CN108883150A - 具有抗血管生成、抗淋巴管生成以及消水肿性质的肽和纳米粒子制剂 - Google Patents
具有抗血管生成、抗淋巴管生成以及消水肿性质的肽和纳米粒子制剂 Download PDFInfo
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Abstract
在各个方面和实施方案中,本发明涉及从IV型胶原的α5原纤维衍生的肽的药物组合物以及其用于医学治疗的用途。所述肽靶向α5β1和αvβ3整联蛋白,并通过多种受体抑制信号传导,并且可用于抑制血管通透性、血管生成、淋巴血管生成。
Description
优先权
本申请要求2015年11月19日提交的美国临时申请案号62/257,569的权益和优先权,其全部内容通过引用并入本文。
发明背景
已经描述了从IV型胶原衍生的肽抑制血管生成和淋巴血管生成的潜能。从IV型胶原的α5原纤维的非胶原结构域的衍生肽基序描述于美国专利9,056,923中,其全部内容通过引用并入本文。举例来说,包含基序NINNV的肽被描述为抑制人类脐静脉内皮细胞(HUVEC)的增殖、迁移和小管形成。Rosca等人,Structure-activity relationship study of collagen derived anti-angiogenic biomimetic peptides,Chem.Biol.Drug Des.80(1):27-37(2012)。
需要更好地了解这些肽的生物靶标、生物活性和医药性质,以支持和/或指导医药用途和产品研发。
发明概要
在各个方面和实施方案中,本发明涉及源自IV型胶原的α5原纤维的肽的药物组合物以及其用于医学治疗的用途。实例性肽包含氨基酸序列LRRFSTAPFAFIDINDVINF(SEQ IDNO:2)、LRRFSTAPFAFININNVINF(SEQ ID NO:3)、LRRFSTAPFAFIDINDVINW(SEQ ID NO:4)、FTNINNVTN(SEQ ID NO:5)或FTDINDVTN(SEQ ID NO:6),或上述中的任一种的衍生物(包括本文所述的各种衍生物)的氨基酸序列。肽靶向α5β1和αVβ3整联蛋白,并通过多种受体抑制信号传导,所述受体包括血管内皮生长因子受体(VEGFR)、肝细胞生长因子受体(HGFR)、胰岛素样生长因子受体(IGFR)和血小板源生长因子受体(PDGFR)。
在一些方面中,本发明提供治疗或预防微血管渗漏或通透性的方法,其包括向需要治疗的患者施用有效量的的肽试剂。微血管渗漏所参与或可加剧病状的病况尤其包括流行性感冒(flu)、阿兹海默氏病(Alzheimer’s disease)、神经病状(例如,多发性硬化)、出血热、脑型疟疾、黄斑变性、黄斑水肿(例如,糖尿病黄斑水肿)、视网膜静脉闭塞(RVO)、糖尿病视网膜病变、湿性AMD、急性呼吸窘迫综合症、肺水肿、气喘、COPD、呼吸道融合病毒、SARS、肺炎、与组织或器官移植相关的微血管渗漏和血管通透性。
在其他方面中,本发明提供治疗癌症并特别是用于改善检查点抑制剂疗法的方法。具体来说,这些实施方案中的方法通过抑制血管生成并使树突细胞成熟和更稳健的淋巴细胞内皮运输来改善免疫检查点抑制剂疗法。所述方法包括向经历免疫检查点抑制剂疗法的癌症患者施用有效量的肽。肽或药物组合物可与免疫检查点抑制剂疗法一起(或在其期间)施用。或者,患者可以用肽治疗一至四周,然后进行免疫检查点抑制剂疗法。
肽可以配制用于全身递送或局部递送,并且在一些实施方案中,肽与聚合纳米粒子或微粒载体配制在一起。在一些实施方案中,本发明提供包含PLGA-PEG共聚物和靶向整联蛋白的缀合肽(例如SEQ ID NO:1到6中的任一种的肽或其衍生物和/或组合)的纳米粒子。在一些实施方案中,纳米粒子是由与肽或如上所述其他结合剂共价连接的可调谐大小的聚(乳酸-共-乙醇酸)聚乙二醇(PLGA-PEG)嵌段共聚物合成。可以使用任何比率的缀合和非缀合聚合物的混合物来产生在表面上具有所需密度的靶向剂的纳米粒子。可对粒子进行设计以提供所需的药效学优点,包括循环性质、生物分布和降解动力学。这些参数尤其包括大小、形状、表面电荷、聚合物组成、配体缀合化学、肽缀合密度。
在一些实施方案中,纳米粒子进一步包含封装的活性剂,其可为本文公开的用于治疗特征在于微血管渗漏的病况(包括流感、阿兹海默氏病、出血热、脑型疟疾、癌症、黄斑变性或黄斑水肿、器官或组织移植和本文所述的其他病况)的活性剂。在一些实施方案中,封装的试剂是本文所述的肽。尽管在一些实施方案中纳米粒子是基本上球形的,但纳米粒子可以任选地为非球形以影响其与细胞、特别是与免疫系统的细胞的相互作用,以避免清除。
在一些实施方案中,粒子是封装药物货物(例如本文所述的肽和/或其他药剂)的微粒。粒子可含有或可不含有与表面缀合肽。在这些实施方案中,粒子可以提供长效药物贮积,以提供肽的持续释放。
从以下详细描述将明了本发明的其他方面和优点。
附图简述
图1显示P07抑制微血管内皮细胞中的VEGF、HGF和IGF信号传导。
图2显示P07抑制小鼠模型中由过量血管渗漏引起的视网膜脱落。
图3显示P07抑制兔眼中VEGF诱导的渗漏模型中的血管渗漏。与未处理的比较渗漏,其设定为1.0。
图4显示P07以剂量依赖性方式抑制正位三阴性乳腺癌(TBNC)异种移植物的生长。
图5显示P07抑制正位TNBC异种移植物中的新血管形成。
图6显示P08缀合的HPLC结果,其表明P08有效地缀合至PLGA-PEG-NHS共聚物并通过反相HPLC定量。
图7显示N07展现大约70-80nm的Z-平均直径。在纳米粒子上具有缀合的P07的样品中可见大小略微增大。
图8显示N07在离子水中展现负的ζ电势,使用PEG上的不同端基可在-25mV附近轻微调谐。中性是甲氧基封端的PEG。负性是羧基封端的PEG。
图9显示粒子与整联蛋白αvβ3和α5β1结合。
图10显示与各种肽竞争的粒子与整联蛋白αvβ3的结合。
图11显示N07粒子与MDA-MB-231和MEC细胞结合。
图12显示测量细胞对用N07预处理的板的粘附的粘附抑制测定结果。%是指具有缀合的P07的PLGA-PEG分子的量。“+”或“-”是指存在或不存在封装的P07。
图13显示N07对MEC细胞增殖的抑制效应。%是指具有缀合的P07的PLGA-PEG分子的量。“+”或“-”是指存在或不存在封装的P07。
图14显示测量细胞对用P07预处理的板的粘附的粘附测定结果。
图15显示使用双重乳化技术用85/15PLGA和P07(也称为M07)制得的微粒(MP)。用SEM对冻干的样品进行成像。(A)0%负载;(B)以重量计0.6%的最终肽负载;(C)1%最终负载。显示的规模是10μM。
图16显示M07,拉伸2.25倍。用SEM对冻干的样品进行成像。(A)空白MP;(B)M07;(C)放大的空白MP;(D)放大的M07。
图17显示未拉伸(左图)或拉伸2倍(右图)的肽负载的NP的TEM图像。
图18显示拉伸的MP中P07负载的凝胶量化。使用银染色和肽标准进行量化。最终P07w/w比率为约1%,这与约1%的拉伸前P07w/w比率相当。
图19显示负载有P07的65/35PLGA微粒中P07的释放。误差杠代表标准偏差。
发明详述
在各个方面和实施方案中,本发明涉及源自IV型胶原的α5原纤维的肽的药物组合物以及其用于医学治疗的用途。实例性肽包含氨基酸序列LRRFSTAPFAFIDINDVINF(SEQ IDNO:2)、LRRFSTAPFAFININNVINF(SEQ ID NO:3)、LRRFSTAPFAFIDINDVINW(SEQ ID NO:4)、FTNINNVTN(SEQ ID NO:5)或FTDINDVTN(SEQ ID NO:6),或上述中的任一种的衍生物的氨基酸序列。本文公开各种衍生物。肽靶向α5β1和αVβ3整联蛋白,并通过多种受体抑制信号传导,所述受体包括血管内皮生长因子受体(VEGFR)、肝细胞生长因子受体(HGFR)、胰岛素样生长因子受体(IGFR)和血小板源生长因子受体(PDGFR)。
靶向整联蛋白的肽包括US 9,056,923中描述的那些,其全部内容通过引用并入本文。举例来说,根据以下公开,肽包括包含氨基酸序列LRRFSTXPXXXXNINNVXNF(SEQ ID NO:1)的肽,其中X是标准氨基酸或非遗传编码的氨基酸。在一些实施方案中,7位的X是M、A或G;9位的X是F、A、Y或G;10位的X是M、A、G、dA或Nle:11位的X是F、A、Y、G或4-ClPhe;12位和18位的X独立地选自Abu、G、S、A、V、T、I、L或烯丙基-Gly。在各个实施方案中,肽含有约30个或更少氨基酸,或约25个或更少氨基酸,或约24个氨基酸,或约23个氨基酸,或约22个氨基酸,或约21个氨基酸,或约20个氨基酸。在其他实施方案中,缺失1到10个氨基酸,例如1个、2个或3个SEQ ID NO:1的氨基酸。举例来说,在一些实施方案中,从N-末端缺失氨基酸。
在一些实施方案中,肽包含氨基酸序列LRRFSTAPFAFIDINDVINF(SEQ ID NO:2),或LRRFSTAPFAFININNVINF(SEQ ID NO:3),或LRRFSTAPFAFIDINDVINW(SEQ ID NO:4),或FTNINNVTN(SEQ ID NO:5),或FTDINDVTN(SEQ ID NO:6),或上述中的任一种的衍生物的氨基酸序列。SEQ ID NO:2的肽在本文中还称为P07。SEQ ID NO:3的肽在本文中还称为P06。SEQ ID NO:4的肽在本文中还称为P08。SEQ ID NO:5的肽在本文中还称为P05。SEQ ID NO:6的肽在本文中还称为P09。SEQ ID NO:2(与SEQ ID NO:1相比)的肽在13和16位具有天冬氨酸,其改善肽的物理性质而不会不利地影响生物活性。SEQ ID NO:2到4的肽的衍生物包括相对于SEQ ID NO:2、3或4具有1到5个氨基酸取代、插入或缺失(例如,统共1、2、3、4或5个氨基酸取代、插入或缺失)的肽。在一些实施方案中,维持SEQ ID NO:2的13和16位的Asp。在一些实施方案中,衍生物中维持序列DINDV或NINNV。氨基酸取代可以任选地在SEQ ID NO:1的相应位置上的X占据的位置。肽通常具有至少8个氨基酸。SEQ ID NO:5或6的肽的衍生物包括包含相对于SEQ ID NO:5或6的序列具有1、2或3个氨基酸取代的肽。在一些实施方案中,氨基酸取代独立地选自保守或非保守取代。在这些或其他实施方案中,肽包括添加到一个或两个末端的1到10个氨基酸(统共)。N-和/或C-末端可以任选地由另一个化学基团(胺或羧基,例如酰胺或硫醇除外)占据,并且可用于缀合其他部分,包括PEG或PLGA-PEG共聚物,如本文进一步详细描述。在一些实施方案中,肽可以药学上可接受的盐的形式提供,或者与其他组分复合或封装在粒子中用于靶向或持续递送到特定组织。
