CN109952369B - 涉及nk细胞和抗pdl1癌症治疗的方法和组合物 - Google Patents
涉及nk细胞和抗pdl1癌症治疗的方法和组合物 Download PDFInfo
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Abstract
公开了涉及通过诱导PDL1和使用抗PDL1抗体治疗癌症的组合物和方法。
Description
本申请要求2016年10月5日提交的美国临时申请No.62/404,520的权益,该临时申请通过引用整体并入本文。
背景技术
1.现已充分确定,PD-L1在大多数肿瘤上的表达是响应于募集到肿瘤部位的CD8T细胞分泌的IFNγ而诱导的。在肿瘤上诱导PD-L1表达引发事件的级联,例如调节性T细胞的增殖,产生免疫抑制环境的吲哚胺-2,3-双加氧酶(IDO)的上调。PD-L1还通过与PD-1受体的相互作用直接阻断细胞毒性T细胞的功能,并导致其无反应性和细胞凋亡。然后这些变化有助于肿瘤进展和转移。
2.利用抗体破坏PD-1/PD-L1相互作用的癌症疗法已经成为迄今为止最令人兴奋的发展之一,导致患有各种恶性肿瘤甚至非常晚期疾病的患者持久、长期的缓解。新的抗PD-L1/抗PD-1疗法能够在癌症中解放瘫痪的免疫系统,其中通过诱导PD-L1和随后的免疫抑制级联停止对肿瘤的初始免疫应答。然而,仅在具有淋巴细胞浸润的PD-L1阳性肿瘤的患者中观察到反应,所述淋巴细胞浸润在肿瘤类型中只限于10-20%的患者。因此,PD-L1/PD-1阻断疗法仅在免疫系统的强烈初始应答诱导PD-L1时有效。所需要的是可以绕过PD-L1免疫抑制级联的新癌症疗法,但不限于已经诱导PD-L1的癌症。
发明内容
3.公开了在受试者中治疗癌症的方法,包括向受试者施用NK细胞(例如,扩增的记忆性(Expanded memory,XM)NK细胞和/或过继性NK细胞)和抗PDL1抗体。
4.在一个方面,通过使初始NK细胞群与PM21颗粒、EX21外泌体或FC21饲养细胞接触来活化或扩增该扩增的记忆性NK细胞。
5.在一个方面,NK细胞可以源自外周血、脐带血、胎盘血、来自CMV血清阳性供体,或衍生自其他来源,例如诱导的多能干细胞、胚胎干细胞或永生化NK细胞样细胞系,例如NK92。
6.还公开了任何前述方面的方法,其进一步包括在向受试者施用扩增的记忆性NK细胞和/或向受试者施用IL-12、IL-15和IL-18中的一者或多者之前使NK细胞与IL-12、IL-15和IL-18中的一者或多者接触,然后用PM21颗粒、EX21外泌体或FC21饲养细胞扩增。
7.还公开了任何前述方面的方法,其进一步包括在将扩增的记忆性NK细胞施用于受试者和/或向受试者施用IL-12、IL-15和IL-18中的一者或多者之前,使所述NK细胞(例如扩增的记忆性(XM)NK细胞)接触IL-12、IL-15和IL-18中的一者或多者。
8.还公开了任何前述方面的方法,其进一步包括向受试者施用PM21颗粒或EX21外泌体。
9.在一个方面,本文公开了在受试者中治疗癌症的方法,包括向受试者施用PM21颗粒或EX21外泌体和抗PDL1抗体。
10.还公开了任何前述方面的方法,其还包括施用IL-12、IL-15和IL-18中的一者或多者。
11.在一个方面,本文公开了包含PM21、EX21或FC21扩增的记忆性NK细胞和抗PDL1抗体的抗癌疗法。
12.还公开了任何前述方面的抗癌疗法,其进一步包含PM21颗粒或EX21外泌体和/或IL-12、IL-15和IL-18中的一者或多者。
13.在一个方面,本文公开了包含PM21颗粒或EX21外泌体和抗PDL1抗体的抗癌疗法。
14.还公开了任何前述方面的抗癌疗法,其还包含IL-12、IL-15和IL-18中的一者或多者。
15.在一个方面,本文公开了在受试者中治疗癌症的方法,包括内源性扩增或活化受试者的NK细胞,然后施用抗PDL1抗体;其中通过向受试者施用PM21颗粒或EX21外泌体来扩增或活化该受试者的NK细胞。
16.还公开了任何前述方面的治疗癌症的方法,其进一步包括向所述受试者施用IL-12、IL-15和IL-18中的一者或多者。
附图说明
17.包含在本说明书中并构成其一部分的附图示出了若干实施例,并与说明书一起示出了所公开的组合物和方法。
18.图1显示PM21-粒子扩增的NK细胞比IL-2活化的NK细胞产生更高水平的IFNγ。将NK细胞用PM21-粒子扩增12天或用100U IL-2预活化过夜,然后在未刺激的NK细胞(左)或单独暴露于K562细胞(中)或一起暴露于细胞因子(IL-12、IL-15和IL-18)(右)的细胞中分析IFNγ的产生。将未刺激和刺激的NK细胞透化并用抗-IFNγAb染色并通过流式细胞术分析。
19.图2A和2B显示PM21NK细胞对SKOV-3细胞具有细胞毒性,并在刺激后分泌IFNγ和TNFα。图2A显示NK细胞用PM21-颗粒扩增14天或用IL2(100U,O/N)活化,然后以递增的比例加入SKOV-3细胞。将细胞温育30分钟,并使用膜联蛋白V-v450染色测定GFP+SKOV-3细胞的活力,同时基于参考孔仅用SKOV-3细胞测定细胞毒性。图2B显示扩增的PM21-NK细胞未经刺激或单独暴露于SKOV-3或在细胞因子IL12/18存在下暴露于SKOV-3细胞4小时。对细胞进行表面标记物染色,透化并染色IFNγ和TNFα,然后通过流式细胞术分析。
20.图3A、3B和3C显示过继转移的PM21NK细胞在SKOV-3细胞上诱导PD-L1并在体内驱动Treg扩增。给NSG小鼠腹膜内注射1×106个SKOV-3细胞。在第8天和第13天用10×106个PM21NK细胞或载体对照处理小鼠,然后进行IL2注射(25000U,3x/周)。在第1次NK细胞注射后第12天处死小鼠,收集肿瘤和腹膜冲洗液用于分析。图3A显示灌注肿瘤以获得单细胞悬浮液并用抗PD-L1染色。图3B显示分析腹膜洗涤细胞以获得在NK细胞和T细胞上PD-1表达的存在以及调节性T细胞(CD3+CD4+CD25明亮FoxP+)的存在(图3C)。
21.图4显示分泌IFNγ的NK细胞诱导PD-L1表达和用抗PDL1mAb组合治疗的示意图。用过继转移的NK细胞攻击PD-L1阴性(或低)肿瘤。NK细胞通过分泌高水平的IFN-γ对肿瘤起反应,这反过来导致在肿瘤细胞上诱导高水平的PD-L1(导致免疫抑制的防御机制)。现在可以用抗PD-L1抗体结合能够抗体依赖性细胞毒性(ADCC)的细胞(如CD16+NK细胞)的过继转移高效靶向PD-L1。在肿瘤上诱导PD-L1还将提供用于通过针对该分子的ADCC或CARs-T细胞用NK细胞进行肿瘤治疗的通用的、可靶向的配体,用于癌症治疗的通用平台。
具体实施方式
22.在公开和描述本发明化合物、组合物、制品、装置和/或方法之前,应理解除非另有说明,否则它们不限于特定的合成方法或特定的重组生物技术方法,或者除非另有说明,否则不限于特定的试剂。当然,可能会有所不同。还应理解,本文使用的术语仅用于描述特定实施方案的目的,而不是限制性的。
A.定义
23.如说明书和所附权利要求中所使用的,单数形式“一”、“一个”和“该”包括复数指示物,除非上下文另有明确规定。因此,例如,提及“药物载体”包括两种或更多种这样的载体的混合物等。
24.范围在本文中可以表示为从“约”一个特定值,和/或到“约”另一个特定值。当表达这样的范围时,另一个实施例包括从一个特定值和/或到另一个特定值。类似地,当通过使用先行词“约”将值表示为近似值时,将理解该特定值形成另一个实施例。将进一步理解,每个范围的端点相对于另一个端点都是重要的,并且独立于另一个端点。还应理解,本文公开了许多值,并且除了值本身之外,每个值在本文中也被公开为“约”该特定值。例如,如果公开了值“10”,则还公开了“约10”。还应理解,当公开值“小于或等于”该值时,“大于或等于该值”和值之间的可能范围也被公开,如本领域技术人员适当理解的。例如,如果公开值“10”,则还公开了“小于或等于10”以及“大于或等于10”。还应理解,在整个申请中,数据以多种不同格式提供,并且该数据表示端点和起始点,以及数据点的任何组合的范围。例如,如果公开了特定数据点“10”和特定数据点15,则应理解,大于、大于或等于、小于、小于或等于、等于10和15以及10至15之间被认为是公开的。还应理解,还公开了两个特定单元之间的每个单元。例如,如果公开了10和15,则还公开了11、12、13和14。
25.在本说明书和随后的权利要求中,将参考许多术语,这些术语应被定义为具有以下含义:
26.“任选的”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,并且该描述包括所述事件或情况发生的实例和不发生的实例。
27.在整个申请中,引用了各种出版物。这些出版物的公开内容通过引用整体并入本申请中,以便更全面地描述其所属领域的现状。对于在参考文献所依据的句子中讨论的包含于其中的材料,所公开的参考文献也单独地和具体地通过引用并入本文。
B.治疗癌症的方法
