CN110167566A - 治疗实体瘤细胞和逃避变体的支架 - Google Patents
治疗实体瘤细胞和逃避变体的支架 Download PDFInfo
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Abstract
描述了可植入支架,其治疗实体瘤和逃避变体并提供针对癌症复发的有效疫苗接种。所述支架包括遗传重编程的淋巴细胞和淋巴细胞激活部分。
Description
关于联邦政府资助的研究或开发的声明
本发明是在政府资助下根据美国国立卫生研究院授予的CA181413进行。政府对本发明享有某些权利。
相关申请的交叉引用
本申请要求2016年12月21日提交的美国临时专利申请号62/437,572的优先权,所述临时专利申请的全部内容以引用的方式并入本文。
对序列表的引用
题为“1QJ8796.txt(Sequence Listing.txt)”,创建于或大约创建于2017年11月30日,文件大小为50KB的计算机可读的文本文件包含用于本申请的序列表并且在此以引用的方式整体并入。
技术领域
本公开提供可植入支架,其治疗实体瘤和逃避变体并提供针对癌症复发的有效疫苗接种。支架包括遗传重编程的淋巴细胞和淋巴细胞激活部分。
背景技术
癌症免疫疗法描述了其中患者免疫系统用于治疗癌症的领域。例如,癌症免疫疗法包括使用疫苗来免疫患者以抵抗癌症的发展。不幸的是,癌症疫苗可能引起的应答可能需要数月才能成熟,并且通常不足以控制晚期疾病。
还尝试更快或有效地刺激患者自身的T细胞以攻击癌细胞。然而,通常由T细胞表达的受体库通常对自身/肿瘤抗原具有低亲和力,所以此方法在抗癌方面尚未取得足够的成功。
新兴的免疫疗法方法涉及用编码嵌合抗原受体(CAR)的基因改变患者来源的淋巴细胞(例如,T细胞),所述嵌合抗原受体被工程化为对肿瘤中选定的大分子靶标具有高亲和力。引入的基因也可产生共刺激信号以引发稳健的T细胞扩增。所述方法涉及从患者中检索T细胞并将它们离体重定向以表达由与共刺激和CD3ζ信号传导结构域融合的肿瘤特异性单链抗体(scFv)构成的CAR,其使得程序化细胞能够以人白细胞抗原(HLA)独立的方式裂解肿瘤靶标。
在临床试验中,采用此类CAR编程的T细胞的疗法在血液恶性肿瘤(即,液体血癌)患者中始终产生阳性结果。然而,当涉及到实体瘤时,这些疗法的有效性受到以下因素的限制:1)淋巴细胞无效归巢到肿瘤部位;2)免疫抑制微环境实体瘤产生;以及3)实体瘤的表型多样性,这意味着CAR编程的T细胞的靶向受体未识别的癌细胞可形成逃脱编程的T细胞的逃避变体。因此,虽然T细胞的遗传重编程仍然是一种有前途的疗法,但是将它们用于治疗实体瘤需要显著的改进。
US 2016/0008399描述一种可植入支架,其极大地改善了遗传重编程的淋巴细胞(例如,T细胞)治疗实体瘤的能力。可植入支架包括遗传重编程的淋巴细胞,至少一个与支架相关的淋巴细胞粘附部分;至少一个与支架相关的淋巴细胞激活部分,和任选地免疫刺激剂。因为支架可植入在实体瘤的部位,所以克服了关于淋巴细胞无效归巢到肿瘤部位的问题。
US 2016/0008399还描述可植入支架如何产生针对肿瘤细胞的延长的第二波保护。特别地,接种在支架内的淋巴细胞在植入后离开支架并以高密度分散在整个例如肿瘤切除床中并进入引流淋巴结以在切除后破坏剩余的残留肿瘤细胞。此步骤将大量肿瘤抗原从垂死的肿瘤细胞释放到组织中。随后肿瘤抗原被抗原呈递细胞(APC)吸收。通过释放免疫刺激剂,支架可激活APC和肿瘤反应性免疫细胞以产生稳健的宿主抗肿瘤免疫应答。此“第二波”抗肿瘤免疫更广泛并涉及协同作用以消除剩余的肿瘤细胞的多种细胞类型。
STING(干扰素基因的刺激剂)通路激动剂是一种有效的免疫刺激剂,其在癌症免疫疗法中一直是热点研究的焦点。然而,如同先前描述的佐剂化合物(例如,R848和相关的咪唑并喹啉TLR7/8激动剂,触发(NOD)样受体的胞壁酰二肽和RIG-I的RNA寡核苷酸配体),用未配制的STING激动剂治疗伴随有全身性炎症毒性,这是使用这些化合物治疗癌症患者的主要障碍。因此,为了临床有效性,需要将高剂量的STING激动剂重复地直接注射到肿瘤病变中,这将此疗法限制在每日接种可接近的部位(例如,皮肤恶性肿瘤)。
发明内容
本公开通过提供改进的可植入支架继续推进癌症免疫疗法。本文公开的可植入支架接种有(i)遗传重编程的淋巴细胞;和(ii)至少一个淋巴细胞激活部分。因此,在特定实施方案中,这些可植入支架的形式可比US 2016/0008399中描述的那些更简单。在特定实施方案中,本文公开的可植入支架还可包括STING激动剂。这些实施方案提供利用STING激动剂的有效免疫刺激作用而没有全身炎症毒性且不需要每日注射的机制。
利用所公开的可植入支架观察到的抗癌作用的稳健性是协同的、意想不到的且显著的。在几乎一半的所有测试受试者中,实现了完全根除实体瘤。因此,有效地治疗了由遗传重编程的淋巴细胞识别的肿瘤细胞以及通常会成为逃避变体的肿瘤细胞。此外,在完全根除实体瘤后,用癌细胞再次攻击受试者。百分之百的再受攻击的受试者未能发展出任何可测量的肿瘤,这证明了自身疫苗部位的有效性。因此,本文公开的可植入支架在持续对抗实体瘤癌症方面提供了显著进步。
在特定实施方案中,支架包括支架基质材料,其选自微图案化金属薄膜或聚合物。在特定实施方案中,遗传重编程的淋巴细胞是T细胞或天然杀伤(NK)细胞。在特定实施方案中,至少一个淋巴细胞激活部分选自白细胞介素15和/或对CD3、CD28和/或CD137具特异性的抗体。在特定实施方案中,支架包括STING激动剂。在特定实施方案中,STING激动剂是c-diGMP。在特定实施方案中,STING激动剂包埋在药物洗脱聚合物内。在特定实施方案中,支架包括淋巴细胞粘附部分。在特定实施方案中,淋巴细胞粘附部分选自纤维蛋白或GFOGER(SEQ ID NO:1)肽。
在特定实施方案中,支架包括:(i)设置在薄膜镍钛诺(TFN)微网格内的遗传重编程的淋巴细胞。遗传重编程的淋巴细胞可包括具有淋巴细胞激活部分的T细胞,所述淋巴细胞激活部分包括对CD3、CD28和/或CD137具特异性的抗体;并且/或者可包括具有淋巴细胞激活部分的NK细胞,所述淋巴细胞激活部分包括白细胞介素-15和对CD137具特异性的抗体。在特定实施方案中,这些实施方案可包括淋巴细胞粘附部分纤维蛋白。在特定实施方案中,这些实施方案可包括c-diGMP。在特定实施方案中,这些实施方案可包括包埋在涂覆到TFN微网格表面上的药物洗脱聚合物内的c-diGMP。在特定实施方案中,这些实施方案可包括包埋在颗粒内的STING激动剂(例如,c-diGMP)。如果使用颗粒,则一个或多个淋巴细胞激活部分可在颗粒的表面上。
在特定实施方案中,包括TFN微网格的支架可包括高密度的细胞(至少7X106个/cm2或至少8X106个细胞/cm2)。TFN微网格可允许高细胞密度,例如,通过将三层细胞填充到TFN微网格的每一层中。
在特定实施方案中,包括TFN微网格的支架可用作长效支架,其可继续递送淋巴细胞长达数天、超过一周和/或超过两周。
在特定实施方案中,支架包括(i)设置在藻酸盐支架基质内的遗传重编程的淋巴细胞。遗传重编程的淋巴细胞可包括具有淋巴细胞激活部分的T细胞,所述淋巴细胞激活部分包括对CD3、CD28和/或CD137具特异性的抗体;并且/或者可包括具有淋巴细胞激活部分的NK细胞,所述淋巴细胞激活部分包括白细胞介素-15和对CD137具特异性的抗体。在特定实施方案中,这些实施方案可包括GFOGER(SEQ ID NO:1)肽淋巴细胞粘附部分。在特定实施方案中,这些实施方案可包括c-diGMP。在特定实施方案中,这些实施方案可包括包埋在涂覆到藻酸盐支架的表面上的药物洗脱聚合物内的c-diGMP。在特定实施方案中,这些实施方案可包括包埋在颗粒内的STING激动剂(例如,c-diGMP)。如果使用颗粒,则一个或多个淋巴细胞激活部分可在颗粒的表面上。
附图说明
本文提交的许多附图采用彩色会更好的理解。申请人将附图的彩色版本视为原始提交的一部分,并保留在以后的程序中呈现附图的彩图的权利。
图1.实体瘤是异质的并且表达通常用作治疗靶标的各种水平的抗原。这是人胰管腺癌的代表性共焦图像,其表现出这些肿瘤的蛋白质表达的显著多样性。细胞角蛋白表达通常发生在腺癌中,因此泛细胞角蛋白抗体用于定义肿瘤细胞群。肿瘤分化抗原间皮素是免疫疗法的可能候选者,并且靶向癌症干细胞标记物EpCAM的治疗目前正处于临床开发阶段。比例尺,100μm。在此图的彩色复制品中,泛细胞角蛋白抗体是绿色,间皮素是红色,并且EpCAM是蓝色。
图2A至图2I.肿瘤特异性CAR-T细胞的全身输注仅产生适度的治疗益处。(图2A)胰管腺癌的原位小鼠模型。(图2B)手术植入后7天的KPC胰腺的明视场显微镜法。苏木精/伊红染色显示在胰腺头部散布有实质组织的浸润性腺癌;相邻的健康组织突出了肿瘤区域的无组织性质。在这些样品中,也清楚看到,形成分化的和未分化的腺泡结构(即,腺体和导管)两者,这是腺癌的标志。对放大(20x)图像的分析揭示了肿瘤微环境内大量募集免疫细胞(包括多形核白细胞)。虚线矩形定位放大的插图。比例尺,100μm。(图2C)流式细胞术数据的热图表示,其定量KPC肿瘤的Rae-1表达的细胞之间的变化。将七天大的肿瘤(用GFP标记以区分它们)解聚成单细胞悬浮液并用针对Rae-1的抗体标记,因此可通过流式细胞术测量此抗原的平均荧光强度;阴影指示与同种型对照相比的相对表达水平。示出来自1,800个随机选择的细胞的结果。(图2D)此示意图描绘用于识别Rae-1的嵌合受体如何包括与鼠CD3ζ细胞内信号传导分子融合的全长小鼠NGK2D。(图2E)流式细胞术测量逆转录病毒转导并在含有G418的培养基中扩增三天后小鼠效应T细胞上的NKG2D CAR的表面表达。(图2F)与KPC胰腺肿瘤细胞反应的NKG2D CAR转导的T细胞的51Cr释放细胞毒性测定。(图2G)将表达萤火虫荧光素酶的KPC肿瘤细胞移植到白化C57BL/6小鼠的胰腺中十天后,向动物注射107个NKG2DCAR转导的T细胞。为了测量编程的淋巴细胞靶向的动力学,在平行实验中,向小鼠注射共表达叩头虫红荧光素酶报告基因的CAR-T细胞。示出来自每个群组(n=10)的五只代表性小鼠中的KPC肿瘤和过继转移的T细胞的连续生物发光成像。(图2H)处理小鼠和对照小鼠的Kaplan-Meier存活率曲线。示出从三个独立实验汇集的每个处理组的十只小鼠;ms,中值存活率。使用对数秩测试进行在此描绘的处理实验组与未处理对照组之间的统计学分析,并且P<0.05被认为是显著的。(图2I)NKG2D CAR-T细胞疗法后KPC肿瘤细胞上Rae-1抗原表达的流式细胞术定量。示出1,800个随机选择的细胞。
图3A,图3B.直接置于胰腺肿瘤上的生物基质可充当CAR编程的T细胞的有效递送平台。(图3A)并入支架中的刺激性微球的明视场显微镜法;以下是微粒组合物的描绘。比例尺,70μm。(图3B)此系列说明了公开的方法:[1]支架;[2]将肿瘤反应性T细胞接种到装置中;[3]切口;[4]原位KPC胰腺肿瘤;[5]-[7]植入T细胞负载装置;[8]伤口闭合;[9]持续释放肿瘤反应性T细胞。
图4A至图4E.聚合物发射的CAR-T细胞在肿瘤部位处稳健扩增并触发肿瘤消退,但不影响缺失靶抗原的细胞。(图4A)KPC肿瘤和过继转移的CAR-T细胞的生物发光成像。用局部注射到肿瘤中,或包含在直接植入肿瘤表面中的生物活性支架中的107个NKG2D转导的淋巴细胞处理小鼠。示出来自每个群组(n=10)的五只代表性小鼠。(图4B)细胞转移后每两天捕获的连续生物发光图像的T细胞信号强度。每条线代表一只动物,并且每个点指示整个动物光子计数。在指示的时间点处,用Wilcoxon秩和测试分析处理组之间光子计数的成对差异。(图4C)定量的KPC生物发光肿瘤信号。(图4D)处理小鼠和对照小鼠的Kaplan-Meier存活率曲线。示出从三个独立实验汇集的每个处理组的十只小鼠。ms,中值存活率。使用对数秩测试进行在此描绘的处理实验组与未处理对照组之间的统计学分析,并且P<0.05被认为是显著的。(图4E)NKG2D CAR-T细胞疗法后KPC肿瘤细胞上Rae-1抗原表达的流式细胞术定量。示出1,800个随机选择的细胞。
图5A,图5B.生物材料载体的设计,其共同递送表达CAR的T细胞和免疫刺激剂(在此实施例中显示为疫苗佐剂)以同时清除异质癌细胞并建立全身性抗肿瘤免疫。(图5A)负载有与肿瘤床相互作用的CAR-T细胞的支架示意图:图1和图2示出并入装置中的含有因子的微球如何刺激表达CAR的T细胞的扩增并促进它们进入周围组织。APC,抗原呈递细胞。图2和图3说明从负载T细胞的支架释放疫苗佐剂,引发宿主免疫细胞以识别和裂解肿瘤细胞,并且从而对抗抗原逃避变体。(图5B)用微粒功能化的多孔藻酸盐基质的宏观和微观视图,所述微粒具有包埋在聚合物核心中的STING激动剂环状-di-GMP(即,c-diGMP或cdGMP,其可互换使用)和系到其磷脂膜上的刺激性抗CD3/CD28/CD137抗体。以下示出c-diGMP的化学结构。
图6A,图6B.支架释放的CAR-T细胞和STING激动剂协同以激活宿主抗原呈递细胞。(图6A,图6B)将表达荧光素酶的KPC肿瘤细胞移植到小鼠胰腺中十天后,将含有7×106个肿瘤反应性CAR-T细胞、6μg c-diGMP或两者组合的支架植入在肿瘤表面上;对照小鼠未接受任何处理。五天后,将胰周淋巴结消化成细胞悬浮液,用以通过流式细胞术进行分析。仅使用未被肿瘤吞噬的淋巴结,并且它们从至少五只动物汇集。(图6A)髓样成熟标记物(CD11b和CD11c)的流式细胞术:右侧所示的直方图描绘对CD11c+CD11b+双阳性细胞群选通后共刺激因子CD86和MHC II类分子的表达。(图6B)胰周淋巴结中成熟和激活(CD11b+CD11c+CD86+MHC-II+)树突细胞的绝对数量。点代表从5只小鼠汇集的样品中每个淋巴结的细胞数,并且数据代表四个单独的研究。
图7A,图7B.c-diGMP和表达CAR的T细胞从支架中的共释放引发内源性肿瘤反应性淋巴细胞。(图7A,图7B)将表达糖蛋白33的KPC肿瘤移植到小鼠体内。用生物材料递送的c-diGMP、CAR-T细胞或两者的组合处理这些小鼠,并通过四聚体染色定量外周血中的宿主gp33特异性T细胞。为了区分内源性和过继转移的T细胞,将同类CD45.1受体小鼠用于这些研究。(图7A)代表性流式细胞术图,其示出对CD45.1+(宿主)CD8+细胞选通的支架植入10天后外周血中gp33四聚体阳性细胞的百分比。示出图代表三个独立的实验。(图7B)引发的(CD45.1+CD8+gp33+)T细胞的绝对数量。示出从三个独立实验汇集的十只小鼠。每个条形代表平均绝对细胞计数±s.e.m。未配对的学生t测试用于测试绝对细胞计数之间的差值。
图8A至图8C.共同递送STING激动剂与表达CAR的T细胞的支架可限制肿瘤免疫逃避。(图8A)KPC-luc肿瘤的连续体内生物发光成像。示出来自每个群组(n=10)的五只代表性小鼠。(图8B)定量的KPC生物发光肿瘤信号;示出从三个独立实验汇集的每个处理组的十只小鼠。(图8C)处理小鼠和对照小鼠的Kaplan-Meier存活率曲线。ms,中值存活率。使用对数秩测试进行在此描绘的处理实验组与未处理对照组之间的统计学分析,并且P<0.05被认为是显著的。
图9A,图9B.支架可引发整体抗肿瘤免疫。(图9A)如相对于图8A至图8C所述,静脉内注射到经历完全肿瘤消退的四只小鼠中的KPC-luc肿瘤细胞的连续体内生物发光成像。将年龄匹配的幼稚小鼠用作对照。(图9B)Kaplan-Meier存活率曲线。
图10A至图10D.(图10A)示意性说明通过将淋巴细胞激活部分(例如,抗CD3/CD28/CD137抗体)共价偶联至细胞支架(例如,薄膜镍钛诺(TFN)微网格)而用所述部分功能化的支架。(图10B)示意性说明通过将淋巴细胞激活部分(例如,抗CD3/CD28/CD137抗体)共价偶联至与细胞支架(例如,TFN微网格)共价偶联或涂覆在细胞支架(例如,TFN微网格)上的淋巴细胞粘附部分(例如,纤维蛋白、胶原蛋白)而用所述部分功能化的细胞支架。(图10C)示意性说明用多层薄膜微网格(例如,TFN微网格)形成并且包埋有超高密度的肿瘤反应性免疫细胞(例如,CAR T细胞)的三维植入物。(图10D)功能化的微图案化金属薄膜(例如TFN微网格)实现了超高的细胞密度。
图11A至图11H.用适当的淋巴细胞粘附部分和刺激性触发物功能化的TFN微网格支持T细胞的快速迁移和稳健扩增。(图11A)TFN微网格图。比例尺:2mm。(图11B)未涂覆(左图)和纤维蛋白涂覆(右图)的TFN微网格的光学显微镜图像。放大率:40x。比例尺:120μm(图11C)未涂覆(左图)和纤维蛋白涂覆(右图)的TFN微网格的电子显微镜图像。放大率:图中示出270x1,100x放大版本(图11D)。(图11E)跟踪30min的淋巴细胞迁移通过未涂覆(左)和纤维蛋白涂覆(右)的TFN微网格的时间推移视频投影;每个阴影颜色代表一个单独的T细胞。比例尺:50μm。以下示出基于来自两个独立实验的30个随机选择的细胞,平均速度和平均T细胞位移的比较。(图11F)包埋在纤维蛋白涂覆的TFN微网格中的人T细胞(Alexa 488标记的:绿色)的高放大率共焦图像。比例尺:100μm。插图示出放大图。比例尺:50μm。(图11G)用T细胞粘附配体(纤维蛋白)和刺激性配体(通过EDC化学与纤维蛋白共价偶联的抗CD3/CD28/CD137抗体)功能化的TFN微网格的示意图。(图11H)在7d测试时间段期间已经离开TFN微网格的T细胞的代表性羧基荧光素琥珀酰亚胺酯(CFSE)测定,其中通过使用流式细胞术测量CFSE稀释(作为细胞分裂的结果)来评估增殖。淋巴细胞群的平均CFSE荧光强度(MFI)在左上方指示。
图12A至图12I.从生物活性TFN微网格中持续释放T细胞。(12A,12B)用抗CD3/CD28/CD137抗体功能化的纤维蛋白和肿瘤反应性CAR T细胞功能化的单层TFN微网格(图12A)或支架(图12B)的示意图。(图12C,图12D).微网格膜或支架的显微照片。(图12E,图12F)通过将它们与含有10ng/mL炎性细胞因子IP-10的三维胶原蛋白凝胶(PureCo1)邻接并在完全RPMI培养基中培养来测量淋巴细胞从TFN微网格的溢出。在第0天或第2天对含有包埋的CAR T细胞的TFN微网格(图12E)或支架(图12F)进行显微镜法。(图12G,图12H)从这些TFN微网格(图12G)或支架(图12H)转移到周围胶原蛋白基质的活T细胞的绝对计数。每行代表一个TFN微网格。数据代表三次独立的实验。(图12I)淋巴细胞在6天后显示出对TFN微网格的高持久性。将TFN微网格负载有CAR-T细胞并紧贴组织模拟物放置6天。6天后在膜上仍然存在超高细胞密度,这指示在肿瘤部位可获得有利的淋巴细胞持久性。
图13A至图13B.从生物活性TFN微网格中发射卵巢癌特异性CAR T细胞根除已建立的多灶性疾病。将100万个OVCAR-3人卵巢癌细胞(表达肿瘤抗原酪氨酸激酶样孤儿受体ROR1和萤火虫荧光素酶)通过外科手术植入NOD scidγ(NSG)小鼠的隔膜中并使其建立8周。在那个时间点,所有动物都发展出卵巢癌病变,模仿扩展到具有卵巢癌的女性的隔膜。用局部注射到肿瘤病变中的对静脉内注射的ROR-1具特异性的10×106个人CAR T细胞或从植入的TFN微网格递送的2x106个细胞处理小鼠。(图13A)所述方法的实施:[1]在隔膜中建立卵巢癌病变;Li:肝脏。Diaph:隔膜。Tu:肿瘤。[2]在肝脏与隔膜之间植入负载有抗ROR1CAR T细胞的TFN微网格。[3]植入后的TFN微网格。(图13B)OVCAR-3-luc肿瘤的连续体内生物发光成像。
图14.用TFN微网格淋巴细胞支架处理的小鼠的Kaplan-Meier存活率曲线。
图15.可使用药物洗脱聚合物将小分子(例如,STING激动剂和/或免疫刺激剂)并入淋巴细胞支架(例如,TFN微网格支架)中。
图16.GFOGER(SEQ ID NO:1)粘附基序的多肽序列。
图17.示例性GFOGER(SEQ ID NO:1)肽(SEQ ID NO:2)的多肽序列。
图18.ICAM-1细胞粘附分子(SEQ ID NO:3)的多肽序列。
图19.FN-III7-10片段(SEQ ID NO:4)的多肽序列。
图20.可用于工程化嵌合抗原受体(SEQ ID NO:14-27)的示例性序列。
具体实施方式
癌症免疫疗法描述了其中患者免疫系统用于治疗癌症的领域。例如,癌症免疫疗法包括使用疫苗来免疫患者以抵抗癌症的发展。不幸的是,癌症疫苗可能引起的应答可能需要数月才能成熟,并且通常不足以控制晚期疾病。
还尝试更快或有效地刺激患者自身的T细胞以攻击癌细胞。然而,通常由T细胞表达的受体库通常对自身/肿瘤抗原具有低亲和力,所以此方法在抗癌方面尚未取得足够的成功。
新兴的免疫疗法方法涉及用编码嵌合抗原受体(CAR)的基因改变患者来源的淋巴细胞(例如,T细胞),所述嵌合抗原受体被工程化为对肿瘤中选定的大分子靶标具有高亲和力。引入的基因也可产生共刺激信号以引发稳健的T细胞扩增。所述方法涉及从患者中检索T细胞并将它们离体重定向以表达由与共刺激和CD3ζ信号传导结构域融合的肿瘤特异性单链抗体(scFv)构成的CAR,其使得程序化细胞能够以人白细胞抗原(HLA)独立的方式裂解肿瘤靶标。
在临床试验中,采用此类CAR编程的T细胞的疗法在血液恶性肿瘤患者中始终产生阳性结果。然而,当涉及到实体瘤时,这些疗法的有效性受到以下因素的限制:1)淋巴细胞无效归巢到肿瘤部位;和2)免疫抑制微环境实体瘤产生。此外,3)CAR编程的T细胞仅识别针对其已经编程的肿瘤抗原。然而,实体瘤的表型多样性意味着CAR编程的T细胞未识别的癌细胞可形成逃脱编程的T细胞的逃避变体。因此,虽然T细胞的遗传重编程仍然是一种有前途的疗法,但是将它们用于治疗实体瘤需要显著的改进。
US 2016/0008399描述一种可植入支架,其极大地改善了遗传重编程的淋巴细胞(例如,T细胞)治疗实体瘤的能力。可植入支架包括遗传重编程的淋巴细胞,至少一个与支架相关的淋巴细胞粘附部分;至少一个与支架相关的淋巴细胞激活部分,和任选地免疫刺激剂。
US 2016/0008399还描述可植入支架如何产生针对肿瘤细胞的延长的第二波保护。特别地,接种在支架内的淋巴细胞在植入后离开支架并以高密度分散在整个例如肿瘤切除床中并进入引流淋巴结以在切除后破坏剩余的残留肿瘤细胞。此步骤将大量肿瘤抗原从垂死的肿瘤细胞释放到组织中。随后肿瘤抗原被抗原呈递细胞(APC)吸收。通过释放免疫刺激剂,支架可激活APC和肿瘤反应性免疫细胞以产生稳健的宿主抗肿瘤免疫应答。此“第二波”抗肿瘤免疫更广泛并涉及协同作用以消除剩余的肿瘤细胞的多种细胞类型。
STING(干扰素基因的刺激剂)通路激动剂是一种有效的免疫刺激剂,其在癌症免疫疗法中一直是热点研究的焦点。然而,如同先前描述的佐剂化合物(例如,R848和相关的咪唑并喹啉TLR7/8激动剂,触发(NOD)样受体的胞壁酰二肽和RIG-I的RNA寡核苷酸配体),用未配制的STING激动剂治疗伴随有全身性炎症毒性,这是使用这些化合物治疗癌症患者的主要障碍。因此,为了临床有效性,需要将高剂量的STING激动剂重复地直接注射到肿瘤病变中,这将此疗法限制在每日接种可接近的部位(例如,皮肤恶性肿瘤)。
本公开通过提供接种有(i)遗传重编程的淋巴细胞;和(ii)至少一个淋巴细胞激活部分的可植入支架继续推进癌症免疫疗法。此支架克服了上述在实体瘤中进行细胞疗法的三个问题,因为1)支架可植入在实体肿瘤部位处,从而克服淋巴细胞无效归巢到肿瘤;通过在支架中包含淋巴细胞刺激抗体来解决免疫抑制肿瘤微环境,所述淋巴细胞刺激抗体促进T细胞增殖和肿瘤细胞杀伤;以及3)在这种支架中包含STING激动剂提供了利用其有效的免疫刺激作用而没有全身炎症毒性且不需要每日注射的机制。
利用所公开的可植入支架观察到的抗癌作用的稳健性是协同的、意想不到的且显著的。在几乎一半的所有测试受试者中,实现了完全根除实体瘤。因此,有效地治疗了由遗传重编程的淋巴细胞识别的肿瘤细胞以及通常会成为逃避变体的肿瘤细胞。此外,在完全根除实体瘤后,用癌细胞再次攻击受试者。百分之百的再受攻击的受试者未能发展出任何可测量的肿瘤,这证明了自身疫苗部位的有效性。因此,本文公开的可植入支架在持续对抗实体瘤癌症方面提供了显著进步。
在特定实施方案中,本文公开的可植入支架还可比US 2016/0008399中描述的那些呈更简单的形式并且更容易制造。本文公开的可植入支架还可包括STING激动剂。
为清楚起见,在本公开中,异质实体瘤是包括表达由遗传重编程的淋巴细胞(例如,遗传重编程的CAR-T细胞)靶向的抗原的肿瘤细胞和不表达靶向抗原的肿瘤细胞的那些。表达靶向抗原的那些肿瘤细胞是靶向的实体瘤细胞。不表达靶向抗原的肿瘤细胞是逃避变体。
现在更详细地描述所公开的可植入支架的各种部件。
可植入支架基质材料。本文公开的可植入支架的结构可由多种材料构造。