保守取代可基于(例如)所涉及的氨基酸残基在以下方面中的相似性来进行:极性、电荷、大小、溶解度、疏水性、亲水性和/或两亲性特性。20个遗传编码的氨基酸可以分成以下六个标准氨基酸组:
(1)疏水性:Met、Ala、Val、Leu、Ile;
(2)中性亲水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)碱性:His、Lys、Arg;
(5)影响链取向的残基:Gly、Pro;以及
(6)芳香族:Trp、Tyr、Phe。
如本文所用的“保守取代”定义为氨基酸与上文所示六个标准氨基酸组的同一组中列出的另一种氨基酸交换。举例来说,Asp由Glu交换在如此修饰的多肽中保留了一个负电荷。另外,甘氨酸和脯氨酸可以基于其破坏α-螺旋的能力而相互取代。上述六个组中的一些优选的保守取代是以下亚组中内交换:(i)Ala、Val、Leu和Ile;(ii)Ser和Thr;(ii)Asn和Gln;(iv)Lys和Arg;以及(V)Tyr和Phe。
如本文所用的“非保守取代”定义为氨基酸与上文所示六个标准氨基酸组(1)到(6)的不同组中列出的另一种氨基酸交换。
在各个实施方案中,肽试剂是约8到约30个氨基酸或约10到约20个氨基酸的肽,并且具有至少4个、至少5个或至少6个SEQ ID NO:2、3、4、5或6的邻接氨基酸。在一些实施方案中,肽含有至少1个、至少2个或至少3个D-氨基酸。在一些实施方案中,肽含有1到约5个(例如1、2或3个)非遗传编码的氨基酸,其任选地选自2-氨基丁酸(Abu)、正亮氨酸(Nle)、4-氯苯丙氨酸(4-ClPhe)和烯丙基甘氨酸(烯丙基Gly)。
实例性肽试剂,其可以是根据本公开的SEQ ID NO:2到6的肽的衍生物,其包括:
LRRFSTMPFMF(Abu)NINNV(Abu)NF(SEQ ID NO:7),
LRRFSTMPAMF(Abu)NINNV(Abu)NF(SEQ ID NO:8),
LRRFSTMPFAF(Abu)NINNV(Abu)NF(SEQ ID NO:9),
LRRFSTMPFMA(Abu)NINNV(Abu)NF(SEQ ID NO:10),
LRRFSTMPF(Nle)F(Abu)NINNV(Abu)NF(SEQ ID NO:11),
LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:12),
LRRFSTMPFMFSNINNVSNF(SEQ ID NO:13),
LRRFSTMPFMFANINNVANF(SEQ ID NO:14),
LRRFSTMPFMFININNVINF(SEQ ID NO:15),
LRRFSTMPFMFTNINNVTNF(SEQ ID NO:16),
LRRFSTMPFMF(AllyGly)NINNV(AllyGly)NF(SEQ ID NO:17),
LRRFSTMPFMFVNINNVVNF(SEQ ID NO:18),
LRRFSTMPFdAFININNVINF(SEQ ID NO:19),
LRRFSTMPFAFININNVINF(SEQ ID NO:20),
LRRFSTAPFAFININNVINF(SEQ ID NO:21),
LRRFSTAPFdAFIDINDVINF(SEQ ID NO:22),
F(Abu)NINNV(Abu)N(SEQ ID NO:23),
FTNINNVTN(SEQ ID NO:24),
FININNVINF(SEQ ID NO:25),
FSNINNVSNF(SEQ ID NO:26),
FANINNVANF(SEQ ID NO:27),
F(AllyGly)NINNV(AllyGly)NF(SEQ ID NO:28),
FVNINNVVNF(SEQ ID NO:29),
A(Abu)NINNV(Abu)NF(SEQ ID NO:30),或
(4-ClPhe)(Abu)NINNV(Abu)NF(SEQ ID NO:31)。
在本文所述的各个方面和实施方案中,肽可以以缀合到表面或封装的纳米粒子和微粒制剂的形式递送。本文中详细描述基于PLGA-PEG聚合物的实例性粒子制剂。
肽试剂可以使用熟知的技术(例如固相合成)化学合成和纯化。参见US 9,051,349,其全部内容通过引用并入本文。
本文所述肽靶向α5β1和αVβ3整联蛋白,并通过多种受体抑制信号传导,所述受体包括血管内皮生长因子受体(VEGFR)、肝细胞生长因子受体(HGFR)、胰岛素样生长因子受体(IGFR)和血小板源生长因子受体(PDGFR)。整联蛋白是作为细胞-细胞与细胞-细胞外基质(ECM)相互作用的桥梁的跨膜受体。自整联蛋白的信号转导影响ECM的化学组成和机械状态,ECM控制许多生物反应,例如调控细胞周期、细胞形状和/或运动性;或者将新受体添加到细胞膜。这可以在细胞表面快速而灵活地对事件作出反应。存在几种类型的整联蛋白,并且细胞在其表面上可能有几种类型。整联蛋白与其他受体(例如钙粘蛋白(即免疫球蛋白超家族细胞粘着分子)、选择蛋白和多配体聚糖)一起工作,以介导细胞-细胞和细胞-基质相互作用。整联蛋白的配体包括纤连蛋白、玻连蛋白、胶原和层粘蛋白。
在一些方面中,本发明提供治疗或预防微血管渗漏或通透性的方法,其包括向需要治疗的患者施用有效量的如所描述的具有SEQ ID NO:1到6中的任一种的氨基酸序列或其衍生物和/或组合的肽。通常呈毛细血管通透性或微血管通透性的形式的血管通透性特征在于血管壁允许小分子(离子、水、营养物质)或甚至全细胞进入和离开血管的能力。血管壁内衬有单层内皮细胞。根据组织的类型和生理状态,严格控制内皮细胞之间的间隙(称为紧密结点)。血管通透性增加可导致水肿,一种特征在于在身体空腔或组织中积聚过多流体的病况。
微血管内皮对炎症和其他刺激有反应,这可在许多医学病症的病状中起关键作用。血管通透性的潜在介质(包括可溶性因子和细胞受体)以及其潜在作用和相互作用是复杂的,并且可以取决于组织和特定病状。举例来说,微血管渗漏尤其可在流行性感冒(流感)、阿兹海默氏病、出血热、脑型疟疾、黄斑变性、黄斑水肿、视网膜静脉闭塞、糖尿病视网膜病变、急性呼吸窘迫综合症、肺水肿、气喘、COPD、呼吸道融合病毒、SARS、肺炎或与器官或组织移植相关的血管通透性或癌症中起作用。本文所述肽可通过经由参与微血管通透性的多种受体抑制信号传导有助于治疗这些病况,所述多种受体包括血管内皮生长因子受体(VEGFR)、肝细胞生长因子受体(HGFR)、胰岛素样生长因子受体(IGFR)和血小板源生长因子受体(PDGFR)。参见图1。
在一些实施方案中,本文所述肽或组合物局部施用于肺、皮肤或眼睛,以防止或减少微血管渗漏或通透性。
在一些实施方案中,患者患有流感或处于流感风险之中。流行性感冒(“流感”)是由流行性感冒病毒引起的传染病。症状包括高烧、流鼻涕、咽喉痛、肌肉疼痛、头痛、咳嗽和疲劳。这些症状通常在暴露于病毒后两天开始。感染可以通过测试喉咙、痰或鼻子是否存在病毒来确认。世界卫生组织向高危人群推荐针对流行性感冒的每年疫苗接种,并且疫苗通常对三种或四种流行性感冒有效。抗病毒药物(例如神经氨酸酶抑制剂(例如,奥司他韦(oseltamivir)等))已用于治疗流行性感冒,尽管其显示出适度的益处,但其必须在感染早期(例如,出现症状立即)使用以提供益处。大约33%患有流行性感冒的人无症状。流感性感冒的症状可在感染后一到两天左右十分突然地开始。通常最早的症状是寒战或寒冷的感觉,但发烧在感染早期也很常见。抗病毒治疗尽管有时提供适度的益处,但存在病毒抗性的风险,这在强效大流行株中会特别成问题。
治疗病毒的有吸引力的替代方法是治疗宿主反应,此不太可能导致耐药性,并且可以提供更大的效能窗口以允许治疗更晚期的疾病。宿主的主要反应之一是炎症反应,其导致肺微血管渗漏和肺损伤,有时导致呼吸衰竭。抑制微血管渗漏的消水肿剂可改善流感的症状。
在一些实施方案中,在流感症状出现之前首先施用肽或包含其的药物组合物。举例来说,患者可能会使用检测患者样品中存在病毒的实验室测试被诊断为患有流感,或患者在接触病毒后处于流感风险之中。暴露可以通过与受感染和/或有症状的个体密切接触来确定。
在其他实施方案中,在出现最早的流感症状后首先施用肽或药物组合物。在一些实施方案中,肽或药物组合物在第一次流感症状出现后1到4天(例如1或2天)内施用。
根据本发明的这个方面,肽降低与流行性感冒病毒相关的肺水肿,从而改善病况的症状和/或严重程度。在一些实施方案中,疾病的总长度可以减少一天、两天、三天、四天或更多天,和/或可显著减轻严重程度和不适。
对于患有流感或处于流感风险之中的患者的治疗,本文所述肽或药物组合物可以每日施用约1次到约5次,例如每日约1次到约3次。在一些实施方案中,肽或药物组合物局部施用于肺,例如通过粉末或溶液气雾剂,或在其他实施方案中全身性施用。
在一些实施方案中,肽与一种或多种针对流感性感冒有活性的抗病毒剂一起施用,或者与一种或多种消炎剂作为单独的药物制剂或作为共配制的产品一起施用。实例性抗病毒剂包括Tamiflu(磷酸奥司他韦)、Relenza(扎那米韦(zanamivir))、Rapivab(帕拉米韦(peramivir))、金刚烷胺(amantadine)和金刚乙胺(rimantadine)。消炎剂包括NSAID,例如阿斯匹林(aspirin)、布洛芬(ibuprofren)、乙酰氨酚(acetaminophen)和萘普生(naproxen)。
