述结节病是肺结节病。
14.根据权利要求6所述的方法,其中所述结节病是肺结节病。
15.根据权利要求8所述的方法,其中所述结节病是肺结节病。
16.根据权利要求10所述的方法,其中所述结节病是肺结节病。
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CN1326353A (zh) * | 1998-11-16 | 2001-12-12 | 赞塔里斯股份公司 | 通过给予生长激素释放化合物或其拮抗剂来治疗肿瘤 |
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CN1326353A (zh) * | 1998-11-16 | 2001-12-12 | 赞塔里斯股份公司 | 通过给予生长激素释放化合物或其拮抗剂来治疗肿瘤 |
CN102170864A (zh) * | 2008-08-07 | 2011-08-31 | 帕尔马根治疗(炎症)有限公司 | 呼吸道疾病的治疗 |
WO2019060601A1 (en) * | 2017-09-21 | 2019-03-28 | University Of Miami | METHOD OF TREATING MYELOID LEUKEMIA |
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