28.如前所述,PD-L1在大多数肿瘤上的表达是响应于由CD8T细胞分泌的IFNγ募集到肿瘤部位而诱导的。这种对肿瘤上PD-L1表达的诱导引发了最终产生免疫抑制环境的事件的级联,并且还通过与PD-1受体的相互作用直接阻断细胞毒性T细胞的功能,并导致细胞毒性T细胞的无反应性和细胞凋亡。然后这些变化有助于肿瘤进展和转移。新的抗PD-L1/抗PD-1疗法能够解放癌症中瘫痪的免疫系统,其中通过诱导PD-L1和随后的免疫抑制级联停止对肿瘤的初始免疫应答。然而,如前所述,抗PDL1/PD1疗法仅限于已经诱导PDL1的癌症。
29.本公开内容旨在通过有目的地诱导癌症上的免疫抑制性PDL1,然后使用抗PDL1疗法来治疗癌症并改善抗PDL1疗法。具体地,本文公开了一种违反直觉的治疗,其故意诱导癌组织上的PDL1表达,然后用抗PDL1抗体消除表达PDL1的细胞。这种有意的诱导通过使用NK细胞发生,包括但不限于PM21颗粒、EX21外泌体、FC21饲养细胞和扩增的记忆性(XM)NK细胞。因此,在一个方面,本文公开了治疗受试者中的癌症的方法,包括向受试者施用PM21颗粒、EX21外泌体、FC21饲养细胞和/或过继性NK细胞和抗PDL1抗体。过继性NK细胞可以是多种来源(例如,来自外周血的NK细胞、脐带血、胎盘血、来自CMV血清阳性供体,或来自其他来源,例如诱导的多能干细胞、胚胎干细胞),或永生化的NK细胞样细胞系如NK92),并通过各种活化或扩增方法处理,包括但不限于PM21颗粒、EX21外泌体、FC21饲养细胞。例如,PM21颗粒、EX21外泌体、活化的FC21饲养细胞和/或扩增的过继性NK细胞可以是XMNK细胞。在一个方面,过继性NK细胞可以是未扩增的IL2活化细胞或用GSK3抑制剂活化的NK细胞。
30.人NK细胞是外周血淋巴细胞的子类,其由CD56或CD16的表达和不存在T细胞受体(CD3)而定义。NK细胞感知并杀死缺乏主要组织相容性复合物(MHC)-I类分子的靶细胞。NK细胞活化受体包括天然细胞毒性受体(NKp30、NKp44和NKp46)和凝集素样受体NKG2D和DNAM-1。它们的配体在受胁迫、转化或感染的细胞上表达,但在正常细胞上不表达,使得正常细胞对NK细胞杀伤具有抗性。NK细胞活化通过抑制性受体(例如杀伤性免疫球蛋白(Ig)样受体(KIR)、NKG2A/CD94和白细胞Ig样受体-1(LIR-1))负调节。接合一种抑制性受体的可足以防止靶裂解。因此,NK细胞有效地靶向表达许多应激诱导的配体并且很少有MHC I类配体的细胞。
31.NK细胞通过各种不同的方法有效地破坏肿瘤细胞、应激细胞和病毒感染的细胞。第一种方法是直接接触靶细胞,渗透其膜,然后注射切割并激活几种凋亡蛋白的蛋白质,从而启动靶细胞的程序性细胞死亡(凋亡)。NK细胞的表面还含有蛋白质配体,可以结合并激活受体,如肿瘤坏死因子(TNF)相关凋亡诱导配体(TRAIL)的受体,靶细胞打开内部信号进行凋亡程序性细胞死亡。
32.当被恶性或病毒受损的细胞激活时,NK细胞也分泌IFN-γ。IFN-γ是巨噬细胞和II类主要组织相容性复合物(MHC)分子表达的诱导物的重要激活剂。然而,如前所述,IFN-γ还具有诱导肿瘤细胞表达具有免疫抑制特性的PDL1的负面作用。然而,通过使用NK细胞靶向肿瘤并在肿瘤环境中表达IFN-γ,与有毒的全身性IFN-γ相反,可以诱导癌细胞诱导PDL1,然后可以使用抗PDL1抗体来消除肿瘤并阻断PDL1的免疫抑制作用。有效地,NK细胞的使用克服了单独抗PDL1抗体疗法的局限性。
33.然而,NK细胞免疫疗法的功效取决于施用于患者的NK细胞的剂量或通过体内扩增输注后达到的NK细胞的剂量。目前可用的技术受限于它们不能达到在患者中实现治疗效果所需的NK细胞扩增水平。缺乏临床活化或扩增方案是基于NK细胞的免疫疗法进展的主要障碍。目前的离体活化和扩增方案使用高剂量细胞因子与在白血病衍生的饲养细胞/刺激细胞系上表达的活化配体的组合,对于转移到大多数中心的临床环境具有显著的缺点,并且不适于直接体内扩增或激活。
34.为了作为癌症治疗方法有效,期望实现达到有效治疗剂量的NK细胞活化和/或扩增的程度。当受刺激的细胞因子(如IL-15或IL-21)和活化受体(如4-1BBL)的配体在刺激细胞表面表达时,NK细胞在体外培养物中以指数方式和优先在外周血单核细胞(PBMC)的混合物中增殖。对于细胞因子IL-15和IL-21,膜结合白细胞介素的交叉呈递,如在正常树突细胞中,比这些细胞因子的可溶形式更有效地诱导NK细胞的扩增。此外,在这样的刺激条件下,NK细胞存活仅需要低浓度的可溶性IL-2,因此允许在PBMC混合物中选择性扩增NK细胞而不会观察到T细胞的增殖。可溶形式的IL-15和IL-21细胞因子或高剂量IL-2比NK细胞更有效地刺激T细胞的增殖。
35.相比之下,发现膜结合IL-21的刺激,例如在PM21颗粒、EX21外泌体或FC21饲养细胞的表面上,刺激NK细胞在无数代的连续繁殖,允许NK细胞的连续扩增,条件是定期用新鲜刺激细胞补充培养物。虽然这些方法允许有效的体外NK细胞扩增,但是对活饲养细胞的需求使得该方法难以转移到不具有大GMP设施和能力的临床环境中。而且,输注到患者体内的NK细胞可能由于缺乏饲养细胞持续刺激而可能停止分裂。此外,仍然缺乏关于体外培养的NK细胞在重新输注到患者体内时按预期发挥功能的信息。通过使用包含一种或多种活化剂、刺激肽、细胞因子和/或粘附分子的质膜(PM)颗粒、外泌体(EX)或饲养细胞(FC)来接触和激活和/或扩增NK细胞这些障碍被克服。NK细胞活化剂和刺激肽的实例包括但不限于41BBL、IL-2、IL-12、IL-21、IL-18、MICA、LFA-1、2B4、BCM/SLAMF2、CCR7和/或其他归巢受体。细胞因子的实例包括但不限于IL-2、IL-12、IL-21和IL-18。粘附分子的实例包括但不限于LFA-1、MICA、BCM/SLAMF2。例如,由表达膜结合的IL-21(分别为FC21细胞、PM21颗粒和EX21外泌体)的饲养细胞制备的质膜颗粒饲养细胞(FC)或(PM颗粒)或外泌体(EX)。膜结合的IL-21表达FC21细胞、PM21颗粒和EX21外泌体可以进一步包含另外的一种或多种活化剂、刺激肽、细胞因子和/或粘附分子,包括但不限于41BBL、IL-2、IL-12、IL-18、MICA、LFA-1、2B4、BCM/SLAMF2、CCR7(例如,PM21颗粒、EX21外泌体、或表达41BBL的FC细胞和膜结合白细胞介素-21)。因此,在一个方面,本文公开了治疗癌症的方法,包括向受试者施用NK细胞(例如,XM NK细胞、已被IL-21刺激的NK细胞、和/或NK细胞衍生的颗粒或外泌体)和抗PDL1抗体,其中NK细胞(例如,XM NK细胞、NK92细胞或任何已被IL-21刺激的NK细胞)通过使天然NK细胞群接触PM21颗粒、EX21外泌体或FC21饲养细胞的细胞而被活化和/或扩增。
36.应理解并在本文中预期PM21颗粒、EX21外泌体和/或FC21饲养细胞可用于所公开的治疗方法中,不仅用于活化和/或扩增外源NK细胞群(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞),而且还可用于激活和/或扩增内源性NK细胞群(例如,XM NK细胞、NK92细胞或任何已被膜结合的IL-21表面表达NK细胞的刺激的NK细胞)。此外,PM21颗粒、EX21外泌体和/或PC21饲养细胞可具有与活化和/或扩增的NK细胞相似的功能特性。因此,在一个方面,本文公开了癌症的治疗,包括向受试者施用PM21颗粒、EX21外泌体和抗PDL1抗体。
37.在一个方面,可以从NK细胞刺激饲养细胞中纯化所公开方法中使用的质膜颗粒或外泌体。用于所要求保护的方法并用于制备本文公开的质膜颗粒(例如PM21颗粒)和外泌体(例如FC21外泌体)的NK细胞刺激饲养细胞可以是经辐射(irradiation)的自体或同种异体外周血单核细胞(PBMC),或未辐射的自体或PBMC、RPMI8866、NK-92、NK-92MI、NK-YTS、NK、NKL、KIL、KIL C.2、NK 3.3、NK-YS、HFWT、K562细胞、用膜结合IL-15和41BBL转染的NK细胞(例如,用膜结合IL-21转染的NK-92、NK-92MI、NK-YTS、NK、NKL、KIL、KIL C.2、NK 3.3、NK-YS、HFWT和/或K562细胞),用膜结合IL-21转染的NK细胞(例如,用膜结合IL-15和41BBL转染的NK-92、NK-92MI、NK-YTS、NK、NKL、KIL、KIL C.2、NK 3.3、NK-YS、HFWT和/或K562细胞),用膜结合的IL-21和41BBL转染的NK细胞(例如,用膜结合IL-21和41BBL转染的NK-92、NK-92MI、NK-YTS、NK、NKL、KIL、KIL C.2、NK 3.3、NK-YS、HFWT和/或K562细胞),或EBV-LCL。在一些方面,NK细胞饲养细胞可以是用膜结合IL-21和41BBL转染的NK-92、NK-92MI、NK-YTS、NK、NKL、KIL、KIL C.2、NK 3.3、NK-YS、HFWT和/或K562细胞,或者用膜结合IL-15和41BBL转染的NK-92、NK-92MI、NK-YTS、NK、NKL、KIL、KILC.2、NK 3.3、NK-YS、HFWT和/或K562细胞。