在其他实施方案中,肽或药物组合物施用以治疗阿兹海默氏病或减缓其进展。血脑屏障(BBB)限制血源产品、病原体和细胞进入大脑,此对于正常神经元功能和信息处理是必需的。死后组织分析指示阿兹海默氏病中BBB损害。然而,BBB破坏的时间仍然难以捉摸。具有高空间和时间分辨率以量化活的人类大脑中的区域BBB通透性的高级动态对比增强的MRI在海马体中显示年龄依赖性的BBB破坏,海马体是对学习和记忆至关重要并在AD中早期受到影响的区域。这些数据表明,BBB破坏是老年人类大脑中的早期事件,其在海马体中开始,并可能促使认知损害。因此,抑制血脑损害和所产生的增加的通透性的药剂可以减缓阿兹海默氏病的进展。在一些实施方案中,施用本发明所述的肽或组合物可维持血脑屏障的完整性,从而减缓或防止阿兹海默氏病的发作或进展。
在一些实施方案中,患者正在经历至少一种用于治疗阿兹海默氏病的额外药剂的治疗,所述药剂可选自乙酰基胆碱酯酶抑制剂(塔克宁(tacrine)、利凡斯的明(rivastigmine)、加兰他敏(galantamine)和多奈派齐(donepezil))或美金刚(memantine)。
对于显示阿兹海默氏病、特别是早期疾病的潜在症状的患者的治疗,本文所述的肽或药物组合物可以每日施用约1次到约5次,例如每日约1次到约3次,以减缓疾病的发作或进展。早期疾病通常可以观察为对学习和记忆的损害越来越严重,其最终导致明确的诊断。在一些情况下,语言、执行功能、感知(失认)或动作执行(失用)困难比记忆问题更为突出。语言问题的特征在于词汇量减少和语言流畅性下降,从而导致口头和书面语言整体贫乏。
在一些实施方案中,将肽或药物组合物施用于患有早期阿兹海默氏病的患者或处于发生阿兹海默氏病风险之中的患者(遗传倾向性,或对一个或多个与AD相关的生物标记呈阳性),其中肽疗法正规化大脑中的循环以减缓或预防疾病进展。
在一些实施方案中,患者具有与血管生成失调或血管渗漏相关的神经病状,例如多发性硬化(MS)或帕金森氏病(Parkinson’s Disease,PD)。在一些实施方案中,肽或药物组合物每日施用1次到3次以预防或延缓疾病进展或改善疾病症状。
在其他实施方案中,患者患有出血热或综合症或处于其风险之中,其是由出血性病毒引起的。这些病毒中最臭名昭著者是埃博拉(Ebola)病毒和马尔堡(Marburg)病毒。患有登革热(Dengue fever)或拉沙热(Lassa fever)的人中也出现出血。在埃博拉中,这种出血性综合症出现在疾病的稍晚时候,通常死亡前24到48小时。出血的病例可为剧烈的,并可发生在鼻子、嘴巴和身体的其他孔口。导致出血的机制以广泛概要已知:病毒引起由肝产生的凝血因子的上调,凝血因子的数量增加导致在小血管中形成凝块,由于肝受病毒攻击而耗尽由肝产生的凝血因子的供应,超激活免疫系统增加了导致血管开始出血的炎性蛋白质的产生,凝血因子的不可用意味着不能阻止出血。即使未出血也会出现许多死亡,但出血的患者具有极高死亡率。在症状首次出现后施用的药剂可能会阻止患者的微血管系统出血,患者原本可能会展现出血性综合症。
在一些实施方案中,患者具有埃博拉病毒或马尔堡病毒。举例来说,患者可具有出血热的早期症状,例如发热和易出血性增加、和/或面部和胸部潮红、小的红色或紫色斑点(瘀斑)。出血热的其他体征和症状包括不适、肌肉疼痛、头痛、呕吐和腹泻。在一些实施方案中,确认患者样品中埃博拉病毒或其他出血热病毒的存在。在一些实施方案中,患者正经历至少一种用于治疗出血热的抗病毒剂或消炎剂(例如静脉内利巴韦林(ribavirin))的治疗。对于患有出血热或处于出血热风险之中的患者的治疗,本文所述的肽或药物组合物可以每日施用约1次到约5次,例如每日约1次到约3次,以减缓疾病的进展。
在其他实施方案中,患者患有脑型疟疾(CM)或处于其风险之中。CM是恶性疟原虫(Plasmodium falciparum)疟疾的最致命并发症之一,并占疟疾相关死亡的很大一部分。世界卫生组织(WHO)将在无性恶性疟原虫寄生虫血症存在下并且不存在脑病的其他病因下终止癫痫发作或校正低血糖症后持续至少1小时的CM定义为昏迷(不能定位疼痛刺激或Blantyre昏迷评分≤2)。高达75%的CM相关死亡在入院24小时内发生。多模态磁共振技术(例如成像、扩散、灌注、血管造影术、光谱学)已显示CM中发生血管损伤,包括血脑屏障破坏和出血。这些效应被认为是由于炎症过程。Penet等人,(J Neurosci.2005年8月10日;25(32):7352-8)已显示使用CM的小鼠模型,主要水肿形成以及减少脑灌注发生在CM中,并伴随着缺血性代谢概况,并且高能量磷酸盐降低和脑乳酸盐升高。其还使用血管造影术,所述血管造影术为主要血液动力学功能障碍提供令人信服的证据。重要的是,其发现水肿通过压迫脑动脉进一步恶化缺血,随后导致最终导致死亡的血流崩溃。这些发现展现了炎症和缺血性病灶的共存,并证明了水肿在实验性脑型疟疾的致死性结果中的主要作用。抑制脑中水肿和/或缺血的药剂可以与直接靶向寄生虫的抗疟疾药剂组合使用,以改善对这些患者的治疗。在一些实施方案中,患者接受选自氯喹(chloroquine)、甲氟喹(mefloquine)、脱氧羟四环素(doxycycline)或阿托伐醌(atovaquone)与氯胍盐酸盐(proguanilhydrochloride)(马拉隆(Malarone))的组合的抗疟疾疗法。
在这些实施方案中,肽维持患有脑型疟疾的患者的血脑屏障和血管完整性。对于患有脑型疟疾或处于其风险之中的患者的治疗,本文所述肽或药物组合物可以每日施用约1次到约5次,例如每日约1次到约3次,以减缓疾病的进展和/或预防死亡。
在其他方面中,本发明提供治疗癌症或正规化肿瘤微环境并特别是用于改善免疫检查点抑制剂疗法的方法。
所述方法包括向经历利用免疫检查点抑制剂的疗法(或在疗法的制备中)的癌症患者施用有效量的具有SEQ ID NO:1到6中任一种的氨基酸序列的肽或其衍生物或组合。血管生成是治疗癌症的药物靶标。VEGF和其受体VEGFR2是血管生成的重要介质。已研发出贝伐珠单抗(Bevacizumab)(一种螯合人类VEGF的抗体)和抑制VEGFR2的其他小分子酪氨酸激酶抑制剂用于各种类型的癌症。VEGF除了众所周知的促血管生成活性之外,还通过抑制树突细胞的成熟用作免疫抑制剂。认为肿瘤产生VEGF既吸引新血管系统,又通过减少成熟的免疫细胞的数量和调节淋巴细胞内皮运输来抑制免疫系统。
肿瘤集合免疫系统以促进其自身成长。在过去几年中,肿瘤抑制免疫系统的许多机制已被破译。许多类型的肿瘤细胞表达表面分子,例如PD-L1和CTLA-4,其与侵入肿瘤以使其静止的T细胞上的受体相互作用。这些发现允许研发所谓的“检查点抑制剂”(例如伊匹单抗(ipilimumab)、曲美目单抗(tremelimumab)、尼沃鲁单抗(nivolumab)和派姆单抗(pembrolizumab)作为癌症药物。这些药物中断肿瘤细胞与细胞毒性T细胞结合、从而使其免于抑制并使其杀死肿瘤细胞的抗体。
已在患有晚期黑色素瘤的患者中进行了至少一项组合贝伐珠单抗与伊匹单抗(一种阻断CTLA-4的抗体)的研究(Cancer Immunol Res.2014年7月;2(7):632-42)。除了阻断VEGF对炎症的作用外,淋巴细胞运输和免疫调节也是明显的。基于这些研究,已开始了组合贝伐珠单抗和其他抗血管生成剂(例如小分子酪氨酸激酶抑制剂)与检查点抑制剂的更多临床试验。
检查点抑制剂的其他靶标(本发明的肽和组合物可以协同为其工作)包括LAG-3、KIR、OX40L、IDO-1和TIM-3。
此外,如本文所公开,肽(例如,SEQ ID NO 1到6和衍生物)对α5β1和αVβ3整联蛋白的特异性表明肽在癌症疗法中的其他医学重要作用。受体被鉴定为α5β1和αVβ3整联蛋白。整联蛋白用作许多不同生长因子受体的共受体。本文所述的肽和其衍生物抑制来自血管内皮生长因子受体(VEGFR2)、肝细胞生长因子受体(c-met)和胰岛素样生长因子受体等的信号传导。在视网膜和脉络膜新血管形成和血管渗漏的小鼠模型中,例如,P07强烈抑制VEGF诱导的新血管形成和渗漏。除了促进血管生成外,VEGF还引起免疫抑制,所述免疫抑制由肿瘤利用来抑制针对其的免疫反应。由于P07阻断了VEGF的信号传导,所以其可以有效地用作免疫系统增强剂,从而促进免疫系统对肿瘤的攻击。这些数据表明P07(以及本文公开的其他肽和衍生物)可以与检查点抑制剂组合而充分工作。通过允许树突细胞成熟和更稳健的淋巴细胞内皮运输,可以有助于同时抑制血管生成和强化免疫反应,从而使检查点抑制剂可以使浸润的细胞毒性T细胞杀死肿瘤细胞。
在一些实施方案中,免疫检查点抑制剂是抗PD-1抗体、抗PD-L1抗体或抗CTLA-4抗体。虽然所述方法可用于针对免疫检查点疗法有效的任何癌症,但在一些实施方案中,癌症是选自以下的肉瘤、癌或实体肿瘤癌:种系肿瘤、中枢神经系统肿瘤、乳腺癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睪丸癌、甲状腺癌、星细胞瘤、神经胶质瘤、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤(包括晚期黑色素瘤)、肾癌、膀胱癌、食管癌、喉癌、腮腺癌、胆道癌、直肠癌、子宫内膜癌、鳞状细胞癌、腺癌、小细胞癌、神经胚细胞瘤、间皮瘤、肾上腺皮质癌、上皮癌、硬纤维瘤肿瘤、促结缔组织增生性小圆细胞瘤、内分泌肿瘤、尤恩氏肉瘤(Ewingsarcoma)家族肿瘤、生殖细胞瘤、肝母细胞瘤、肝细胞癌、淋巴瘤、黑色素瘤、非横纹肌肉瘤软组织肉瘤、骨肉瘤、外周型原始神经外胚层瘤、视网膜母细胞瘤、横纹肌肉瘤和威尔姆氏肿瘤(Wilms tumor)。在一些实施方案中,癌症是非小细胞肺癌、黑色素瘤、前列腺癌、转移性肾细胞癌。通常,癌症对PD-1、PD-L1或CTLA-4呈阳性,并且检查点抑制剂疗法是抑制PD-1与PD-L1或CTLA-4与B7之间的相互作用的药剂。