在特定实施方案中,支架基质材料包括微图案化金属薄膜。微图案化金属薄膜由至少一种金属材料配制而成,在其结构中包括重复图案,并且具有100μm或更小的厚度。可用于微图案化金属薄膜的示例性金属包括(Elgiloy Specialty Metals,Elgin,IL)、不锈钢和镍钛诺。在特定实施方案中,薄膜镍钛诺(TFN)微网格用作支架基质材料(例如,Rigberg等人,J Vasc Surg.2009年8月;50(2):375-80)。镍钛诺是指镍和钛合金家族,其包含50%与60%之间的镍和40%与50%之间的钛。镍钛诺合金中高达2%的镍可用钴代替。TFN微网格是通过溅射沉积工艺在微图案化硅晶片上产生的块状材料的变体。TFN微网格的一个特定优点是,因为其基于光刻技术,可对TFN微网格孔的大小和形状进行精细控制。TFN微网格可是指薄片或膜形状的镍钛诺(例如,100μm、10μm、1μm或0.1μm厚)。为了增强单层TFN微网格的细胞装载能力,具有交替TFN层和细胞层的三明治状的逐层薄膜可被制造成三维结构(如图10C所示)。
在特定实施方案中,支架基质材料包括生物相容性聚合物。示例性生物相容性聚合物包括琼脂、琼脂糖、藻酸盐、藻酸盐/磷酸钙粘固剂(CPC)、β-半乳糖苷酶(β-GAL)、(1,2,3,4,6-五乙酰基a-D-半乳糖)、纤维素、甲壳质、壳聚糖(参见,例如,Levengood等人,J.Mater.Chem.B,2014,2,3161-3184,其描述多孔壳聚糖支架)、胶原蛋白、弹性蛋白、明胶、透明质酸胶原蛋白、羟基磷灰石、聚(3-羟基丁酸酯-共-3-羟基-己酸酯)(PHBHHx)、聚(丙交酯)、聚(己内酯)(PCL)、聚(丙交酯-共-乙交酯)(PLG)、聚环氧乙烷(PEO)、聚(乳酸-共-乙醇酸)(PLGA;参见,例如,Omar等人,Sci.Transl.Med.2009年11月25日;1(8):8ra19,其描述多孔PLGA支架)、聚环氧丙烷(PPO)、聚(乙烯醇)(PVA)、丝、大豆蛋白和大豆蛋白分离物,单独使用或与任何其他聚合物组合物组合,采用任何浓度和任何比例。使用不同等级以不同比例共混不同聚合物类型可产生从每种贡献聚合物中借用的特征。也可采用各种末端基团化学。
当使用可注射的可植入支架时,支架基质(例如,聚合物)可对植入后变化的环境条件作出应答。具有这些特征的聚合物是本领域普通技术人员已知的。例如,在特定实施方案中,使用可注射的原位凝胶形成系统。在特定实施方案中,聚合物制剂可响应于温度变化(热凝胶化),响应于pH变化或响应于光而在体内凝胶化。例如,可使用响应于紫外(UV)光而凝胶化的聚合物。在特定实施方案中,聚合物制剂可响应于离子交联而在体内凝胶化。在特定实施方案中,聚合物制剂可响应于溶剂交换而在体内凝胶化。在特定实施方案中,使用的凝胶是热可逆的、pH可逆的或光可逆的。在特定实施方案中,使用的凝胶是高粘度和剪切稀化的。在另外的胶凝实施方案中,凝胶可以是由任何适当的聚合物形成的凝胶。Kim等人,Nature Biotechnology 33,64-72(2015)中描述了由中孔二氧化硅棒制成的可注射的、自发组装的支架。
自组装肽支架也可用作支架基质材料(参见,例如,Zacco等人,Biomacromolecules.2015年7月13日;16(7):2188-97)。
在特定实施方案中,藻酸盐单独或与一种或多种其他材料组合用作支架基质材料。藻酸盐易于加工,呈水溶性和非免疫原性。藻酸盐是一种可生物降解的阴离子多糖,其具有提供容易胶凝的游离羟基。在可替代的实施方案中,聚合物可以是由藻酸盐和壳聚糖的1∶1溶液形成的聚电解质复合物混合物(PEC)。
在特定实施方案中,结构(例如,支架基质材料)可由藻酸盐/碳酸钙/葡糖酸-δ-内酯混合物形成,诸如0.5%-5%藻酸盐,0.5-15g/L碳酸钙和1-50g/L葡糖酸-δ-内酯的比例为2∶1∶1(藻酸盐∶CaCO3∶GDL)。聚合物结构还可包括不同量的明胶与不同量的藻酸盐的组合。取决于混合物中的材料和材料的比例,结构可任选地交联。也可使用胶原蛋白/藻酸盐混合支架,诸如Lee等人,Chem.Mater.,2012,24(5),881-891中所述的那些。
在特定实施方案中,具有溶解在酸性溶液中的不同量的聚合物的聚合物溶液可用于形成本文公开的结构。可根据溶解的聚合物的量来调整酸的浓度。在一个方面中,酸性溶液是1%(v/v)乙酸。在特定实施方案中,溶液中聚合物的量为0.5%-5%(w/v)和其间的任何全部或部分增量。例如,溶液中聚合物的量(w/v)可以是0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%或5%。在特定实施方案中,溶液中聚合物的量为2.4%(w/v)。在其他各种实施方案中,将聚合物溶解在水、酸、乙酸、莰烯或莰烯-萘中的至少一种中。
当并入明胶时,可根据溶解的明胶与聚合物(在特定实施方案中,藻酸盐)的量来调整酸的浓度。在一个方面中,酸性溶液是1%(v/v)乙酸。在特定实施方案中,溶液中明胶的量为1%-10%(w/v)和其间的任何全部或部分增量。例如,溶液中藻酸盐的量(w/v)可以是1%、2%、3%、4%、5%、6%、7%、8%、9%或10%。在特定实施方案中,溶液中藻酸盐的量为5.5%(w/v)。在特定实施方案中,聚合物溶液包含2.4%(w/v)藻酸盐溶液和5.5%(w/v)明胶溶液的组合。在其他各种实施方案中,将明胶与不同量的藻酸盐组合溶解在水、酸、乙酸、莰烯或莰烯-萘中的至少一种中。
在特定实施方案中,基于聚合物的支架可如下形成:可制备在去离子(DI)水中的一定容重(w/v)的聚合物溶液,并用0.45微米的瓶过滤器过滤以除去任何颗粒,并且然后冷冻至-80℃。可将冷冻样品在4.5升台式冷冻干燥系统(Labconco,Kansas City,MO)中冻干。可将过滤的冻干聚合物用水或缓冲液重构成各种浓度(0.1%-5%)的溶液。
交联可用例如氯化钙和/或碳酸钙进行。碳酸钙是一种缓慢的交联剂,样品需要长达数小时才能完全交联。为了增加反应速度,可添加葡糖酸δ内酯(GDL)。氯化钙是一种快速交联剂,样品将在几分钟内完全凝胶化。在一种方法中,可在冷冻之前向聚合物溶液中添加CaCl2。其他方法包括在初始冷冻之前将碳酸钙+GDL的5.5%(w/v)溶液添加到聚合物溶液中。
在特定实施方案中,可将聚合物溶液在速度混合器中脱气并缓慢倒入铸件中以防止形成气泡。当将聚合物溶液移液到小模具中时,通过将微量移液管放置在模具槽的开口端上并反复冲洗整个管道系统直到冲洗掉残余空气,可避免形成气泡。
冷冻铸造可用于形成本文公开的支架。如本领域技术人员所理解的,可将各种聚合物溶液冷冻铸造成各种大小的铸件。应控制冷却速率,因为其影响孔的大小和对准,以及脊形成。在特定实施方案中,冷却速率的范围可以是0.1-100℃/分钟(m)和其间的任何全部或部分增量。在特定实施方案中,冷却速率的范围可以是1-10℃/m,以及其间的任何全部或部分增量。例如,冷却速率(℃/m)可以是0.1、0.5、1、2、3、4、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5或10。
在特定实施方案中,在制备藻酸盐支架中,可通过搅拌制备藻酸盐/碳酸钙/葡糖酸-δ-内酯混合物,浓度为0.5重量%-5重量%的藻酸盐,0.5-15g/L的碳酸钙和1-50g/L葡糖酸-δ-内酯,体积比为2∶1∶1(藻酸盐∶CaCO3∶GDL),作为“预胶凝”过程。在特定实施方案中,所得的混合物可以恒定的冷却速率(0.1°/min-10°/min)冷冻铸造(定向冷冻),直至呈固体并冻干直至干燥。干燥的支架可在0.1重量%-2.5重量%的氯化钙中交联5-30分钟,并在任何进一步使用支架之前在HEPES缓冲盐水中洗涤。
在特定实施方案中,在制备藻酸盐-壳聚糖支架中,藻酸盐-壳聚糖聚电解质复合物(PEC)混合物可通过在冰上以1∶1至1∶9范围内的藻酸盐(在水中制备)和壳聚糖(在1%乙酸中制备)的溶液(两种方式)以及0.5%-5%范围内的总聚合物含量进行超声处理或均质化来制备。可用NaOH将所得的混合物的pH调整至10.0。在特定实施方案中,藻酸盐-壳聚糖PEC混合物可以恒定的冷却速率(0.1°/min-10°/min)冷冻铸造,直至呈固体并冻干直至干燥。干燥的支架可在0.1%-2.5%的氯化钙中交联5-30分钟,并在任何进一步使用支架之前在PBS中洗涤。
可植入支架也可使用3D生物打印由各种材料制造(参见,例如,Singh等人,Polymers 2016,8(1),19;以及An等人,Engineering,第1卷,第2期,2015年6月,第261-268页)。
淋巴细胞激活部分。本文公开的可植入支架的特定实施方案还可包括淋巴细胞激活部分(LAM)。LAM包括激活淋巴细胞的任何化合物,并且可并入或附接于本文公开的可植入支架。淋巴细胞的激活是指已被充分刺激以诱导可检测的细胞增殖、细胞因子产生或效应子功能诸如肿瘤靶向和/或杀伤的淋巴细胞状态。如果淋巴细胞是T细胞,则激活还导致对T细胞类型特定的细胞表面标记物的表达。示例性LAM包括IL-15、CD3、CD27、CD28、CD80、CD86、4-1BB、CD137、OX40、CD30、CD40、LFA-1、CD2、CD7、LIGHT、NKG2C、B7-H3和CD83配体或抗体、CD1d、预负载有α-半乳糖基神经酰胺的重组CD1d分子和/或负载有限定的肿瘤抗原或肽以选择性地扩增包埋在支架内的特定淋巴细胞类型的重组主要组织相容性复合物(MHC)分子。NK细胞的示例性LAM包括IL-15和CD137。
STING激动剂。“STING”是“干扰素基因的刺激剂”的缩写,其也被称为“内质网干扰素刺激剂(ERIS)”、“IRF3激活介质(MITA)”、“MPYS”或“跨膜蛋白173(TM173)”。STING是一种跨膜受体蛋白并由人类中的基因TMEM173编码。STING的激活通过IRF3(干扰素调节因子3)途径产生I型干扰素(例如,IFN-a和IFN-β);并且通过NF-κB途径和/或NLRP3炎性体产生促炎细胞因子(例如,IFN-a和IL-1β)。
人和鼠STING通过两种方式自然激活:通过入侵细菌或古细菌释放的外源(3′,3)环状二核苷酸(c-diGMP、c-diAMP和c-GAMP)的结合;以及通过(2′,3′)环状鸟苷一磷酸-腺苷一磷酸((2′,3′)c-GAMP)的结合,这是一种内源性环状二核苷酸,其在外源双链DNA(例如,由入侵细菌\病毒或原生动物释放)存在下由酶环状GMP-AMP合成酶(cGAS;也称为C6orfl50或MB21D1)产生。
术语“STING激动剂”是指在体外或体内激活STING受体的物质。如果出现以下情况,化合物可被视为STING激动剂:(i)在含有STING的人或动物细胞中体外诱导I型干扰素;以及(ii)在不含STING或不含功能性STING的人或动物细胞中不体外诱导I型干扰素。确定配体是否为STING激动剂的典型测试是将配体在野生型人或动物细胞系和对应的细胞系中孵育,其中STING编码基因因少量碱基或更长缺失已发生遗传失活(例如,纯合的STING敲除细胞系)。STING的激动剂将在野生型细胞中诱导I型干扰素,但在STING失活的细胞中不会诱导I型干扰素。
在特定实施方案中,STING激动剂包括在两个核苷酸之间具有一个或两个磷酸二酯键和/或一个或两个硫代磷酸酯二酯键的环状分子。这包括(3′,5′)-(3′,5′)核苷酸键(缩写为(3′,3′));(3′,5′)-(2′,5′)核苷酸键(缩写为(3′,2′));(2′,5′)-(3′,5′)核苷酸键(缩写为(2′,3′));和(2′,5′)-(2′,5′)核苷酸键(缩写为(2′,2′))。“核苷酸”是指与糖部分的5′、3′或2′位置的磷酸基团连接的任何核苷。
在特定实施方案中,STING激动剂包括下式的化合物:
在特定实施方案中,R1和R2可独立地是9-嘌呤、9-腺嘌呤、9-鸟嘌呤、9-次黄嘌呤、9-黄嘌呤、9-尿酸或9-异鸟嘌呤,如下所示:
在特定实施方案中,STING激动剂可包括二硫代-(RP,RP)-[环状[A(2′,5′)pA(3′,5′)p]](也称为2′-5′,3′-5′混合磷酸二酯键(ML)RR--S2c-di-AMP或ML RR--S2CDA)、MLRR--S2-c-di-GMP(ML-CDG)、ML RR--S2cGAMP或它们的任何混合物。
c-diGMP的结构在图5B中示出。c-diAMP的结构包括:
c-GAMP的结构包括:
STING激动剂的另外特定实例包括:
STING激动剂的实例还包括DMXAA:
STING激动剂的另外实例描述于WO2016/145102中。
接下来描述另外的免疫刺激剂和淋巴细胞粘附部分的任选用途。
另外的免疫刺激剂。在特定实施方案中,可包括除STING激动剂之外的免疫刺激剂。在特定实施方案中,免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
示例性细胞因子包括IL-2、IL-7、IL-12、IL-15、IL-18、IL-21、TNFα、IFN-α、IFN-β、IFN-γ或GM-CSF。在特定实施方案中,免疫刺激剂可以是细胞因子和/或细胞因子的组合,诸如IL-2、IL-12或IL-15与IFN-α、IFN-β或IFN-γ或GM-CSF的组合,或它们的任何有效组合,或细胞因子的任何其他有效组合。以上鉴定的细胞因子刺激TH1应答,但也可使用刺激TH2应答的细胞因子,诸如IL-4、IL-10、IL-11或它们的任何有效组合。此外,可使用刺激TH1应答的细胞因子和刺激TH2应答的细胞因子的组合。
示例性抗体包括抗PD1、抗PDL1、抗CTLA-4、抗TIM3、激动性抗CD40、激动性抗-4-1BB和/或双特异性抗体(例如,BITE-抗体:抗CD3/抗体-肿瘤抗原)。示例性小分子药物包括TGF-β抑制剂、SHP抑制剂、STAT-3抑制剂和/或STAT-5抑制剂。可使用任何能够下调免疫抑制信号或致癌途径的siRNA(诸如kras),而可使用编码免疫刺激蛋白的任何质粒DNA(诸如小环DNA)。示例性疫苗佐剂包括任何种类的Toll样受体配体或它们的组合(例如,CpG、Cpg-28(TLR9激动剂)、聚核糖肌苷聚核糖胞苷酸(聚(I:C))、αα-半乳糖神经酰胺、MPLA、Motolimod(VTX-2337,由VentiRx开发的新型TLR8激动剂)、IMO-2055(EMD1201081)、TMX-101(咪喹莫特)、MGN1703(TLR9激动剂)、G100(TLR4激动剂吡喃葡萄糖基脂质A的稳定乳剂)、Entolimod(沙门菌鞭毛蛋白的衍生物,也称为CBLB502)、Hiltonol(TLR3激动剂)和咪喹莫特)和/或热休克蛋白90(Hsp90)的抑制剂,诸如17-DMAG(17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
也可使用衍生自前面段落中提到的分子的免疫刺激剂。例如,RLI是IL-15-IL-15受体-α融合蛋白,其表现出的效力是单独的IL-15的50倍高。IL-15在多个点影响抗肿瘤免疫应答。其可将单核细胞分化为刺激性抗原呈递细胞;促进肿瘤反应性T细胞的效应子功能和增殖;并募集和激活NK细胞。
淋巴细胞粘附部分。所公开的支架可包括淋巴细胞粘附部分,以促进淋巴细胞从植入支架移出。淋巴细胞粘附部分包括细胞粘附部分,诸如模拟细胞外基质(诸如胶原蛋白)的细胞粘附多肽。如本文所用,“细胞粘附多肽”是指每分子具有至少两个氨基酸的化合物,其能够通过细胞表面分子(诸如整联蛋白)结合。细胞粘附多肽可以是已知在细胞粘附中起作用的细胞外基质的任何蛋白质,包括纤维蛋白、纤连蛋白、玻连蛋白、层粘连蛋白、弹性蛋白、纤维蛋白原、I型、II型和V型胶原蛋白,如Boateng等人,Am.J.Physiol.-CellPhysio.288:30-38(2005)所述。另外,细胞粘附多肽可以是衍生自这些蛋白质中的任一种的任何肽,包括含有结合结构域的片段或序列。细胞粘附多肽包括具有整联蛋白结合基序(诸如ICAM-1基序)的那些,以及作为功能等同物的相关肽。细胞粘附多肽也可以是美国专利公开号20060067909中描述的任何肽。
在特定实施方案中,所述结构包括具有淋巴细胞粘附部分的化合物,诸如用于α1β1整联蛋白的配体,用于α2β1整联蛋白的配体,用于α4β1整联蛋白的配体,用于α5β1整联蛋白的配体,用于淋巴细胞功能相关抗原(LFA-1)的配体,或它们的组合。在特定实施方案中,配体与一种整联蛋白特异性相互作用。在特定实施方案中,配体不是完整的纤连蛋白分子或不是完整的胶原蛋白分子。
淋巴细胞粘附部分可以是肽、抗体或小有机分子。小有机分子是指分子量为500道尔顿或更低的碳基分子。抗体或其整联蛋白结合片段可以是单链的、人源化的或嵌合的。在特定实施方案中,淋巴细胞粘附部分可以是胶原蛋白模拟肽,例如稳定的三螺旋的胶原蛋白-模拟肽,其包含来自I型胶原蛋白的GFOGER(SEQ ID NO:1)粘附基序,GFP*GER(SEQ IDNO:1),其中P*为4-羟基脯氨酸,其由α2β1整联蛋白识别。此肽采用类似于I型胶原蛋白的天然结构的稳定的三螺旋构象。“GFOGER(SEQ ID NO:1)肽”可是指含有GFOGER(SEQ ID NO:1)粘附基序的胶原蛋白-模拟肽。示例性GFOGER(SEQ ID NO:1)肽序列是GGYGGGPC(GPP)5GFP*GER(GPP)5GPC(SEQ ID NO:2),其中P*是4-羟基脯氨酸。
特定实施方案利用ICAM-1作为淋巴细胞粘附部分。ICAM-1是Ig样细胞粘附分子,其结合促进细胞-细胞粘附的整联蛋白,并且是淋巴细胞功能相关(LFA)抗原的配体。ICAM-1主要存在于单核细胞和内皮细胞上,并且在许多细胞上可广泛诱导或上调,包括T细胞、B细胞、胸腺细胞、树突细胞、内皮细胞、成纤维细胞、角质形成细胞、软骨细胞和上皮细胞。此蛋白质对细胞毒性T细胞相互作用具有共刺激作用,并用于许多细胞间结合相互作用。在特定实施方案中,ICAM-1包括SEQ ID NO:3。
特定实施方案利用FNIII7-10作为淋巴细胞粘附部分。FNIII7-10是跨越纤连蛋白的第7-10个III型重复单元的纤连蛋白片段。纤连蛋白的序列在本领域中是已知的。在特定实施方案中,FNIII7-10包括SEQ ID NO:4。
可利用各种方法将LAM、STING激动剂、另外的免疫刺激剂和/或淋巴细胞激活部分并入本文公开的可植入支架中或其上。出于本讨论的目的,将LAM、STING激动剂、另外的免疫刺激剂和/或淋巴细胞激活部分称为“组分”。
组分可存在于结构的可注射形式内或包埋于支架的孔内,附接于支架的表面,涂覆在支架的表面上,和/或包埋于支架本身内。
在特定实施方案中,可将组分并入聚合物链的主链中。例如,可创建在主链中含有YIGSR(SEQ ID NO:5)的聚合物,如Jun等人,J.Biomaterials Sci.,Polymer Ed.15(1),73-94(2004)所述。
在特定实施方案中,可将组分接枝到聚合物上。在一种方法中,具有含有反应性官能团(诸如环氧化物、卤化物、胺、醇、磺酸盐、叠氮基、酸酐或羧酸部分)的侧分支的聚合物可使用常规偶联技术诸如碳二亚胺反应经由反应性侧分支与多肽的胺末端共价连接。例如,将含RGD(Arg-Gly-Asp)的肽接枝到聚合物主链上,如Lin等人,J.BiomedicalMaterials Res,28(3),329-42(1994)所述。在另一个实例中,将含RGD的肽接枝到聚乙二醇基聚合物的侧分支上,如Hansson等人,Biomaterials,26,861-872(2005)所述。在特定实施方案中,可将组分直接偶联至可植入支架主链(图10A中所示),或在支架形成(例如,模制)之前使用碳二亚胺化学偶联至淋巴细胞粘附部分(例如,纤维蛋白,胶原蛋白;图10B中所示)。
从制造角度来看,这些方法的优点在于植入的支架完全由单一的可生物降解材料构成,而不使用颗粒作为第二组分。此外,将LAM整合到支架中的策略可避开使用淋巴细胞粘附部分的需要。不受理论束缚,在这些实施方案中,支架包埋的淋巴细胞沿展示的LAM(例如,抗CD3、抗CD28、抗CD137抗体、IL-15)迁移,其充当粘附分子和刺激性触发物。此方法使得颗粒和淋巴细胞粘附部分的使用在本文公开的实施方案中是任选的。
在制造中,3D生物打印可更好地确保明确限定的支架孔隙率和组成,并可促进GMP制造。在这种情况下,组分也可打印到支架中以更好地确保这些组分在支架内的受控空间分布。
如先前所指示,TFN微网格是通过溅射沉积工艺在微图案化硅晶片上产生的块状材料的变体。TFN微网格的一个特定优点是,因为其基于光刻技术,还可对其微网格孔的大小和形状进行精细控制。
在特定实施方案中,支架还可用包含一种或多种组分的生物活性涂层(例如,药物洗脱聚合物)涂覆。在特定实施方案中,支架至少部分地用生物活性涂层涂覆。可以各种方式将生物活性涂层施加到支架的表面上,包括使用本领域已知的涂覆方法。例如,可通过常规静电喷涂方法将生物活性涂层(例如,药物洗脱聚合物)喷涂到支架上,从而导致带电液滴沉积到支架的表面上。当涂层液干燥时,组分(例如,多肽和/或小分子)保持粘附于支架表面,例如,通过与多肽上的侧链基团的分子间结合。在特定实施方案中,沉积的生物活性涂层可在支架的表面上形成单层。
在特定实施方案中,生物活性涂层可通过任何类型的化学或物理结合手段结合到支架的表面,包括共价、极性、离子、配位、金属、静电或分子间偶极(包括范德华)键。生物活性涂层可另外包括改变支架表面的其他组分,例如聚赖氨酸、聚鸟氨酸或其他糖蛋白。
可用作药物洗脱聚合物的示例性生物相容性聚合物包括琼脂、琼脂糖、藻酸盐、藻酸盐/磷酸钙粘固剂(CPC)、β-半乳糖苷酶(β-GAL)、(1,2,3,4,6-五乙酰基a-D-半乳糖)、纤维素、甲壳质、壳聚糖(参见,例如,Levengood等人,J.Mater.Chem.B,2014,2,3161-3184,其描述多孔壳聚糖支架)、胶原蛋白、弹性蛋白、明胶、透明质酸胶原蛋白、羟基磷灰石、聚(3-羟基丁酸酯-共-3-羟基-己酸酯)(PHBHHx)、聚(丙交酯)、聚(己内酯)(PCL)、聚(丙交酯-共-乙交酯)(PLG)、聚环氧乙烷(PEO)、聚(乳酸-共-乙醇酸)(PLGA;参见,例如,Omar等人,Sci.Transl.Med.2009年11月25日;1(8):8ra19,其描述多孔PLGA支架)、聚环氧丙烷(PPO)、聚(乙烯醇)(PVA)、丝、大豆蛋白和大豆蛋白分离物,单独使用或与任何其他聚合物组合物组合,采用任何浓度和任何比例。
在特定实施方案中,为了放置生物活性涂层,可将支架的表面涂覆在聚赖氨酸或聚鸟氨酸(0.1-1.0mg/ml,持续3-10分钟)中,然后涂覆在蛋白质中,诸如LAM(例如,抗CD3、抗CD28和/或抗CD137抗体、和/或IL-15)和/或GFOGER(SEQ ID NO:1)肽或纤维蛋白(10μg/ml-250μg/ml,持续30分钟-24小时)。
在特定实施方案中,为了放置生物活性涂层,可将支架的表面涂覆在聚赖氨酸或聚鸟氨酸(0.5mg/ml,持续6分钟)中,然后涂覆在蛋白质中,诸如LAM(例如,抗CD3、抗CD28和/或抗CD137抗体和/或IL-15)和/或GFOGER(SEQ ID NO:1)肽或纤维蛋白(10μg/ml-250μg/ml,持续30分钟-24小时)。
在特定实施方案中,将支架的表面涂覆有LAM和/或GFOGER(SEQ ID NO:1)肽。例如,纯化的LAM和/或GFOGER(SEQ ID NO:1)肽或纤维蛋白可作为三氟乙酸(TFA)盐储存,并在0.1%TFA和0.01%叠氮化钠中重构成10mg/mL,并在使用前在4℃下储存。在用乙醇冲洗支架以除去污染物,在新鲜乙醇中清洗,在ddH2O中冲洗之后,可将它们浸泡在磷酸盐缓冲盐水(PBS)中。LAM和/或GFOGER(SEQ ID NO:1)肽或纤维蛋白然后可通过将支架在LAM和/或GFOGER(SEQ ID NO:1)肽或纤维蛋白在PBS中的溶液中孵育而被动地吸附到支架上。在植入之前,可将支架在PBS中冲洗以去除未结合的肽。
在特定实施方案中,可将生物活性涂层诸如药物洗脱聚合物涂覆在支架基质材料(例如,TFN微网格或藻酸盐)上。药物洗脱聚合物可例如含有小分子(例如,STING激动剂),并且可随时间(例如,3、4或5天、1周或2周)缓慢洗脱小分子。
在特定实施方案中,药物洗脱聚合物(例如,PLGA)作为单层直接涂覆支架基质的表面,并且淋巴细胞支架的其他组分(例如,淋巴细胞激活部分)可施加在药物洗脱聚合物上。药物洗脱聚合物可用于例如将小分子或药物从涂层缓慢洗脱到植入淋巴细胞支架的环境中。
如所指示的,可将组分直接并入可植入支架的结构中或其上。在特定实施方案中,可将组分并入颗粒中或其上。多孔颗粒可由能够形成多孔网络的任何材料构造。示例性材料包括各种材料,诸如生物相容性聚合物、金属、过渡金属和类金属。示例性生物相容性聚合物包括琼脂、琼脂糖、藻酸盐、藻酸盐/磷酸钙粘固剂(CPC)、β-半乳糖苷酶(β-GAL)、(1,2,3,4,6-五乙酰基a-D-半乳糖)、纤维素、甲壳质、壳聚糖、胶原蛋白、弹性蛋白、明胶、透明质酸胶原蛋白、羟基磷灰石、聚(3-羟基丁酸酯-共-3-羟基-己酸酯)(PHBHHx)、聚(丙交酯)、聚(己内酯)(PCL)、聚(丙交酯-共-乙交酯)(PLG)、聚(乳酸-共-乙醇酸)(PLGA)、聚(乙烯醇)(PVA)、丝、大豆蛋白和大豆蛋白分离物,单独使用或与任何其他聚合物组合物组合,采用任何浓度和任何比例。使用不同等级以不同比例共混不同聚合物类型可产生从每种贡献聚合物中借用的特征。也可采用各种末端基团化学。示例性金属、过渡金属和类金属包括锂、镁、锌、铝和二氧化硅。在特定实施方案中,多孔颗粒包括二氧化硅。中孔二氧化硅的极高表面积(超过1,000m2/g)使STING激动剂的负载水平超过常规载体诸如脂质体或聚合物缀合物。在另外的实施方案中,孔的大小范围事10-20nm。
