CN111093669A - 用于治疗癌症的腺苷受体拮抗剂的微颗粒制剂 - Google Patents
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Abstract
本发明提供了包含微粒的组合物,其中所述微粒包含至少一种腺苷2a受体拮抗剂(A2ARA)、至少一种药学上可接受的聚合物和至少一种药学上可接受的带负电荷的药剂,其中所述微粒任选地具有小于约‑40mV的高度负的ζ电位。本发明还提供了本发明的微粒的药物组合物,以及使用本发明的组合物增强有需要的患者的免疫应答以及作为抗癌免疫疗法的方法。
Description
相关申请
本申请要求于2017年8月14日提交的美国第62/545,290号临时专利申请的优先权,其全部公开内容通过引用整体并入本文。
本发明涉及用于治疗癌症的免疫疗法,特别是涉及腺苷2a受体拮抗剂(A2ARA)的微粒或纳米颗粒激活免疫细胞杀死肿瘤的用途。
背景技术
免疫疗法正在迅速发展为具有高潜力的癌症治疗方法。免疫检查点疗法的最新进展已获得FDA批准并成功推出了用于治疗各种癌症的多种产品。这些新药产品的基础是于阻断肿瘤与肿瘤浸润T细胞之间的抑制途径。
肿瘤微环境具有免疫抑制性质,可防止免疫细胞杀死肿瘤。肿瘤中的许多免疫抑制机制是与正常组织中的生理免疫调节所共有的,并且对于保持免疫系统处于控制状态以防止自身免疫(autoimmunity)至关重要。然而,肿瘤利用这种生理免疫调节机制来保护其组织免受免疫攻击。结果,这些机制成为免疫癌症治疗的主要障碍。例如,CTLA-4是一种生理机制,其通过阻止CD28–B7相互作用的共刺激信号来负向调节T细胞活性。PD-1在与其配体PD-L1和PD-L2相互作用时也提供T细胞抑制信号。肿瘤中免疫抑制机制的鉴定致使FDA批准抗CTLA-4和抗PD-1抗体用于癌症治疗。
除PD-1和CTLA-4外,还发现了其他免疫检查点分子。例如,已知细胞外腺苷是免疫功能的抑制剂。CD73产生的腺苷还通过激活T细胞和自然杀伤(NK)细胞上的A2A受体来抑制抗肿瘤免疫应答。在大多数免疫细胞中,A2A腺苷受体(A2AR)是主要表达的亚型。刺激A2AR通常提供抑制T细胞(增殖、细胞因子产生、细胞毒性)、NK细胞(细胞毒性)、NKT细胞(细胞因子产生、CD40L上调)、巨噬细胞/树突细胞(抗原呈递、细胞因子产生)和中性粒细胞(氧化爆发)的免疫抑制信号。实际上,已经发现肿瘤中细胞外腺苷水平升高的存在在逃避抗肿瘤免疫应答中起重要作用。肿瘤中富含腺苷的环境可能诱导对肿瘤细胞无反应(anergic)的T细胞。与此变化一致,A2AR刺激在T细胞上诱导免疫调节分子,例如CTLA-4和PD-1。抗原呈递细胞(APC)也是腺苷的靶标。A2AR和A2BR似乎分别主要靶向淋巴样细胞和髓样细胞。腺苷介导的免疫抑制的影响似乎是持久的,而不是短暂的,因为腺苷暴露的结果可以诱导M2型肿瘤相关巨噬细胞、Treg细胞、MDSC和“无反应”效应T细胞。这些事实表明细胞外腺苷是阴性免疫检查点分子,其在建立免疫抑制性肿瘤微环境中起重要作用。因此,靶向腺苷依赖性途径以改善癌症治疗是合理的。利用拮抗剂对A2AR和A2BR的阻断作用可以使腺苷依赖性免疫抑制失活。例如,最近的报道表明,阻断A2A受体可以增强抗PD-1在联合疗法中治疗癌症的功效。
单核细胞和巨噬细胞是先天免疫系统的重要组成部分。它们包括最近被认为是负责识别和清除病原体和死细胞的专职吞噬细胞的异源家族。单核细胞和巨噬细胞主要通过吞噬作用、炎性细胞因子的释放、活性氧(ROS)以及获得性免疫系统的激活,在炎症的引发和消退中起关键作用。单核细胞和巨噬细胞起源于骨髓中常见的骨髓祖细胞。在正常情况下,单核细胞在自发凋亡之前会在血液中循环很短的时间。
巨噬细胞是大型吞噬细胞,几乎存在于每个器官中。它们往往构成一个具有受遗传和环境影响的独特生物活性的高度异质的库(pool)。巨噬细胞在癌症免疫学中起关键作用。例如,诸如肿瘤相关巨噬细胞(TAM)的免疫细胞可占高达50%的乳腺肿瘤质量。巨噬细胞可大致分为两种类型:M1(抗肿瘤)和M2(肿瘤前)巨噬细胞。这些亚型可能不是在募集(recruitment)前预先确定的,而是在到达后被肿瘤微环境“编程(programmed)”或“驯化(educated)”。TAM通常具有M2特性,并促进肿瘤发展、转移和对化疗的抗药性。在临床上,TAM的高肿瘤密度与对化学疗法的抗药性和人类肿瘤的较差临床结果显著相关。近来,已开发出靶向TAM的促肿瘤作用的药物化合物。这些化合物具有多种作用,包括将TAM变为M1巨噬细胞。
巨噬细胞源自单核细胞,响应于分化因子,例如粒细胞-巨噬细胞集落刺激因子(GM-CSF)、巨噬细胞集落刺激因子(M-CSF)和集落刺激因子-1(CSF-1)。对比研究表明,单核细胞和巨噬细胞之间的基因表达存在差异,并且它们的寿命不同。与单核细胞不同,巨噬细胞的寿命很长,从数月到数年不等。据报道,在局部肿瘤环境中施用的超生理剂量的GM-CSF诱导了sVEGFR-1肿瘤产生的VEGF的生成和血管生成。意外地,与未经治疗的肿瘤相比,GM-CSF可以募集显著更多的巨噬细胞至这些肿瘤。曾经,这种作用可能被认为对肿瘤治疗有害,因为许多研究表明,TAM的去除导致血管生成和转移的减少。但是,由于GM-CSF似乎维持了募集到肿瘤中的M1巨噬细胞表型,或者由于GM-CSF“重新驯化”或“重新编程”了M2 TAM回到M1表型,所以这表明增加M1巨噬细胞是有益的,并说明影响巨噬细胞的M1/M2极性为宿主免疫细胞提供了再次发挥其作为抗肿瘤细胞的初始作用的机会。
由于它们在免疫调节中起着关键作用,因此可以利用巨噬细胞和单核细胞来递送治疗剂。使用单核细胞和巨噬细胞作为递送A2AR拮抗剂的靶向位点以抑制与腺苷有关的免疫抑制途径将是有益的。