38.应理解并在本文中考虑NK细胞的活化和/或扩增可在施用NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞、或来自各种来源或活化方法的任何类型的NK细胞)之前离体进行,或与NK细胞(例如,XM NK细胞,NK92细胞或任何已被膜结合IL-21刺激的NK细胞)施用的同时或之后在体外发生。例如,NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)可前通过使NK细胞(例如,XM NK细胞,NK92细胞或任何已被膜结合IL-21刺激的NK细胞)在使用XM NK细胞前1-28天之间(优选1-21天之间)接触PM21颗粒、EX21外泌体或FC细胞从而在给药前进行离体扩增和/或活化。例如,在施用NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)之前,使NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)可以与PM21颗粒、EX21外泌体或FC细胞接触至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天。
39.NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)的活化和/或扩增的益处不会随着向受试者施用NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)的停止而停止。NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)的持续和进一步扩增和/或活化可通过直接施用PM21颗粒和/或EX21外泌体到受试者在体内发生。因此,在一个方面,本文公开了治疗受试者中的癌症的方法,包括向受试者施用NK细胞(例如,XM NK细胞、NK92细胞或任何已被膜结合IL-21刺激的NK细胞)和抗PDL1抗体,所述方法还包括直接向受试者施用PM21颗粒和/或EX21外泌体。PM21颗粒和/或EX21外泌体的施用可以在NK细胞施用时和/或之后发生(例如,XM NK细胞、NK92细胞或已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)。例如,PM21颗粒和/或EX21外泌体可以在施用NK细胞(例如,XM NK细胞、或任何表面表达IL-21的NK细胞)后每周施用至少1、2、3、4、5、6或7次。
40.进一步认识到NK细胞(例如,XM NK细胞或任何表面表达IL-21的NK细胞)的额外益处可通过暴露NK细胞(例如,XM NK细胞、NK92细胞或已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)于IL-12、IL-15和/或IL-18中的一者或多者而发生。这种暴露可以在向受试者施用NK细胞(例如,XM NK细胞、NK92细胞或已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)之前、与受试者施用NK细胞同时和/或之后发生。在一个方面,IL-12、IL-15和/或IL-18中的一者或多者可以在NK细胞的离体培养期间施用于NK细胞(例如,XM NK细胞、NK92细胞或已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)。IL-12、IL-15和IL-18的额外益处也可通过在向受试者施用NK细胞之前、同时、甚至之后持续直接向受试者施用IL-15、IL-15和IL-18而获得。在一个方面,本文公开了在受试者中治疗癌症的方法,包括向受试者施用NK细胞(例如,XM NK细胞、或已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)和抗PDL1抗体,并进一步包括向受试者施用IL-12、IL-15和/或IL-18中的一者或多者,其中IL-12、IL-15和/或IL-18中的一者或多者在施用NK细胞(例如,XM NK细胞、或已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)之前、同时和/或之后施用。
41.如前所述,PDL1不一定存在于所有癌症中,并且需要存在以使抗PDL1疗法有效。因此,为了使抗PDL1抗体在癌症治疗中有效,需要诱导PDL1,其通过施用记忆样NK细胞或PM21或FC21NK细胞或任何类型的衍生自各种来源或活化方法且响应于感测肿瘤并因此在肿瘤上诱导PDL1表达的NK细胞。在一个方面,NK细胞(例如,XM NK细胞,或已经被膜结合IL-21刺激的NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)可以与抗PDL1抗体同时施用。然而,因为抗体可能具有更短的半衰期,所以预期在施用抗PDL1抗体之前也可以施用响应肿瘤而分泌IFNγ的NK细胞。例如,本文预期NK细胞可在施用抗PDL1抗体之前的1至21天,更优选1至14天施用。例如,本文公开了治疗癌症的方法,包括向受试者施用NK细胞和抗PDL1抗体,其中在施用抗PDL1抗体之前的1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21施用NK细胞。
42.NK细胞的来源对于治疗的功效是至关重要的,因为转移的NK细胞的排斥会阻碍治疗过程。因此,本文考虑了NK细胞(例如,XM NK细胞,或已被膜结合IL-21刺激的NK细胞,或衍生自各种来源或活化方法的任何类型的NK细胞)来自NK细胞的自体、单倍体相同或同种异体供体来源。NK细胞也可以来源于脐带血、胎盘血,或来自各种类型的干细胞,或来自NK细胞样细胞系如NK92。
43.在一些方面,通过直接给予受试者PM21颗粒和/或EX21外泌体来活化和/或扩增内源性NK细胞也可以完全避免任何排斥转移的NK细胞的可能性。因此,并且在一个方面,本文公开了在受试者中治疗癌症的方法,包括向受试者施用PM21颗粒或EX21外泌体和抗PDL1抗体。可以根据需要经常施用以在受试者中实现期望量的XM NK细胞。例如,PM21颗粒和/或EX21外泌体可以在施用PM21颗粒和/或EX21外泌体的初始施用后每周施用至少1、2、3、4、5、6或7次。
44.如上所述,PDL1不一定存在于所有癌症中,并且需要存在以使抗PDL1抗体疗法有效并且需要诱导PDL1。从而,施用PM21颗粒和EX21外泌体可以扩增和/或活化内源NK细胞以在体内转化成XM NK细胞并增强向肿瘤的分泌IFN-γ,其诱导PDL1表达并允许有效使用抗PDL1抗体。在一个方面,PM21颗粒和/或EX21外泌体可以与抗PDL1抗体同时施用。然而,因为抗体可能具有更短的半衰期,所以预期在施用抗PDL1抗体之前扩增和/或活化内源性XMNK细胞可能是有利的。例如,本文预期PM21颗粒和/或EX21外泌体可在施用抗PDL1抗体之前1至21天、更优选1至14天施用。例如,本文公开了治疗癌症的方法,包括向受试者施用PM21颗粒和/或EX21外泌体和抗PDL1抗体,其中在施用抗PDL1抗体之前的1、2、3、4、5、6、7、8 9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、或60天施用施用PM21颗粒和/或EX21外泌体。
45.如上所述,通过另外暴露于IL-12、IL-15和IL-18,可以发生对XM NK细胞的额外益处。在向受试者施用PM21颗粒和/或EX21外泌体之前、同时、甚至之后继续向受试者直接施用IL-15、IL-12和IL-18也可以获得该益处。在一个方面,本文公开了治疗受试者中的癌症的方法,其包括向受试者施用PM21颗粒和/或EX21外泌体和抗PDL1抗体,其进一步包括向受试者施用IL-12、IL-15和/或IL-18中的一者或多者,其中IL-12、IL-15和/或IL-18中的一者或多者的施用在将PM21颗粒和/或EX21外泌体施用于受试者之前、同时和/或之后。当由PM21颗粒、EX21外泌体或FC21饲养细胞扩增和/或活化的XM NK细胞进一步暴露于细胞因子时,得到的XM NK细胞分别可称为CaPM21NK细胞(细胞因子和PM21颗粒刺激的XM NK细胞)、CEX21NK细胞(细胞因子和EX21外泌体刺激的XM NK细胞)和CFC21NK细胞(细胞因子和FC21饲养细胞刺激的XM NK细胞)。