特定实施方案的有用颗粒还包括基于脂质基递送系统的那些,包括阳离子脂质、可离子化的阳离子脂质、脂质样分子和pH敏感的两亲物;和/或(ii)树枝状聚合物(由聚酰氨基胺(PAMAM)和聚丙烯亚胺(PPI)合成的高度支化的球形大分子)和嵌段共聚物诸如PAA/BMA/DMAEMA和PDMAEMA。
颗粒可以是各种不同的形状,包括球形、立方形、金字塔形、椭圆形、圆柱形、环形等。可以各种方式将组分包含在多孔纳米颗粒中。例如,可将组分包封在多孔颗粒中。在其他方面,组分可与表面缔合(例如,共价和/或非共价地)或紧邻颗粒表面。在特定实施方案中,可将组分并入颗粒中,例如,整合在颗粒的材料中。例如,可将组分并入聚合物颗粒的聚合物基质中。本领域普通技术人员将认识到将组分携带在如本文所述的可植入支架内的各种方式。
在特定实施方案中,颗粒包括脂质体。脂质体是包括至少一个同心脂质双层的微观囊泡。选择形成囊泡的脂质以达到最终复合物的特定程度的流动性或刚性。在特定实施方案中,脂质体提供脂质组合物,其是围绕颗粒的外层。
脂质体可以是中性的(胆固醇)或双极性的并包括磷脂,诸如磷脂酰胆碱(PC)、磷脂酰乙醇胺(PE)、磷脂酰肌醇(PI)和鞘磷脂(SM)和其他类型的双极性脂质,包括二油酰磷脂酰乙醇胺(DOPE),具有14-22的烃链长,并且是饱和的或具有一个或多个C=C双键。能够单独或与其他脂质组分组合产生稳定脂质体的脂质的实例是磷脂,诸如氢化大豆磷脂酰胆碱(HSPC)、卵磷脂、磷脂酰乙醇胺、溶血卵磷脂、溶血磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、鞘磷脂、脑磷脂、心磷脂、磷脂酸、脑苷脂、二硬脂酰基磷脂酰乙醇胺(DSPE)、二油酰磷脂酰胆碱(DOPC)、二棕榈酰磷脂酰胆碱(DPPC)、棕榈酰油酰磷脂酰胆碱(POPC)、棕榈酰油酰磷脂酰乙醇胺(POPE)和二油酰磷脂酰乙醇胺4-(N-马来酰亚胺基-甲基)环己烷-1-羧酸酯(DOPE-mal)。可并入脂质体中的另外的不含磷的脂质包括硬脂胺、十二烷胺、十六烷胺、肉豆蔻酸异丙酯、三乙醇胺-月桂基硫酸酯、烷基-芳基硫酸酯、棕榈酸乙酰酯、蓖麻油酸甘油酯、硬脂酸十六烷基酯、两性丙烯酸聚合物、聚乙氧基化脂肪酸酰胺和以上提及阳离子脂质(DDAB、DODAC、DMRIE、DMTAP、DOGS、DOTAP(DOTMA)、DOSPA、DPTAP、DSTAP、DC-Chol)。带负电荷的脂质包括能够形成囊泡的磷脂酸(PA)、二棕榈酰磷脂酰甘油(DPPG)、二油酰磷脂酰甘油(DOPG)、双十六烷基磷酸酯。在特定实施方案中,用于产生本文公开的脂质体的脂质包括胆固醇、氢化大豆磷脂酰胆碱(HSPC)和衍生的形成囊泡的脂质PEG-DSPE。
形成脂质体的方法描述于,例如,美国专利号4,229,360;4,224,179;4,241,046;4,737,323;4,078,052;4,235,871;4,501,728;和4,837,028,以及Szoka等人,Ann.Rev.Biophys.Bioeng.9:467(1980)和Hope等人,Chem.Phys.Lip.40:89(1986)。
颗粒的大小可在宽范围内变化,并且可以不同的方式测量。例如,本公开的颗粒可具有100nm的最小尺寸。本公开的颗粒还可具有等于或小于500nm、小于150nm、小于100nm、小于90nm、小于80nm、小于70nm、小于60nm、小于50nm、小于40nm、小于30nm、小于20nm或小于10nm的最小尺寸。在特定实施方案中,颗粒可具有范围在5nm与500nm之间、在10nm与100nm之间、在20nm与90nm之间、在30nm与80nm之间、在40nm与70nm之间以及在40nm与60nm之间的最小尺寸。在特定实施方案中,所述尺寸是颗粒的直径。在特定实施方案中,颗粒群可具有等于或小于500nm、小于100nm、小于90nm、小于80nm、小于70nm、小于60nm、小于50nm、小于40nm、小于30nm、小于20nm或小于10nm的平均最小尺寸。在特定实施方案中,可植入支架中的颗粒群可具有范围在5nm与500nm之间、在10nm与100nm之间、在20nm与90nm之间、在30nm与80nm之间、在40nm与70nm之间以及在40nm与60nm之间的平均直径。颗粒的尺寸可使用例如常规技术确定,例如动态光散射和/或电子显微镜。
在特定实施方案中,支架包括原始细胞作为颗粒。原始细胞可通过脂质体与多孔二氧化硅纳米颗粒的融合形成。球形中孔二氧化硅核的高孔体积和表面积允许高容量包封一系列货物,包括组分。其组成可被改变用于特定的生物学应用的支撑的脂质双层可充当模块式可重新配置的支架,允许附接各种功能分子,诸如本文其他地方所述的组分。
当需要时,可通过并入表面活性剂、洗涤剂、络合剂、内相粘度增强剂、表面活性分子、共溶剂、螯合剂、稳定剂、纤维素衍生物、聚山梨醇酯、PVA或蔗糖来改变各种物质从颗粒中的释放。盐和缓冲液也可用于改变释放特性。
在特定实施方案中,可将包括TFN微网格的淋巴细胞支架涂覆在医疗装置上。TFN在细胞支架中是独特的,因为其可容易地并入到微创医疗装置中,诸如支架或另一种圆柱形装置。微创医疗装置可是指可使用微创手术放置/植入的医疗装置。微创手术可以是仅需要非常小的切口(例如,小于1cm或小于2cm)的手术,和/或与需要更大切口的手术相比,与缩短的伤口愈合时间、降低的相关疼痛或感染风险相关。覆盖有TFN微网格的支架的实例在图12D中示出。这种独特的装置有助于将抗癌淋巴细胞直接递送到实体瘤部位而无需开放手术。
遗传重编程的淋巴细胞。本文公开的支架结构包括包埋的淋巴细胞。可使用能够靶向和杀死肿瘤细胞,靶向肿瘤细胞以被其他细胞类型杀死或以其他方式介导肿瘤细胞杀死的任何类型的淋巴细胞。淋巴细胞可对施用支架的个体而言是自体的。
淋巴细胞包括T细胞、B细胞和自然杀伤(NK)细胞。本公开集中于包埋的T细胞和/或NK细胞的使用,但也可单独或组合使用其他类型的淋巴细胞。
已经发现了几种不同的T细胞子集,每种具有不同的功能。T细胞包括辅助细胞(CD4+ T细胞)和细胞毒性T细胞(CTL、CD8+ T细胞),其包括溶细胞性T细胞。
T辅助细胞在免疫过程中协助其他白细胞,包括将B细胞成熟为浆细胞和激活细胞毒性T细胞和巨噬细胞等功能。这些细胞也称为CD4+ T细胞,因为它们在其表面上表达CD4蛋白。当辅助T细胞通过在抗原呈递细胞(APC)的表面上表达的MHC II类分子呈递有肽抗原时,它们被激活。一旦被激活,它们迅速分裂并分泌调节或协助主动免疫应答的称为细胞因子的小蛋白质。
细胞毒性T细胞破坏病毒感染的细胞和肿瘤细胞,并且还涉及移植排斥。这些细胞也称为CD8+ T细胞,因为它们在其表面表达CD8糖蛋白。这些细胞通过与MHC I类相关的抗原结合识别它们的靶标,所述抗原存在于身体的几乎每个细胞的表面上。
大多数T细胞具有作为几种蛋白质的复合物存在的T细胞受体(TCR)。实际的TCR由两条独立的肽链构成,这些肽链由独立的T细胞受体α和β(TCRα和TCRβ)基因产生并称为α-和β-TCR链。γ-δ(γΔ)T细胞代表在其表面上具有不同TCR的T细胞的一小部分。然而,在γΔT细胞中,TCR由一条γ链和一条Δ链构成。这组T细胞比αβT细胞少得多(总T细胞的2%)。
如本文所用,“中枢记忆”T细胞(或“TCM”)是指经历过抗原的CTL,其表面上表达CD62L或CCR-7和CD45RO,并且与原初细胞相比,不表达或具有降低的CD45RA表达。在特定实施方案中,中枢记忆细胞对于CD62L、CCR7、CD2S、CD127、CD45RO和CD95的表达是阳性的,并且与原初细胞相比,具有降低的CD54RA表达。
如本文所用,“效应记忆”T细胞(或“TEM”)是指经历过抗原的T细胞,其与中枢记忆细胞相比,其表面上不表达或具有降低的CD62L表达,并且与原初细胞相比,不表达或具有降低的CD45RA表达。在特定实施方案中,与原初细胞或中枢记忆细胞相比,效应记忆细胞对于CD62L和CCR7的表达是阴性的,并且具有变化的CD28和CD45RA表达。
如本文所用,“原初”T细胞是指表达CD62L和CD45RA的未经历过抗原的T淋巴细胞,并且与中枢或效应记忆细胞相比不表达CD45RO。在特定实施方案中,原初CD8+ T淋巴细胞的特征在于原初T细胞的表型标记物的表达,包括CD62L、CCR7、CD28、CD127和CD45RA。
如本文所用,“效应子”或“TE”T细胞是指经历过抗原的细胞毒性T淋巴细胞,其不表达或具有降低的CD62L、CCR7、CD28表达,并且与中枢记忆或原初T细胞相比,对于粒酶B和穿孔素是阳性的。
NK细胞是细胞毒性淋巴细胞,其可快速应答于病毒感染或肿瘤形成。NK细胞可在没有MHC表达或抗体的情况下识别“应激”细胞,并且可释放含有蛋白质诸如穿孔素的溶细胞性颗粒,其可在附近细胞的细胞膜中形成孔。NK细胞可在包括IL-12、IL-15、IL-18、IL-2和CCL5的细胞因子存在下被激活。在配体与NK细胞激活受体结合后,NK细胞可能被激活。可促成NK细胞激活的受体包括CD137、CD2和CD44。
本文所述的每种淋巴细胞类型可包埋在本文公开的支架中。在特定实施方案中,原代淋巴细胞类型是CTL。CTL可占50%或更多的包埋的淋巴细胞群、55%或更多的包埋的淋巴细胞群、60%或更多的包埋的淋巴细胞群、65%或更多的包埋的淋巴细胞群、70%或更多的包埋的淋巴细胞群、75%或更多的包埋的淋巴细胞群、80%或更多的包埋的淋巴细胞群、85%或更多的包埋的淋巴细胞群、90%或更多的包埋的淋巴细胞群、95%或更多的包埋的淋巴细胞群或100%包埋的淋巴细胞群。
淋巴细胞的各种组合也可用于本文公开的支架中。在特定实施方案中,支架包括CD8+细胞、NK细胞、非变异NKT细胞(iNKT细胞)、Th17CD4+细胞和/或B细胞的混合物。在特定实施方案中,支架包括CD8+细胞和NK细胞的混合物。在特定实施方案中,CD8+细胞和NK细胞的混合物是50∶50混合物。在特定实施方案中,支架包括CD8+细胞和iNKT细胞的混合物。在特定实施方案中,CD8+细胞和iNKT细胞的混合物是50∶50混合物。所公开的细胞类型的所有其他可能组合也可在本文公开的支架内使用。
在特定实施方案中,淋巴细胞可从切除的肿瘤中分离和扩增。在特定实施方案中,受试者可用肿瘤抗原(例如,针对Her2)接种疫苗,并且疫苗诱导的T细胞群可扩增并包埋到支架中。
支架内的淋巴细胞可以是非遗传修饰的或遗传修饰的,或者可以非遗传修饰形式和遗传修饰形式的组合提供。可进行遗传修饰以增强生长、存活、免疫功能和/或肿瘤细胞靶向。遗传修饰的实例包括允许以下表达的那些:嵌合抗原受体(CAR)、αβ T细胞受体(或其修饰)和/或促炎细胞因子;或阻断抑制剂信号的表达(例如,杀伤细胞免疫球蛋白样受体)。CAR修饰和/或αβ T细胞受体修饰允许修饰的淋巴细胞特异性靶向细胞类型。
在一个方面中,遗传修饰的淋巴细胞可具有改善的肿瘤识别,引发增加的天然T细胞增殖和/或细胞因子产生。编码不同配体结合结构域、不同间隔区长度、不同细胞内结合结构域和/或不同跨膜结构域的不同潜在CAR核酸构建体可在体内(在动物模型中)和/或体外测试以鉴定相对于非遗传修饰的淋巴细胞和/或其他CAR具有改善功能的CAR,并且在特定实施方案中,使用本文公开的支架作为体内筛选工具。
示例性CAR表达配体结合结构域,其靶向例如NKG2D配体、间皮素、Her2、WT-1和/或EGRF。示例性T细胞受体修饰靶向黑素瘤相关抗原(MAGE)A3TCR。
通过在TCR或CAR的细胞外组分内包括结合一个或多个相关细胞标记物的结合结构域,可靶向特定的下列癌症:
在不限制前述的情况下,细胞标记物还包括A33;BAGE;Bc1-2;β-连环蛋白;B7H4;BTLA;CA125;CA19-9;CD3、CD5;CD19;CD20;CD21;CD22;CD25;CD28;CD30;CD33;CD37;CD40;CD52;CD44v6;CD45;CD56;CD79b;CD80;CD81;CD86;CD123;CD134;CD137;CD151;CD171;CD276;CEA;CEACAM6;c-Met;CS-1;CTLA-4;细胞周期蛋白B1;DAGE;EBNA;EGFR;EGFRvIII、肝配蛋白B2;ErbB2;ErbB3;ErbB4;EphA2;雌激素受体;FAP;铁蛋白;α-胎儿蛋白(AFP);FLT1;FLT4;叶酸结合蛋白;卷曲蛋白;GAGE;G250;GD-2;GHRHR;GHR;GITR;GM2;gp75;gp100(Pmel17);gp130;HLA;HER-2/neu;HPV E6;HPV E7;hTERT;HVEM;IGF1R;IL6R;KDR;Ki-67;LewisA;Lewis Y;LIFRβ;LRP;LRP5;LTβR;MAGE;MART;间皮素;MUC;MUC1;MUM-1-B;myc;NYESO-1;O-乙酰基GD-2;O-乙酰基GD3;OSMRβ;p53;PD1;PD-L1;PD-L2;PRAME;孕酮受体;PSA;PSMA;PTCH1;RANK;ras;Robo1;ROR1;存活素;TCRα;TCRβ;腱生蛋白;TGFBR1;TGFBR2;TLR7;TLR9;TNFR1;TNFR2;TNFRSF4;TWEAK-R;TSTA酪氨酸酶;VEGF;和WT1。
特定的癌细胞细胞标记物包括:
在特定实施方案中,可使用2A2、R12和R11mAh(ROR1)和FMC63mAb(CD19)的VL和VH链段构建ROR1特异性和CD19特异性CAR。R11和R12的可变区序列在Yang等人,Plos One 6(6):e21018,2011年6月15日中提供。每个scFV可以通过(Gly4Ser)3(SEQ ID NO:13)蛋白质连接到来源于IgG4-Fc的间隔区结构域(UniProt数据库:P01861,SEQ ID NO:14),所述间隔区结构域包括′铰链-CH2-CH3′(229AA,SEQ ID NO:15),′铰链-CH3’(119AA,SEQ ID NO:16)或仅′铰链’(12AA,SEQ ID NO:17)序列。所有间隔区可在位于天然IgG4-Fc蛋白的位置108处的′铰链′结构域内都包含S→P取代,并且可连接到人CD28的27AA跨膜结构域(SEQ IDNO:18,对于示例性全长CD28,参见UniProt:P10747)和效应子结构域信号传导模块,其包括(i)人CD28的41 AA细胞质结构域,其中位于天然CD28蛋白的位置186-187处具有LL→GG取代(SEQ ID NO:19)或(ii)人4-1BB的42AA细胞质结构域(UniProt:Q07011,SEQ ID NO:20),每个都可连接到人CD3ζ的同种型3的112AA细胞质结构域(UniProt:P20963,SEQ ID NO:21)。所述构建体编码T2A核糖体跳跃元件(SEQ ID NO:22))和嵌合受体下游的tEGFR序列(SEQ ID NO:23)。tEGFR可用结合序列的标记盒替换或补充,诸如II (SEQID NO:24;IBA GMBH Ltd.,Gottingen,DE)、Myc标记(SEQ ID NO:25)、V5标记(SEQ ID NO:26)、(Sigma-Aldrich,St.Louis,MO)标记(SEQ ID NO:27)、His标记或本文公开的其他肽或分子。可合成编码每种转基因的密码子优化的基因序列(Life Technologies),并使用NheI和Notl限制位点将其克隆到epHIV7慢病毒载体中。epHIV7慢病毒载体可通过用EF-1启动子替换pHIV7的巨细胞病毒启动子而衍生自pHIV7载体。可使用包装载体pCHGP-2、pCMV-Rev2和pCMV-G以及Calphos转染试剂(Clontech)在293T细胞中产生ROR1-嵌合受体、CD19-嵌合受体、tEGFR或编码标记盒的慢病毒。
可使用识别HER2上的膜近端表位的HER2特异性mAb的VL和VH链段构建HER2特异性嵌合受体,并且可将scFV连接到IgG4铰链/CH2/CH3、IgG4铰链/CH3和IgG4铰链仅细胞外间隔区结构域,并且连接到CD28跨膜结构域、4-1BB和CD3ζ信号传导结构域。
如所指示,每个CD19嵌合受体可包括对应于CD19特异性mAb FMC63序列的单链可变片段(scFv:VL-VH);衍生自IgG4-Fc的间隔区,其包括′铰链-CH2-CH3′结构域(229AA,长间隔区)或仅′铰链′结构域(12AA,短间隔区);以及具有膜近端CD28或4-1BB共刺激结构域的CD3ζ的信号传导模块,呈单独或串联形式。转基因盒可包括嵌合受体基因下游的截短的EGFR(tEGFR),并被可切割的T2A元件分开,以用作嵌合受体修饰的细胞的转导、选择和体内追踪的标记序列。tEGFR可用结合ExoCBM的标记盒替换或补充,诸如II(SEQID NO:24)、Myc标记(SEQ ID NO:25)、V5标记(SEQ ID NO:26)、标记(SEQ ID NO:27)、His标记或本文公开的其他肽或分子。
工程化CAR的其他常见特征诸如间隔区、细胞内结构域、共刺激结构域和跨膜结构域是本领域技术人员已知的。
在特定实施方案中,可能希望将功能基因引入淋巴细胞中以允许体内阴性选择,如例如Lupton等人,Mol.and Cell Biol.,11:6(1991);和Riddell等人,Human GeneTherapy 3:319-338(1992)所述;还参见Lupton等人的公布PCT/US91/08442和PCT/US94/05601,其描述了使用由将优势阳性选择标记物与阴性选择标记物融合而得到的双功能可选择融合基因。这可根据已知技术(参见例如美国专利号6,040,177,第14-17栏)或其变型来进行,这些变型对于本领域技术人员而言基于本公开是显而易见的。例如,预期刺激因子(例如,淋巴因子或细胞因子)的过表达可能对治疗的受试者具有毒性。因此,在本公开的范围内包括致使本公开的细胞易于进行体内阴性选择的基因区段。“阴性选择”是指由于个体体内状况的改变可使输注的细胞消除。阴性选择表型可由插入赋予对施用药剂(例如,化合物)的敏感性的基因而产生。阴性选择基因是本领域已知的,并且尤其包括以下:单纯疱疹病毒I型胸苷激酶(HSV-I TK)基因,其赋予更昔洛韦敏感性;细胞次黄嘌呤磷酸核糖基转移酶(HPRT)基因、细胞腺嘌呤磷酸核糖基转移酶(APRT)基因和细菌胞嘧啶脱氨酶。
在包埋在本文公开的支架中之前,可将所需基因引入淋巴细胞中。细胞的遗传重编程可包括例如基因序列的插入、基因序列的改变和/或基因序列的缺失。在特定实施方案中,可通过将用于遗传重编程的载体引入淋巴细胞中来对淋巴细胞进行遗传重编程。特定实施方案可将核苷酸递送在基因编辑系统内。基因编辑系统修改或影响细胞内源基因组的特定序列。基因编辑系统可用于靶向基因组编辑,例如基因破坏,通过同源重组进行基因编辑,以及用于基因治疗以将治疗基因插入在具有人基因组的适当染色体靶位点处。
特定实施方案利用转录激活因子样效应子核酸酶(TALEN)作为基因编辑系统。TALEN是指融合蛋白,其包括转录激活因子样效应子(TALE)DNA结合蛋白和DNA切割结构域。TALEN用于通过在DNA中诱导双链断裂(DSB)来编辑基因和基因组,其诱导细胞中的修复机制。通常,两个TALEN必须结合并侧接靶DNA位点的每一侧,以使DNA切割结构域二聚化并诱导DSB。通过与外源双链供体DNA片段非同源末端连接(NHEJ)或通过同源重组(HR)在细胞中修复DSB。
如所指示,已经将TALEN工程化以结合例如内源基因组的靶序列,并在靶序列的位置处切割DNA。TALEN的TALE是黄单胞菌属(Xanthomonas)细菌分泌的DNA结合蛋白。TALE的DNA结合结构域包括高度保守的33或34个氨基酸重复序列,在每个重复序列的第12和第13位置处具有不同的残基。称为重复可变二残基(RVD)的这两个位置显示出与特定核苷酸识别的强相关性。因此,通过改变RVD中的氨基酸并且并入非常规RVD氨基酸,可改善靶向特异性。
可用于TALEN融合体的DNA切割结构域的实例是野生型和变体FokI内切核酸酶。FokI结构域用作二聚体,其需要两个具有用于靶序列上的位点的独特DNA结合结构域的构建体。FokI切割结构域在分隔两个反向半位点的五或六个碱基对间隔序列内切割。
特定实施方案利用MegaTAL作为基因编辑系统。MegaTAL具有单链稀有切割核酸酶结构,其中TALE与大范围核酸酶的DNA切割结构域融合。也称为归巢内切核酸酶的大范围核酸酶是在同一结构域中具有DNA识别和核酸酶功能两者的单肽链。与TALEN相反,megaTAL仅需要递送单个肽链用于功能活性。
具体实施方案利用锌指核酸酶(ZFN)作为基因编辑系统。ZFN是经过工程化以结合和切割特定位置处的DNA的一类位点特异性核酸酶。ZFN用于将DSB引入DNA序列中的特定位点,这使得ZFN能够靶向多种不同细胞中基因组内的独特序列。此外,在双链断裂之后,发生同源重组或非同源末端连接以修复DSB,从而实现基因组编辑。
ZFN通过将锌指DNA结合结构域与DNA切割结构域融合来合成。DNA结合结构域包括三至六个作为转录因子的锌指蛋白。DNA切割结构域包括例如FokI内切核酸酶的催化结构域。
例如,指导RNA可例如与基因编辑系统诸如CRISPR-Cas系统一起使用。CRISPR-Cas系统包括CRISPR重复序列和一组CRISPR相关基因(Cas)。
通常,任何能够导致递送的核苷酸的功能性表达的系统都可在本公开内容内使用。
基因的引入可通过本领域已知的任何方法进行,包括转染、电穿孔、显微注射、脂质转染、磷酸钙介导的转染、用含有基因序列的病毒或噬菌体载体(例如,慢病毒载体或质粒)感染、细胞融合、染色体介导的基因转移、微细胞介导的基因转移、原生质体融合等。用于将外源基因引入细胞中的许多技术是本领域已知的(参见例如,Loeffler和Behr,Meth.Enzymol,217,599-618(1993);Cohen等人,Meth.Enzymol,217,618-644(1993);Cline,Pharmac.Ther,29,69-92(1985))并且可根据本公开使用,条件是淋巴细胞的必需的发育和生理功能不被破坏。在特定实施方案中,所述技术提供基因向细胞的稳定转移,使得基因可由细胞表达,并且优选地可通过其细胞后代遗传和表达。在特定实施方案中,所述技术提供了基因在细胞内的瞬时表达。
可用于遗传修饰淋巴细胞的重组DNA技术领域中通常已知的方法描述于Ausubel等人(编辑),1993,Current Protocols in Molecular Biology,John Wiley&Sons,NY;以及Kriegler,1990,Gene Transfer and Expression,A Laboratory Manual,Stockton出版社,NY。
在特定实施方案中,淋巴细胞将在支架植入受试者时或其附近包埋在支架内,例如在植入48小时内、植入36小时内、植入24小时内、植入12小时内、植入6小时内、植入3小时内、植入1小时内或植入30分钟内。通常,淋巴细胞负载到预模制的支架中将在植入30分钟内发生,而负载将更常见地更接近于使用支架的可注射形式的实际植入时间(例如,5分钟内;2分钟内、1分钟内或30秒内)发生。
淋巴细胞可以是新鲜的淋巴细胞,或可以是先前冷冻保存的淋巴细胞。如果使用先前冷冻保存的淋巴细胞,则应将它们快速解冻(例如,在保持在37℃-41℃下的水浴中)并在解冻后立即冷冻。可能需要进一步处理淋巴细胞以防止解冻时细胞聚集。为了防止聚集,可使用各种方法,包括在冷冻之前和/或之后添加DNA酶,低分子量葡聚糖和柠檬酸盐,羟乙基淀粉等。必要时,由于潜在的细胞毒性,应除去冷冻保护剂。除去冷冻保护剂后,必要时,可进行细胞计数和/或活力测试。
可使用多种将淋巴细胞包埋在本文公开的结构中的方法(“包埋”也称为“接种”)。例如,可使用被动(静态)接种。在特定实施方案中,将淋巴细胞重悬于细胞培养基(例如,RPMI)中。然后将此细胞悬浮液滴加到冻干支架的顶部。在使用静态接种的特定实施方案中,将淋巴细胞悬浮液接种到结构上,并且然后在没有搅拌的情况下孵育一段时间,然后暴露于动态培养条件,例如进入缓慢搅拌的旋转烧瓶中。在特定实施方案中,可使用动态接种。对于动态接种,可将结构和淋巴细胞悬浮液一起放入例如容器中,并且然后将容器在温和搅拌下孵育一段时间,使淋巴细胞自身包埋在结构内。在另外的实施方案中,可使用旋转系统(包括离心机)和/或真空系统。在另外的实施方案中,可使用基于片的淋巴细胞接种、静电淋巴细胞接种、磁性淋巴细胞接种、过滤淋巴细胞接种和/或振荡灌注淋巴细胞接种。也可使用这些方法的各种组合。各种生物水凝胶的使用也是适当的。关于各种接种选项的讨论,参见Li等人,Biotechnol.Prog,17,935-944(2001);Wendt等人,Biotechnology andBioengineering,84,205-214(2003);Yang,等人,J.Biomed.Mater.Res,55,379-386(2001);和Sittinger等人,Int.J.Artif.Organs,20,57(1997)。