将A2AR拮抗剂递送至肿瘤微环境是重要的。然而,由于它们的亲脂性、差的溶解性、水解不稳定性和分子尺寸,因此不能将A2AR拮抗剂有效地递送至肿瘤微环境。当前没有可用的方法提供特异性针对肿瘤微环境的A2AR拮抗剂的靶向递送。此外,尚不存在在肿瘤微环境中持续递送A2AR拮抗剂使得效应T细胞可以从A2AR拮抗剂中获得恒定和持续的刺激作用的方法。
因此,本发明的目的是提供一种药物制剂,其可以被单核细胞和巨噬细胞有效吸收并随后转移至肿瘤微环境,提供A2AR拮抗剂的持续释放,从而提高例如免疫细胞杀死癌性肿瘤的能力。
发明内容
本发明提供了包含微粒的组合物,其中所述微粒包含至少一种腺苷2a受体拮抗剂(A2ARA)、至少一种药学上可接受的聚合物和任选地至少一种药学上可接受的带负电荷的药剂,其中所述微粒具有带负电荷的表面。本发明还提供了本发明的微粒的药物组合物,以及使用本发明的组合物增强有需要的患者的免疫应答以及作为抗癌免疫疗法的方法。
具体实施方式
术语“大约”或“基本上包含”是指在特定值或组成的可接受误差范围内的值或组成,如本领域普通技术人员所确定的,这将部分取决于该值或组成如何测量或确定,即测量系统的局限性。例如,根据本领域的实践,“约”可以表示在1个或大于1个标准偏差之内。或者,“大约”或“基本上包含”可以指高达20%的范围。此外,特别是关于生物系统或过程,这些术语可以表示多达一个值的一个数量级或5倍。当在本申请和权利要求书中提供特定值或组成时,除非另有说明,否则应假定“约”或“基本上包含”的含义在该特定值或组成的可接受误差范围内。
如本文所述,除非另有说明,任何浓度范围、百分比范围、比率范围或整数范围应理解为包括在所述范围内的任何整数的值,以及在适当时包括其分数(例如整数的十分之一和百分之一百)。
本发明提供了用于免疫疗法以治疗癌症的微粒的组合物,其中所述微粒可以具有增加的靶向能力、生物利用度、溶解度和缓释性能,该组合物包含至少一种A2AR拮抗剂(A2ARA)的微粒。术语“持续递送”或“持续释放”在本文中是指例如通过在特定时间段内保持基本恒定的药物水平以预定速率将A2ARA递送或释放到肿瘤微环境中。术语“控释”和“缓释(extended release)”、减速释放(retarded release)、延长释放、缓慢释放(slowrelease)、速率控释应理解为用于相同目的。
本发明的一个方面提供了一种药物制剂,其包含至少一种A2AR拮抗剂(A2ARA)、任选的药学上可接受的带负电荷的药剂和药学上可接受的聚合物,其中所述药学上可接受的聚合物包封A2ARA以形成微粒,其中所述微粒具有带负电荷的表面。
如本文所用,“药学上可接受的”包括在合理的医学判断范围内,当与人和动物的组织接触时适合于医学或兽医用途的,不会引起过度的毒性、刺激、过敏反应或其他问题或并发症,且具有合理的收益/风险比的那些化合物、材料、组合物和/或剂型。优选地,药学上可接受的材料(例如,由其产生的聚合物或微粒/纳米颗粒)适合或被批准用于人类医学用途。
药学上可接受的聚合物包括但不限于:聚丙交酯(PLA)、聚(丙交酯-共-乙交酯)(PLGA)、聚ε-己内酯(PCL)。优选地,本发明的微粒包含PLGA。优选地,PLGA的平均分子量为约500至约1,000,000Da,优选为约1,000至约50,000Da。优选地,PLGA包含多个带负电的端基。
如本文所用,术语“微粒”通常是指具有在微米(μm)范围和纳米(nm)范围内的有效平均粒径的颗粒。因此,术语“微粒”包括“纳米颗粒”,并且两个术语都可以在本文中使用。术语“微粒”不旨在表达任何特定的形状限制。微粒包括但不限于具有通常多面体或球形几何形状的那些。
如本文所用,当指的是A2ARA被聚合物包封在微粒内时,术语“包封(encapsulates)”、“封装(encapsulated)”等是指在微粒内而不是在微粒表面上更可能发现A2ARA。
优选地,本发明的微粒的有效粒径为约1nm至约10μm。优选地,微粒的有效粒径为约10微米以下、优选约5微米以下、优选约3微米以下、优选约2微米以下、优选约900nm以下、优选约700nm以下、优选约600nm以下、优选约500nm以下。
例如,“有效平均粒径小于约5微米”是指在添加A2ARA活性剂之前,通过标准技术测量时,微粒组合物的至少50%的微粒具有小于约5微米的平均粒径。在其他实施方案中,本发明的组合物的至少约70%、至少约90%、至少约95%或至少约99%(按重量计)的微粒具有小于有效平均值的粒径,即小于约5微米。通过本领域技术人员众所周知的常规粒径测量技术确定粒径。这样的技术包括,例如,沉降场流分馏、光子相关光谱、光散射、动态光散射、光衍射和圆盘离心。
本发明的微粒的负电荷密度可以通过“ζ电位”来定量。具有负表面电荷的微粒的ζ电位通常在pH为4-10,优选5-8的颗粒的水性悬浮液中测量。优选地,通过本发明的方法制备的微粒或纳米颗粒的ζ电位可以为约-20mV至约-200mV,优选约-30mV至约-100mV,最优选-35mV至-85mV。比约-40mV更负的ζ电位在本文中被称为“高度带负电的颗粒”。本文所述的微粒包括腺苷受体拮抗剂。腺苷受体拮抗剂可以识别多种腺苷受体亚型(即,腺苷Ai受体拮抗剂、腺苷A2A受体拮抗剂、腺苷A2B受体拮抗剂或腺苷A3受体拮抗剂),或可以对一种或多种腺苷受体亚型具有选择性。在一些实施方案中,腺苷受体拮抗剂可以特异性拮抗腺苷受体A2A。在一些实施方案中,拮抗剂对腺苷受体A2A具有选择性。本文所述的腺苷受体拮抗剂可破坏个体的腺苷功能和/或反应性。