在各个实施方案中,患者可患有早期癌症(例如,I期或II期),或者处于晚期(III期或IV期)。I期癌症局限于身体的一部分。II期癌症在局部进展,III期癌症一样。是否将癌症命名为II期或III期可取决于癌症的特定类型。举例来说,II期可指示仅在横膈膜的一侧淋巴结受侵袭,而III期指示在横膈膜的上方和下方淋巴结受侵袭。因此,II期和III期的具体准则因诊断而异。IV期癌症经常转移,或传播到其他器官或整个身体。
在一些实施方案中,癌症是不可切除的。不可切除的癌症是恶性病,由于转移病灶的数量或者因为其处于手术危险区域而不能手术移除。
在一些实施方案中,患者对单独的免疫检查点抑制剂无反应或仅部分有反应。虽然肽或药物组合物可以与免疫检查点抑制剂疗法一起(或在其期间)施用,但在一些实施方案中,患者用肽治疗1到4周,然后用免疫检查点抑制剂疗法治疗。
在一些实施方案中,施用肽或药物组合物以减少与器官或组织移植相关的微血管渗漏或血管通透性或淋巴管生成,从而降低急性或超急性排斥的发病率。举例来说,在处于急性或超急性排斥的风险之中时,可向接受者施用肽用于皮肤移植、角膜异体移植、肾、肺或心脏移植或其他器官或组织移植。举例来说,肽可以每日施用至少一次,持续一至八周或一至四周。
在上述各个实施方案中,肽可根据所需途径和/或剂量以各种形式施用。
肽可以药学上可接受的盐形式递送,并且可以包括本领域已知的任何数量的载体。术语“药学上可接受的盐”包括用相对无毒的酸或碱制备的盐。如本文所用的“药学上可接受的载体”打算包括但不限于水、盐水、右旋糖溶液、人类血清白蛋白、脂质体、水凝胶、微粒和纳米粒子。
根据所治疗的特定病况,可将肽试剂配制成液体或固体剂型,并全身或局部施用。所述试剂可以(例如)以所属领域技术人员已知的定时或持续低释放形式递送。配制和施用的技术可参见Remington:The Science and Practice of Pharmacy(第20版)Lippincott,Williams&Wilkins(2000)。合适的途径可包括经口、经颊、通过吸入喷雾、舌下、直肠、经皮、阴道、经粘膜、经鼻或经肠施用;非经肠递送,包括肌内、皮下、髓内注射以及鞘内、直接室内、静脉内、关节内、胸骨内、滑膜内、肝内、病灶内、颅内、腹膜内、鼻内或眼内注射或其他递送模式。
尽管施用的形式和/或途径可以改变,但在一些实施方案中,肽或药物组合物是非经肠施用(例如,通过皮下、静脉内或肌内施用),或在一些实施方案中是直接施用于肺。局部施用于肺可以使用各种配制策略来实现,包括药物气溶胶,其可以为溶液气溶胶或粉末气溶胶。粉末制剂通常包含小的粒子。合适的粒子可以使用本领域已知的任何方式制备,例如通过在喷气磨机、球磨机或振动磨机中研磨,筛分,微沉淀,喷雾干燥,冻干或控制结晶。通常,粒子的直径为约10微米或更小。粉末制剂可以任选地含有本领域技术人员已知的至少一种颗粒药物上可接受的载体。合适的药物载体的实例包括但不限于糖类,包括单糖、二糖、多糖和糖醇,例如阿拉伯糖、葡萄糖、果糖、核糖、甘露糖、蔗糖、海藻糖、乳糖、麦芽糖、淀粉、聚葡萄糖、甘露醇或山梨醇。或者,溶液气雾剂可以使用本领域技术人员已知的任何方式制备,例如,设置有适于递送计量剂量的组合物的阀的气溶胶小瓶。如果活性成分的可吸入形式是可雾化的水性、有机或水性/有机分散液,则吸入装置可以是雾化器,例如常规气动雾化器,例如喷气雾化器,或超声波雾化器,其可以含有(例如)1至50ml、通常1到10ml的分散液;或手持式雾化器,其允许更小的雾化体积,例如10μl到100μl。
对于注射,本公开的药剂可以配制并在水溶液中,例如在生理上相容的缓冲液(例如汉克氏溶液(Hank′s solution)、林格氏溶液(Ringer′s solution)或生理盐水缓冲液)中稀释。
使用药学上可接受的惰性载体将本文公开的用于实践本公开的化合物配制成适合全身施用的剂量在本公开的范围内。通过适当选择载体和合适的生产实践,本公开的组合物、特别是配制为溶液的那些组合物可以非经肠施用,例如通过静脉内注射。可以使用本领域熟知的药学上可接受的载体将所述化合物容易地配制成适合经口施用的剂量。所述载体使本公开的化合物能够配制成片剂、丸剂、胶囊、液体、凝胶、糖浆、浆液、悬浮剂等,用于由待治疗的个体(例如,患者)经口摄取。
对于经鼻或吸入递送,本公开的试剂也可以通过本领域技术人员已知的方法配制,并且可以包括(例如但不限于)增溶、稀释或分散物质(例如盐水)、防腐剂(例如苄醇)、吸收促进剂和氟碳。
在一些实施方案中,肽用聚合纳米粒子或微粒载体配制。举例来说,在一些实施方案中,微粒或纳米粒子包含具有一个或多个可降解键(例如酯键、二硫键、酰胺键、酸酐键和易于酶促降解的键)的物质。在特定的实施方案中,微米或纳米粒子包含生物可降解聚合物或聚合物的共混物,其是选自由以下组成的组:聚(乳酸-共-乙醇酸)(PLGA)、聚(β-氨基酯)(PBAE)、聚己内酯(PCL)、聚乙醇酸(PGA)、聚乳酸(PLA)、聚(丙烯酸)(PAA)、聚-3-羟基丁酸酯(P3HB)和聚(羟基丁酸酯-共-羟基戊酸酯)。在其他实施方案中,本领域中使用的不可降解的聚合物(例如聚苯乙烯)与上述一种或多种可降解的聚合物共混以产生共聚物体系。因此,在一些实施方案中,不可降解的聚合物与生物可降解的聚合物共混。
在一些实施方案中,本发明提供包含PLGA-PEG共聚物和靶向整联蛋白的缀合肽的纳米粒子。缀合肽可以是SEQ ID NO:1到31中任何一个或更多个的肽或其衍生物。举例来说,N07是本文中用于基于P07的肽缀合的纳米粒子的名称,其具有抗血管生成和抗致瘤性质。N07具有活体外抗血管生成和抗致瘤活性,从而特异性结合到整联蛋白αVβ3复合物,以及具有携带封装药物货物的能力。
在一些实施方案中,纳米粒子含有缀合到表面的额外的药物或靶向剂。举例来说,纳米粒子可以由PLGA-PEG-X和PLGA-PEG-Y聚合物制成,其中X是所述肽,并且Y是另一种药物或靶向剂。靶向剂可为组织选择性靶向剂,或可对癌细胞具有选择性。在这些实施方案中,纳米粒子(具有缀合肽和任选地额外的靶向剂)可以用于治疗癌症,包括如上所述的实体肿瘤,并且包括成胶质细胞瘤或乳腺癌(包括三阴性乳腺癌)。
除此之外或替代地,可以使用其他靶结合剂(包括替代整联蛋白结合部分),并且这些靶结合剂包括抗体和其抗原结合部分。靶结合剂的各种形式包括单结构域抗体、重组仅重链抗体(VHH)、单链抗体(scFv)、鲨鱼仅重链抗体(VNAR)、微蛋白(半胱氨酸结蛋白,打结素)、DARPin、四连接素、亲和体;穿膜抗体(Transbody)、抗运载蛋白、阿德耐汀(AdNectin)、亲和素(Affilin)、微体、肽适配体、菲乐体(phylomer)、斯塔都体(stradobody)、巨型抗体、伊维体(eVibody)、非那体(fynomer)、犰狳重复蛋白、Kunitz结构域、阿维体(avimer)、阿曲体(atrimer)、普鲁体(probody)、免疫体、三功能单抗(triomab)、特洛伊体(troybody)、派普体(pepbody)、疫苗体(vaccibody)、单抗体、多体(DuoBody)、Fv、Fab、Fab′、F(ab′)2、肽模拟分子或合成分子,或者如美国专利号或专利公开号US 7,417,130、US 2004/132094、US 5,831,012、US 2004/023334、US 7,250,297、US 6,818,418、US2004/209243、US 7,838,629、US 7,186,524、US 6,004,746、US 5,475,096、US 2004/146938、US 2004/157209、US 6,994,982、US 6,794,144、US 2010/239633、US 7,803,907、US 2010/119446和/或US 7,166,697中所描述,所述专利的内容全文以引用方式并入本文中。还参见Storz MAbs.2011年5月到6月;3(3):310-317。
在一些实施方案中,纳米粒子是由与肽(例如,包含SEQ ID NO:1至6中任一种的序列或其衍生物)或如上所述其他结合剂共价连接的可调谐大小的聚(乳酸-共-乙醇酸)聚乙二醇(PLGA-PEG)嵌段共聚物合成。可以使用各种比率的缀合和非缀合聚合物的混合物来产生在表面上具有所需密度的靶向剂的纳米粒子。粒子的可调谐特征的描述可参见表1。
在一些实施方案中,缀合到粒子上的肽具有如所描述的SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6的氨基酸序列或其衍生物(例如,包括SEQ ID NO:7-31的肽)。在一些实施方案中,纳米粒子是由PLGA-PEG-肽缀合物形成,或在其他实施方案中,肽缀合到预先形成的粒子。
如本文所用术语“纳米粒子”是指具有至少一个在约1nm到约1000nm范围内(包括1nm与1000nm之间的任何整数值(包括约1、2、5、10、20、50、60、70、80、90、100、200、500和1000nm以及其之间的所有整数和分数整数))的尺寸的粒子。在一些实施方案中,纳米粒子具有至少一个约50到约100nm的尺寸(例如直径)。在一些实施方案中,纳米粒子的直径为约70到100nm。
在一些实施方案中,粒子是微粒。术语“微粒”包括至少一个在至少约1微米(μm)范围内的尺寸的粒子。如本文使用的术语“粒子”意欲包括纳米粒子和微粒。
可对粒子进行设计以提供所需的药效学优点,包括循环性质、生物分布和降解动力学。这些参数尤其包括大小、表面电荷、聚合物组成、配体缀合化学、肽缀合密度。举例来说,在一些实施方案中,粒子具有PLGA聚合物核和由PLGA-PEG共聚物的PEG部分形成的亲水壳,其中PLGA-PEG聚合物的一部分具有肽的末端连接。亲水壳可进一步包含官能团惰性的酯封端的PLGA-PEG聚合物,例如PLGA-PEG-MeOH聚合物。在一些实施方案中,一些或所有未缀合的聚合物具有其他末端基团(例如羧基)以微调表面性质。