46.所公开的组合物和方法可用于治疗发生不受控制的细胞增殖的任何疾病,例如癌症。可以用所公开的组合物治疗的代表性但非限制性的癌症列表如下:淋巴瘤,B细胞淋巴瘤,T细胞淋巴瘤,蕈样真菌病,霍奇金病,骨髓性白血病,膀胱癌,脑癌,神经系统癌症,头颈癌,头颈部鳞状细胞癌,肾癌,小细胞肺癌和非小细胞肺癌等肺癌,神经母细胞瘤/胶质母细胞瘤,卵巢癌,胰腺癌,前列腺癌,皮肤癌,肝癌癌,黑色素瘤,口腔、喉咙、喉和肺的鳞状细胞癌,结肠癌,宫颈癌,宫颈癌,乳腺癌和上皮癌,肾癌,泌尿生殖系统癌,肺癌,食道癌,头颈癌,大肠癌,造血系统癌症;睾丸癌;结肠癌和直肠癌,前列腺癌或胰腺癌。
47.本文公开的化合物和方法还可用于治疗癌前病症,例如宫颈和肛门发育不良,其他发育不良,严重发育异常、增生、非典型增生和瘤形成。
48.应理解并在本文中预期,除了癌症之外还有许多其他疾病和病症可通过所公开的方法治疗。因此,本文还公开了在受试者中治疗外来病原体的疾病的方法,包括向受试者施用XM NK细胞或其他类型的NK细胞(例如,已被膜结合IL-21刺激的NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)和抗PDL1抗体,其中所述疾病是病毒、细菌、真菌或寄生虫感染的结果。
49.因此,在一个方面,本文公开了治疗受试者中的病毒感染的方法,包括向受试者施用XM NK细胞或其他类型的NK细胞(例如,已被膜结合IL-21刺激的NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)和抗PDL1抗体,其中所述病毒选自由单纯疱疹病毒-1、单纯疱疹病毒-2、水痘-带状疱疹病毒组成的病毒、Epstein-Barr病毒、巨细胞病毒、人疱疹病毒-6、天花病毒、水泡性口炎病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒、鼻病毒、冠状病毒、甲型流感病毒、流感病毒B、麻疹病毒、多瘤病毒、人乳头瘤病毒、呼吸道合胞病毒、腺病毒、柯萨奇病毒、登革病毒、腮腺炎病毒、脊髓灰质炎病毒、狂犬病病毒、劳氏肉瘤病毒、呼肠孤病毒、黄热病病毒、埃博拉病毒、马尔堡病毒、拉沙热病毒、东部马脑炎病毒、日本脑炎病毒、圣路易斯脑炎病毒、墨累谷热病毒、西尼罗河病毒、裂谷热病毒、轮状病毒A、轮状病毒B、轮状病毒C、辛德毕斯病毒、猿猴免疫缺陷病毒、人类T细胞白血病病毒1型、汉坦病毒、风疹病毒、猴免疫缺陷病毒、人类免疫缺陷病毒1型和人类免疫缺陷病毒2型组成的病毒组。
50.还公开了治疗受试者的细菌感染的方法,包括向受试者施用XM NK细胞或其他类型的NK细胞和抗PDL1抗体,其中所述细菌选自由结核分枝杆菌、牛分枝杆菌、牛分枝杆菌BCG菌株、BCG亚菌株、鸟分枝杆菌、胞内分枝杆菌、非洲分枝杆菌、堪萨斯分枝杆菌、海洋分枝杆菌、溃疡分枝杆菌、鸟分枝杆菌副结核分枝杆菌亚种、星状诺卡氏菌、其他诺卡氏菌、嗜肺军团菌、其他军团菌、伤寒沙门氏菌、其他沙门氏菌、志贺菌、鼠疫耶尔森氏菌、溶血巴斯德氏菌、多杀巴斯德氏菌、其他巴斯德氏菌、大叶性肺炎放线杆菌、单核细胞增生利斯特氏菌、伊氏利斯特氏菌、流产布鲁氏菌、其他布鲁氏菌、反刍类考德里氏体、肺炎衣原体、沙眼衣原体、鹦鹉热衣原体、伯氏考克斯氏体、其他立氏立克次体、埃里希氏体菌、金黄色葡萄球菌、表皮葡萄球菌、肺炎链球菌、酿脓链球菌、无乳链球菌、炭疽芽孢杆菌、大肠埃希氏菌、霍乱弧菌、空肠弯曲菌、脑膜炎奈瑟氏球菌、淋病奈瑟氏球菌、绿脓杆菌、其他假单胞菌、流感嗜血菌、杜氏嗜血菌、其他流感嗜血杆菌、破伤风梭菌、其他艰难梭菌、小肠结肠炎耶尔森氏菌和其他耶尔森氏菌组成的细菌组。
51.还公开了治疗受试者的真菌感染的方法,包括向受试者施用XM NK细胞或其他类型的NK细胞(例如,已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)和抗PDL1抗体,其中真菌选自由白色念珠菌、新型隐球菌、荚膜组织胞浆菌、烟曲霉、粗球霉菌、巴西副球孢子菌、皮炎芽生菌、卡氏肺孢子菌、马尔尼菲蓝状菌和交链孢菌组成的真菌组。
52.还公开了治疗受试者的寄生虫感染的方法,包括向受试者施用XM NK细胞或其他类型的NK细胞(例如,已经被膜结合IL-21刺激的任何NK细胞,或来自各种来源或活化方法的任何类型的NK细胞)和抗PDL1抗体,其中寄生虫选自由弓形虫、恶性疟原虫、间日疟原虫、疟疾疟原虫、其他疟原虫物种、布鲁塞锥虫、克鲁兹锥虫、利什曼原虫、其他利什曼原虫物种、曼氏血吸虫、其他血吸虫物种和溶组织内阿米巴组成的寄生虫组。
C.组成
53.公开了用于制备公开的组合物的组分以及在本文公开的方法中使用的组合物本身。本文公开了这些和其他材料,并且应当理解,当公开这些材料的组合、子集、相互作用、基团等时,虽然可能未明确公开这些化合物的各种个体和集体组合的特定参考和排列,但每个都在本文中特别考虑和描述。例如,如果公开和讨论了特定的抗PDL1抗体、PM21颗粒、EX21外泌体或FC21饲养细胞,并且讨论了可以对包括抗PDL1抗体、PM21颗粒、EX21外泌体或FC21饲养细胞的许多分子进行许多修饰,则抗PDL1抗体、PM21颗粒、EX21外泌体或FC21饲养细胞的每种组合和排列以及可能的修饰都被特别考虑,除非明确指出相反的情况。因此,如果公开了一类分子A、B和C以及一类分子D、E和F以及公开了组合分子的实例A-D,那么即使每个都没有单独列举,每个都是单独和共同考虑的含义组合,A-E、A-F、B-D、B-E、B-F、C-D、C-E和C-F被认为是公开的。同样,还公开了这些的任何子集或组合。因此,例如,将考虑公开A-E、B-F和C-E的子组。该概念适用于本申请的所有方面,包括但不限于制备和使用所公开的组合物的方法中的步骤。因此,如果存在可以执行的各种附加步骤,则应理解,可以利用所公开方法的任何特定实施例或实施例的组合来执行这些附加步骤中的每一个。
54.所公开的治疗癌症的方法利用抗PDL1抗体与PM21、EX21或FC21XM NK细胞和/或PM21颗粒和/或EX21外泌体的组合。因此,在一个方面,本文公开了包含PM21、EX21或FC21XM NK细胞和抗PDL1抗体的抗癌疗法。应理解并在本文中预期,除XM NK细胞之外或代替XM NK细胞,所公开的抗癌疗法可包含PM21颗粒和/或EX21外泌体。因此,一方面是包含PM21、EX21或FC21XM NK细胞的抗癌疗法和进一步包含PM21颗粒和/或EX21外泌体的抗PDL1抗体。一方面还公开了包含PM21颗粒和/或EX21外泌体和抗PDL1抗体的抗癌疗法。另外,任何上述公开的抗癌疗法可包含IL-12、IL-15和IL-18中的一者或多者。
55.应理解并在本文中考虑所公开的疗法可以在一种试剂盒中提供,该试剂盒包含一种或多种抗PDL1抗体,一种或多种PM21颗粒、EX21外泌体和/或FC21饲养细胞,和或IL-12、IL-15和IL-18中的一者或多者。在一些方面,包含疗法的试剂盒还可以包含NK细胞或XMNK细胞。
1.抗体
56.本文公开的抗癌疗法和治疗癌症的方法包括使用抗PDL1抗体。应理解并在本文中预期所公开的方法和疗法可包含和/或利用任何已知的抗PDL1抗体,特别是先前显示具有治疗效果的任何抗体,包括但不限于Genentech的阿特珠单抗(atezolizumab)。
(1)抗体一般介绍
57.术语“抗体”在本文中以广义使用,包括多克隆和单克隆抗体。除完整的免疫球蛋白分子外,术语“抗体”中还包括那些免疫球蛋白分子的片段或聚合物,以及免疫球蛋白分子或其片段的人或人源化形式,只要它们因与PDL1相互作用的能力(例如与PD1相互作用而抑制PDL1)而被选择。可以使用本文所述的体外测定法或通过类似方法测试抗体的所需活性,之后根据已知的临床测试方法测试它们的体内治疗和/或预防活性。人免疫球蛋白有五大类:IgA、IgD、IgE、IgG和IgM,其中一些可进一步分为亚类(同种型),例如IgG-1、IgG-2、IgG-3和IgG-4;IgA-1和IgA-2。本领域技术人员将识别可比较的小鼠类别。对应于不同类免疫球蛋白的重链恒定结构域分别称为α、δ、ε、γ和μ。
58.如本文所用的术语“单克隆抗体”是指从基本上同质的抗体群体获得的抗体,即群体内的个体抗体是相同的,除了可能存在于抗体分子的一小部分中的可能天然发生的突变。本文中的单克隆抗体特别包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类或亚类的抗体中的相应序列相同或同源,而其余的链与来自另一个物种或属于另一个抗体类或亚类的抗体以及这些抗体的片段中的相应序列相同或同源,只要它们表现出所需的拮抗活性即可。
59.所公开的单克隆抗体可以使用产生单克隆抗体的任何方法制备。例如,公开的单克隆抗体可以使用杂交瘤方法制备,例如Kohler和Milstein,Nature,256:495(1975)所述的方法。在杂交瘤方法中,通常用免疫剂免疫小鼠或其它合适的宿主动物以引发产生或能够产生特异性结合免疫剂的抗体的淋巴细胞。或者,可以在体外免疫淋巴细胞。