如本文所用,“腺苷2a受体拮抗剂(A2ARA)”是指特异性结合腺苷2a受体的拮抗剂分子。术语“对...特异性”、“特异性结合”,“与……特异性结合”在本文中可互换使用,并且是指根据本领域已知的方法确定的拮抗剂区分腺苷2a受体和无关受体的能力,例如使用基于细胞的测定法进行选择性分析。在A2a腺苷受体上是拮抗剂的任何分子均可用于本发明的方法。实例包括但不限于小分子拮抗剂、基因治疗剂、核酶、反义寡核苷酸或选择性结合编码腺苷受体的mRNA的另一种催化核酸、以及可降低组织(包括但不限于抗体、酶、蛋白质或肽、融合蛋白)内腺苷总水平的药物。优选地,A2ARA选自小分子。
优选的A2ARA的实例包括但不限于:咖啡因、茶碱、8-苯基茶碱、SCH58261、伊曲茶碱(istradefylline)、吡唑并[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶或其取代的衍生物(例如甲氧基联芳基或喹啉取代)、SCH412348、SCH420814、稠合的杂环吡唑并[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶或其取代的衍生物(例如四羟基异喹啉或氮杂异喹啉衍生物)、芳基哌嗪取代的3H-[1,2,4]-三唑并[5,l-i]嘌呤-5-胺、芳基茚并嘧啶(arylindenopyrimidine)、芳基茚并嘧啶或其取代的衍生物、吡唑并[4,3-e]-1,2,4-三唑并[4,3-c]嘧啶-3-酮和噻唑并三唑并嘧啶(thiazolotriazolopyrimidine)、1,2,4-三唑并[1,5-c]嘧啶或其取代衍生物、嘌呤或其取代的衍生物、噻吩并[3,2-d]嘧啶、吡唑并[3,4-d]嘧啶和6-芳基嘌呤、苄基取代的三唑并[4,5-d]嘧啶、三唑并9H-嘌呤、氨甲基取代的噻吩并[2,3-d]嘧啶、2-氨基咪唑并吡啶、4-吗啉代-苯并噻唑或其取代的衍生物、4-芳基和4-吗啉代的苯并呋喃、吡啶酮取代的吡嗪、杂环取代的2-氨基噻唑、三取代的嘧啶、哌嗪取代的嘧啶乙酰胺、酰基氨基嘧啶、嘧啶、吡啶或三嗪羧酰胺、它们的混合物或组合及它们的药学上可接受的盐。
优选的A2ARA的实例还包括但不限于:CPI-444、CVT-6883(3-乙基-1-丙基-8-(1-(3-三氟甲基苄基)-1H-吡唑-4-基)-3,7-二氢嘌呤-2,6-二酮)、PBF-509、伊曲茶碱(KW-6002)(8-[(E)-2-(3,4-二甲氧基苯基)乙烯基]-1,3-二乙基-7-甲基-嘌呤-2,6-二酮)、Preladenant(SCH420814)(2-(2-呋喃基)-7-(2-(4-(4-(2-甲氧基乙氧基)苯基)-1-哌嗪基)乙基)-7H-吡唑并(4,3-e)(1,2,4)三唑并(1,5-c)嘧啶-5-胺)、Tozadenant(SYN115)(4-羟基-N-(4-甲氧基-7)-吗啉代苯并[d]噻唑-2-基)-4-甲基哌啶-1-羧酰胺)、维帕丁奈(Vipadenant)(BIIB014)(3-(4-氨基-3-甲基苄基)-7-(2-呋喃基)-3H-(1,2,3)三唑并(4,5-d)嘧啶-5-胺)、HTL-1071、ST1535(2-丁基-9-甲基-8-(三唑-2-基)嘌呤-6-胺)、SCH412348((7-(2-(4-二氟苯基)-1-哌嗪基)乙基)-2-(2-呋喃基)-7H-吡唑并(4,3-e)(1,2,4)三唑并(1,5-c)嘧啶-5-胺)、MRE2029F20、SCH442416(2-(2-呋喃基)-7-[3-(4-甲氧基苯基)丙基]-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶-5-胺)、MRS1754(N-(4-氰基苯基)-2-[4-(2,3,6,7-四氢-2,6-二氧代-1,3-二丙基-1H-嘌呤-8-基)苯氧基]-乙酰胺)、SCH58261(2-(2-呋喃基)-7-(2-苯乙基)-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶-5-胺)、PSB603 a98-[4-[4-(4-氯苯基)哌嗪-1-磺酰基)苯基]]-丙基黄嘌呤(a98-[4-[4-(4-Chlorophenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthinea0)和ZM241385(4-(2-[7-氨基-2-(2-呋喃基)[1,2,4]三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚)。
优选地,本发明的微粒中存在的A2ARA的量可以为微粒的约0.01-50重量%、或微粒的约0.05-25重量%、约0.1-10重量%、约0.2-5重量%、0.5-3重量%、1-5重量%或2-5重量%。
优选地,本发明的微粒的ζ电位为约-40mV以下、约-35mV以下、约-30mV以下、约-25mV以下、或约-20mV以下。最优选地,微粒具有约-35mV以下的负ζ电位。
优选地,微粒或纳米颗粒的ζ电位为约-25mV以下、约-30mV以下、约-35mV以下、-40mV以下、约-45mV以下、或约-50mV以下。例如-40mV至-65mV。
因此,微粒优选包含药学上可接受的带负电荷的药剂,以增加微粒的负表面电荷。尽管要结合到微粒中的负电荷可以为例如:羧酸根、磺酸根、硝酸根、氟根、氯离子、碘根、过硫酸根和许多其他带负电荷的化学基团的形式,最优选的为羧酸根。因此,在某些实施方案中,负电荷主要,主要或仅由羧基赋予。优选地,药学上可接受的带负电荷的药剂选自聚丙烯酸(PAA)和透明质酸(HA)、其类似物或衍生物、或其组合/混合物。羧基可以来自例如PLGA、来自聚丙烯酸和/或来自透明质酸。这种药剂优选是药学上可接受的含羧基药剂,例如用于制备在表面上具有额外羧基的PLGA微粒的药剂。优选地,含羧基的药剂包括但不限于:透明质酸或其类似物或衍生物、明胶多糖、羟乙基甲基丙烯酸、聚丙烯酸、聚甲基丙烯酸、氨基酸或其盐、衍生物、共聚物和混合物。优选地,药学上可接受的带负电的药剂可以覆盖微粒或纳米颗粒的表面,和/或至少部分地掺入到所述微粒或纳米颗粒中以增加微粒或纳米颗粒上的负表面电荷。