本文所述的肽可以使用任何可用的方法化学缀合到粒子上。用于肽缀合的官能团包括PEG-COOH、PEG-NH2、PEG-SH。参见(例如)Hermanson,BlOCONJUGATE TECHNIQUES,Academic Press,New York,1996。活化官能团包括烷基和酰卤、胺、硫氢基、醛、不饱和键、酰肼、异氰酸酯、异硫氰酸酯、酮和其他已知可激活用于化学键结的基团。或者,可以通过使用小分子-偶合剂缀合肽。偶合剂的非限制性实例包括碳二亚胺、马来酰亚胺、N-羟基琥珀酰亚胺酯、双氯乙胺、双功能醛(例如戊二醛)、酸酐等。
在实例性实施方案中,纳米粒子具有可以针对特定活体内生物降解速率进行调谐(通过调整PLGA聚合物的LA∶GA比率和/或分子量)的核(PLGA)。在一些实施方案中,PLGA基于LA∶GA比率为20∶1到1∶20,包括L/G为以下的组合物:5/95、10/90、15/85、20/80、25/75、30/70、35/65、40/60、45/55、50/50、55/45、60/40、65/35、70/30、75/25、80/20、85/15、90/10或95/5。PLGA通过水解其酯键来降解。降解PLGA所需的时间与单体的比率有关:乙交酯单元含量越高,与主要乳酸交酯单元相比,降解所需的时间就越少。另外,用酯封端的聚合物(与游离羧酸相反)具有更长的降解半衰期。
在一些实施方案中,用于制作纳米粒子的PLGA聚合物具有约10K到约70K范围内(例如约20K、约25K、约30K、约40K、约50K、约60K或约70K)的分子量,以提供可调谐的粒径。在一些实施方案中,用于制作微粒的PLGA聚合物的分子量在约20K到约200K(例如100K到约200K)范围内。聚合物的PEG部分通常在2K到5K的范围内。在各个实施方案中,PLGA-PEG-肽与未缀合的PLGA-PEG的比率在约1∶20到约20∶1,例如约1∶15到约15∶1,或约1∶10到约10∶1,或约1∶5到约5∶1,或约1∶2到约2∶1的范围内。在一些实施方案中,PLGA-PEG-肽与未缀合的共聚物的比率为约1∶1。在一些实施方案中,至少50%的聚合物具有缀合的肽。在一些实施方案中,纳米粒子的大小(平均直径)在约50到约200nm的范围内,或在约50到约100nm的范围内。在一些实施方案中,纳米粒子在去离子水中具有在约-5mV到约-40mV、并且在一些实施方案中约-10mV到约-30mV范围内(例如,约-20、约-25或约-30mV)的ζ电势。
在一些实施方案中,纳米粒子进一步包含封装的活性剂,其可为本文公开的用于治疗特征在于微血管渗漏的病况(包括流感、阿兹海默氏病、出血热、脑型疟疾、癌症)、预防急性排斥和本文所述其他病况的活性剂。在这些实施方案中,纳米粒子提供活性剂的持续释放。举例来说,在一些实施方案中,活性剂是化学治疗剂,例如以下中的一种或多种:氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、天冬酰胺酶、比卡鲁胺(bicalutamide)、博来霉素(bleomycin)、布舍瑞林(buserelin)、白消安(busulfan)、喜树碱(camptothecin)、卡培他滨(capecitabine)、卡铂(carboplatin)、卡莫司汀(carmustine)、氮芥苯丁酸(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯膦酸(clodronate)、秋水仙碱(colchicine)、环磷酰胺(cyclophosphamide)、环丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、放线菌素D(dactinomycin)、道诺霉素(daunorubicin)、己二烯雌酚(dienestrol)、乙底酚(diethylstilbestrol)、多西他赛(docetaxel)、多柔比星(doxorubicin)、泛艾霉素(epirubicin)、雌氮芥(estramustine)、依托泊苷(etoposide)、依西美坦(exemestane)、非格司亭(filgrastim)、氟达拉滨(fludarabine)、氟氢可的松(fludrocortisone)、氟尿嘧啶(fluorouracil)、氟甲睪酮(fluoxymesterone)、氟他胺(flutamide)、吉西他滨(gemcitabine)、金雀异黄酮(genistein)、戈舍瑞林(goserelin)、羟基脲(hydroxyurea)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊马替尼(imatinib)、伊立替康(irinotecan)、伊罗替康(ironotecan)、来曲唑(letrozole)、甲酰四氢叶酸(leucovorin)、柳培林(leuprolide)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、甲基二氯乙基胺(mechlorethamine)、甲羟助孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美法仑(melphalan)、巯嘌呤(mercaptopurine)、美司钠(mesna)、甲氨蝶呤(methotrexate)、丝裂霉素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、尼鲁米特(nilutamide)、诺考达唑(nocodazole)、奥曲肽(octreotide)、奥沙利铂(oxaliplatin)、太平洋紫杉醇(paclitaxel)、帕米膦酸(pamidronate)、喷司他汀(pentostatin)、普卡霉素(plicamycin)、卟菲尔钠(porfimer)、丙卡巴肼(procarbazine)、雷替曲塞(raltitrexed)、雷帕霉素(rapamycin)、利妥昔单抗(rituximab)、链脲霉素(streptozocin)、舒拉明(suramin)、他克莫司(tacrolimus)、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睪固酮(testosterone)、硫鸟嘌呤(thioguanine)、噻替派(thiotepa)、二茂钛二氯化物(titanocene dichloride)、托泊替康(topotecan)、曲妥珠单抗(trastuzumab)、维甲酸(tretinoin)、长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)和长春瑞滨(vinorelbine)。
尽管在一些实施方案中纳米粒子基本上是球形,但纳米粒子可以任选地为非球形。
有各种物理和化学性质可以影响材料与生物系统相互作用的方式。在基于微米和纳米粒子的材料的情况下,材料的选择、粒子的大小分布和形状分布都是影响粒子活性的关键参数。先前已显示,粒子的大小和形状都可以影响粒子与体内各种细胞的相互作用方式。举例来说,粒子的形状可以影响各种细胞类型摄取粒子的程度,其中椭球体形粒子通常比球形粒子更难以被细胞摄取。因此,拉伸粒子的形状可以减少粒子由(例如)免疫系统细胞的不想要的摄取,从而延长粒子在体内的半衰期。粒子的大小也影响细胞对粒子的摄取和与粒子的相互作用的能力。因此,可通过调谐粒子的大小和形状分布来实现基于粒子的系统的活性的优化。
在一些实施方案中,纳米粒子的尺寸和/或用于拉伸粒子的方法如WO 2013/086500中所公开,其全部内容通过引用并入本文。
在特定实施方案中,三维微米或纳米粒子包含长椭球体,其中沿x轴的尺寸(a)大于沿y轴的尺寸(b),并且其中沿y轴的尺寸(b)基本上等于沿z轴的尺寸(c),使得长椭球体可以由方程a>b=c来描述。在其他实施方案中,椭球体是三轴椭球体,其中沿x轴的尺寸(a)大于沿y轴的尺寸(b),并且其中沿y的尺寸(b)轴的尺寸大于沿z轴的尺寸(c),使得三轴椭球体可以用方程a>b>c来描述。在其他实施方案中,椭球体是扁椭球体,其中沿x轴的尺寸(a)等于沿y轴的尺寸(b),并且其中沿y轴的尺寸(b)轴大于沿z轴的尺寸(c),使得扁椭球体可以由方程a=b>c来描述。然而,目前公开的不对称粒子不包括其中a=b=c的实施方案。
在另一实施方案中,微粒或纳米粒子具有约1.1到约5的纵横比。在其他实施方案中,纵横比的范围为约5到约10。在一些实施方案中,纵横比的范围为约1.5到约3.5。
在一些实施方案中,粒子是封装药物货物(例如本文所述肽,和/或其他药剂)的微粒。在这些实施方案中,粒子可含有或可不含有缀合到表面的肽。在这些实施方案中,粒子可以提供长效药物贮存,以提供肽的持续释放。实例性粒子形式包括在WO 2014/197892中描述的那些,其通过引用并入本文中。在一些实施方案中,粒子不纳入聚(β-氨基酯)(PBAE),并且因此聚合物基本上由PLGA-PEG嵌段共聚物组成。这些粒子可用于眼内注射,例如,用于治疗黄斑变性(例如,湿或干年龄相关的黄斑变性)或糖尿病黄斑水肿。在一些实施方案中,货物允许将活性剂的组合递送到所需位点。在一些实施方案中,施用纳米粒子用于治疗癌症。在这些或其他实施方案中,粒子的大小(平均直径)在1μm到500μm的范围内,例如在约1μm到约250μm的范围内。根据持续的肽或药物释放的持续时间,粒子可注射约每日一次注射到约每六个月一次,或约每周或约每月一次。