在特定实施方案中,包括TFN微网格的淋巴细胞支架可包括高密度细胞(至少7X106个/cm2或至少8X106个细胞/cm2)。TFN微网格可允许高细胞密度,例如,通过将三层细胞填充到TFN微网格的每一层中(参见例如图10D)。堆叠多层微图案化金属薄膜(例如,TFN微网格)也可用于实现高密度的细胞。
也可使用本文公开的蛋白质和蛋白质序列的有效变体。变体包括具有一个或多个保守氨基酸取代的肽。如本文所用,“保守取代”涉及用一种氨基酸取代以下保守取代组中一组中的另一种氨基酸:第1组:丙氨酸(Ala),甘氨酸(Gly),丝氨酸(Ser),苏氨酸(Thr);第2组:天冬氨酸(Asp),谷氨酸(Glu);第3组:天冬酰胺(Asn),谷氨酰胺(Gln);第4组:精氨酸(Arg),赖氨酸(Lys),组氨酸(His);第5组:异亮氨酸(Ile),亮氨酸(Leu),甲硫氨酸(Met),缬氨酸(Val);以及第6组:苯丙氨酸(Phe),酪氨酸(Tyr),色氨酸(Trp)。
另外,氨基酸可通过类似的功能或化学结构或组成(例如,酸性、碱性、脂族、芳香族、含硫的)来分组为保守取代组。例如,出于取代的目的,脂族组可包括Gly、Ala、Val、Leu和Ile。含有被认为是彼此保守取代的氨基酸的其他组包括:含硫的:Met和半胱氨酸(Cys);酸性:Asp、Glu、Asn和Gln;小的脂族非极性或轻微极性的残基:Ala、Ser、Thr、Pro和Gly;极性、带负电荷的残基及其酰胺:Asp、Asn、Glu和Gln;极性、带正电的残基:His、Arg和Lys;大的脂族非极性残基:Met、Leu、Ile、Val和Cys;以及大的芳香族残基:Phe、Tyr和Trp。另外的信息见于Creighton(1984)Proteins,W.H.Freeman and Company。
变体还包括与SEQ ID NO:1-27中任一个具有至少70%序列同一性、80%序列同一性、85%序列、90%序列同一性、95%序列同一性、96%序列同一性、97%序列同一性、98%序列同一性或99%序列同一性的序列。
“同一性%”是指如通过比较序列所确定的两个或更多个蛋白质序列之间的关系。在本领域中,“同一性”还意指如通过此类序列串之间的匹配所确定的蛋白质之间的序列相关性程度。“同一性”(经常称为“相似性”)可通过已知方法来容易地计算,所述方法包括在以下中描述的那些:Computational Molecular Biology(Lesk,A.M.,编辑)OxfordUniversity Press,NY(1988);Biocomputing:Informatics and Genome Projects(Smith,D.W.,编辑)Academic Press,NY(1994);Computer Analysis of Sequence Data,第I部分(Griffin,A.M.,和Griffin,H.G.,编辑)Humana出版社,NJ(1994);Sequence Analysis inMolecular Biology(Von Heijne,G,编辑)Academic Press(1987);和Sequence AnalysisPrimer(Gribskov,M.和Devereux,J.,编辑)Oxford University Press,NY(1992)。设计确定同一性的优选方法以得到所测试序列之间的最佳匹配。可公开获得的计算机程序中编纂了确定同一性和相似性的方法。序列比对和同一性百分比计算可以使用Lasergene生物信息学计算软件包(Inc.,Madison,WI)的Megalign程序进行。序列的多重比对还可使用Clustal比对方法(Higgins和Sharp CABIOS,5,151-153(1989),以默认参数(缺口罚分=10,缺口长度罚分=10)来执行。相关程序还包括GCG程序包(Wisconsin PackageVersion 9.0,Genetics Computer Group(GCG),Madison,WI);BLASTP、BLASTN、BLASTX(Altschul,等人,J.Mol.Biol.215:403-410(1990));以及结合Smith-Waterman 算法的FASTA程序(Pearson,Comput.Methods Genome Res.,[Proc.Int.Symp.](1994),Meeting Date 1992,111-20.编辑:Suhai,Sandor.发行者:Plenum,New York,N.Y.)。在本公开的上下文内,将理解在将序列分析软件用于分析的情况下,分析的结果是基于所引用的程序的“默认值”。如本文所用,“默认值”将意指在首次初始化时用软件最初加载的值或参数的任何集合。
本公开还提供本文所述的分子和/或肽的盐、溶剂化物、水合物、N-氧化物、前药和/或活性代谢物。合适的酸加成盐可由无机酸或有机酸,特别是药学上可接受的有机酸制备。此类无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。适当的有机酸可选自脂族、脂环族、芳香族、芳脂族、杂环、羧酸和磺酸类有机酸。
合适的碱加成盐可由金属盐或有机盐制备。金属盐可由铝、钙、锂、镁、钾、钠和锌制备。有机盐可由N,N′-二苯乙烯-二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺、赖氨酸、精氨酸、普鲁卡因和任何药学上可接受的有机碱制备。
使用方法。本文所述的支架可放置在实体瘤、不可切除的肿瘤和/或未切除的肿瘤细胞附近,以在受试者中具有抗肿瘤作用。如本文所用,术语“受试者”或“个体”通常是指哺乳动物,诸如人,但也可以是另一种哺乳动物,诸如狗、猫、兔、牛、马等。
“肿瘤”是由细胞(称为瘤细胞或肿瘤细胞)的异常生长形成的肿胀或病变。“肿瘤细胞”是一种异常细胞,其通过快速、不受控制的细胞增殖分裂,并在引发新分裂的刺激停止后继续分裂。肿瘤显示部分或完全缺乏结构组织和与正常组织的功能协调,并且通常形成独特的组织块,其可以是良性的、恶化前的或恶性的。
如本文所用,抗肿瘤效应是指可通过肿瘤体积减小、肿瘤细胞数量降低、转移瘤数量降低、预期寿命增加或与癌性病状相关联的各种生理症状减少表现出来的生物效应。抗肿瘤效应也可通过复发减少或复发前时间增加来表现。因此,本文公开的支架可用于治疗多种癌症,可阻止或显著延迟转移,和/或可阻止或显著延迟复发。如图9A和图9B所示,淋巴细胞支架可在根除/减少初始肿瘤后继续提供抗肿瘤免疫,并且可阻止和/或减少继发性肿瘤的转移或发展。
癌症(医学术语:恶性赘瘤)是指其中一组细胞呈现不受控制的生长(超出正常限值的分裂)、侵袭(侵入相邻组织上并破坏相邻组织)且有时转移的一类疾病。“转移”是指癌细胞从其原始增殖位点扩散到身体的另一部分。转移的形成是一个非常复杂的过程,并且取决于恶性细胞从原发性肿瘤的脱离、细胞外基质的侵袭、渗透内皮基底膜进入体腔和血管以及然后通过血液运输之后浸润靶器官。最后,靶位点处新肿瘤(即,继发性肿瘤或转移性肿瘤)的生长取决于血管生成。即使在移除原发性肿瘤之后也经常发生肿瘤转移,因为肿瘤细胞或组分可能保留并发展转移潜力。
可用本文公开的支架和方法的抗肿瘤效应治疗的癌症包括例如肾上腺癌、脑癌、乳腺癌、宫颈癌、结肠癌、结肠直肠癌、耳、鼻和咽喉(ENT)癌症、子宫内膜癌、食道癌、胃肠癌、神经胶质瘤、头颈癌、肠癌、肾癌、肝癌、肺癌、淋巴结癌、黑素瘤、神经母细胞瘤、卵巢癌、胰腺癌、前列腺癌、直肠癌、精原细胞瘤、皮肤癌、胃癌、畸胎瘤、甲状腺癌、子宫癌及其转移瘤。
在不限制本公开的范围的情况下,注意到以下癌症类型:
脑肿瘤(胶质母细胞瘤):预计美国每年新发病例数为10,000例。当前没有可用的治疗方法。胶质母细胞瘤显示非常具有浸润性的生长,并且不能完全切除。90%的肿瘤在原始切除的肿瘤的2cm范围内复发。装载有化疗的生物材料晶片被美国食品和药物管理局(FDA)批准(MGI Pharma,Inc.,Woodcliff Lake,NJ)用于胶质母细胞瘤。然而,由于组织渗透不足,因此生物材料植入物递送的化疗大多是无效的。相比之下,从本文公开的支架部署的肿瘤反应性淋巴细胞可主动迁移到受影响的组织,寻找并破坏残留的肿瘤细胞。
胰腺癌:预计2012年美国将发生的胰腺癌新发病例数为43,920例。只有20%在诊断时具有可切除的疾病(80%的患者由于肿瘤在诊断时已经晚期而未进行手术)。甚至手术被认为是一种姑息性的冒险,其5年生存率仅为20%。局部复发通常归因于难以实现显微镜下的阴性手术切缘。超过当前支架在手术切除肿瘤后根除残留疾病的能力,所述支架还可为具有不可手术的疾病的胰腺肿瘤患者(80%的患者)提供高效的治疗选项。在特定实施方案中,将支架直接植入到不可切除的已建立的胰腺癌上。
卵巢癌:预计2012年美国有22,000例新病例。尽管通过手术和化疗进行多模式治疗,但大多数卵巢癌患者的预后较差(美国每年估计死亡人数为15,500人)。卵巢癌主要在腹膜腔内散发。当前正在几个中心研究卵巢癌患者的过继性T细胞疗法。然而,迄今为止临床结果是令人失望的,因为输注的T细胞存活率低,并且未能对抗肿瘤细胞释放的免疫抑制因子而使T细胞功能失调。包埋有肿瘤反应性淋巴细胞的多个支架可通过腹腔镜植入卵巢癌患者的腹膜腔中,在那里它们在延长的时间段内释放肿瘤反应性淋巴细胞和STING激动剂。
如本领域普通技术人员所理解的,在切除后,将支架植入实体瘤、不可切除的肿瘤细胞附近和/或植入肿瘤切除床中。支架可以多种不同的大小和形状获得,并且可形状相符,以适应各个受试者的特定需求。在特定实施方案中,使用超声引导将支架注射到(或物理接触)实体瘤、未切除或非切除的肿瘤细胞附近。根据肿瘤的阶段、大小或严重程度,可为支架提供不同的治疗强度。可通过改变支架的大小、支架的体积、包埋在支架内的淋巴细胞的数量、支架内淋巴细胞激活部分的数量、支架内STING激动剂的存在或量等来操控治疗强度。这些参数中的每一个都可由治疗医师评估和确定。
出于本公开的目的,术语“附近”是指实体瘤、不可切除的肿瘤、不可切除的肿瘤细胞和/或肿瘤切除床的10cm内、9cm内、8cm内、7cm内、6cm内、5cm内、4cm内、3cm内、2cm内、1cm内、0.9cm内、0.8cm内、0.7cm内、0.6cm内、0.5cm内、0.4cm内、0.3cm内、0.2cm内或0.1cm内的距离。
本领域普通技术人员还应理解,支架仅可在具有实体瘤、不可切除的肿瘤、不可切除的肿瘤细胞和/或肿瘤切除床的受试者中在切除时或第一次治疗时植入一次。另外,支架可植入多次以提供数月或数年的持续治疗。这种治疗方案可由治疗医师确定。
在特定实施方案中,包括TFN微网格的淋巴细胞支架可用作长效支架(参见例如图12I)。TFN微网格可用作不可生物降解的支架基质材料,并且因此基于TFN-微网格的淋巴细胞支架可继续递送淋巴细胞数天、超过一周和/或超过两周。
如本文所用,术语“手术治疗失败”是指在先前已经历肿瘤切除的受试者中癌症复发。手术治疗失败可能包转移性复发。
包括以下实施例和示例性实施方案以说明本公开的特定实施方案。按照本公开,本领域普通技术人员应认识到,在不脱离本公开的精神和范围的情况下,可对本文所公开的特定实施方案做出许多改变并且仍获得相似或类似结果。
示例性实施方案。
1.一种淋巴细胞支架,其包括(i)遗传重编程的淋巴细胞,其设置在包括微图案化金属薄膜的支架基质内,和(ii)淋巴细胞激活部分。
2.如实施方案1所述的淋巴细胞支架,其还包括STING激动剂。
3.如实施方案2所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
4.如实施方案2所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP。
5.如实施方案1-4中任一项所述的淋巴细胞支架,其还包括药物洗脱聚合物。
6.如实施方案5所述的淋巴细胞支架,其中所述STING激动剂包埋在所述药物洗脱聚合物内。
7.如实施方案5或6所述的淋巴细胞支架,其中所述药物洗脱聚合物包括PLGA。
8.如实施方案1-7中任一项所述的淋巴细胞支架,其中所述淋巴细胞包括T细胞和/或天然杀伤细胞。
9.如实施方案1-8中任一项所述的淋巴细胞支架,其中所述淋巴细胞包括CD8+ T细胞。
10.如实施方案1-9中任一项所述的淋巴细胞支架,其包括至少2x106个淋巴细胞。
11.如实施方案1-9中任一项所述的淋巴细胞支架,其包括至少7x106个淋巴细胞。
12.如实施方案1-11中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括IL-15、或对CD3、CD28或CD137具特异性的抗体中的至少一种。
13.如实施方案1-12中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括对CD3、CD128和CD137具特异性的抗体。
14.如实施方案1-13中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括IL-15和CD137。
15.如实施方案1-14中任一项所述的淋巴细胞支架,其还包括免疫刺激剂。
16.如实施方案15所述的淋巴细胞支架,其中所述免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
17.如实施方案15所述的淋巴细胞支架,其中所述免疫刺激剂选自(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
18.如实施方案15-17中任一项所述的淋巴细胞支架,其中所述免疫刺激剂包埋在药物洗脱聚合物内。
19.如实施方案1-18中任一项所述的淋巴细胞支架,其还包括淋巴细胞粘附部分。
20.如实施方案19所述的淋巴细胞支架,其中所述淋巴细胞粘附部分和所述淋巴细胞激活部分共价连接。
21.如实施方案19或20所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括纤维蛋白。
22.如实施方案19-21中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
23.如实施方案19-22中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括GFOGER(SEQ ID NO:1)肽。
24.如实施方案19-23中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
25.如实施方案19-24中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括ICAM-1肽。
26.如实施方案19-25中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
27.如实施方案19-26中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
28.如实施方案19-27中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
29.如实施方案2-28中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到所述支架基质。
30.如实施方案2-29中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分包埋在所述支架基质内。
31.如实施方案2-30中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分在覆盖所述支架基质表面的至少一部分的生物活性涂层内。
32.如实施方案31所述的淋巴细胞支架,其中所述生物活性涂层包括药物洗脱聚合物。
33.如实施方案32所述的淋巴细胞支架,其还包括淋巴细胞粘附部分,其中:所述STING激动剂在所述药物洗脱聚合物内,所述药物洗脱聚合物在所述支架基质的表面上形成单层,并且所述淋巴细胞粘附部分直接涂覆所述药物洗脱聚合物。
34.如实施方案2-33中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到颗粒。
35.如实施方案34所述的淋巴细胞支架,其中所述颗粒连接到所述支架和/或包埋在所述支架基质内。
36.如实施方案2-35中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分与原始细胞的脂质体结合。
37.如实施方案36所述的淋巴细胞支架,其中所述支架基质内的所述原始细胞与所述淋巴细胞的比率为0.5∶1;1∶1;5∶1;或10∶1。
38.如实施方案1-37中任一项所述的淋巴细胞支架,其中所述淋巴细胞支架包括7x106至1x1010个原始细胞。
39.如实施方案1-38中任一项所述的淋巴细胞支架,其中所述微图案化金属薄膜包括TFN微网格。
40.一种淋巴细胞支架,其由支架基质、遗传重编程的淋巴细胞和三个淋巴细胞激活部分组成。
41.如实施方案40所述的淋巴细胞支架,其中所述支架基质包括藻酸盐支架、胶原蛋白/藻酸盐支架、壳聚糖支架、自组装肽支架、中孔二氧化硅支架、微图案化金属薄膜支架或PLGA支架。
42.如实施方案40或41所述的淋巴细胞支架,其中所述微图案化金属薄膜支架包括TFN微网格支架。
43.如实施方案40-42中任一项所述的淋巴细胞支架,其中所述支架基质包括藻酸盐支架。
44.如实施方案40-43中任一项所述的淋巴细胞支架,其中所述支架基质包括聚合的钙交联的藻酸盐支架。
45.如实施方案40-44中任一项所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是遗传重编程的T细胞和/或天然杀伤细胞。
46.如实施方案40-45中任一项所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是CD8+ T细胞。
47.如实施方案40-46中任一项所述的淋巴细胞支架,其包括至少2x106个遗传重编程的淋巴细胞。
48.如实施方案40-46中任一项所述的淋巴细胞支架,其包括至少7x106个遗传重编程的淋巴细胞。
49.如实施方案40-48中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括对CD3、CD28和/或CD137具特异性的抗体。
50.如实施方案40-49中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分连接到所述支架。
51.如实施方案40-50中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分包埋在所述支架内。
52.一种淋巴细胞支架,其包括:支架基质、遗传重编程的淋巴细胞和淋巴细胞激活部分。
53.如实施方案52所述的淋巴细胞支架,其还包括STING激动剂。
54.如实施方案53所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
55.如实施方案52或53所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP。
56.如实施方案52-55中任一项所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是遗传重编程的T细胞和/或天然杀伤细胞。
57.如实施方案52-56中任一项所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是CD8+ T细胞。
58.如实施方案52-57中任一项所述的淋巴细胞支架,其包括至少2X106或至少7x106个遗传重编程的淋巴细胞。
59.如实施方案52-58中任一项所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括IL-15和/或对CD3、CD28和/或CD137具特异性的抗体。
60.如实施方案52-59中任一项所述的淋巴细胞支架,其还包括免疫刺激剂。
61.如实施方案60所述的淋巴细胞支架,其中所述免疫刺激剂包括细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
62.如实施方案60或61所述的淋巴细胞支架,其中所述免疫刺激剂包括(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
63.如实施方案52-62中任一项所述的淋巴细胞支架,其还包括淋巴细胞粘附部分。
64.如实施方案63所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括纤维蛋白。
65.如实施方案63或64所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
66.如实施方案63-65中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括GFOGER(SEQ ID NO:1)肽。
67.如实施方案63-66中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
68.如实施方案63-67中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括ICAM-1肽。
69.如实施方案63-68中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
70.如实施方案63-69中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
71.如实施方案63-70中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
72.如实施方案53-71中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到所述支架基质。
73.如实施方案53-72中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分包埋在所述支架基质内。
74.如实施方案53-73中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分在覆盖所述支架基质表面的至少一部分的生物活性涂层内。
75.如实施方案53-74中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到颗粒。
76.如实施方案75所述的淋巴细胞支架,其中所述颗粒连接到所述支架基质和/或包埋在所述支架基质内。
77.如实施方案53-76中任一项所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分与原始细胞的脂质体结合。
78.如实施方案77所述的淋巴细胞支架,其中所述支架基质内的所述原始细胞与所述淋巴细胞的比率为0.5∶1;1∶1;5∶1;或10∶1。
79.如实施方案53-78中任一项所述的淋巴细胞支架,其中所述淋巴细胞支架包括7x106至1x1010个原始细胞。
80.如实施方案52-79中任一项所述的淋巴细胞支架,其中所述支架基质包括藻酸盐支架、胶原蛋白/藻酸盐支架、壳聚糖支架、自组装肽支架、中孔二氧化硅支架、微图案化金属薄膜支架或PLGA支架。
81.如实施方案80所述的淋巴细胞支架,其中所述微图案化金属薄膜支架包括TFN微网格支架。
82.如实施方案80或81所述的淋巴细胞支架,其中所述支架基质包括藻酸盐支架。
83.如实施方案80-82中任一项所述的淋巴细胞支架,其中所述支架基质包括聚合的钙交联的藻酸盐支架。
84.一种淋巴细胞支架,其包括:(i)支架基质材料,(ii)具有抗癌活性的天然杀伤细胞,和(iii)淋巴细胞激活部分,其包括IL-15和对CD137具特异性的抗体。
85.如实施方案84所述的淋巴细胞支架,其中所述支架基质材料包括微图案化金属薄膜。
86.如实施方案84或85所述的淋巴细胞支架,其中所述微图案化金属薄膜包括TFN微网格。
87.如实施方案84-86中任一项所述的淋巴细胞支架,其还包括STING激动剂。
88.如实施方案113所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
89.如实施方案84-88中任一项所述的淋巴细胞支架,其还包括药物洗脱聚合物。
90.如实施方案89所述的淋巴细胞支架,其中所述药物洗脱聚合物包括PLGA。
91.如实施方案87或88所述的淋巴细胞支架,其中所述STING激动剂包埋在药物洗脱聚合物内。
92.如实施方案84-91中任一项所述的淋巴细胞支架,其还包括淋巴细胞粘附部分。
93.如实施方案92所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括纤维蛋白。
94.如实施方案92或93所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