基于制剂中使用的药学上可接受的聚合物(例如PLGA)的重量,本发明中使用的药学上可接受的带负电荷的药剂的量为0.01%-30%,优选为0.1%-15%。
本发明的另一方面提供了制备包含所述A2ARA和药学上可接受的聚合物的药物制剂的方法,其中药学上可接受的聚合物包封A2ARA分子以形成颗粒,该方法为单乳液方法,其包括:(a)将A2ARA与药学上可接受的聚合物一起溶解在第一溶剂中以形成聚合物-A2ARA溶液;(b)在第二溶剂中乳化聚合物-A2ARA溶液以形成乳液,其中第一溶剂不可与第二溶剂混溶或仅与第二溶剂部分混溶;和(c)去除第一溶剂以形成颗粒。产生带负电荷的颗粒的方法也可以在美国专利公开第2016/0310426号中找到,该专利通过引用并入本文。
优选地,在步骤(a)中,将A2ARA溶解在第一溶剂的第一部分中以形成溶液,然后在第一溶剂的第二部分中与单独制备的聚合物溶液混合。
优选地,聚合物-A2ARA溶液还包含表面活性剂。可用于制备本发明的微粒的表面活性剂包括但不限于:聚乙烯醇、聚乙烯吡咯烷酮、吐温系列、普朗尼克(Pluronic)系列、泊洛沙姆(Poloxamer)系列、Triton X-100等。下面在本文中提供了其他合适的表面活性剂。优选地,在步骤(b)之前将表面活性剂溶解在第二溶剂中。
优选地,该方法进一步包括在形成乳液之前将额外的活性药物成分(API)溶解或分散在第二溶剂中。
优选地,该方法进一步包括在第一溶剂中溶解或分散第一额外的API(除A2ARA之外),以及在第二溶剂中溶解或分散第二额外的API(除A2ARA之外)。
优选地,使用选自:超声处理、搅拌、均质化、微流化及它们的组合的方法进行乳化。
优选地,该方法进一步包括将生物或化学实体(entity)吸附或结合到A2ARA的所述颗粒的表面。
优选地,本发明还提供一种制备包含A2ARA和药学上可接受的聚合物的药物制剂的方法,其中药学上可接受的聚合物包封A2ARA分子以形成颗粒,该方法为双乳液法,其包括:(a)将A2ARA与药学上可接受的聚合物一起溶解在第一溶剂以形成聚合物-A2ARA溶液;(b)向聚合物-A2ARA溶液中加入少量(例如0.5重量%、1重量%、5重量%)的第二溶剂以形成混合物,其中第一溶剂不可与第二溶剂混溶或仅与第二溶剂部分混溶;(c)乳化混合物以形成第一乳液;(d)在第三溶剂中乳化第一乳液以形成第二乳液;和(e)除去第一溶剂以形成所述颗粒。
优选地,第二溶剂和第三溶剂为相同的溶剂。优选地,第二溶剂和第三溶剂均为水。优选地,第三溶剂进一步包含表面活性剂。优选地,表面活性剂选自:洗涤剂(detergent)、湿润剂、乳化剂、发泡剂和分散剂。优选地,表面活性剂为聚乙烯醇(PVA)。
优选地,该方法还包括在形成第一乳液之前将额外的API溶解或分散在第二溶剂中。优选地,将A2ARA化合物溶解在步骤(b)的第二溶剂中而不是步骤(a)的第一溶剂中。优选地,该方法进一步包括在第一溶剂中溶解或分散第一额外的API(除A2ARA之外),以及在第二溶剂中溶解或分散第二额外的API(除A2ARA之外)。
优选地,使用选自:超声处理、搅拌、均质化、微流化及它们的组合的方法进行乳化。
优选地,该方法进一步包括将生物或化学实体吸附或结合到所述A2ARA颗粒的表面。
优选地,第一溶剂不可与水混溶,或选自乙酸乙酯、二氯甲烷和氯仿。
优选地,将水混溶性溶剂与非水混溶性溶剂混合作为共溶剂以溶解聚合物或A2ARA或两者。
优选地,第二溶剂为水,或者第三溶剂为水。
优选地,聚合物溶液具有选自以下的浓度:1μg/mL-1g/mL(w/w)、1mg/mL-500mg/mL(w/w)和10mg/mL-250mg/mL(w/w)。
优选地,本发明还提供一种制备包含A2ARA和药学上可接受的聚合物的药物制剂的方法,其中药学上可接受的聚合物包封A2ARA分子以形成颗粒,该方法为沉淀方法,其包括:(1)将A2ARA与药学上可接受的聚合物一起溶解在第一溶剂中;(2)任选地向第一溶剂中加入包含表面稳定剂的第一溶液以形成配制物(formulation);和(3)将步骤(2)的配制物沉淀到包含在第二溶剂中的表面稳定剂的第二溶液中,其中第二溶剂可与第一溶剂混溶,并且对于聚合物和A2ARA都是非溶剂。优选地,第一溶剂选自:DMSO、DMF、丙酮、醇、乙腈和THF。优选地,第二溶剂选自:水、甲醇、乙醇、异丙醇、苯甲醇。在某些实施方案中,第二溶剂为水。优选地,该方法进一步包括通过离心、渗析或渗滤去除不想要的稳定剂或任何杂质(如果存在的话)。
本发明还提供了用于在有需要的患者中增强免疫应答的方法。该方法包括向有此需要的患者施用治疗有效量的本发明的A2ARA微粒组合物。优选地,患者需要抗癌免疫疗法。
药剂(例如药物组合物)的“治疗有效量”是指在所需的剂量和时间段内有效实现所需治疗或预防效果的量。药剂的治疗有效量例如消除、减少、延迟、最小化或防止疾病的不利影响。几种活性成分的组合的治疗有效量可以为每种活性成分的治疗有效量。可选择地,为了减少由治疗引起的副作用,几种活性成分的组合的治疗有效量可以是有效产生累加作用或协同作用并且组合治疗有效的单个活性成分的量,但如果活性成分单独使用,则可以是一种或几种活性成分的亚治疗量。