在其他方面中,本发明提供鉴别一个或多个细胞上整联蛋白表达的方法。举例来说,在一些实施方案中,所述方法包括使具有缀合到表面(如上文所述)的SEQ ID NO:1、SEQID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6的肽(或如所述SEQ IDNO:1-6中的任一种的衍生物,包括SEQ ID NO:7到31的肽)的纳米粒子或微粒与一个或多个细胞接触,并可视化或检测纳米粒子与细胞的结合。在一些实施方案中,纳米粒子进一步包含可检测标记,例如荧光、发光、酶促或放射性标记,其可缀合到PLGA-PEG聚合物的一部分,封装于纳米粒子中,或通过其他部分间接结合。在一些实施方案中,细胞可能处于溶液或培养物中。对于活体外应用,结合可以通过直接可视化结合粒子、流式细胞术或通过从溶液中拉下细胞来确定。在一些实施方案中,使用磁性粒子而非聚合粒子来允许用于分离表达靶向整联蛋白的细胞的便利方法。
在其他实施方案中,向患者施用纳米粒子,并且例如在肿瘤附近使整联蛋白过表达的血管系统成像。
实施例
实施例1:P07抑制VEGF、HGF和IGF的信号传导
P07的靶标鉴别为α5β1和αVβ3整联蛋白。整联蛋白用作许多生长因子受体(例如VEGFR、肝细胞生长因子受体(HGFR或c-met)、胰岛素样生长因子受体(IGFR)和血小板源生长因子受体(PDGFR))的共受体。与这种机制一致,发现P07抑制来自这些受体的信号传导(图1)。
这些受体和其他受体参与血管生成和微血管通透性。这种多因素抑制使得涉及多种机制的疾病可由P07和其衍生物有效地治疗。
实施例2:P07抑制多眼模型中的新血管形成
发现P07在过表达血管内皮生长因子(VEGF)的人类形式的转基因小鼠中的视网膜中抑制血管渗漏。这个模型中的血管渗漏非常严重,以致汇集在视网膜后面的血液导致视网膜脱落。在这个模型中,P07几乎完全阻断视网膜脱落(图2)。
也在兔眼中的水肿模型中测试P07。在这个模型中,人类VEGF直接注入眼内,从而导致局部血管系统渗漏。VEGF注射后3天,通过测量因静脉内施用的荧光黄钠的渗漏所产生的眼内荧光量来评价这种渗漏的程度。当VEGF注射前在眼中存在约50μg的P07时,血管渗漏被显著抑制(图3)。这些结果表明P07是强效的活体内消水肿剂。
实施例3:P07抑制癌症组织生长
P07抑制正位三阴性乳腺癌(TNBC)异种移植物(图4)和小细胞肺癌(SCLC)和成胶质细胞瘤异种移植物(未显示)的生长。反应性肿瘤显著减少血管系统(图5)。
这些结果指示,P07当与免疫检查点抑制剂组合时可具有协同效应。P07和免疫检查点抑制剂可以同时抑制血管生成,并通过允许树突细胞成熟和更稳健的淋巴细胞内皮输送强化针对肿瘤的免疫反应,并且检查点抑制剂可允许浸润性细胞毒性T细胞杀死肿瘤细胞。
实施例4:P07缀合的纳米粒子(N07)的性质
N07是具有抗血管生成和抗致瘤性质的肽缀合的纳米粒子。N07特异性结合到整联蛋白αVβ3复合物,并具有携带封装的药物货物的能力。
N07是由与N07共价缀合的可调谐大小的聚(乳酸-共-乙醇酸)聚乙二醇(PLGA-PEG)嵌段共聚物合成。可以使用任何比率的缀合和非缀合聚合物的混合物来产生在表面上具有所需密度的P07的纳米粒子。粒子的可调谐特征的描述显示于表1中。
表1
可调谐的参数 | 可用范围 |
PLGA的分子量 | 10kDa-70kDa |
PEG的分子量 | 2kDa-5kDa |
缀合到肽的聚合物的百分比 | 0-100% |
N07是由P07肽和PLGA-PEG嵌段共聚物合成。P07是通过固态合成在New EnglandPeptide产生,并通过HPLC/MS评价其纯度。所述肽在N-末端具有胺并在C-末端具有酰胺。PLGA-PEG嵌段共聚物购自并通过凝胶渗透色谱(GPC)和傅立叶转换红外光谱(FTIR)评价纯度和分子量。
为了缀合,将P07以100mg/ml溶解于DMSO中并添加到DMF中的170mg/ml NHS官能化的PLGA-PEG(PLGA-PEG-NHS)。将40摩尔过量的二异丙基乙胺(DIPEA)添加到混合物中并在室温下搅拌过夜。然后将混合物逐滴添加到醚和甲醇的冷混合物中,并以22,000×g离心。然后用甲醇反复洗涤沉淀并旋转去除未反应的肽。丢弃上清液,并将沉淀物在真空下干燥几小时,得到固体PLGA-PEG-SP2043。其他货物(例如药物和染料)也可以通过类似的方法缀合到PLGA-PEG。
将PLGA-PEG-P07和PLGA-PEG的混合物以10mg/ml溶解于DMF中,并在磁力搅拌下将其逐滴添加到去离子水中,以在称为纳米沉淀的过程中形成纳米粒子。在纳米沉淀前将所需货物添加到DMF混合物中,此产生在疏水PLGA核中具有负载货物的纳米粒子。搅拌几小时后,将粒子过滤并用超离心管柱(EMD Millipore,UFC810096)浓缩。
使用HPLC评价PLGA-PEG-NHS与P07的缀合效率。在一些情况下,c-末端F由W置换以允许从W残基读取吸光度和荧光。将反应混合物的PLGA-PEG-P07在醚和甲醇中沉淀之前在DMSO中稀释并运行穿过水-乙腈移动相中的Agilent Poroshell 300管柱。通过220nm(肽主链)和280nm(色氨酸,W)处的吸光度和通过295/348nm激发/发射(色氨酸)处的荧光检测肽。通过对游离的P07峰进行积分来测定未反应的P07的量。将PLGA-PEG-P07反应混合物与PLGA-PEG-COOH或PLGA-mPEG和P07的对照反应混合物进行比较,两者都不会经历形成PLGA-PEG-P07的反应。反应的P07对游离的P07峰无贡献,因此P07峰相对于对照反应降低指示与PLGA-PEG-NHS共聚物缀合。将结果与游离肽的标准曲线进行比较以确保所有积分值都落入肽浓度的线性范围内。结果显示于表2和图6中。
表2
量化的信号 | 缀合效率 |
荧光(295/348nm) | 0.869 |
吸光度(280nm) | 0.920 |
吸光度(220nm) | 0.854 |
LavaPepTM表征:使用LavaPepTM肽量化试剂盒(Gel公司,LP022010)直接检测N07表面上的肽。将超纯水中的3-5mg/ml的粒子在黑暗中与96孔板中的LavaPep工作溶液一起培育1小时。LavaPep工作溶液中的epicocconone染料与肽上的Arg残基相互作用而高度发荧光。在Biotek HT Synergy读板仪上于530/590nm处读取荧光。将来自纳米粒子的信号与已知量的游离肽的标准稀释曲线进行比较。量化结果显示于表3中,表明了SP2043有效缀合到PLGA-PEG-NHS共聚物并纳入纳米粒子中。
表3
大小表征:将N07以1mg/ml悬浮于水中并使用Malvern Zetasizer Nano ZS90进行分析。测量并记录Z-平均直径和基于强度的大小分布。结果显示于表4和图7中,表明了N07展现出约70-80nm的Z-平均直径,并且在纳米粒子上具有缀合的P07的样品中看到略微大小增大。
表4
样品 | Z-平均值(d.nm) | PDI |
PLGA-PEG-COOH | 68.24±0.26 | 0.23 |
PLGA-PEG-COOH/P07(50/50) | 73.39±1.03 | 0.18 |
PLGA-PEG-P07 | 77.59±2.65 | 0.29 |
ζ-电势:将N07以1mg/ml悬浮于超纯水中并使用Malvern Zetasizer Nano ZS90进行分析。测量并记录表面ζ电势。结果显示于图8中,表明N07在去离子水中展现负的ζ电势,使用PEG上的不同端基,其在25mV下非常轻微可调谐。在图8中,中性是甲氧基封端的PEG,阴性是羧基封端的PEG。
实施例5:PLGA-PEG-P07与整联蛋白αvβ3和整联蛋白α5β1靶标的结合
粒子如上所述制备,完全由PLGA-PEG-P07或PLGA-mPEG制成。根据制造商的说明书用Alexafluor 488TFP-酯标记整联蛋白αvβ3、整联蛋白α5β1和人类血清白蛋白。将粒子在室温下与整联蛋白在PBS中培育过夜,以及对照样品与整联蛋白或HSA在PBS中培育过夜而无粒子。然后使用Sephacryl S-500HR培养基通过SEC离心旋转管柱将粒子与游离的整联蛋白或HSA蛋白分离。分离后,在Biotek Synergy HT微读板仪上测量荧光信号,以评价由粒子通过SEC培养基带来的整联蛋白的量。结果显示于图9中。
重复上述方案用于与整联蛋白αvβ3结合,但是添加竞争样品。简言之,将100倍过量的各种肽(P07和已显示无活性的P07序列的部分乱码)添加到靶向粒子和Alexafluor488标记的游离整联蛋白的溶液中,并在室温下培育过夜。使用Sephacryl S-500HR培养基通过SEC离心离心柱分离溶液。与上文所述,使用荧光来评价由粒子通过SEC培养基带来的整联蛋白的量。结果显示于图10中。
测试纳米粒子与MDA-MB-231和微血管内皮细胞(MEC)细胞的结合。如上所述制备粒子,并且添加1重量%的TAMRA染料。纳米沉淀后,用Amicon超速离心过滤器(MWCO 100,000)浓缩粒子,并用SEC旋转离心管柱使用Sephacryl S-500HR培养基过滤以去除游离的TAMRA染料或其他游离的聚合物或肽材料。然后以100,000个细胞/ml和1mg/ml粒子将细胞与纳米粒子一起培育。纳米粒子由靶向PLGA-PEG-P07聚合物或非靶向PLGA-mPEG聚合物制成。在37℃下培育1小时后,将细胞在离心机中旋转并移除上清液。将细胞重新悬浮于PBS中,且所得信号在Biotek Synergy HT微读板仪上,以评价随着细胞带来的荧光粒子的量。结果显示于图11中。
测试粒子抑制MB-MDA-231细胞和微血管内皮细胞(MEC)的粘附的能力。在用于活体外测定之前,使用超速离心管柱将粒子从超纯水转移到适当的培养基,在培养基中浓缩到10mg/ml,并且添加到96孔板中。向板中添加单独的培养基和具有100μM和25μM AXT201(已知的粘附抑制剂)的培养基作为阳性和阴性对照。将MDA-MB-231或MEC细胞以20,000个细胞/孔添加到粒子、肽和培养基中。将96孔板在37℃和5%CO2下培育约2小时。然后将孔用具有Ca2+和Mg2+的DPBS洗涤两次,然后用含有4μg/ml钙黄绿素AM染料的培养基填充。然后将板培育30分钟,并再次用具有Ca2+和Mg2+的DPBS洗涤。然后在Biotek Synergy HT上于485/528nm激发/发射下读取荧光以量化粘附到孔表面的细胞的数量。结果显示于图12中,表明N07具有针对MDA-MD-231肿瘤细胞和MEC细胞的抗粘附活性。在图12中,%是指具有缀合的P07的PLGA-PEG分子的量。“+”或“-”是指存在或不存在封装的P07。