95.如实施方案92-94中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括GFOGER(SEQ ID NO:1)肽。
96.如实施方案92-95中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
97.如实施方案84-96中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括ICAM-1肽。
98.如实施方案84-97中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
99.如实施方案84-98中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
100.如实施方案84-99中任一项所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
101.一种治疗受试者中包括逃避变体肿瘤细胞的异质实体瘤的方法,其包括将如实施方案1-100中任一项所述的淋巴细胞支架在足以导致破坏所述受试者中的所述异质实体瘤的所述异质实体瘤细胞附近植入所述受试者中,从而治疗包括逃避变体肿瘤细胞的所述异质实体瘤。
102.一种对受试者接种疫苗以防止癌症复发的发展的方法,其包括将如实施方案1-100中任一项所述的淋巴细胞支架在异质实体瘤附近或在所述受试者中的实体瘤切除床内植入所述受试者中,从而对所述受试者接种疫苗以防止癌症复发的发展。
103.一种治疗有需要的受试者中的肿瘤细胞的方法,其包括将如实施方案1-100中任一项所述的淋巴细胞支架在肿瘤切除床内植入所述受试者中,从而治疗所述受试者中的所述肿瘤细胞。
104.如实施方案103所述的方法,其中所治疗的肿瘤细胞是肾上腺癌细胞、脑癌细胞、乳腺癌细胞、宫颈癌细胞、结肠癌细胞、结肠直肠癌细胞、耳、鼻和咽喉(ENT)癌细胞、子宫内膜癌细胞、食道癌细胞、胃肠癌细胞、神经胶质瘤细胞、头颈癌细胞、肠癌细胞、肾癌细胞、肝癌细胞、肺癌细胞、淋巴结癌细胞、黑素瘤细胞、神经母细胞瘤细胞、卵巢癌细胞、胰腺癌细胞、前列腺癌细胞、直肠癌细胞、精原细胞瘤细胞、皮肤癌细胞、胃癌细胞、畸胎瘤细胞、甲状腺癌细胞或子宫癌细胞。
105.如实施方案103所述的方法,其中所治疗的肿瘤细胞是胶质母细胞瘤细胞、胰腺癌细胞或卵巢癌细胞。
106.一种减少原发性肿瘤切除后转移性复发引起的手术治疗失败的方法,其包括将如实施方案1-100中任一项所述的淋巴细胞支架施用于受试者的肿瘤切除床,从而减少原发性肿瘤切除后转移性复发引起的手术治疗失败。
107.如实施方案106所述的方法,其中所述原发性肿瘤包括精原细胞瘤细胞、黑素瘤细胞、畸胎瘤细胞、神经母细胞瘤细胞、神经胶质瘤细胞、直肠癌细胞、子宫内膜癌细胞、肾癌细胞、肾上腺癌细胞、甲状腺癌细胞、皮肤癌细胞、脑癌细胞、宫颈癌细胞、肠癌细胞、肝癌细胞、结肠癌细胞、胃癌细胞、头颈癌细胞、胃肠癌细胞、淋巴结癌细胞、食道癌细胞、结肠直肠癌细胞、胰腺癌细胞、耳、鼻和咽喉(ENT)癌细胞、乳腺癌细胞、前列腺癌细胞、子宫癌细胞、卵巢癌细胞或肺癌细胞。
108.一种治疗癌症受试者的方法,其包括将涂覆有包括TFN微网格、遗传修饰的淋巴细胞和淋巴细胞激活部分的淋巴细胞支架的医疗装置植入所述受试者中。
109.如实施方案108所述的方法,其中所述植入包括微创手术。
110.如实施方案108所述的方法,其中所述医疗装置包括支架。
111.一种形成淋巴细胞支架以治疗受试者中的实体瘤的试剂盒,其包括(i)支架基质;和(ii)淋巴细胞激活部分,其包括对CD3、CD28和CD137具特异性的抗体。
112.如实施方案111所述的试剂盒,其还包括多孔颗粒。
113.如实施方案111或112所述的试剂盒,其还包括脂质体。
114.如实施方案111-113中任一项所述的试剂盒,其还包括原始细胞。
115.如实施方案111-114中任一项所述的试剂盒,其还包括STING激动剂。
116.如实施方案115所述的试剂盒,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
117.如实施方案115所述的试剂盒,其中所述STING激动剂包括c-diGMP。
118.如实施方案111-117中任一项所述的试剂盒,其还包括免疫刺激剂。
119.如实施方案118所述的试剂盒,其中所述免疫刺激剂包括细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
120.如实施方案118或119所述的试剂盒,其中所述免疫刺激剂包括(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
121.如实施方案111-120中任一项所述的试剂盒,其还包括淋巴细胞粘附部分。
122.如实施方案121所述的试剂盒,其中所述淋巴细胞粘附部分包括纤维蛋白。
123.如实施方案121或122所述的试剂盒,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
124.如实施方案121-123中任一项所述的试剂盒,其中所述淋巴细胞粘附部分包括GFOGER(SEQ ID NO:1)肽。
125.如实施方案121-124中任一项所述的试剂盒,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
126.如实施方案121-125中任一项所述的试剂盒,其中所述淋巴细胞粘附部分包括ICAM-1肽。
127.如实施方案121-126中任一项所述的试剂盒,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
128.如实施方案121-127中任一项所述的试剂盒,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
129.如实施方案121-128中任一项所述的试剂盒,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
130.如实施方案111-129中任一项所述的试剂盒,其中所述试剂盒包括7x106至1x1010个颗粒、脂质体或原始细胞。
131.如实施方案111-130中任一项所述的试剂盒,其还包括遗传重编程的淋巴细胞。
132.如实施方案131所述的试剂盒,其中所述遗传重编程的淋巴细胞包括T细胞和/或天然杀伤细胞。
133.如实施方案131或132所述的试剂盒,其中所述遗传重编程的淋巴细胞包括CD8+ T细胞。
134.如实施方案131-133中任一项所述的试剂盒,其中所述淋巴细胞包括至少7x106个淋巴细胞。
135.如实施方案131-134中任一项所述的试剂盒,其中所述支架基质包括藻酸盐、胶原蛋白、壳聚糖、自组装肽、中孔二氧化硅、TFN微网格或PLGA。
136.如实施方案135所述的试剂盒,其中所述支架基质包括藻酸盐。
137.如实施方案111-136中任一项所述的试剂盒,其还包括钙。
138.如实施方案111-137中任一项所述的试剂盒,其还包括药物洗脱聚合物。
139.如实施方案138所述的试剂盒,其中所述药物洗脱聚合物涂覆在所述支架基质上。
140.如实施方案138所述的试剂盒,其中STING激动剂或免疫刺激剂包埋在所述药物洗脱聚合物内。
141.如实施方案111-140中任一项所述的试剂盒,其中所述药物洗脱聚合物包括PLGA。
142.一种可植入医疗装置,其包括:(i)微图案化金属薄膜支架,(ii)遗传重编程的淋巴细胞,和(iii)淋巴细胞激活部分。
143.如实施方案142所述的可植入医疗装置,其还包括STING激动剂和/或免疫刺激剂。
144.如实施方案143所述的可植入医疗装置,其还包括药物洗脱聚合物,其中所述STING激动剂和/或所述免疫刺激剂包埋在所述药物洗脱聚合物内。
145.如实施方案142-144中任一项所述的可植入医疗装置,其中所述微图案化金属薄膜支架具有三维形状。
146.如实施方案145所述的可植入医疗装置,其中所述三维形状是圆柱形。
147.如实施方案142-146中任一项所述的可植入医疗装置,其包括支架。
148.如实施方案142-147中任一项所述的可植入医疗装置,其包括微创医疗装置。
149.如实施方案142-148中任一项所述的可植入医疗装置,其中所述微图案化金属薄膜支架堆叠成层。
150.如实施方案142-149中任一项所述的可植入医疗装置,其中所述微图案化金属薄膜包括TFN微网格。
151.如实施方案142-150中任一项所述的可植入医疗装置,其中所述遗传重编程的淋巴细胞的浓度为至少7X106个细胞/cm3。
实施例。方法。人胰管腺癌。对于人胰腺癌的共焦成像(PDA,图1),从进行PDA的胰腺切除术的患者获得新鲜肿瘤,所述患者根据癌症联盟机构审查委员会(CC-IRB)批准的研究方案,在Fred Hutchinson癌症研究中心提供书面知情同意书。
细胞系。鼠胰管腺癌细胞系KPC(由Sunil Hingorani博士(Fred Hutchinson癌症研究中心,西雅图,华盛顿州)馈赠)来源于17周大的转基因KPC(LSL-KrasG12D;p531ox/+)小鼠的自发形成的胰腺肿瘤。将此细胞系在具有10%热灭活的胎牛血清(FBS)、2mM L-谷氨酰胺、1.5g/L碳酸氢钠、4.5g/L葡萄糖、10mM HEPES、1.0mM丙酮酸钠和0.05mM 2-巯基乙醇的IMDM培养基中培养。将PhoenixTM Eco逆转录病毒包装细胞系(Orbigen)在含有10%FBS、2mM谷氨酸、100U/mL青霉素和100μg/mL链霉素的DMEM中培养。对于体内生物发光成像,将KPC细胞系用萤火虫荧光素酶(F-luc)进行逆转录病毒转导。
小鼠和体内肿瘤模型。将动物安置在Fred Hutchinson癌症研究中心的动物设施中,并在其机构动物护理和使用委员会批准的动物方案的背景下使用。对于胰管腺癌的原位小鼠模型,将1x105个KPC肿瘤细胞通过手术植入雌性Albino B6(C57BL/6J-Tyr<c-2J>)小鼠的胰腺头部中(杰克逊实验室(Jackson Laboratories)),并允许在治疗前建立一周。为了在图7A、图7B所示的流式细胞术研究中区分过继转移和内源性T细胞,由分离自野生型(CD45.2+)C57BL/6小鼠的脾细胞生成NKG2D CAR T细胞。基因转移后,将T细胞用于处理B6.SJL-Ptprca Pepcb/BoyJ受体小鼠(杰克逊实验室),其表达全白细胞标记物CD45.1。
逆转录病毒载体和病毒生产。SFG-CBR-luc(表达叩头虫红荧光素酶)和SFG-F-1uc(表达萤火虫荧光素酶)由Michel Sadelain博士(Memorial Sloan-Kettering癌症中心,纽约)友情提供。逆转录病毒载体pFb-chNKG2D-IRES-Neo由Charles Sentman博士(黎巴嫩达特茅斯的Geisel医学院)提供,并且已在前面描述过。Zhang,等人,Blood 106,1544-1551(2005)。NKG2D CAR包括与CD3ζ的细胞质部分融合的全长小鼠NKG2D(UniProt IDNo.O54709)。为了生成逆转录病毒颗粒,使用标准磷酸钙方法将Phoenix Eco细胞(1.5×106/10cm培养板)用10μg载体-DNA转染过夜;第二天,将它们在10mL新鲜DMEM中再孵育一天,然后过滤逆转录病毒上清液(0.45-μm,Nalgene)并使用Ultracel 100K膜(Millipore)浓缩10倍。
靶向肿瘤的淋巴细胞的制备。为了生成胰腺癌特异性(NKG2D CAR转导的)T细胞,收获C57BL/6J小鼠的脾脏,在过滤器上浸渍,并重悬于ACK裂解缓冲液(Biosource)中。通过将脾细胞(3×106/mL)与1ng/mL白细胞介素-7(PeproTech)和2μg/mL刀豆球蛋白A(Calbiochem)在完全RPMI 1640中在37℃下孵育来制备效应CD8+ T细胞。两天后,通过Ficoll梯度分离(GE Healthcare)除去死细胞,并使用小鼠CD8阴性分离试剂盒(StemcellTechnologies)分离CD8+细胞。通过逆转录病毒转导将NKG2D CAR引入T细胞中。将浓缩的表达NKG2D CAR的逆转录病毒(1mL)预加载到涂有RetroNectin(TakiraBio)的六孔非组织培养物处理的培养皿上,并在37℃下孵育1小时。添加等体积的分离的T细胞(补充有10ngmIL-2/mL的3×106个细胞/mL)并以2000×g离心30分钟)。在旋转接种(spinoculation)后6小时,添加1mL含有10ng mIL-2(PeproTech)的新鲜预热的RPMI。感染后两天,再在含有G418(0.5mg/mL)和25U/mL重组人(rHu)IL-2的RPMI-10培养基中3天选择转导的原代T细胞(0.5-1x10/mL)。使用Histopaque-1083(Sigma,St Louis,MO)分离活细胞,并在过继转移之前在没有G418的情况下扩增2天。对于生物发光T细胞成像实验,将靶向T细胞用叩头虫红荧光素酶(CBR-luc)进行遗传标记。Dobrenkov,等人,J Nucl Med 49,1162-1170(2008)。在此旋转接种后六小时,添加1mL含有50IU IL-2的RPMI,并在1天后将转导的T细胞用于实验。
刺激性脂质涂覆的二氧化硅微球的制备。马来酰亚胺官能化脂质膜的制备。将脂质储备溶液在氯仿中配制。将140mL DOPC(10mg/mL)、30mL DSPE-PEG(2000)马来酰亚胺(5mg/mL)、150mL胆固醇(5mg/mL)和50mL 18∶1PEG 2000-PE(5mg/mL,均购自Avanti PolarLipids)合并以获得55∶5∶30∶10重量比的DOPC:DSPE-PEG(2000)马来酰亚胺:胆固醇:PEG2000-PE和2.5mg总脂质。在氮气流下蒸发氯仿,并在真空下除去残余溶剂过夜。
二氧化硅微粒的胺改性。将500mg球形硅胶(15μm粒径,孔径,SorbentTechnologies)悬浮于4mL 25%的3-[2-(2-氨基乙基氨基)乙基氨基]丙基三甲氧基硅烷(AEPTMS)的乙醇溶液中,然后在室温下轻轻混合5h。通过离心(2min,1000x g)除去未反应的AEPTMS并倾析上清液。用乙醇(4x2mL)洗涤胺改性的二氧化硅,然后空气干燥2天。
将STING激动剂负载到中孔二氧化硅微粒中。在pH 7.2的磷酸盐缓冲盐水(PBS)中制备100mg/mL胺改性的二氧化硅悬浮液,并将360μL的所述悬浮液与500μL的c-di-GMP(InvivoGen,2mg/mL在PBS中)合并,轻轻涡旋1h,然后用400μL PBS稀释。
脂质在二氧化硅上的吸附。将400μL的SiO2/c-di-GMP悬浮液添加到2.5mg批次的脂质膜中,并涡旋15s,间隔10min,总共持续1h。将颗粒以3500×g沉淀2min,用PBS(2×1mL)洗涤,然后重悬于250μL PBS中。
抗体与脂质涂覆颗粒的缀合。如前所述,用二硫苏糖醇(DTT)选择性地还原抗小鼠CD3、CD28和CD137抗体(BioXcell)的铰链区二硫键。Kwong,等人,Cancer Res 73,1547-1558(2013)。用脱盐柱除去DTT后,将这些轻微还原的抗体(抗CD3:200μg;抗CD28和CD137:400μg)添加到250μL马来酰亚胺官能化颗粒中,在旋转之前短暂涡旋2h,并以3500×g离心2min。用PBS(2x1mL)洗涤沉淀,然后悬浮在125μL PBS中。
支架制造。如前所述,在用高碘酸钠氧化以产生水解不稳定键之后,藻酸盐支架由富含G嵌段(≥60%)的高分子量(250kDa)超纯藻酸钠粉末(Novamatrix Pronova UP MVG藻酸盐)生产。Boontheekul,等人,Biomaterials 26,2455-2465(2005)。
简言之,将200μL 0.25%高碘酸钠逐滴添加到10mL 1%藻酸盐水溶液中,并在暗处在25℃下搅拌5h,然后通过与等摩尔乙二醇搅拌30min淬灭反应。使用截留分子量为3,500的膜,将样品用去离子水透析三天,然后冻干。将氧化的藻酸盐溶液在MES溶液(0.1MMES,0.3M NaCl,pH 6.5)中重构,并使用碳二亚胺化学51共价缀合至胶原蛋白-模拟肽“GFOGER50”(获自MIT Biopolymers工厂):依次添加磺基-NHS,EDC(均为ThermoScientific)和GFOGER(SEQ ID NO:1)肽,并且24h后再次透析溶液(MWCO 20kDa透析膜,Thermo Scientific)并冻干。
为了制备支架,将藻酸盐储备液在PBS中重构成7mL 2%w/v溶液,并升温至55℃,然后与7×106个刺激性微球在含水悬浮液混合。通过在涡旋的同时添加1.4mL 0.1%(w/v)氯化钙溶液来引发轻度交联,然后立即对每15mm圆形Teflon涂覆的模具转移700μL以形成2mm厚的支架。将它们在-78℃冷冻并冻干,以得到多孔基质,将其在4℃下储存在干燥器中。
T细胞接种到支架上。离体扩增后,将对4T1乳腺肿瘤抗原具特异性或基因工程化以表达NKG2D-CAR的小鼠CD8+效应T细胞在PBS中洗涤两次,并以14×106个细胞/mL的浓度重悬于未补充的RPMI培养基中。添加5%AlgiMatrix固化缓冲液(Invitrogen)后,立即将500μL此细胞悬浮液接种到24孔组织培养板中的每个冻干支架的顶部上。在植入肿瘤切除腔或腹膜腔中之前,使细胞在冰上注入这些基质中30min。
细胞毒性测定。使用如别处所述的标准51Cr释放测定法测量T细胞的体外细胞毒活性。Erskine,J Vis Exp,e3683(2012)。简言之,将4T1乳腺肿瘤、ID8-VEGF卵巢肿瘤或B16F10黑素瘤对照肿瘤细胞用51Cr在37℃下标记1h,用含有10%FCS的RPMI洗涤,并以1×105个肿瘤细胞/mL的浓度重悬于相同的培养基中。在96孔板(最终体积,200μL)中以不同的效应细胞与靶细胞比率将T细胞添加到悬浮液中,并在37℃下孵育4h,然后将来自每个孔的30μL上清液转移至Lumaplate-96微孔板(Packard Bioscience)中,以使用Top Count NXT微孔板闪烁计数器(Packard Bioscience)进行分析。使用可商购获得的试剂盒(R&DSystems)基于通过流式细胞术测量的IFN-γ+CD8+ T细胞的总数计算效应细胞数。
体内生物发光和成像。将D-荧光素(Xenogen)的PBS溶液(15mg/mL)用作F-luc(4T1乳腺肿瘤和ID8-VEGF卵巢肿瘤的成像)和CBR-luc47(T细胞成像)的底物。用Xenogen IVIS光谱成像系统(Xenogen,Alameda,CA)采集生物发光图像。在向用150mg/kg 2%异氟烷(Forane,Baxter Healthcare)麻醉的动物腹膜内注射D-荧光素后10min,使用LivingImage软件版本4.3.1(Xenogen)采集(并随后定量)数据。采集时间的范围是10sec至5min。
流式细胞术。与FACSCanto流式细胞仪(BD Biosciences)一起使用的抗重组膜联蛋白V(用于定量凋亡细胞)和其他抗体购自eBioscience。
共焦显微镜法。为了通过共焦显微镜法使支架可视化,使用标准EDC/NHS化学将Hilyte Fluor 647(Anaspec)与藻酸盐缀合,然后将1份缀合物与9份GFOGER(SEQ ID NO:1)肽修饰的藻酸盐混合以制造如上所述的支架。在即将接种到这些支架中之前用CellTracker Orange CMTMR(Invitrogen)标记T细胞。植入后三天,将肿瘤切除床在OCT(Tissue-Tek)中快速冷冻以产生冷冻切片,其用2%多聚甲醛固定,安装在ProLong GoldAntifade试剂(Invitrogen)中,并用Zeiss LSM 780NLO激光扫描共焦显微镜成像。
统计学。使用单向ANOVA计算T细胞迁移参数的测量差值的统计显著性,然后进行Dunnett比较测试。使用Wilcoxon秩和测试在选定的时间点处分析生物发光肿瘤和T细胞信号的成对差异,并使用对数秩测试表征存活率数据。使用GraphPad Prism软件6.0版进行所有统计分析。
研究批准。根据IACUC方案并在Fred Hutchinson癌症研究中心IACUC的批准下,在联邦、州和地方指南下进行小鼠的实验和处理。
结果。静脉内注射肿瘤反应性T细胞不能清除胰管腺癌。为了在临床相关环境中测试新的免疫治疗方法,使用源自LSL-KrasG12D;p531ox/+(KPC)小鼠产生的自发性胰腺肿瘤的细胞系进行所述实验(Hingorani,等人Cancer Cell 7,469-483(2005));这允许产生具有快速且可预测的生长动力学的胰腺癌的免疫活性的原位鼠模型。用荧光素酶对KPC细胞进行遗传标记,以便使用生物发光成像非侵入性地定量肿瘤负荷。当原位地移植到非KPC同窝出生仔畜的胰腺中时,这些肿瘤细胞可再现地发展成在基因突变、组织学外观和抗原/靶表达的异质性方面模拟人胰腺癌的病变(图2A至图2C)。
首次证实,在此KPC模型中,常规静脉内注射胰腺癌特异性淋巴细胞不能根除肿瘤。为了产生这些淋巴细胞,用编码嵌合天然杀伤受体(包括与CD3ζ30的细胞质信号传导结构域连接的NKG2D;图2D)的逆转录病毒转导小鼠T细胞,所述逆转录病毒对由表达这些受体的T细胞识别的KPC抗原Rae-1具特异性(图2E,图2F)。为了跟踪和量化转移的T细胞相对于KPC肿瘤的体内迁移和积累,将叩头虫荧光素酶的载体包括在质粒中。结果证实,尽管静脉内输注的T细胞在脾脏和肝脏中以高水平积累,但它们无法有效地进入KPC肿瘤部位(图2G),从而与未治疗的对照动物相比产生适度的4天存活优势(图2H)。此外,与对照淋巴细胞相比,输注CAR-T细胞后Rae-1靶抗原表达水平仅略低(图2I)。
经由生物活性载体递送显著改善T细胞在肿瘤部位的扩增和功能,但抗原阴性肿瘤亚型逃避被这些细胞消除。上述结果促使探索使用生物材料将肿瘤反应性T细胞局部递送至胰腺肿瘤部位的潜力,并产生维持它们的方法。最近开发了一种将抗癌免疫细胞包埋在可再吸收的聚合物装置中的方法,所述聚合物装置可通过手术植入在切除肿瘤的位置或者在不可切除的肿瘤上(图3A),并且描述于US2016/0008399和Stephan,等人,NatBiotechnol 33,97-101(2015)中。已经位于它们的靶位点,递送的淋巴细胞立即开始消除癌细胞。多孔支架由聚合藻酸盐制成,所述聚合藻酸盐是一种可铸的天然存在的多糖,由于其优异的生物相容性和生物降解性,已被FDA批准用于人类。Baldwin&Kiick,Biopolymers94,128-140(2010)。为了使它们能够作为活性T细胞的有效递送载体,这些装置用促进迁移的大分子(例如,胶原蛋白-模拟肽)和刺激性触发物(例如,展示抗CD3、抗CD28和抗CD137抗体的包埋式微粒;图3A)来加强。在引入表达荧光素酶的KPC肿瘤细胞后十天,将含有7×106个NKG2D-CAR+ T细胞的支架直接植入在所得胰腺肿瘤的顶部上(图3B)。第二组接受相同剂量的直接注射到肿瘤中的细胞,并且对照小鼠未接受任何处理。生物发光成像用于定量肿瘤生长,并且在平行实验中,用于跟踪淋巴细胞的组织分布、扩增和持久性。发现直接注射到胰腺肿瘤中的CAR-T细胞在免疫抑制微环境中持久性很差,并且仅在疾病进展中产生暂时延迟(21天,与未处理的对照组中14.5天的中值总生存期相比,图4A至图4D)。相比之下,植入支架递送的T细胞在肿瘤部位经历显著增殖(在第8天相对于注射的T细胞,峰值光子计数为166倍高,P<0.0001,图4A,图4B)并且明显减少KPC肿瘤生长(图4A,图4C)。然而,尽管它们使处理小鼠的存活率增加一倍以上,但是T细胞负载的支架未能完全清除疾病,因为所有小鼠最终都发展出Rae-1低/阴性免疫逃逸变体(图4E)。
CAR-T细胞和STING激动剂从支架的组合释放导致宿主抗原呈递细胞的协同成熟和激活。上述观察结果指示,用CAR-T细胞靶向单一抗原不太可能防止抗原阴性细胞的生长-即使当肿瘤饱和含有从可植入支架递送的最佳刺激的抗癌T细胞时也是如此。因此,接下来寻求协同地发起宿主T细胞应答以努力消除残留的CAR抗性肿瘤细胞类型(参见图5A)。完整的免疫系统能够生成有效的肿瘤特异性应答,但需要刺激才能这样做。不幸的是,肿瘤抑制位于其引流淋巴结中的抗原呈递细胞的成熟和激活,并且从而防止肿瘤反应性T细胞分化成溶细胞性效应子。为了逆转这种抑制作用,使用支架以实现免疫刺激性STING激动剂环状-di-GMP(c-diGMP)的高局部浓度,以通过募集并刺激抗原呈递细胞使肿瘤环境更有利于T细胞引发(图5B)。通过其主要组织相容性复合物II类(MHC-II)和T细胞共刺激分子(例如,CD86)的高表达定义的树突细胞(DC)是最有效的抗原呈递细胞并且能够协调适应性抗肿瘤免疫应答。与已建立的KPC肿瘤相关的肿瘤相关淋巴结的免疫表型分析显示,其DC中少于6%(在流式细胞术中被识别为CD11c+CD11b+)被适当激活,如通过其CD86的表达所证明的;大多数DC是耐受性的(CD86阴性;图6A)。从植入的支架仅释放c-diGMP通过大部分这些DC上调CD86和MHC-II表达,并且使其在引流淋巴结中的总频率增加38倍(图6B)。植入在没有STING激动剂的情况下制造的CAR-T细胞负载的支架后,CDl1c+CD86+成熟DC的数量仅适度增加(9.4倍),但这些细胞上的MHC-II表达水平是c-diGMP处理组的两倍多(图6A,图6B)。从植入的基质中释放c-diGMP和CAR-T细胞两者产生DC的协同激活,如激活的DC频率的稳健增加所反映(与单独的c-diGMP相比3.7倍高)。值得注意的是,这些细胞表达高水平的共刺激分子以及MHC-II,从而指示它们可有效地交叉呈递肿瘤抗原并发起抗肿瘤T细胞应答(图6B)。