术语“免疫疗法”是指通过包括诱导、增强、抑制或以其他方式改变免疫应答的方法来治疗患有疾病、或有患上疾病或复发的风险的个体。个体的“治疗”或“疗法”是指对个体进行的任何类型的干预或过程,或向个体施用活性剂,其目的是逆转、减轻、改善、抑制、减慢或预防发作与疾病相关的症状、并发症、病状或生化指标的开始、进展(progression)、发展(development)、严重程度或复发。
本发明还提供一种在有此需要的个体中治疗癌症的方法,该方法包括施用治疗有效量的本文所述的微粒A2ARA组合物。在某些实施方案中,癌症包括乳腺癌、胰腺癌、肺癌、皮肤癌、膀胱癌、血液癌、肾癌、脑癌、成胶质细胞瘤、食道癌、胃癌和结肠癌。
根据本发明的治疗癌症的方法包括治疗癌性肿瘤(包括但不限于实体瘤)的方法,其包括将本发明的微粒注射或植入到肿瘤微环境中的步骤。根据本发明的治疗癌症的方法包括治疗肿瘤的方法,该方法包括肿瘤内注射本发明的微粒或植入本发明的微粒的步骤。
如本文所用,“治疗”(及其语法变化,例如“处理”或“救治”)是指改变被治疗个体中疾病自然病程的临床干预,并且可以用于预防或在临床病理学的病程中进行。理想的治疗效果包括但不限于预防疾病的发生或复发、减轻症状、减少疾病的任何直接或间接病理后果、预防转移、降低疾病进展的速度、缓解或减轻疾病状态、缓解或改善预后。在一些实施方案中,本发明的组合用于延迟疾病的发展或减慢疾病的进展。
本发明的微粒组合物可用于治疗、预防、管理和减缓患者中的癌症以及其他异常细胞增殖相关疾病的扩散。在某些实施方案中,本发明提供了治疗癌症的方法,所述癌症包括由上皮组织例如泌尿生殖系统、消化系统和呼吸系统的腺体、乳房、皮肤和内膜引起的肿瘤。可以治疗或预防肺癌、癌症和前列腺癌。可以治疗或预防的乳腺癌包括浸润性癌(例如浸润性导管癌、浸润性小叶癌、浸润性导管和小叶癌、髓样癌、粘液性(胶体)癌、佩吉特病(Paget's disease)、乳头状癌、小管癌(tubular carcinoma)、腺癌(NOS)和上皮癌(carcinoma)(NOS))和非浸润性癌(例如导管内癌、原位小叶癌(LCIS)、导管内LCIS和乳头状癌)。本发明还可用于治疗或预防转移性乳腺癌。转移性乳腺癌的非限制性实例包括骨癌、肺癌和肝癌。
可以用本文描述的方法治疗或预防的前列腺癌,包括局部、区域和转移性前列腺癌。局限性前列腺癌包括A1-A2、T1a-T1b、T1c、B0-B2或T2a-T2c。也考虑了C1-C2或T3a-N0、延伸到前列腺之外但是没有牵连淋巴结的前列腺癌。区域性前列腺癌包括D1或N1-M0,而转移性前列腺癌包括D2或M1。转移性前列腺癌包括骨癌和脑癌。
提供了使用A2a受体拮抗剂与基于细胞的疫苗组合或交替使用来治疗或预防异常细胞增殖的方法。在这些实施方案的某些中,基于细胞的疫苗是基于与要预防的肿瘤匹配的细胞。例如,如果患者患有前列腺癌或有患前列腺癌的风险,则基于细胞的疫苗将基于前列腺癌肿瘤细胞。在这些情况下,通常会照射细胞或防止细胞复制。在特定的实施方案中,细胞经遗传修饰以分泌集落刺激因子(colony stimulating factor)。
可以用本发明治疗或预防的其他癌症,包括但不限于肠癌、膀胱癌、脑癌、子宫颈癌、结肠癌、直肠癌、食道癌、眼癌、头颈癌、肝癌、肾癌、喉癌、肺癌、皮肤癌、卵巢癌、胰腺癌、垂体癌、胃(stomach)癌、睾丸癌、胸腺癌、甲状腺癌、子宫癌和阴道癌以及肾上腺皮质癌、类癌瘤、内分泌癌、子宫内膜癌、胃癌(gastric cancer)、妊娠滋养细胞肿瘤、胰岛细胞癌和间皮瘤。
可以用本发明治疗或预防的淋巴瘤,包括由淋巴或脾脏引起的肿瘤,其可以引起淋巴细胞的过量产生,包括霍奇金氏病和非非霍奇金氏淋巴瘤。术语“霍奇金病”旨在包括通过本领域技术人员已知的REAL和世界卫生组织(WHO)类别进行分类的疾病,包括经典霍奇金病(即结节性硬化症、混合细胞型、淋巴细胞消减型或淋巴细胞丰富型)或淋巴细胞优势霍奇金氏病。术语“非霍奇金淋巴瘤”用于指由WHO分类的30种淋巴瘤(Harris N L etal.(2000)Lymphoma classification-from controversy to consensus:the REAL andWHO Classification of lymphoid neoplasms.Ann Oncol.11(suppl1):S3-S10),包括但不限于:B细胞非霍奇金淋巴瘤,例如小淋巴细胞淋巴瘤(SLL/CLL)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤边缘区淋巴瘤(MZL)、结外淋巴瘤(MALT淋巴瘤)、淋巴结淋巴瘤(单核细胞样B细胞淋巴瘤)、脾脏淋巴瘤、弥漫性大细胞淋巴瘤、伯基特淋巴瘤(burkitt's lymphoma)和淋巴母细胞性淋巴瘤;T细胞非霍奇金淋巴瘤,例如淋巴母细胞性淋巴瘤、外周T细胞淋巴瘤;肝脾γ-δT细胞淋巴瘤、皮下脂膜炎样淋巴瘤、血管免疫母细胞性T细胞淋巴瘤(AILD)、结外NK/T细胞淋巴瘤、鼻型(nasal type)淋巴瘤、肠道T细胞淋巴瘤(+/-与肠病相关)(EATL)、成人T细胞白血病/淋巴瘤(与HTLV-1相关)、蕈样真菌病/赛塞里综合征(mycosis fungoides/Sezary syndrome)、间变性大细胞淋巴瘤(ALCL),包括原发性皮肤(primary cuteous)淋巴瘤和原发性系统型(primary systemic)淋巴瘤。
可以用本发明治疗或预防的白血病包括但不限于慢性和急性的髓样和淋巴细胞性(有时称为B或T细胞白血病)或髓系白血病(myeloid leukemias)。髓系白血病包括慢性髓系白血病(CML)和急性髓系白血病(AML)(即急性非淋巴细胞性白血病(acutenonlymphocytic leukemia)(ANLL))。淋巴细胞性白血病包括急性淋巴细胞性白血病(ALL),慢性淋巴细胞性白血病(CLL)(即慢性粒细胞性白血病)和毛细胞白血病(hairycell leukemia)(HCL)。