60.单克隆抗体也可以通过重组DNA方法制备。编码所公开的单克隆抗体的DNA可以使用常规方法容易地分离和测序(例如,通过使用能够与编码鼠抗体的重链和轻链的基因特异性结合的寡核苷酸探针)。还可以使用噬菌体展示技术产生和筛选抗体或活性抗体片段的文库,例如Burton等的美国专利No.5,804,440和Barbas等的美国专利No.6,096,441中所述。
61.体外方法也适用于制备单价抗体。消化抗体以产生其片段,特别是Fab片段,可以使用本领域已知的常规技术完成。例如,可以使用木瓜蛋白酶进行消化。木瓜蛋白酶消化的实例描述于1994年12月22日公开的WO 94/29348和美国专利号4,342,566中。木瓜蛋白酶消化抗体通常产生两个相同的抗原结合片段,称为Fab片段,每个片段具有单个抗原结合位点和残留的Fc片段。胃蛋白酶处理产生具有两个抗原结合位点的片段,并且仍然能够交联抗原。
62.如本文所用,术语“抗体或其片段”包括具有双重或多重抗原或表位特异性的嵌合抗体和杂合抗体以及片段,例如F(ab’)2、Fab’、Fab、Fv、sFv等,包括杂合片段。因此,提供了保留结合其特异性抗原的能力的抗体片段。例如,维持PDL1结合活性的抗体片段包括在术语“抗体或其片段”的含义内。此类抗体和片段可以通过本领域已知的技术制备,并且可以根据实施例中提出的方法和用于产生抗体和筛选抗体的特异性和活性的一般方法筛选特异性和活性(参见Harlow和Lane,Antibodies,A Laboratory Manual.Cold SpringHarbor Publications,纽约,(1988))。
63.“抗体或其片段”的含义中还包括抗体片段和抗原结合蛋白(单链抗体)的缀合物。
64.无论是否与其他序列连接,片段还可以包括特定区域或特定氨基酸残基的插入、缺失、取代或其他选择的修饰,条件是抗体或抗体片段的活性与未修饰的抗体或抗体片段相比没有显著改变或受损。这些修饰可以提供一些额外的性质,例如去除/添加能够二硫键结合的氨基酸,以增加其生物寿命,改变其分泌特征等。在任何情况下,抗体或抗体片段必须具有生物活性,例如与其同源抗原的特异性结合。可以通过诱变蛋白质的特定区域,然后表达和测试表达的多肽来鉴定抗体或抗体片段的功能或活性区域。这些方法对于本领域技术人员来说是显而易见的,并且可以包括编码抗体或抗体片段的核酸的位点特异性诱变。(Zoller,M.J.Curr.Opin.Biotechnol.3:348-354,1992)。
65.如本文所用,术语“抗体”或“抗体”还可以指人抗体和/或人源化抗体。许多非人抗体(例如,衍生自小鼠、大鼠或兔的抗体)在人体中是具有天然抗原性的,因此当施用于人时可以产生不希望的免疫应答。因此,在该方法中使用人或人源化抗体用于减少施用于人的抗体会引起不希望的免疫应答的机会。
(2)人体抗体
66.可以使用任何技术制备公开的人抗体。所公开的人抗体也可以从转基因动物中获得。例如,已描述了能够响应于免疫接种产生完整的人抗体库转基因突变小鼠(参见例如Jakobovits等,Proc.Natl.Acad.Sci.USA,90:2551-255(1993);Jakobovits等,Nature,362:255-258(1993);Bruggermann等,Year in Immunol.,7:33(1993))。具体而言,这些嵌合和种系突变小鼠中抗体重链连接区(J(H))基因的纯合缺失导致内源性抗体产生的完全抑制,并且人种系抗体基因阵列成功转移到这种种系突变小鼠导致在抗原攻击后产生人抗体。使用如本文所述的Env-CD4-共受体复合物选择具有所需活性的抗体。
(3)人源化抗体
67.抗体人源化技术通常涉及使用重组DNA技术来操纵编码抗体分子的一条或多条多肽链的DNA序列。因此,人源化形式的非人抗体(或其片段)是嵌合抗体或抗体链(或其片段,例如sFv、Fv、Fab、Fab'、F(ab’)2,或抗体的其他抗原结合部分),其含有来自整合到人(受体)抗体框架中的非人(供体)抗体的一部分抗原结合位点。
68.为了产生人源化抗体,来自受体(人)抗体分子的一个或多个互补决定区(CDR)的残基被来自已知具有所需抗原结合性质(例如针对靶抗原具有一定水平的特异性和亲和力)的供体(非人)抗体分子的一个或多个CDR的残基替换。在一些情况下,人抗体的Fv框架(FR)残基被替换为相应的非人残基。人源化抗体还可含有既不在受体抗体中也不在导入的CDR或框架序列中发现的残基。通常,人源化抗体具有从非人源引入的一个或多个氨基酸残基。在实践中,人源化抗体通常是人抗体,其中一些CDR残基和可能的一些FR残基被来自啮齿动物抗体中类似位点的残基取代。人源化抗体通常含有抗体恒定区(Fc)的至少一部分,通常是人抗体的至少一部分(Jones等,Nature,321:522-525(1986),Reichmann等,Nature,332:323-327(1988),以及Presta,Curr.Opin.Struct.Biol.,2:593-596(1992))。
69.用于人源化非人抗体的方法是本领域熟知的。例如,可以根据Winter和同事的方法产生人源化抗体(Jones等,Nature,321:522-525(1986),Riechmann等,Nature,332:323-327(1988),Verhoeyen等,Science,239:1534-1536(1988)),通过用啮齿动物CDR或CDR序列取代人抗体的相应序列。可用于产生人源化抗体的方法也描述于美国专利No.4,816,567(Cabilly等),美国专利No.5,565,332(Hoogenboom等),美国专利No.5,721,367(Kay等),美国专利No.5,837,243(Deo等),美国专利No.5,939,598(Kucherlapati等),美国专利No.6,130,364(Jakobovits等)和美国专利No.6,180,377(Morgan等)。
(4)施用抗体
70.可以如本文所公开的进行抗体的施用。还存在用于抗体递送的核酸方法。广泛中和的抗PDL1抗体和抗体片段也可以作为编码抗体或抗体片段的核酸制剂(例如DNA或RNA)施用于患者或受试者,使得患者或受试者自身的细胞摄取核酸并产生和分泌编码的抗体或抗体片段。核酸的递送可以通过任何方式进行,例如,如本文所公开的。
2.制药载体/药物产品的递送
71.如上所述,组合物也可以以药学可接受的载体形式在体内给药。“药学上可接受的”是指不是在生物学上或其他方面不期望的材料,即,该材料可以与核酸或载体一起施用于受试者,而不会引起任何不期望的生物学效应或以任何有害的方式与药物组合物的其他组分(该组分包含于该药物组合物)相互作用。如本领域技术人员所熟知的,自然地选择载体以使活性成分的任何降解最小化并使受试者中的任何不良副作用最小化。
72.组合物可以口服、肠胃外(例如静脉内)、肌内注射、腹膜内注射、透皮、体外、局部等给药,包括局部鼻内给药或通过吸入给药。如本文所用,“局部鼻内给药”是指通过一个或两个鼻孔将组合物递送到鼻和鼻通道中,并且可以包括通过喷雾机制或液滴机制递送,或通过核酸或载体的雾化递送。通过吸入剂施用组合物可以通过喷雾或液滴机制通过鼻或口进行。通过插管也可以直接输送到呼吸系统的任何区域(例如,肺)。给药所需组合物的确切量将因受试者而异,取决于受试者的人种、年龄、体重和一般状况、所治疗的过敏性疾病的严重程度、所用的特定核酸或载体、其给药方式等等。因此,不可能为每种组合物指定确切的量。然而,本领域普通技术人员仅使用本文教导给出的常规实验可确定适当的量。
73.如果使用,肠胃外施用组合物通常使用注射。注射剂可以以常规形式制备,可以是液体溶液或悬浮液,适于在注射前在溶液中悬浮的溶液的固体形式,或者是乳液。最近修订的肠胃外给药方法包括使用缓释或持续释放系统,以保持恒定的剂量。参见,例如,美国专利No.3,610,795,其通过引用结合到本文中。
74.材料可以是溶液、悬浮液(例如包入微粒、脂质体或细胞中)。这些可以通过抗体、受体或受体配体靶向特定细胞类型。以下参考文献是使用该技术将特定蛋白质靶向肿瘤组织的实例(Senter等,Bioconjugate Chem.,2:447-451,(1991);Bagshawe,K.D.,Br.J.Cancer,60:275-281,(1989);Bagshawe,等,Br.J.Cancer,58:700-703,(1988);Senter等,Bioconjugate Chem.,4:3-9,(1993);Battelli等,CancerImmunol.Immunother.,35:421-425,(1992);Pietersz和McKenzie,Immunolog.Reviews,129:57-80,(1992);以及Roffler等,Biochem.Pharmacol,42:2062-2065,(1991))。诸如“隐形的”(stealth)和其他抗体缀合的脂质体(包括靶向结肠癌的脂质介导的药物),通过细胞特异性配体的受体介导的DNA靶向,淋巴细胞定向的肿瘤靶向以及体内鼠神经胶质瘤细胞的高度特异性治疗性逆转录病毒靶向的载体。以下参考文献是使用该技术将特定蛋白质靶向肿瘤组织的实例(Hughes等,Cancer Research,49:6214-6220,(1989);以及Litzinger和Huang,Biochimica et Biophysica Acta,1104:179-187,(1992))。通常,受体参与胞吞作用途径,不管是组成型还是配体诱导的途径。这些受体聚集在网格蛋白包被的凹坑中,通过网格蛋白包被的囊泡进入细胞,通过其中受体被分选的酸化内体,然后再循环到细胞表面,在细胞内储存,或在溶酶体中降解。内化途径具有多种功能,例如营养摄取、活化蛋白质的去除、大分子的清除、病毒和毒素的机会性进入、配体的解离和降解以及受体水平调节。许多受体遵循一种以上的细胞内途径,这取决于细胞类型、受体浓度、配体类型、配体化合价和配体浓度。已经综述了受体介导的胞吞作用的分子和细胞机制(Brown和Greene,DNA andCellBiology 10:6,399-409(1991))。