针对MEC增殖的抑制测试粒子。在MEC细胞上进行使用MTT Vybrant测定试剂盒的基于比色的增殖测定。将2000个细胞/孔平铺在不含酚红的ECM-2MV培养基中的96孔板中,并使其粘附超过18-20小时。将无粒子的初始培养基用以5mg/ml悬浮于培养基中的N07粒子或培养基中的AXT201肽或仅培养基替代。四天后,根据制造商的建议,用100ul MTT试剂代替培养基。四小时后,向每孔中添加100ul SDS溶液并在37℃下再培育4小时。在BiotekSynergy HT读板仪上读取570nm处的吸光度,以捕获因活细胞中的粒腺体还原酶而产生的从MTT到甲月替的变化。结果显示于图13中,表明N07针对MEC细胞具有抗增殖活性。在图13中,%是指具有缀合的P07的PLGA-PEG分子的量。“+”或“-”是指存在或不存在封装的P07。
测试PEG-P07缀合抑制粘附的能力。将NHS官能化的PEG 8和PEG 24以约150mg/ml溶解于DMF中。以100mg/ml在DMSO中以1∶1摩尔比添加肽以及添加40倍摩尔过量的DIPEA。使混合物在冷醚和甲醇中沉淀并洗涤数次以去除DIPEA、溶剂和游离的PEG。然后将所得混合物用于使用如上所述的MDA-MB-231细胞以及阳性和阴性对照的粘附测定中。结果显示于图14中,表明PEG-P07的粘附活性。
实施例6:拉伸肽缀合的粒子
操纵粒子的大小和形状以优化粒子的活性。成功地制备并拉伸粒子。肽在整个过程中保持稳定,在拉伸方案之前和之后肽的负载保持不变。
微粒形成:首先在试管中将聚(乳酸交酯-共-乙交酯)(即PLGA)以20mg/mL溶解于二氯甲烷DCM中并涡旋以完全溶解。将P07于二甲亚砜DMSO中的肽原液(20mg/mL)微量移液到PLGA/DCM溶液。肽与PLGA的初始质量比可以变化;例如1∶50和1∶20的肽:PLGA。对于空白微粒,仅移液等体积的DMSO。将混合物在冰上与试管一起进行超声波处理。以‘30’的振幅设定(其大约等于5-10W)进行超声波处理20秒。立即将这种原始乳液倒入50mL 1%聚(乙烯醇)PVA溶液中,并以3.6-3.8krpm匀浆化1分钟。然后将全部体积转移到100mL 0.5%PVA溶液中并在化学通风橱中搅拌约3.5小时。然后进行三个洗涤步骤。对于每个洗涤步骤,将微粒溶液在4℃下以4krpm离心5分钟,然后去除上清液。随后,添加40mL冷冻的Milli-Q水,重新悬浮微粒沉淀并重复洗涤步骤。在最后的离心步骤后,添加5mL水以使样品重新悬浮。将样品在液氮中快速冷冻并立即放入冻干器中。冻干后,将所有微粒均存储于-20℃。
纳米粒子形成:首先在试管中将PLGA以所需浓度(通常为20mg/mL或40mg/mL)溶解于DCM中并涡旋以完全溶解。将DMSO中的肽原液(例如P07)(20mg/mL)微量移液到PLGA/DCM溶液。肽与PLGA的质量比可以变化。实例性配方是1∶50的肽:PLGA。对于空白纳米粒子,仅移液等体积的DMSO。将混合物在冰上与试管一起进行超声波处理。以‘30’的振幅设定(其大约等于5-10W)进行超声波处理(Misonix)20秒。立即将这种原始乳液倒入50mL 1%PVA溶液中,并以‘30’到‘100’的任何振幅设定在冰上超声波处理2分钟。然后将全部体积转移到100mL 0.5%PVA溶液中并在化学通风橱中搅拌约3.5小时。然后进行三个洗涤步骤。对于每个洗涤步骤,将纳米粒子溶液在4℃下以17krpm离心10分钟,然后去除上清液。随后,添加30mL冷冻的Milli-Q水,重新悬浮纳米粒子沉淀并重复洗涤步骤。在最后的离心步骤后,添加5mL水以使样品重新悬浮。将样品在液氮中快速冷冻并立即放入冻干器中。冻干后,将所有纳米粒子均存储于-20℃。
微粒拉伸:将冻干的PLGA粒子以2.5mg/mL的浓度溶解于10%PVA/2%甘油溶液中,并将10mL这种溶液沉积到矩形皮氏培养皿中干燥过夜。将所得膜切割成一定大小并装载在两个铝底座之间并加热到90℃。测量膜长度并使用定制拉伸装置将膜缓慢拉伸以产生所需的拉伸倍数(例如2倍拉伸的椭球体粒子)。然后使膜冷却到室温并从铝块中移出。将PVA膜溶解于水中,并将所得粒子悬浮液洗涤3次。粒子在使用前冻干。
SEM和TEM表征:对于扫描电子显微镜(SEM),将冻干的粒子放置在碳带(ElectronMicroscopy Sciences,Hatfield,PA)上,所述碳带放置在铝底座上。将样品用金-钯溅镀,并利用JHU School of Medicine MicFac的LEO/Zeiss FESEM进行SEM成像。利用SEM图像的ImageJ分析进行微粒样品的定大小。结果显示于图15中。拉伸的粒子显示于图16中。
对于透射电子显微镜(TEM),首先将纳米粒子以1mg/mL重新悬浮于水中。将10uL样品滴在碳涂覆的铜栅上,并在化学通风橱中干燥2小时。然后使用Philips CM120系统进行未染色的TEM成像。结果显示于图17中,其显示未拉伸(左图)或2倍拉伸(右图)的肽负载的NP。
微粒负载和释放量化:为了测量加载,将已知质量的微粒溶解于DMSO中。对于肽负载的微粒和相应的空白微粒,通过运行凝胶电泳(Bio-Rad Mini-PROTEAN系统)和银染分析进行量化。使用12孔10-20%Mini-PROTEAN tris-三(羟甲基)甲基甘氨酸凝胶,以及在Milli-Q水中稀释至1倍的10×tris/三(羟甲基)甲基甘氨酸/SDS运行缓冲液。每个凝胶含有标准系列的已知量的肽。肽标准系列包括每孔0、62.5、125、250和500ng的肽。其余孔包括蛋白标准品以及微粒样品,二者都负载肽和空白作为对照。将DMSO样品与样品缓冲液以体积计1∶1混合。样品缓冲液由1×PBS中的24%甘油制成。运行凝胶电泳直至蛋白标准品的2.5kDa带远离凝胶行进约三分之二。对于凝胶染色遵循银染色方案。对于研发步骤,一旦开始出现最低肽标准品(在这种情况下为62.5ng),就添加终止溶液。用数字照相机捕获凝胶图像,并用ImageJ使用凝胶带强度量化功能进行分析。结果显示于图18中。
为了测量释放,将已知质量的微粒悬浮于1×PBS中,放置于37℃烘箱中的振荡器上。在不同的时间点,将样品以约2.5krcf离心5min。收集上清液并储存于-80℃,并向样品中添加新鲜的PBS。通过运行凝胶电泳、银染色和凝胶带分析进行释放到上清液中的肽的量化。结果显示于图19中。
Claims (61)
1.一种治疗或预防微血管渗漏的方法,其包括向需要治疗的患者施用有效量的具有SEQ ID NO:1到6中任一种的氨基酸序列的肽或其衍生物。
2.如权利要求1所述的方法,其中所述衍生物是SEQ ID NO:7到31中任一种的肽。
3.如权利要求1所述的方法,其中所述患者患有流感或处于流感风险之中。
4.如权利要求3所述的方法,其中在最早的流感症状的3天内首先施用所述肽。
5.如权利要求3所述的方法,其中在最早的流感症状后首先施用所述肽。
6.如权利要求3所述的方法,其中在最早的流感症状前首先施用所述肽。
7.如权利要求1到6中任一项所述的方法,其中所述肽使肺中的水肿减轻。
8.如权利要求7所述的方法,其中将所述肽每日施用1到5次。
9.如权利要求7所述的方法,其中将所述肽局部施用至所述肺。
10.如权利要求1到9中任一项所述的方法,其中所述患者正经历至少一种抗病毒剂和/或消炎剂的治疗。
11.如权利要求1所述的方法,其中具有与血管生成失调或微血管渗漏相关的神经病状,所述神经病状任选地为MS或PD。
12.如权利要求1所述的方法,其中所述患者患有阿兹海默氏病或被鉴别为处于阿兹海默氏病风险之中,并且所述肽维持血脑屏障的完整性,从而减缓或预防阿兹海默氏病的发作或进展。
13.如权利要求12所述的方法,其中所述患者正经历至少一种用于治疗阿兹海默氏病的额外药剂的治疗。
14.如权利要求11到13中任一项所述的方法,其中将所述肽每日施用1到5次。
15.如权利要求1所述的方法,其中所述患者患有出血热或处于出血热风险之中。
16.如权利要求15所述的方法,其中所述患者具有埃博拉病毒。
17.如权利要求15所述的方法,其中所述患者正经历至少一种用于治疗所述出血热的抗病毒剂的治疗。
18.如权利要求15到17中任一项所述的方法,其中将所述肽每日施用1到5次。
19.如权利要求1所述的方法,其中所述患者患有脑型疟疾。
20.如权利要求19所述的方法,其中所述肽减轻与脑型疟疾相关的脑水肿和/或缺血。
21.如权利要求19所述的方法,其中所述患者正经历抗疟疾疗法。
22.如权利要求19所述的方法,其中所述肽维持患有脑型疟疾的患者的血脑屏障和血管完整性。
23.如权利要求19到22中任一项所述的方法,其中将所述肽每日施用1到5次。
24.一种治疗癌症的方法,其包括向正经历或准备经历免疫检查点抑制剂疗法的癌症患者施用有效量的具有SEQ ID NO:1到6的氨基酸序列的肽或其衍生物。
25.如权利要求24所述的方法,其中所述衍生物是SEQ ID NO:7到31中任一种的肽。
26.如权利要求24所述的方法,其中所述免疫检查点抑制剂是抗PD-1抗体、抗PD-L1抗体或抗CTLA-4抗体。
27.如权利要求24或26中任一项所述的方法,其中所述癌症是选自非小细胞肺癌、黑色素瘤、前列腺癌、转移性肾细胞癌。
28.如权利要求24到27中任一项所述的方法,其中所述癌症对PD-1、PD-L1或CTLA-4呈阳性。
29.如权利要求24到28中任一项所述的方法,其中所述检查点抑制剂疗法是抑制PD-1与PD-L1之间或者CTLA-4与B7之间的相互作用的药剂。