可以用本发明治疗或预防的肉瘤(Sarcomas)包括肌肉、腱、纤维组织、脂肪、血管神经和滑膜组织的骨骼和软组织肉瘤。非限制性实例包括纤维肉瘤、横纹肌肉瘤、脂肪肉瘤、滑膜肉瘤、血管肉瘤、神经纤维肉瘤、胃肠道间质瘤、卡波西氏肉瘤(Kaposi'ssarcoma)、尤因氏肉瘤(Ewing's sarcoma)、腺泡状软组织肉瘤(alveolar soft-partsarcoma)、血管肉瘤、隆突性皮肤纤维肉瘤、上皮样肉瘤、骨外软骨肉瘤(extraskeletalchondrosarcoma)、骨外骨肉瘤、纤维肉瘤、平滑肌肉瘤、脂肪肉瘤、恶性纤维组织细胞瘤、恶性血管外皮瘤(malignant hemangiopericytoma)、恶性间叶瘤(malignantmesenchymoma)、恶性神经鞘瘤(malignant schwannoma)、恶性周围神经鞘膜瘤(malignantperipheral nerve sheath tumor)、骨旁骨肉瘤、周围神经外胚层肿瘤(peripheralneuroectodermal tumor)、横纹肌肉瘤、滑膜肉瘤(synovial sarcoma)和肉瘤、NOS。
用本发明可以治疗或预防除癌症以外的异常细胞增殖的疾病。作为非限制性实例,与血管平滑肌细胞异常增殖相关的疾病包括良性肿瘤。良性肿瘤的非限制性实例包括良性骨肿瘤、脑肿瘤和肝肿瘤。
优选地,本发明还提供与本发明的微粒与其他抗癌治疗剂和抗癌剂的组合疗法,包括但不限于:其他抗癌免疫疗法(例如施用检查点抑制剂)、其他免疫调节剂(例如免疫抑制剂和免疫增强剂)、放射疗法和化学疗法。
与细胞增殖异常有关的其他疾病包括例如动脉粥样硬化和再狭窄(restenosis)。还包括与过度增殖和组织肥大细胞积聚异常增殖有关的疾病,例如皮肤肥大细胞增生症(cutaneous mastocytosis)(CM)和色素性荨麻疹。还考虑了与肾小球系膜细胞(xesangialcell)增生的异常增生相关的疾病,包括但不限于IgA肾病、膜性增生性肾小球肾炎(GN)、狼疮性肾炎和糖尿病性肾病。
银屑病(Psoriasis)可以通过本发明治疗或预防,包括但不限于斑块状银屑病,滴状银屑病,反转型银屑病(inverse Psoriasis),脂溢性银屑病,指甲型银屑病,全身性红皮病型银屑病(generalized erythrodermic psoriasis)(也称为银屑病剥脱性红皮病(psoriatic exfoliative erythroderm)),脓疱性银屑病和Von Zumbusch型银屑病。
本发明也可以用于治疗或预防淋巴管肌瘤病(LAM)以及本领域技术人员已知的与异常细胞增殖有关的其他疾病。
本文所述的A2ARA微粒组合物可以通过任何常规方式施用至个体,包括但不限于:经口、直肠、眼、肠胃外(例如静脉内、肌内或皮下)、脑池内、颅内、肺、阴道内、腹膜内、局部(例如散剂、软膏或滴剂)、或通过口腔或鼻腔喷雾剂。优选地,通过注射或通过植入到肿瘤或肿瘤微环境的至少一部分中而在瘤内或肿瘤微环境施用微粒组合物。术语“瘤内”旨在包括施用于病变处,即病灶内。
如本文所用,术语“个体”用于表示动物,优选哺乳动物,包括人或非人。术语患者和个体在本文中可互换使用。
本文所述的微粒组合物可以配制成任何合适的剂型,包括但不限于液体分散体、凝胶、气溶胶、软膏、乳膏、控释制剂、速熔制剂(fast melt formulation)、冻干制剂、片剂、胶囊剂、缓释制剂(delayed release formulation)、延迟释放制剂、脉冲式释放制剂以及速释和控释混合制剂。
适用于肠胃外注射的组合物可包括生理学上可接受的无菌水性溶液或非水性溶液、分散液、悬浮液或乳剂、以及用于重建为无菌注射液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂或赋形剂(vehicle)的实例,包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其合适的混合物、植物油(例如橄榄油)和可注射的有机酯如油酸乙酯。可以例如通过使用诸如卵磷脂的包衣,在分散液的情况下通过维持所需的粒径以及通过使用表面活性剂来维持适当的流动性。
A2ARA微粒组合物还可包含助剂,例如防腐剂、湿润剂、乳化剂和分散剂(dispensing agent)。可以通过各种抗细菌和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等来确保防止微生物的生长。还可能需要包括等渗剂,例如糖、氯化钠等。通过使用延迟吸收的药剂,例如单硬脂酸铝和明胶,可以延长可注射药物剂的吸收。
用于口服的固体剂型包括但不限于胶囊剂、片剂、丸剂、粉剂和颗粒剂。在此类固体剂型中,将活性剂与以下至少一种混合:(a)一种或多种惰性辅料(或载体),例如柠檬酸钠或磷酸二钙;(b)填料(filler)或填充剂(extender),例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(c)粘合剂,例如羧甲基纤维素、藻酸盐(alignates)、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(d)保湿剂,例如甘油;(e)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些复合硅酸盐和碳酸钠;(f)缓凝剂(solution retarder),例如石蜡;(g)吸收促进剂,例如季铵化合物;(h)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(i)吸附剂,例如高岭土和膨润土;(j)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠或它们的混合物。对于胶囊剂、片剂和丸剂,剂型还可以包含缓冲剂。