a)药学上可接受的载体
75.所述组合物,包括抗体,可以在治疗上与药学上可接受的载体组合使用。
76.合适的载体及其制剂描述于Remington:The Science and Practice ofPharmacy(第19版)A.R.Gennaro编辑,Mack Publishing Company,Easton,PA 1995。通常,在制剂中使用适量的药学上可接受的盐以使制剂等渗。药学上可接受的载体的实例包括但不限于盐水、林格氏溶液和右旋糖溶液。溶液的pH优选为约5至约8,更优选约7至约7.5。另外的载体包括持续释放制剂,例如含有抗体的固体疏水聚合物的半透性基质,该基质是成型制品的形式,例如薄膜、脂质体或微粒。对于本领域技术人员显而易见的是,某些载体可能是更优选的,这取决于例如给药途径和给药组合物的浓度。
77.药物载体是本领域技术人员已知的。这些通常是用于向人施用药物的标准载体,包括诸如无菌水、盐水和生理pH下的缓冲溶液的溶液。组合物可以肌肉内或皮下给药。其他化合物将根据本领域技术人员使用的标准程序给药。
78.除所选分子外,药物组合物还可包括载体、增稠剂、稀释剂、缓冲剂、防腐剂、表面活性剂等。药物组合物还可包含一种或多种活性成分,例如抗微生物剂、抗炎剂、麻醉剂等。
79.药物组合物可以多种方式给药,这取决于是否需要局部或全身治疗,以及待治疗的区域。给药可以是局部给药(包括眼科、阴道、直肠、鼻内)、口服、吸入或肠胃外给药(例如通过静脉内滴注、皮下、腹膜内或肌内注射)。所公开的抗体可以通过静脉内、腹膜内、肌肉内、皮下、腔内或经皮给药。
80.肠胃外给药的制剂包括无菌水溶液或非水溶液、悬浮液和乳液。非水溶剂的实例是丙二醇、聚乙二醇、植物油如橄榄油、和可注射的有机酯(如油酸乙酯)。含水载体包括水、醇/水溶液、乳液或悬浮液、包括盐水和缓冲介质。肠胃外载体包括氯化钠溶液、林格氏葡萄糖、右旋糖和氯化钠、乳酸林格氏液或固定油。静脉内载体包括液体和营养补充剂、电解质补充剂(例如基于林格氏葡萄糖的补充剂)等。还可以存在防腐剂和其他添加剂,例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等。
81.用于局部给药的制剂可包括软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体和粉末。常规的药物载体、水性、粉末或油性基质、增稠剂等可能是必需的或期望的。
82.用于口服给药的组合物包括粉末或颗粒、悬浮液或水或非水介质中的溶液、胶囊、小药囊或片剂。可能需要增稠剂、调味剂、稀释剂、乳化剂、分散助剂或粘合剂。
83.一些组合物可以作为药学上可接受的酸或碱加成盐给药,通过与无机酸如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸和磷酸反应形成,有机酸,如甲酸、乙酸、丙酸、乙二醇四乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸和富马酸,或与钠等无机碱反应氢氧化物,氢氧化铵、氢氧化钾和有机碱如单、二、三烷基和芳基胺和取代的乙醇胺。
b)治疗用途
84.用于施用组合物的有效剂量和时间表可凭经验确定,并且进行此类测定是在本领域技术范围内的。给予组合物的剂量范围足够大,以产生影响疾病症状的所需效果。剂量不应大到引起不良副作用,例如不希望的交叉反应、过敏反应等。通常,剂量将随着患者的年龄、状况、性别和疾病程度、给药途径或是否包括在该方案中的其他药物而变化,并且可以由本领域技术人员确定。在任何禁忌症的情况下,个体医师可以调整剂量。剂量可以变化,并且可以每天一次或多次给药,持续一天或几天。对于给定类别的药物产品,可以在文献中找到关于适当剂量的指导。例如,可以在关于抗体的治疗用途的文献中找到选择抗体的合适剂量的指导,例如,Handbook of Monoclonal Antibodies,Ferrone等编著,NogesPublications,Park Ridge,N.J.,(1985)第22章第303-357页;Smith等,Antibodies inHuman Diagnosis and Therapy,Haber等编著,Raven Press,纽约(1977),第365-389页。单独使用的抗体的典型日剂量可以为按体重每天约1μg/kg至最多100mg/kg或更多,取决于上述因素。
85.在施用用于治疗、抑制或预防癌症的公开组合物(例如抗体)后,可以以本领域技术人员熟知的各种方式评估治疗性抗体的功效。例如,本领域普通技术人员将理解,本文公开的组合物(例如抗体)通过观察组合物降低肿瘤大小或转移速率而有效治疗或抑制受试者中的癌症。
3.组合治疗
86.公开了治疗癌症的方法,包括向受试者施用所公开的组合物之一与已治疗的疾病或病症的治疗剂的组合。例如,公开了治疗癌症的方法,其包括给予有效量的包含抗PDL1抗体和/或PM21颗粒和/或EX21外泌体的组合物与已知的癌症治疗剂组合,例如但不限于化学治疗剂、免疫治疗剂、放射治疗剂或疼痛治疗剂。
87.存在两种不同类型的免疫疗法:被动免疫疗法使用免疫系统的组分来指导针对癌细胞的靶向细胞毒活性,而不必在患者中启动免疫应答,而主动免疫疗法主动触发内源性免疫应答。被动策略包括使用B细胞响应特定抗原产生的单克隆抗体(mAb)。20世纪70年代杂交瘤技术的发展和肿瘤特异性抗原的鉴定使得可以特异性靶向肿瘤细胞以免受免疫系统破坏的mAb的药物开发。到目前为止,单克隆抗体一直是免疫治疗的最大成功案例;2012年最畅销的三种抗癌药物是单克隆抗体。其中有利妥昔单抗(Rituxan,Genentech),其与在B细胞恶性肿瘤如非霍奇金淋巴瘤(NHL)表面高表达的CD20蛋白结合。利妥昔单抗经FDA批准用于治疗NHL和慢性淋巴细胞白血病(CLL)以及化疗。另一种重要的单克隆抗体是曲妥珠单抗(赫赛汀;Genentech),其通过靶向HER2的表达彻底改变了HER2(人表皮生长因子受体2)阳性乳腺癌的治疗。
88.产生最佳“杀伤”(killer)CD8T细胞应答还需要T细胞受体激活加共刺激,其可通过结合肿瘤坏死因子受体家族成员提供,包括OX40(CD134)和4-1BB(CD137)。OX40特别令人感兴趣,因为用活化(激动剂)抗OX40mAb处理可增强T细胞分化和细胞溶解功能,从而增强针对肿瘤的抗肿瘤免疫力。
89.在一些实施方案中,所公开的疫苗与过继细胞疗法(ACT)组合使用,所述过继细胞疗法例如嵌合抗原受体(CAR)、T细胞受体(TCR)和肿瘤浸润性淋巴细胞(TIL)。
90.术语“肿瘤浸润淋巴细胞”或“IL”是指离开血流并迁移到肿瘤中的白细胞。淋巴细胞(包括肿瘤浸润淋巴细胞,例如T细胞)的扩增可以通过本领域已知的许多方法中的任何一种来完成。例如,在饲养细胞和白细胞介素-2(IL-2)、IL-7、IL-15、IL-21或其组合的存在下,使用非特异性T细胞受体刺激可以快速扩增T细胞。非特异性T细胞受体刺激可以是例如包括约30ng/ml的OKT3、一种小鼠单克隆抗CD3抗体(可从Ortho-McNeil(R),Raritan,N.J.或Miltenyi Biotec,Bergisch Gladbach,Germany获得)。或者,在T细胞生长因子的存在下(例如约200-400Ill/ml,例如300IU/ml IL-2或IL-15,优选IL-2),T细胞的快速扩增可以通过体外用一种或多种抗原(包括其抗原部分,例如表位)或可任选地从载体(例如人白细胞抗原A2(HLA-A2)结合肽,例如约0.3μM MART-1:26-35(27L)或gp100:209-217(210M))表达的癌症细胞刺激外周血单核细胞(PBMC)来实现。体外诱导的T细胞通过用在脉冲到表达HLA-A2的抗原呈递细胞上的癌症抗原的相同抗原再刺激而快速扩增。或者,可以用经辐射的自体淋巴细胞或经辐射的HLA-A2+同种异体淋巴细胞和IL-再次刺激T细胞。