联合CAR-T细胞/STING激动剂疗法引发稳健的肿瘤特异性宿主淋巴细胞应答。为了测量宿主中肿瘤特异性T细胞的激活,使用表达淋巴细胞脉络丛脑膜炎病毒(LCMV)糖蛋白gp33的KPC胰腺肿瘤模型。作为替代物胰腺肿瘤抗原,此蛋白质能够使用流式细胞术分析支架如何影响CD8+ T细胞中四聚体阳性细胞的频率。为了区分支架递送的和内源的T细胞,用CD45.2标记物对供体细胞进行遗传标记,并将CD45.1-转基因小鼠用作宿主。用生物材料支架处理小鼠,所述生物材料支架被工程化以将c-diGMP、CAR-T细胞或两者的组合释放到肿瘤中。对照小鼠未接受处理。如所预期的,在未处理的小鼠中很少发生自发的抗肿瘤T细胞应答(图7A),从而证实尽管它们表达gp33异种抗原,但KPC-gp33肿瘤仍然是高度免疫抑制的。虽然用c-diGMP负载的支架或单独用淋巴细胞制备的支架处理产生宿主抗肿瘤T细胞活性,但总体应答是适度的(外周血gp33四聚体阳性T细胞数分别增加1.3倍和2倍;图7A,图7B)。相比之下,c-diGMP和表达CAR的T细胞的组合引起协同抗肿瘤应答,其是仅释放淋巴细胞的植入物的平均6.4倍高(图7A,图7B)。
支架可触发宿主抗肿瘤免疫性,足以清除肿瘤并消除转移瘤。为了测量共递送STING激动剂和CAR编程的T细胞的支架提供的抗肿瘤益处,使用单独用c-diGMP或用c-diGMP和CAR-T细胞两者功能化的支架处理携带原位KPC肿瘤的小鼠;对照小鼠未接受处理。通过连续生物发光成像定量肿瘤生长。发现从支架组合释放CAR-T细胞和c-diGMP在十只处理小鼠中的四只中根除了KPC肿瘤(图8A至图8C),并且其他六只显示实质性肿瘤消退,生存期平均提高37天。尽管单独的STING激动剂从未产生完全清除,但与对照组相比,其存活时间增加了6天。为了确定支架是否引起全面的抗肿瘤免疫,经历完全肿瘤消退的四只小鼠(图9A,图9B)用104个表达荧光素酶的KPC肿瘤细胞全身给药进行再次攻击;将没有肿瘤的小鼠用作对照。然后使用生物发光成像来定量处理组之间肺转移瘤的生长速率的差异。结果证实,用CAR-T细胞/STING激动剂免疫疗法治愈的所有小鼠都完全免于这种再次攻击,在施用KPC细胞后4周没有可测量的肿瘤块。相比之下,对照动物在其肺中快速形成转移性病灶并迅速死于其疾病(图9B)。因此,使用CAR编程的T细胞和STING激动剂的适当配制的组合疗法可消除局部肿瘤并触发足够强大的全身宿主抗肿瘤免疫性以防止未治疗的远处转移。
这项工作展示了癌症疗法的新概念,其实现了快速肿瘤清除和全身抗肿瘤免疫性两者。开发的支架使外科医生能够将抗癌淋巴细胞以及强效STING激动剂以高局部浓度并在延长时间段内直接递送到肿瘤。这不仅最大化例如胰腺肿瘤手术后的治疗成功率,还降低医疗成本,因为使用所公开的支架进行单次治疗可能使患者免于复杂的第二次或第三次手术、昂贵的延长住院时间、放射和化疗周期以及昂贵的姑息护理。更广泛地说,此平台最终可通过为外科医生提供适当的工具将治疗简单并安全地直接应用于实体肿瘤,以便将重点从广泛影响的基于化学和放射的方法转移到肿瘤特异性免疫治疗。
如本领域普通技术人员将理解的,本文所公开的每个实施方案可包括以下项、基本上由或由以下项组成:其特别陈述的元件、步骤、成分或组分。如本文所用的过渡术语“包括(comprise)”或“包括(comprises)”意指包括但不限于,并且允许包括未指定的元件、步骤、成分或组分,甚至在较大的量时。过渡短语“由...组成”排除未指定的任何元件、步骤、成分或组分。过渡短语“基本上由...组成”将实施方案的范围限制为指定的元件、步骤、成分或组分以及并不实质地影响所述实施方案的那些。如本文所用,材料效应将在本文公开的抗肿瘤活性的至少两个测量中导致要求保护的支架或方法的抗肿瘤作用的统计学显著降低。
除非另外指示,否则说明书和权利要求书中所用的表示成分的量,诸如分子量、反应条件的性质等的所有数字应理解为在所有情况下都由术语“约”修饰。因此,除非有相反的指示,否则说明书和所附权利要求书中所陈述的数值参数都是近似值,所述值可根据本发明要寻求获得的所需性质而变化。在最低限度并且不试图限制对权利要求书范围的等效范围的原则的应用,每个数值参数均应至少根据报道的有效数字的数值和通过应用普通四舍五入技术来解读。当要求进一步清楚时,术语“约”当与陈述的数值或范围结合使用时具有本领域技术人员合理地归于它的含义,即将稍微大于或稍微小于陈述值或范围表示为在以下范围内:陈述值的±20%;陈述值±19%;陈述值±18%;陈述值±17%;陈述值±16%;陈述值±15%;陈述值±14%;陈述值±13%;陈述值±12%;陈述值±11%;陈述值±10%;陈述值±9%;陈述值±8%;陈述值±7%;陈述值±6%;陈述值±5%;陈述值±4%;陈述值±3%;陈述值±2%;或陈述值±1%。
尽管阐述本发明的宽泛范围的数值范围和参数是近似值,但在特定实例中所阐述的数值尽可能精确地加以报告。然而,任何数值固有地包含必然由它们各自测试测量值中发现的标准偏差所产生的某些误差。
除非本文另外指示或者与上下文含义明显相悖,否则在描述本发明的上下文中(尤其在所附权利要求书的上下文中)使用的术语“一个/种”、“所述”以及类似的指代语应解读为涵盖单数和复数指代语。本文中所列举数值的范围仅意在作为一种对落在所述范围内的每个单独数值单独提及的简便方法。除非本文另外指示,否则每个单独数值都并入到本说明书中,如同本文中单独列举了每个单独数值一样。可按任何适合的顺序执行本文所描述的所有方法,除非本文另外指示或明显与上下文矛盾。本文提供的任何和所有实施例或示例性语言(例如,“诸如”)仅意在更好地说明本发明,而不会对以其他方式要求保护的本发明的范围构成限制。本说明书中的语言不应解读为指示任何未要求保护的要素是实践本发明所必需的。
本文所公开的本发明的替代性元素或实施方案的分组不应被解读为限制。每个组成员可单独或者以与组中的其他成员或本文发现的其他要素的任何组合被提及和要求保护。出于便利和/或可专利性的原因,预期组中的一个或多个成员可包括在组中或从组中删除。当出现任何这种包括或删除时,本说明书被认为包含所修改的组,因此满足所附权利要求书中使用的所有马库什组的书面说明。
本文描述了本发明的某些实施方案,包括为本发明人所知用于实施本发明的最佳方式。当然,本领域普通技术人员在阅读前面的说明后将会明了这些所述实施方案的变型。本发明人预期本领域的熟练技术人员会适时采用此类变型,而且本发明人预期能以除了本文具体描述的方式之外的方式来实施。因此,本发明包括在随附的适用法律允许的权利要求中叙述的主题的所有修改和等效物。此外,除非本文另有指示或与上下文明显矛盾,否则在所有可行变型中的上述元素的任何组合都涵盖在本发明内。
此外,整个本说明书对专利和印刷的出版物做了很多引用。上文引用的各参考文献和印刷的出版物的全部内容都单独以引用的方式并入本文。
最后,应理解,本文所公开的本发明的实施方案是对本发明原理的说明。可用的其他修改形式也在本发明的范围内。因此,例如,但不限于,可根据本文的教义利用本发明的替代性配置。因而,本发明不限于明确示出和描述的方案。
本文示出的细节是作为实施例并且仅出于对本发明的优选实施方案的说明性讨论的目的,并且之所以呈现这些细节,是为了提供认为是本发明的各种实施方案的原理和概念方面的最有用和易理解的描述的内容。在这点上,除对于本发明的基本理解所必需的之外,没有企图更详细地示出本发明的结构细节,借助于附图和/或实施例所作的描述使得本领域技术人员明了如何可以在实践中实施本发明的若干形式。
除非在以下实施例中明确并毫无疑问地修改或是当含义的应用使得任何构建无意义或基本上无意义,否则在本公开中使用的定义和解释意指并且旨在控制任何未来构建。在术语的构建将使它无意义或基本上无意义的情况下,定义应从韦氏字典(Webster′sDictionary),第3版或本领域普通技术人员已知的字典诸如生物化学和分子生物学牛津字典(Anthony Smith编著,牛津大学出版社,Oxford,2004)中取得。
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<110> 弗莱德哈钦森癌症研究中心
<120> 治疗实体瘤细胞和逃避变体的支架
<130> F053-0056PCT
<150> US 62/437572
<151> 2016-12-21
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130 135 140
Asn Leu Thr Val Val Leu Leu Arg Gly Glu Lys Glu Leu Lys Arg Glu
145 150 155 160
Pro Ala Val Gly Glu Pro Ala Glu Val Thr Thr Thr Val Leu Val Arg
165 170 175
Arg Asp His His Gly Ala Asn Phe Ser Cys Arg Thr Glu Leu Asp Leu
180 185 190
Arg Pro Gln Gly Leu Glu Leu Phe Glu Asn Thr Ser Ala Pro Tyr Gln
195 200 205
Leu Gln Thr Phe Val Leu Pro Ala Thr Pro Pro Gln Leu Val Ser Pro
210 215 220
Arg Val Leu Glu Val Asp Thr Gln Gly Thr Val Val Cys Ser Leu Asp
225 230 235 240
Gly Leu Phe Pro Val Ser Glu Ala Gln Val His Leu Ala Leu Gly Asp
245 250 255
Gln Arg Leu Asn Pro Thr Val Thr Tyr Gly Asn Asp Ser Phe Ser Ala
260 265 270
Lys Ala Ser Val Ser Val Thr Ala Glu Asp Glu Gly Thr Gln Arg Leu
275 280 285
Thr Cys Ala Val Ile Leu Gly Asn Gln Ser Gln Glu Thr Leu Gln Thr
290 295 300
Val Thr Ile Tyr Ser Phe Pro Ala Pro Asn Val Ile Leu Thr Lys Pro
305 310 315 320
Glu Val Ser Glu Gly Thr Glu Val Thr Val Lys Cys Glu Ala His Pro
325 330 335
Arg Ala Lys Val Thr Leu Asn Gly Val Pro Ala Gln Pro Leu Gly Pro
340 345 350
Arg Ala Gln Leu Leu Leu Lys Ala Thr Pro Glu Asp Asn Gly Arg Ser
355 360 365
Phe Ser Cys Ser Ala Thr Leu Glu Val Ala Gly Gln Leu Ile His Lys
370 375 380
Asn Gln Thr Arg Glu Leu Arg Val Leu Tyr Gly Pro Arg Leu Asp Glu
385 390 395 400
Arg Asp Cys Pro Gly Asn Trp Thr Trp Pro Glu Asn Ser Gln Gln Thr
405 410 415
Pro Met Cys Gln Ala Trp Gly Asn Pro Leu Pro Glu Leu Lys Cys Leu
420 425 430
Lys Asp Gly Thr Phe Pro Leu Pro Ile Gly Glu Ser Val Thr Val Thr
435 440 445
Arg Asp Leu Glu Gly Thr Tyr Leu Cys Arg Ala Arg Ser Thr Gln Gly
450 455 460
Glu Val Thr Arg Glu Val Thr Val Asn Val Leu Ser Pro Arg Tyr Glu
465 470 475 480
Ile Val Ile Ile Thr Val Val Ala Ala Ala Val Ile Met Gly Thr Ala
485 490 495
Gly Leu Ser Thr Tyr Leu Tyr Asn Arg Gln Arg Lys Ile Lys Lys Tyr
500 505 510
Arg Leu Gln Gln Ala Gln Lys Gly Thr Pro Met Lys Pro Asn Thr Gln
515 520 525
Ala Thr Pro Pro
530
<210> 4
<211> 368
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Pro Leu Ser Pro Pro Thr Asn Leu His Leu Glu Ala Asn Pro Asp Thr
1 5 10 15
Gly Val Leu Thr Val Ser Trp Glu Arg Ser Thr Thr Pro Asp Ile Thr
20 25 30
Gly Tyr Arg Ile Thr Thr Thr Pro Thr Asn Gly Gln Gln Gly Asn Ser
35 40 45
Leu Glu Glu Val Val His Ala Asp Gln Ser Ser Cys Thr Phe Asp Asn
50 55 60
Leu Ser Pro Gly Leu Glu Tyr Asn Val Ser Val Tyr Thr Val Lys Asp
65 70 75 80
Asp Lys Glu Ser Val Pro Ile Ser Asp Thr Ile Ile Pro Ala Val Pro
85 90 95
Pro Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg
100 105 110
Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu Val
115 120 125
Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu Ser Ile
130 135 140
Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu Pro Gly Thr
145 150 155 160
Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln His Glu Ser Thr
165 170 175
Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp Ser Pro Thr Gly Ile
180 185 190
Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe Thr Val His Trp Ile Ala
195 200 205
Pro Arg Ala Thr Ile Thr Gly Tyr Arg Ile Arg His His Pro Glu His
210 215 220
Phe Ser Gly Arg Pro Arg Glu Asp Arg Val Pro His Ser Arg Asn Ser
225 230 235 240
Ile Thr Leu Thr Asn Leu Thr Pro Gly Thr Glu Tyr Val Val Ser Ile
245 250 255
Val Ala Leu Asn Gly Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln
260 265 270
Ser Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr
275 280 285
Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg
290 295 300
Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln
305 310 315 320
Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu
325 330 335
Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg
340 345 350
Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr
355 360 365
<210> 5
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 聚合物主链中的序列
<400> 5
Tyr Ile Gly Ser Arg
1 5
<210> 6
<211> 750
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Met Trp Asn Leu Leu His Glu Thr Asp Ser Ala Val Ala Thr Ala Arg
1 5 10 15
Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Phe
20 25 30
Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile Lys Ser Ser Asn Glu
35 40 45
Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys Ala Phe Leu Asp Glu
50 55 60
Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Gln Ile
65 70 75 80
Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile
85 90 95
Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Ala His
100 105 110
Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile
115 120 125
Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe
130 135 140
Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Ile Val Pro Pro
145 150 155 160
Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr
165 170 175
Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met
180 185 190
Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val
195 200 205
Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Lys Gly
210 215 220
Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys
225 230 235 240
Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly
245 250 255
Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr
260 265 270
Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly
275 280 285
Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys
290 295 300
Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Arg
305 310 315 320
Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn
325 330 335
Phe Ser Thr Gln Lys Val Lys Met His Ile His Ser Thr Asn Glu Val
340 345 350
Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro
355 360 365
Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly
370 375 380
Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val Arg
385 390 395 400
Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile
405 410 415
Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr
420 425 430
Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala
435 440 445
Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val
450 455 460
Asp Cys Thr Pro Leu Met Tyr Ser Leu Val His Asn Leu Thr Lys Glu
465 470 475 480
Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser
485 490 495
Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile
500 505 510
Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu
515 520 525
Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn
530 535 540
Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu
545 550 555 560
Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys Tyr His Leu Thr Val
565 570 575
Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val
580 585 590
Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala
595 600 605
Asp Lys Ile Tyr Ser Ile Ser Met Lys His Pro Gln Glu Met Lys Thr
610 615 620
Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr
625 630 635 640
Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Phe Asp Lys Ser
645 650 655