液体微粒组合物包括用于口服的剂型,包括药学上可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂(elixir)。液体剂型可包含本领域常用的惰性稀释剂,例如水或其他溶剂、增溶剂和乳化剂。乳化剂的实例为乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(例如棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇、失水山梨糖醇的脂肪酸酯或这些物质的混合物等。
以下非限制性实施例进一步说明了本发明。
实施例
实施例1-包含SCH442416(2-(2-呋喃基)-7-[3-(4-甲氧基苯基)丙基]-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶-5-胺)(高选择性A2ARA)的纳米颗粒的制备。
将约5mg的SCH442416溶解在8mL的乙酸乙酯中。将该溶液超声处理1分钟以确保完全溶解。将约200mg聚乳酸-羟基乙酸共聚物(PLGA)溶解在相同的8mL SCH溶液中。将得到的溶液倒入盛有40mL的用乙酸乙酯饱和的0.5%聚乙烯醇(PVA)溶液的4盎司的玻璃瓶中。然后立即使用IKA旋转定子(roto stator)在23,800rpm下将混合物均质1分钟。将所得乳液转移到100mL烧杯中,并以610rpm磁力搅拌3小时。形成颗粒并硬化后,使用切向流过滤将乳液用100mL蒸馏水洗涤3次,并冷冻干燥。所获得的颗粒的平均直径为555nm。
实施例2-含SCH442416和荧光染料的带负电荷的纳米颗粒的制备。
将约5mg的SCH442416(SCH)溶于8mL乙酸乙酯。将该溶液超声处理1分钟以确保完全溶解。将约200mg的聚乳酸-羟基乙酸共聚物(PLGA)与2mg香豆素-6溶解在同一8mL SCH溶液中。将得到的溶液倒入盛有40mL的用乙酸乙酯饱和的0.5%聚乙烯醇(PVA)溶液的4盎司的玻璃瓶中。然后立即使用IKA旋转定子在23,800rpm下将混合物均质1分钟。将所得乳液转移到100mL烧杯中,并以610rpm磁力搅拌3小时。形成颗粒并硬化后,使用切向流过滤将乳液用100mL蒸馏水洗涤3次,并冷冻干燥。所获得的颗粒的平均直径为555.4nm。
实施例3-含SCH442416的带负电的纳米颗粒的制备。
将约5mg的SCH442416(SCH)溶于8mL乙酸乙酯。将该溶液超声处理1分钟以确保完全溶解。将约200mg聚乳酸-羟基乙醇共聚物(PLGA)溶解在同样的8mL SCH溶液中。将得到的溶液倒入盛有40mL的用乙酸乙酯饱和的0.5%的聚乙烯醇(PVA)溶液和120mg的35重量%的聚(丙烯酸)溶液的4盎司的玻璃瓶中。然后立即使用IKA旋转定子在24000rpm下将混合物均质1分钟。将所得乳液转移至100mL烧杯中,并以610rpm磁力搅拌3小时。形成颗粒并硬化后,使用切向流过滤将乳液用100mL蒸馏水洗涤3次,并冷冻干燥。所获得的颗粒的平均直径为525.4nm,ζ电位为-45.8mV。
实施例4-含SCH442416和亲脂性荧光染料DiD'油的带负电的纳米颗粒的制备。
将约5mg的SCH-442416(SCH)溶于8mL乙酸乙酯。将该溶液超声处理1分钟以确保完全溶解。将约200mg的聚乳酸-羟基乙酸共聚物(PLGA)与2mg的DiD'油:DiIC18(5)油(1,1'-双十八烷基-3,3,3',3'-四甲基吲哚二碳菁高氯酸盐(1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindodicarbocyanine Perchlorate))一起溶解在同一8mL SCH溶液中。将得到的溶液倒入盛有40mL的用乙酸乙酯饱和的0.5%的聚乙烯醇(PVA)溶液和120mg的35重量%的聚(丙烯酸)溶液的4盎司的玻璃瓶中。然后立即使用IKA旋转定子在24000rpm下将混合物均质1分钟。将所得乳液转移到100mL烧杯中,并以610rpm磁力搅拌3小时。形成颗粒并硬化后,使用切向流过滤将乳液用100mL蒸馏水洗涤3次,并冷冻干燥。所获得的颗粒的平均直径为598.4nm,ζ电位为-46.7mV。
实施例5-含SCH58261(2-(呋喃-2-基)-7-苯乙基-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶-5-胺)(高选择性A2ARA)的带负电的纳米颗粒的制备。
将约4mg的SCH58261(SCH)溶解在0.25mL的二甲基亚砜(DMSO)中。将该溶液超声处理1分钟以确保完全溶解。将约200mg聚乳酸-羟基乙酸共聚物(PLGA)溶解在7.75mL乙酸乙酯中,并与SCH/DMSO溶液混合。将得到的溶液倒入盛有40mL的用乙酸乙酯饱和的0.5%的聚乙烯醇(PVA)溶液和120mg的35重量%的聚(丙烯酸)溶液的4盎司的玻璃瓶中。然后立即使用IKA旋转定子以25000rpm将混合物均质1分钟。将所得乳液转移到100mL烧杯中,并以610rpm磁力搅拌3小时。形成颗粒并硬化后,使用切向流过滤将乳液用100mL蒸馏水洗涤3次,并冷冻干燥。所获得的颗粒的平均直径为561.5nm,ζ电位为-44.8mV。