30.一种纳米粒子,其包含PLGA-PEG共聚物和靶向整联蛋白的缀合的肽。
31.如权利要求30所述的纳米粒子,其中所述肽包含SEQ ID NO:1到6中任一种的氨基酸序列或其衍生物。
32.如权利要求31所述的方法,其中所述衍生物是SEQ ID NO:7到31中任一种的肽。
33.如权利要求30到32中任一项所述的纳米粒子,其中所述纳米粒子是由PLGA-PEG-肽缀合物形成。
34.如权利要求33所述的纳米粒子,其中所述纳米粒子有效抑制血管生成和/或淋巴血管生成。
35.如权利要求33所述的纳米粒子,其中至少50%的聚合物具有缀合的肽。
36.如权利要求30到35中任一项所述的纳米粒子,其进一步包含封装的活性剂。
37.如权利要求36所述的纳米粒子,其中所述纳米粒子提供所述活性剂的持续释放。
38.如权利要求36或37所述的纳米粒子,其中所述活性剂是化学治疗剂。
39.如权利要求36或37所述的纳米粒子,其中所述活性剂是肽试剂或靶向型抗癌症疗法。
40.如权利要求30到39中任一项所述的纳米粒子,其具有约50nm到约500nm或约50nm到约100nm内的平均直径。
41.如权利要求30到40中任一项所述的纳米粒子,其中所述纳米粒子含有缀合到表面的另一药物或靶向剂。
42.如权利要求40所述的纳米粒子,其中所述纳米粒子具有-10到-40mV范围内的ζ电势。
43.如权利要求30到42中任一项所述的纳米粒子,其中所述纳米粒子是球形的。
44.如权利要求30到42中任一项所述的纳米粒子,其中所述粒子是非球形的。
45.一种封装SEQ ID NO:1到6中任一种的肽或其衍生物的微粒,其中所述纳米粒子或所述微粒提供长效贮存。
46.如权利要求45所述的微粒,其中所述衍生物是SEQ ID NO:7到31中任一种的肽。
47.如权利要求45或46所述的微粒,其中粒子聚合物基本上由PLGA-PEG聚合物组成。
48.如权利要求45或47中任一项所述的微粒,其中所述粒子是不超过每周一次或不超过每月一次地进行施用。
49.如权利要求45到48中任一项所述的微粒,其中所述微粒具有约1μm到约100μm范围内的平均直径。
50.如权利要求45到49中任一项所述的微粒,其中所述粒子是球形的。
51.如权利要求45到50中任一项所述的微粒,其中所述粒子是椭球体形的。
52.一种治疗年龄相关性黄斑变性、糖尿病黄斑水肿、视网膜静脉闭塞或糖尿病视网膜病变的方法,其包括向有需要的患者施用如权利要求30到51中任一项所述的纳米粒子或微粒。
53.如权利要求52所述的方法,其中通过眼内注射来施用所述纳米粒子或所述微粒。
54.如权利要求52或53所述的方法,其中大约每日一次到大约每月一次到大约每6个月一次地注射所述纳米粒子或所述微粒。
55.一种鉴别整联蛋白的方法,其包括:使如权利要求30所述的纳米粒子与一个或多个细胞接触,以及可视化或检测所述纳米粒子与所述细胞的结合。
56.如权利要求55所述的方法,其中所述细胞处于溶液或培养物中。
57.如权利要求55所述的方法,其中向患者施用所述纳米粒子,使整联蛋白过表达的血管系统成像。
58.一种治疗实体肿瘤的方法,其包括向有需要的患者施用有效量的如权利要求30到44中任一项所述的纳米粒子。
59.如权利要求58所述的方法,其中实体肿瘤是成胶质细胞瘤或乳腺癌。
60.如权利要求59所述的方法,其中所述乳腺癌是三阴性乳腺癌。
61.一种治疗特征在于血管生成或血管渗漏的疾病的方法,其包括施用有效量的如权利要求30到44中任一项所述的纳米粒子。
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US (1) | US20180339024A1 (zh) |
EP (1) | EP3377080B1 (zh) |
JP (1) | JP2018535224A (zh) |
KR (1) | KR20180081608A (zh) |
CN (1) | CN108883150A (zh) |
AU (1) | AU2016358125A1 (zh) |
BR (1) | BR112018010052A2 (zh) |
CA (1) | CA3005284A1 (zh) |
IL (1) | IL259376A (zh) |
MX (1) | MX2018006194A (zh) |
SG (2) | SG11201804003VA (zh) |
WO (1) | WO2017087825A1 (zh) |
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WO2019028427A1 (en) | 2017-08-03 | 2019-02-07 | Asclepix Therapeutics, Llc. | METHODS OF IDENTIFYING AND PREPARING PHARMACEUTICAL AGENTS TO ACTIVATE TIE2 RECEPTOR |
WO2019232203A2 (en) * | 2018-05-31 | 2019-12-05 | Yale University | Methods and compositions to alleviate vascular permeability |
EP3946418A4 (en) * | 2019-03-26 | 2023-02-22 | Asclepix Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR TREATING OCULAR DISEASE |
WO2021178949A1 (en) * | 2020-03-06 | 2021-09-10 | The Board Of Trustees Of The Leland Stanford Junior University | Antibody fragments conjugated to peg-plga nanoparticles improve immunotherapy against cancer cells |
GB202004514D0 (en) | 2020-03-27 | 2020-05-13 | Inst De Medicina Molecular Joaeo Lobo Antunes | Treatment of Immunosuppressive Cancer |
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- 2016-11-18 US US15/776,971 patent/US20180339024A1/en not_active Abandoned
- 2016-11-18 BR BR112018010052A patent/BR112018010052A2/pt not_active IP Right Cessation
- 2016-11-18 WO PCT/US2016/062816 patent/WO2017087825A1/en active Application Filing
- 2016-11-18 CN CN201680078709.0A patent/CN108883150A/zh active Pending
- 2016-11-18 KR KR1020187017365A patent/KR20180081608A/ko unknown
- 2016-11-18 AU AU2016358125A patent/AU2016358125A1/en not_active Abandoned
- 2016-11-18 EP EP16867239.2A patent/EP3377080B1/en active Active
- 2016-11-18 SG SG11201804003VA patent/SG11201804003VA/en unknown
- 2016-11-18 SG SG10202004259PA patent/SG10202004259PA/en unknown
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- 2016-11-18 JP JP2018526543A patent/JP2018535224A/ja active Pending
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Also Published As
Publication number | Publication date |
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IL259376A (en) | 2018-07-31 |
SG10202004259PA (en) | 2020-06-29 |
BR112018010052A2 (pt) | 2019-02-05 |
AU2016358125A1 (en) | 2018-07-05 |
SG11201804003VA (en) | 2018-06-28 |
JP2018535224A (ja) | 2018-11-29 |
US20180339024A1 (en) | 2018-11-29 |
MX2018006194A (es) | 2018-12-06 |
EP3377080B1 (en) | 2024-02-14 |
EP3377080A1 (en) | 2018-09-26 |
WO2017087825A1 (en) | 2017-05-26 |
KR20180081608A (ko) | 2018-07-16 |
CA3005284A1 (en) | 2017-05-26 |
EP3377080A4 (en) | 2019-07-31 |
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