Asn Pro Ile Val Leu Arg Met Met Asn Asp Gln Leu Met Phe Leu Glu
660 665 670
Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg
675 680 685
His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu Ser
690 695 700
Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val Asp
705 710 715 720
Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Tyr Val Ala Ala
725 730 735
Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala
740 745 750
<210> 7
<211> 123
<212> PRT
<213> 智人(Homo sapiens)
<400> 7
Met Lys Ala Val Leu Leu Ala Leu Leu Met Ala Gly Leu Ala Leu Gln
1 5 10 15
Pro Gly Thr Ala Leu Leu Cys Tyr Ser Cys Lys Ala Gln Val Ser Asn
20 25 30
Glu Asp Cys Leu Gln Val Glu Asn Cys Thr Gln Leu Gly Glu Gln Cys
35 40 45
Trp Thr Ala Arg Ile Arg Ala Val Gly Leu Leu Thr Val Ile Ser Lys
50 55 60
Gly Cys Ser Leu Asn Cys Val Asp Asp Ser Gln Asp Tyr Tyr Val Gly
65 70 75 80
Lys Lys Asn Ile Thr Cys Cys Asp Thr Asp Leu Cys Asn Ala Ser Gly
85 90 95
Ala His Ala Leu Gln Pro Ala Ala Ala Ile Leu Ala Leu Leu Pro Ala
100 105 110
Leu Gly Leu Leu Leu Trp Gly Pro Gly Gln Leu
115 120
<210> 8
<211> 622
<212> PRT
<213> 智人(Homo sapiens)
<400> 8
Met Ala Leu Pro Thr Ala Arg Pro Leu Leu Gly Ser Cys Gly Thr Pro
1 5 10 15
Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln
20 25 30
Pro Ser Arg Thr Leu Ala Gly Glu Thr Gly Gln Glu Ala Ala Pro Leu
35 40 45
Asp Gly Val Leu Ala Asn Pro Pro Asn Ile Ser Ser Leu Ser Pro Arg
50 55 60
Gln Leu Leu Gly Phe Pro Cys Ala Glu Val Ser Gly Leu Ser Thr Glu
65 70 75 80
Arg Val Arg Glu Leu Ala Val Ala Leu Ala Gln Lys Asn Val Lys Leu
85 90 95
Ser Thr Glu Gln Leu Arg Cys Leu Ala His Arg Leu Ser Glu Pro Pro
100 105 110
Glu Asp Leu Asp Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro
115 120 125
Asp Ala Phe Ser Gly Pro Gln Ala Cys Thr His Phe Phe Ser Arg Ile
130 135 140
Thr Lys Ala Asn Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln
145 150 155 160
Arg Leu Leu Pro Ala Ala Leu Ala Cys Trp Gly Val Arg Gly Ser Leu
165 170 175
Leu Ser Glu Ala Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu
180 185 190
Pro Gly Arg Phe Val Ala Glu Ser Ala Glu Val Leu Leu Pro Arg Leu
195 200 205
Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg
210 215 220
Ala Ala Leu Gln Gly Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp
225 230 235 240
Ser Val Ser Thr Met Asp Ala Leu Arg Gly Leu Leu Pro Val Leu Gly
245 250 255
Gln Pro Ile Ile Arg Ser Ile Pro Gln Gly Ile Val Ala Ala Trp Arg
260 265 270
Gln Arg Ser Ser Arg Asp Pro Ser Trp Arg Gln Pro Glu Arg Thr Ile
275 280 285
Leu Arg Pro Arg Phe Arg Arg Glu Val Glu Lys Thr Ala Cys Pro Ser
290 295 300
Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys Lys
305 310 315 320
Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln Met
325 330 335
Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val Leu
340 345 350
Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser Val
355 360 365
Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp Ile
370 375 380
Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu Glu
385 390 395 400
Val Asn Lys Gly His Glu Met Ser Pro Gln Val Ala Thr Leu Ile Asp
405 410 415
Arg Phe Val Lys Gly Arg Gly Gln Leu Asp Lys Asp Thr Leu Asp Thr
420 425 430
Leu Thr Ala Phe Tyr Pro Gly Tyr Leu Cys Ser Leu Ser Pro Glu Glu
435 440 445
Leu Ser Ser Val Pro Pro Ser Ser Ile Trp Ala Val Arg Pro Gln Asp
450 455 460
Leu Asp Thr Cys Asp Pro Arg Gln Leu Asp Val Leu Tyr Pro Lys Ala
465 470 475 480
Arg Leu Ala Phe Gln Asn Met Asn Gly Ser Glu Tyr Phe Val Lys Ile
485 490 495
Gln Ser Phe Leu Gly Gly Ala Pro Thr Glu Asp Leu Lys Ala Leu Ser
500 505 510
Gln Gln Asn Val Ser Met Asp Leu Ala Thr Phe Met Lys Leu Arg Thr
515 520 525
Asp Ala Val Leu Pro Leu Thr Val Ala Glu Val Gln Lys Leu Leu Gly
530 535 540
Pro His Val Glu Gly Leu Lys Ala Glu Glu Arg His Arg Pro Val Arg
545 550 555 560
Asp Trp Ile Leu Arg Gln Arg Gln Asp Asp Leu Asp Thr Leu Gly Leu
565 570 575
Gly Leu Gln Gly Gly Ile Pro Asn Gly Tyr Leu Val Leu Asp Leu Ser
580 585 590
Val Gln Glu Ala Leu Ser Gly Thr Pro Cys Leu Leu Gly Pro Gly Pro
595 600 605
Val Leu Thr Val Leu Ala Leu Leu Leu Ala Ser Thr Leu Ala
610 615 620
<210> 9
<211> 556
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met
1 5 10 15
Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp
20 25 30
Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln
35 40 45
Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu
50 55 60
Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ser
65 70 75 80
Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu
85 90 95
Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr
100 105 110
Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp
115 120 125
Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro
130 135 140
Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala
145 150 155 160
Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Val Pro Pro
165 170 175
Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro
180 185 190
Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser
195 200 205
Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser
210 215 220
Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp
225 230 235 240
Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala
245 250 255
Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu
260 265 270
Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly
275 280 285
Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu
290 295 300
Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg
305 310 315 320
Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val
325 330 335
Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu
340 345 350
Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala
355 360 365
Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp
370 375 380
Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly
385 390 395 400
Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu
405 410 415
Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu
420 425 430
Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly
435 440 445
Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu
450 455 460
Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser
465 470 475 480
Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Gly
485 490 495
Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro Gln
500 505 510
Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp Ala
515 520 525
Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala Trp
530 535 540
Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg
545 550 555
<210> 10
<211> 297
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro
1 5 10 15
Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg
20 25 30
Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu
35 40 45
Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile
50 55 60
Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile
65 70 75 80
Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile
85 90 95
Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu
100 105 110
Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile
115 120 125
Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser
130 135 140
His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro
145 150 155 160
Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn
165 170 175
Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly
180 185 190
Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile
195 200 205
Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys
210 215 220
Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile
225 230 235 240
Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro
245 250 255
Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu
260 265 270
Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser
275 280 285
Ser Pro Ile Glu Asn Asp Ser Ser Pro
290 295
<210> 11
<211> 937
<212> PRT
<213> 智人(Homo sapiens)
<400> 11
Met His Arg Pro Arg Arg Arg Gly Thr Arg Pro Pro Leu Leu Ala Leu
1 5 10 15
Leu Ala Ala Leu Leu Leu Ala Ala Arg Gly Ala Ala Ala Gln Glu Thr
20 25 30
Glu Leu Ser Val Ser Ala Glu Leu Val Pro Thr Ser Ser Trp Asn Ile
35 40 45
Ser Ser Glu Leu Asn Lys Asp Ser Tyr Leu Thr Leu Asp Glu Pro Met
50 55 60
Asn Asn Ile Thr Thr Ser Leu Gly Gln Thr Ala Glu Leu His Cys Lys
65 70 75 80
Val Ser Gly Asn Pro Pro Pro Thr Ile Arg Trp Phe Lys Asn Asp Ala
85 90 95
Pro Val Val Gln Glu Pro Arg Arg Leu Ser Phe Arg Ser Thr Ile Tyr
100 105 110
Gly Ser Arg Leu Arg Ile Arg Asn Leu Asp Thr Thr Asp Thr Gly Tyr
115 120 125
Phe Gln Cys Val Ala Thr Asn Gly Lys Glu Val Val Ser Ser Thr Gly
130 135 140
Val Leu Phe Val Lys Phe Gly Pro Pro Pro Thr Ala Ser Pro Gly Tyr
145 150 155 160
Ser Asp Glu Tyr Glu Glu Asp Gly Phe Cys Gln Pro Tyr Arg Gly Ile
165 170 175
Ala Cys Ala Arg Phe Ile Gly Asn Arg Thr Val Tyr Met Glu Ser Leu
180 185 190
His Met Gln Gly Glu Ile Glu Asn Gln Ile Thr Ala Ala Phe Thr Met
195 200 205
Ile Gly Thr Ser Ser His Leu Ser Asp Lys Cys Ser Gln Phe Ala Ile
210 215 220
Pro Ser Leu Cys His Tyr Ala Phe Pro Tyr Cys Asp Glu Thr Ser Ser
225 230 235 240
Val Pro Lys Pro Arg Asp Leu Cys Arg Asp Glu Cys Glu Ile Leu Glu
245 250 255
Asn Val Leu Cys Gln Thr Glu Tyr Ile Phe Ala Arg Ser Asn Pro Met
260 265 270
Ile Leu Met Arg Leu Lys Leu Pro Asn Cys Glu Asp Leu Pro Gln Pro
275 280 285
Glu Ser Pro Glu Ala Ala Asn Cys Ile Arg Ile Gly Ile Pro Met Ala
290 295 300
Asp Pro Ile Asn Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp
305 310 315 320
Tyr Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro
325 330 335
Trp Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe
340 345 350
Pro Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln
355 360 365
Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp
370 375 380
Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Lys Glu Lys Asn
385 390 395 400
Lys Met Glu Ile Leu Tyr Ile Leu Val Pro Ser Val Ala Ile Pro Leu
405 410 415
Ala Ile Ala Leu Leu Phe Phe Phe Ile Cys Val Cys Arg Asn Asn Gln
420 425 430
Lys Ser Ser Ser Ala Pro Val Gln Arg Gln Pro Lys His Val Arg Gly
435 440 445
Gln Asn Val Glu Met Ser Met Leu Asn Ala Tyr Lys Pro Lys Ser Lys
450 455 460
Ala Lys Glu Leu Pro Leu Ser Ala Val Arg Phe Met Glu Glu Leu Gly
465 470 475 480
Glu Cys Ala Phe Gly Lys Ile Tyr Lys Gly His Leu Tyr Leu Pro Gly
485 490 495
Met Asp His Ala Gln Leu Val Ala Ile Lys Thr Leu Lys Asp Tyr Asn
500 505 510
Asn Pro Gln Gln Trp Thr Glu Phe Gln Gln Glu Ala Ser Leu Met Ala
515 520 525
Glu Leu His His Pro Asn Ile Val Cys Leu Leu Gly Ala Val Thr Gln
530 535 540
Glu Gln Pro Val Cys Met Leu Phe Glu Tyr Ile Asn Gln Gly Asp Leu
545 550 555 560
His Glu Phe Leu Ile Met Arg Ser Pro His Ser Asp Val Gly Cys Ser
565 570 575
Ser Asp Glu Asp Gly Thr Val Lys Ser Ser Leu Asp His Gly Asp Phe
580 585 590
Leu His Ile Ala Ile Gln Ile Ala Ala Gly Met Glu Tyr Leu Ser Ser
595 600 605
His Phe Phe Val His Lys Asp Leu Ala Ala Arg Asn Ile Leu Ile Gly
610 615 620