实施例6-含SCH58261和亲脂性荧光染料DiR'的高度带负电的微粒(1-1.5μm)的制备。
将约2.5mg的SCH58261(SCH)溶解在0.25mL的二甲基亚砜(DMSO)中。将该溶液超声处理1分钟以确保完全溶解。将约100mg的聚乳酸-羟基乙酸共聚物(PLGA)与0.2mg的DiR'染料:DiIC18(7)1,1'-双十八烷基-3,3,3',3'-四甲基吲哚三碳菁碘化物(1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindotricarbocyanine Iodide)一起溶解在3mL乙酸乙酯中。加入PLGA/染料溶液,并与SCH溶液混合。将得到的溶液倒入盛有10mL的用乙酸乙酯饱和的1.0%聚乙烯醇(PVA)溶液和70mg的35wt%的聚(丙烯酸)溶液的15mL玻璃小瓶中。然后立即使用组织混合器以最大速度将混合物均质30秒。将所得乳液转移至50mL烧杯中,并以400rpm磁力搅拌3小时。颗粒形成并硬化后,使用Heraeus Biofuge 22R离心机将其在5300rcf下将颗粒离心(spun down)10分钟,然后倒出所有上清液。将小球(pellet)重悬并用50mL蒸馏水洗涤,然后将颗粒在5300rcf下再次离心10分钟。所获得的颗粒的平均直径为1.452μm,负ζ电位为-41.3mV。
实施例7-含SCH58261和亲脂性荧光染料DiR'的微粒(1-1.5μm)的制备。
将约4mg SCH58261(SCH)溶解在0.3mL二甲基亚砜(DMSO)中。将该溶液超声处理1分钟以确保完全溶解。将约200mg的聚乳酸-羟基乙酸共聚物(PLGA)与DiR'染料(0.2mg)一起溶解在10mL乙酸乙酯中。加入PLGA/染料溶液,并与SCH溶液混合。将所得溶液倒入盛有30mL的0.1%聚乙烯醇(PVA)溶液的50mL锥形管中。然后立即使用IKA旋转定子以13,000rpm将混合物均质2分钟。将所得乳液转移至100mL烧杯中,并以400rpm磁力搅拌5小时。颗粒形成并硬化后,使用Heraeus Biofuge 22R离心机以5,300rcf的速度离心10分钟,然后倒出所有上清液。将小球重悬并用50mL蒸馏水洗涤,并在5,300rcf下再次离心5分钟。所获得的颗粒的平均直径1.299μm,ζ电位为-33.1mV。
本文所指的专利和科学文献建立了本领域技术人员可获得的知识。本文引用的所有美国专利和已公开或未公开的美国专利申请均通过引用并入本文。本文引用的所有公开的外国专利和专利申请均通过引用并入本文。本文引用的所有其他公开的参考文献、文件、手稿和科学文献通过引用并入本文。
尽管已经参照本发明的优选实施方案具体示出和描述了本发明,但是本领域技术人员将理解,在不脱离所附权利要求所涵盖的本发明范围的情况下,可以在形式和细节上进行各种改变。还应当理解,本文描述的实施方案不是互相排斥的,并且根据本发明,来自各个实施方案的特征可以整体或部分地组合。
Claims (15)
1.一种包含微粒的组合物,其中所述微粒包含至少一种腺苷2a受体拮抗剂(A2ARA)、至少一种药学上可接受的聚合物和任选地至少一种药学上可接受的带负电荷的药剂,其中所述微粒具有带负电荷的表面。
2.根据权利要求1所述的组合物,其中所述至少一种药学上可接受的聚合物为PLGA。
3.根据权利要求1所述的组合物,其包含至少一种药学上可接受的带负电荷的药剂。
4.一种治疗有需要的个体中的癌症的方法,其包括施用有效量的权利要求1所述的微粒组合物。
5.一种增强有需要的患者中的免疫应答的方法,所述方法包括向患者施用治疗有效量的权利要求1所述的A2ARA微粒组合物。
6.根据权利要求4所述的方法,其中所述患者需要免疫疗法以治疗癌症。
7.根据权利要求1所述的方法,其中所述微粒的ζ电位为约-25mV以下。
8.根据权利要求1所述的方法,其中所述微粒的ζ电位为约-35mV以下。
9.根据权利要求4所述的方法,其进一步包括施用检查点抑制剂、化学疗法、放射线或它们的任何组合。
10.一种治疗癌性肿瘤的方法,其包括瘤内注射或瘤内植入权利要求1所述的微粒的步骤。
11.一种治疗癌性肿瘤的方法,其包括将权利要求1所述的微粒注入所述肿瘤微环境的步骤。
12.一种将A2ARA持续递送至肿瘤微环境的方法,其包括将权利要求1所述的微粒注入所述肿瘤微环境的步骤。
13.根据权利要求1所述的组合物,其中微粒的有效粒径为约1nm至约10μm。
14.根据权利要求13所述的组合物,其中所述微粒的有效粒径选自10微米以下、5微米以下、3微米以下、2微米以下、900nm以下、700nm以下、600nm以下和500nm以下。
15.根据权利要求1所述的组合物,其被配制为用于经口、直肠、眼、肠胃外、脑池内、颅内、肺、阴道内、腹膜内、局部、肿瘤内通过注入到所述肿瘤微环境中,通过口腔或鼻喷雾剂施用至个体。
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US20210007992A1 (en) | 2021-01-14 |
US10702476B2 (en) | 2020-07-07 |
EP3668517A1 (en) | 2020-06-24 |
WO2019036438A1 (en) | 2019-02-21 |
US20230181469A1 (en) | 2023-06-15 |
US20190046448A1 (en) | 2019-02-14 |
EP3668517A4 (en) | 2021-02-17 |
AU2018317390A1 (en) | 2020-04-02 |
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