91.2,例如。扩增的TIL的特异性肿瘤反应性可以通过本领域已知的任何方法测试,例如通过在与肿瘤细胞共培养后测量细胞因子(例如,干扰素-γ)释放。在一个实施方案中,自体ACT方法包括在细胞快速扩增之前富集培养的TIL用于CD8+T细胞。在IL-2中培养TIL后,T细胞耗尽CD4+细胞并使用例如CD8微珠分离(例如,使用CliniMACS<plus>CD8微珠系统(Miltenyi Biotec))富集CD8+细胞。在一些实施方案中,促进自体T细胞生长和活化的T细胞生长因子与自体T细胞同时或随后与自体T细胞一起施用于哺乳动物。T细胞生长因子可以是促进自体T细胞生长和活化的任何合适的生长因子。
92.合适的T细胞生长因子的实例包括白细胞介素(IL)-2、IL-7、IL-15、IL-12和IL-21,它们可以单独使用或以各种组合使用,例如IL-2和IL-7、IL-2和IL-15、IL-7和IL-15、IL-2、IL-7和IL-15、IL-12和IL-7、IL-12和IL-15、或IL-12和IL2。
93.许多抗癌药物也可用于与本方法和组合物组合。以下是可与辐射联合使用的抗癌(抗肿瘤)药物的非详尽清单:阿西维辛、阿柔比星、Acodazole
94.盐酸盐、AcrQnine、阿多来新(adozelesin)、阿地白介素(aldesleukin)、六甲蜜胺(altretamine)、安波霉素(ambomycin)、醋酸阿美蒽醌(ametantrone acetate)、氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、蒽霉素(anthramycin)、天冬酰胺酶(asparaginase)、曲林菌素(asperlin)、阿扎胞苷(azacitidine)、阿扎替派(azetepa)、阿佐霉素(azotomycin)、巴马司他(batimastat)、苯佐替派(benzodepa)、比卡鲁胺(bicalutamide)、盐酸比生群(bisantrenehydrochloride)、甲横酸双萘法特(bisnafide dimesylate)、比折来新(bizelesin)、硫酸博来霉素(bleomycin sulfate)、布喹那钠(brequinar sodium)、溴匹立明(bropirimine)、白消安(busulfan)、放线菌素c(cactinomycin)、卡普睾酮(calusterone)、卡醋胺(caracemide)、卡贝替姆(carbetimer)、卡铂(carboplatin)、卡莫司汀(carmustine)、盐酸卡柔比星(carubicin hydrochloride)、卡折来新(carzelesin)、西地芬戈(cedefingol)、苯丁酸氮芥(chlorambucil)、西罗霉素(cirolemycin)、顺钼(cisplatin)、克拉屈滨(cladribine)、甲磺酸克立那托(crisnatol mesylate)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、更生霉素(dactinomycin)、盐酸柔红霉素(daunorubicin hydrochloride)、地西他滨(decitabine)、右奥马钼(dexormaplatin)、地扎胍宁(dezaguanine)、甲磺酸地扎胍宁(dezaguanine mesylate)、地吖醌(diaziquone)、多西紫杉醇(docetaxel)、阿霉素(doxorubicin)、盐酸阿霉素(doxorubicinhydrochloride)、屈洛昔芬(droloxifene)、枸橼酸屈洛昔芬(droloxifene citrate)、屈他雄酮丙酸酯(dromostanolone propionate)、达佐霉素(duazomycin)、依达曲沙(edatrexate)、盐酸依氟鸟氨酸(eflomithine hydrochloride)、依沙芦星(elsamitrucin)、恩洛钼(enloplatin)、恩普氨酯(enpromate)、依匹哌唳(epipropidine)、盐酸表柔比星(epirubicin hydrochloride)、厄布洛唑(erbulozole)、盐酸依索比星(esorubicin hydrochloride)、雌莫司汀(estramustine)、雌莫司汀磷酸钠(estramustinephosphate sodium)、依他硝唑(etanidazole)、乙碘油(ethiodized oil)i 131、依托泊苷(etoposide)、磷酸依托泊苷(etoposide phosphate)、氯苯乙啼胺(etoprine)、盐酸法倔唑(fadrozole hydrochloride)、法扎拉滨(fazarabine)、芬维a胺(fenretinide)、氟尿苷(floxuridine)、磷酸氟达拉滨(fludarabine phosphate)、氟尿啼唳(fluorouracil)、氟西他滨(flurocitabine)、憐喹酮(fosquidone)、福司曲星钠(fostriecin sodium)、吉西他滨(gemcitabine)、盐酸吉西他滨(gemcitabine hydrochloride)、胶体金(gold au 198)、羟基脲(hydroxyurea)、盐酸伊达比星(idarubicin hydrochloride)、异环憐酸胺(ifosfamide)、伊莫福新(ilmofosine)、异丙钼(iproplatin)、盐酸伊立替康(irinotecanhydrochloride)、醋酸兰瑞肽(lanreotide acetate)、来曲唑(letrozole)、醋酸亮丙瑞林(leuprolide acetate)、盐酸利阿唑(liarozole hydrochloride)、洛美曲索钠(lometrexolsodium)、洛莫司汀(lomustine)、盐酸洛索蒽醌(losoxantronehydrochloride)、马索罗酚(masoprocol)、美坦生(maytansine)、盐酸双氯乙基甲胺(mechlorethamine hydrochloride)、醋酸甲地孕酮(megestrol acetate)、醋酸美仑孕酮(melengestrol acetate)、马法兰(melphalan)、美诺立尔(menogaril)、巯嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、甲氨蝶呤钠(methotrexate sodium)、氯苯氨啶(metoprine)、美妥替哌(meturedepa)、米丁度胺(mitindomide)、米托卡星(mitocarcin)、丝裂红素(mitocromin)、米托洁林(mitogillin)、米托马星(mitomalcin)、丝裂霉素(mitomycin)、米托司培(mitosper)、米托坦(mitotane)、盐酸米托葱酉昆(mitoxantrone hydrochloride)、麦考酚酸(mycophenolic acid)、诺考达唑(nocodazole)、诺拉霉素(nogalamycin)、奥马钼(ormaplatin)、奥昔舒仑(oxisuran)、紫杉醇(paclitaxel)、培门冬酶(pegaspargase)、培利霉素(peliomycin)、溴新斯的明(pentamustine)、硫酸培洛霉素(peplomycin sulfate)、培磷酰胺(perfosfamide)、哌泊溴焼(pipobroman)、哌泊舒凡(piposulfan)、盐酸吡罗蒽醌(piroxantrone hydrochloride)、普卡霉素(plicamycin)、普洛美坦(plomestane)、卟吩姆钠(porfimer sodium)、泊非霉素(porfiromycin)、泼尼莫司汀(prednimustine)、盐酸丙卡巴餅(procarbazinehydrochloride)、嘌呤霉素(puromycin)、盐酸票罗霉素(puromycin hydrochloride)、吡唑呋喃菌素(pyrazofurin)、利波腺苷(riboprine)、罗谷亚胺(rogletimide)、沙芬戈(safmgol)、盐酸沙芬戈(safingol hydrochloride)、司莫司汀(semustine)、辛曲秦(simtrazene)、磷乙酰天冬氨酸钠(sparfosate sodium)、司帕霉素(sparsomycin)、盐酸错螺胺(spirogermanium hydrochloride)、螺莫司汀(spiromustine)、螺钼(spiroplatin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、氯化锶sr 89、磺氯苯脲(sulofenur)、他利霉素(talisomycin)、紫杉醇(taxane)、紫杉烷(taxoid)、替可加兰钠(tecogalansodium)、替加氟(tegafur)、盐酸替洛蒽醌(teloxantrone hydrochloride)、替莫泊芬(temoporfin)、替尼泊苷(teniposide)、替罗昔隆(teroxirone)、睾内酪(testolactone)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine)、塞替派(thiotepa)、噻唑呋林(tiazofurin)、替拉扎明(tirapazamine)、托泊替坎盐酸盐(topotecan hydrochloride)、枸橼酸托瑞米芬(toremifene citrate)、乙酸曲托龙(trestolone acetate)、磷酸曲西立滨(triciribine phosphate)、三甲曲沙(trimetrexate)、三甲曲沙葡糖醛酸盐(trimetrexate glucuronate)、曲普瑞林(triptorelin)、盐酸土布洛唑(tubulozolehydrochloride)、乌拉莫司汀(uracil mustard)、乌瑞替派(uredepa)、伐普肽(vapreotide)、维替泊芬(verteporfin)、硫酸长春碱(vinblastine sulfate)、硫酸长春新碱(vincristine sulfate)、长春地辛(vindesine)、硫酸长春地辛(vindesine sulfate)、硫酸长春匹定(vinepidine sulfate)、硫酸长春甘酯(vinglycinate sulfate)、硫酸长春罗新(vinleurosine sulfate)、酒石酸长春瑞滨(vinorelbine tartrate)、硫酸长春罗定(vinrosidine sulfate)、硫酸长春利定(vinzolidine sulfate)、伏氯唑(vorozole)、折尼钼(zeniplatin)、净司他丁(zinostatin)、盐酸佐柔比星(zorubicin hydrochloride)。
95.在一些方面,癌症治疗剂、抗PDL1抗体、PM21颗粒和/或EX21外泌体可以配制在相同的组合物中。在一些方面,癌症治疗剂、抗PDL1抗体、PM21颗粒和/或EX21外泌体可以配制在不同的组合物中。
96.尽管上面使用参考而描述了设计和产生可以改变结合的化合物,但是也可以筛选已知化合物的文库,包括天然产物或合成化学品以及包括蛋白质的生物活性物质,以寻找可改变底物结合或酶活性的化合物。
D.实施例
97.提出以下实施例以向本领域普通技术人员提供如何制备和评价本文要求保护的化合物、组合物、制品、装置和/或方法的完整公开和描述,并且旨在纯粹地示例性的并且不旨在限制本公开。已经努力确保关于数字(例如,量、温度等)的准确性,但是应该考虑一些误差和偏差。除非另有说明,否则份数是重量份,温度是℃或环境温度,压力是大气压或接近大气压。
98.新的抗PD-L1/抗PD-1疗法能够在癌症中解放瘫痪的免疫系统,其中通过诱导PD-L1和随后的免疫抑制级联来终止对肿瘤的初始免疫应答。当使用高细胞毒性NK细胞(例如PM21-粒子扩增的NK细胞(PM21-NK))进行过继细胞治疗时,观察到肿瘤在其细胞表面上表达PD-L1的类似反应。这些PM21-NK细胞比未扩增的NK细胞或IL-2激活的NK细胞分泌高得多的IFN-γ,以响应通常存在于肿瘤床中的肿瘤靶标和细胞因子(IL-12、IL-18)(图1)。NK细胞也具有选择性,仅针对恶性细胞而非健康细胞。因此,过继转移的PM21-NK细胞可以特异性地将IFNγ递送至肿瘤细胞并诱导PD-L1而无需全身性IFN-γ施用,从而放过健康的正常细胞。如图2所示,PM21颗粒扩增的NK细胞对SKOV-3细胞具有细胞毒性。细胞毒性至少部分是细胞因子IFN-γ和TNF-α表达的结果,其在暴露于SKOV-3细胞时生产增加,并且还通过施用IL-12和/或IL-18进一步刺激。在暴露于IFNγ的多种肿瘤细胞系中观察到PD-L1表达的诱导。在携带人源化NSG-卵巢癌的小鼠中的临床前研究提供证据表明过继转移的PM21NK细胞和用分泌大量IFN-γ的PM21-NK细胞扩增的NK细胞诱导人卵巢肿瘤上的PD-L1(图3A)。为了进一步证明PM21-NK或FC-NK细胞是肿瘤上PD-L1的特异性诱导物,过继转移的NK细胞是高纯度的(99.99%NK细胞)并且实际上不含T细胞。在腹膜中发现的细胞中,PD-1在T细胞上表达,但不在NK细胞中表达(图3B)。此外,过继转移后从小鼠收集的血液中>99%的hCD45+人淋巴细胞是NK细胞。为了证实肿瘤在被PM21-NK或FC21-NK细胞攻击时表达PD-L1,在具有腹水累积的小鼠中发现了更高丰度的调节性T细胞(Treg)(图3C)。已知Treg由PD-L1诱导并响应于来自NK细胞的IFNγ刺激的肿瘤上的PD-L1表达而快速增殖。尽管PM21-NK细胞对肿瘤的PD-L1的免疫抑制诱导有助于肿瘤逃离免疫系统,但是这种机制可以有利地用于诱导通用可靶向抗原的表达,该抗原可以标记多种肿瘤类型(图4)。用人源化PD-L1抗体与PM21-NK细胞一起治疗可以通过抗-PD-L1Ab与CD16(IgG受体FcγRIII)的结合引发的抗体依赖性细胞介导的细胞毒性(ADCC)从NK细胞释放高效的靶向抗肿瘤应答(图4)。
Claims (15)
1.扩增的记忆NK细胞和抗PDL1抗体在制备用于治疗癌症的药物中的用途,其中所述扩增的记忆NK细胞是通过在体外或离体地使初始NK细胞群与IL-12、IL-15和IL-18接触,以及在体外或离体地用具有膜结合的IL-21的质膜颗粒扩增所述NK细胞而获得的,所述具有膜结合的IL-21的质膜颗粒包含PM21颗粒。
2.根据权利要求1所述的用途,其中NK细胞与PM21颗粒的接触在施用包含所述扩增的记忆NK细胞的药物之前的1至21天之间进行。
3.根据权利要求1所述的用途,其中所述扩增的记忆NK细胞源自外周血、脐带血或干细胞。
4.根据权利要求1所述的用途,其中所述PM21颗粒还包含41BBL。
5.根据权利要求1所述的用途,其中在施用所述抗PDL1抗体之前1至14天之间施用所述包含扩增的记忆NK细胞的药物。
6.根据权利要求1所述的用途,其中所述扩增的记忆NK细胞和抗PDL1抗体经配制用于同时施用。
7.根据权利要求1所述的用途,其中所述扩增的记忆NK细胞是自体的、单倍体相同的或同种异体的NK细胞。
8.根据权利要求1所述的用途,其中所述药物还包括IL-12、IL-15和IL-18中的一者或多者。
9.根据权利要求8所述的用途,其中所述IL-12、IL-15和IL-18经配制用于与所述扩增的记忆NK细胞同时施用。
10.根据权利要求8所述的用途,其中所述IL-12、IL-15和IL-18经配制用于在施用所述扩增的记忆NK细胞之前施用。
11.根据权利要求8所述的用途,其中所述IL-12、IL-15和IL-18经配制用于在施用所述扩增的记忆NK细胞后施用。
12.根据权利要求1所述的用途,其中所述药物还包括PM21颗粒或EX21外泌体。
13.根据权利要求12所述的用途,其中所述PM21颗粒或EX21外泌体经配制用于与所述扩增的记忆NK细胞同时施用。
14.根据权利要求12所述的用途,其中所述PM21颗粒或EX21外泌体经配制用于在施用所述扩增的记忆NK细胞后每周施用至少1、2、3次。
15. 根据权利要求1-14中任一项所述的用途,其中所述抗PD-L1抗体是F(ab’)2片段、Fab’ 片段、Fab片段、Fv片段或sFv片段。
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CA3039532A1 (en) | 2018-04-12 |
JP2023078140A (ja) | 2023-06-06 |
KR20240042177A (ko) | 2024-04-01 |
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CN109952369A (zh) | 2019-06-28 |
SG11201903032SA (en) | 2019-05-30 |
KR20190066035A (ko) | 2019-06-12 |
AU2017340633B2 (en) | 2024-01-11 |
AU2024202350A1 (en) | 2024-05-02 |
JP2019534258A (ja) | 2019-11-28 |
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WO2018067825A1 (en) | 2018-04-12 |
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EP3523416A1 (en) | 2019-08-14 |
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AU2017340633A1 (en) | 2019-05-23 |
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