Glu Gln Leu His Val Lys Ile Ser Asp Leu Gly Leu Ser Arg Glu Ile
625 630 635 640
Tyr Ser Ala Asp Tyr Tyr Arg Val Gln Ser Lys Ser Leu Leu Pro Ile
645 650 655
Arg Trp Met Pro Pro Glu Ala Ile Met Tyr Gly Lys Phe Ser Ser Asp
660 665 670
Ser Asp Ile Trp Ser Phe Gly Val Val Leu Trp Glu Ile Phe Ser Phe
675 680 685
Gly Leu Gln Pro Tyr Tyr Gly Phe Ser Asn Gln Glu Val Ile Glu Met
690 695 700
Val Arg Lys Arg Gln Leu Leu Pro Cys Ser Glu Asp Cys Pro Pro Arg
705 710 715 720
Met Tyr Ser Leu Met Thr Glu Cys Trp Asn Glu Ile Pro Ser Arg Arg
725 730 735
Pro Arg Phe Lys Asp Ile His Val Arg Leu Arg Ser Trp Glu Gly Leu
740 745 750
Ser Ser His Thr Ser Ser Thr Thr Pro Ser Gly Gly Asn Ala Thr Thr
755 760 765
Gln Thr Thr Ser Leu Ser Ala Ser Pro Val Ser Asn Leu Ser Asn Pro
770 775 780
Arg Tyr Pro Asn Tyr Met Phe Pro Ser Gln Gly Ile Thr Pro Gln Gly
785 790 795 800
Gln Ile Ala Gly Phe Ile Gly Pro Pro Ile Pro Gln Asn Gln Arg Phe
805 810 815
Ile Pro Ile Asn Gly Tyr Pro Ile Pro Pro Gly Tyr Ala Ala Phe Pro
820 825 830
Ala Ala His Tyr Gln Pro Thr Gly Pro Pro Arg Val Ile Gln His Cys
835 840 845
Pro Pro Pro Lys Ser Arg Ser Pro Ser Ser Ala Ser Gly Ser Thr Ser
850 855 860
Thr Gly His Val Thr Ser Leu Pro Ser Ser Gly Ser Asn Gln Glu Ala
865 870 875 880
Asn Ile Pro Leu Leu Pro His Met Ser Ile Pro Asn His Pro Gly Gly
885 890 895
Met Gly Ile Thr Val Phe Gly Asn Lys Ser Gln Lys Pro Tyr Lys Ile
900 905 910
Asp Ser Lys Gln Ala Ser Leu Leu Gly Asp Ala Asn Ile His Gly His
915 920 925
Thr Glu Ser Met Ile Ser Ala Glu Leu
930 935
<210> 12
<211> 168
<212> PRT
<213> 智人(Homo sapiens)
<400> 12
Met Gly His His His His His His His His His His Ser Ser Gly His
1 5 10 15
Ile Glu Gly Arg His Met Arg Arg Val Pro Gly Val Ala Pro Thr Leu
20 25 30
Val Arg Ser Ala Ser Glu Thr Ser Glu Lys Arg Pro Phe Met Cys Ala
35 40 45
Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met
50 55 60
His Ser Arg Lys His Thr Gly Glu Lys Pro Tyr Gln Cys Asp Phe Lys
65 70 75 80
Asp Cys Glu Arg Arg Phe Phe Arg Ser Asp Gln Leu Lys Arg His Gln
85 90 95
Arg Arg His Thr Gly Val Lys Pro Phe Gln Cys Lys Thr Cys Gln Arg
100 105 110
Lys Phe Ser Arg Ser Asp His Leu Lys Thr His Thr Arg Thr His Thr
115 120 125
Gly Glu Lys Pro Phe Ser Cys Arg Trp Pro Ser Cys Gln Lys Lys Phe
130 135 140
Ala Arg Ser Asp Glu Leu Val Arg His His Asn Met His Gln Arg Asn
145 150 155 160
Met Thr Lys Leu Gln Leu Ala Leu
165
<210> 13
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 13
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 14
<211> 327
<212> PRT
<213> 智人(Homo sapiens)
<400> 14
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
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Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
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Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
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Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 15
<211> 229
<212> PRT
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<223> 铰链-CH2-CH3
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Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
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Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
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Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 16
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 铰链-CH3
<400> 16
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gln Pro Arg
1 5 10 15
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
20 25 30
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
35 40 45
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
50 55 60
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
65 70 75 80
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
85 90 95
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
100 105 110
Leu Ser Leu Ser Leu Gly Lys
115
<210> 17
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 铰链
<400> 17
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 18
<211> 28
<212> PRT
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<400> 18
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
1 5 10 15
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 19
<211> 41
<212> PRT
<213> 智人(Homo sapiens)
<400> 19
Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 20
<211> 42
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Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
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Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 21
<211> 112
<212> PRT
<213> 智人(Homo sapiens)
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Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
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Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
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Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
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Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
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Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
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Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
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<210> 22
<211> 24
<212> PRT
<213> 智人(Homo sapiens)
<400> 22
Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp
1 5 10 15
Val Glu Glu Asn Pro Gly Pro Arg
20
<210> 23
<211> 357
<212> PRT
<213> 智人(Homo sapiens)
<400> 23
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly
20 25 30
Glu Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe
35 40 45
Lys Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala
50 55 60
Phe Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu
65 70 75 80
Leu Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile
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Gln Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu
100 105 110
Glu Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala
115 120 125
Val Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu
130 135 140
Ile Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr
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Ala Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys
165 170 175
Thr Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly
180 185 190
Gln Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu
195 200 205
Pro Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys
210 215 220
Val Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu
225 230 235 240
Asn Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met
245 250 255
Asn Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala
260 265 270
His Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val
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Met Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His
290 295 300
Val Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro
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Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala
325 330 335
Thr Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly
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Ile Gly Leu Phe Met
355
<210> 24
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 链霉素标记II
<400> 24
Trp Ser His Pro Gln Phe Glu Lys
1 5
<210> 25
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Myc标记
<400> 25
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
<210> 26
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> V5标记
<400> 26
Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr
1 5 10
<210> 27
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FLAG标记
<400> 27
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
Claims (205)
1.一种淋巴细胞支架,其包括(i)遗传重编程的淋巴细胞,其设置在包括薄膜镍钛诺(TFN)微网格的支架基质内,(ii)淋巴细胞粘附部分,其包括纤维蛋白,和(iii)淋巴细胞激活部分,其包括对CD137具特异性的抗体。
2.如权利要求1所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞包括T细胞,并且所述淋巴细胞激活部分包括对CD3、CD28和CD137具特异性的抗体。
3.如权利要求1所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞包括天然杀伤(NK)细胞,并且所述淋巴细胞激活部分包括白细胞介素15和对CD137具特异性的抗体。
4.如权利要求1所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞包括T细胞和NK细胞,并且所述淋巴细胞激活部分包括对CD137具特异性的抗体。
5.如权利要求1所述的淋巴细胞支架,其还包括STING激动剂。
6.如权利要求5所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
7.如权利要求6所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP。
8.一种淋巴细胞支架,其包括(i)遗传重编程的淋巴细胞,其设置在包括微图案化金属薄膜的支架基质内,和(ii)淋巴细胞激活部分。
9.如权利要求8所述的淋巴细胞支架,其还包括STING激动剂。
10.如权利要求9所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
11.如权利要求10所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP。
12.如权利要求11所述的淋巴细胞支架,其还包括药物洗脱聚合物。
13.如权利要求12所述的淋巴细胞支架,其中所述STING激动剂包埋在所述药物洗脱聚合物内。
14.如权利要求12所述的淋巴细胞支架,其中所述药物洗脱聚合物包括PLGA。
15.如权利要求8所述的淋巴细胞支架,其中所述淋巴细胞是T细胞和/或天然杀伤细胞。
16.如权利要求8所述的淋巴细胞支架,其中所述淋巴细胞是CD8+T细胞。
17.如权利要求8所述的淋巴细胞支架,其包括至少2x106个淋巴细胞。
18.如权利要求8所述的淋巴细胞支架,其包括至少7x106个淋巴细胞。
19.如权利要求8所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括IL-15、或对CD3、CD28或CD137具特异性的抗体中的至少一种。
20.如权利要求8所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括对CD3、CD128和CD137具特异性的抗体。
21.如权利要求8所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括IL-15和CD137。
22.如权利要求8所述的淋巴细胞支架,其还包括免疫刺激剂。
23.如权利要求22所述的淋巴细胞支架,其中所述免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
24.如权利要求22所述的淋巴细胞支架,其中所述免疫刺激剂选自(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
25.如权利要求22所述的淋巴细胞支架,其中所述免疫刺激剂包埋在药物洗脱聚合物内。
26.如权利要求8所述的淋巴细胞支架,其还包括淋巴细胞粘附部分。
27.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分和所述淋巴细胞激活部分共价连接。
28.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括纤维蛋白。
29.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
30.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括GFOGER(SEQID NO:1)肽。
31.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
32.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括ICAM-1肽。
33.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
34.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
35.如权利要求26所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
36.如权利要求9所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到所述支架基质。
37.如权利要求9所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分包埋在所述支架基质内。
38.如权利要求9所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分在覆盖所述支架基质表面的至少一部分的生物活性涂层内。
39.如权利要求38所述的淋巴细胞支架,其中所述生物活性涂层包括药物洗脱聚合物。
40.如权利要求39所述的淋巴细胞支架,其还包括淋巴细胞粘附部分,其中:所述STING激动剂在所述药物洗脱聚合物内,所述药物洗脱聚合物在所述支架基质的表面上形成单层,并且所述淋巴细胞粘附部分直接涂覆所述药物洗脱聚合物。
41.如权利要求9所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到颗粒。
42.如权利要求41所述的淋巴细胞支架,其中所述颗粒连接到所述支架和/或包埋在所述支架基质内。
43.如权利要求9所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分与原始细胞的脂质体结合。
44.如权利要求43所述的淋巴细胞支架,其中所述支架基质内的所述原始细胞与所述淋巴细胞的比率为0.5∶1;1∶1;5∶1;或10∶1。
45.如权利要求43所述的淋巴细胞支架,其中所述淋巴细胞支架包括7x106至1x1010个原始细胞。
46.如权利要求8所述的淋巴细胞支架,其中所述微图案化金属薄膜包括TFN微网格。
47.一种淋巴细胞支架,其由支架基质、遗传重编程的淋巴细胞和三个淋巴细胞激活部分组成。
48.如权利要求47所述的淋巴细胞支架,其中所述支架基质是藻酸盐支架、胶原蛋白/藻酸盐支架、壳聚糖支架、自组装肽支架、中孔二氧化硅支架、微图案化金属薄膜支架或PLGA支架。
49.如权利要求48所述的淋巴细胞支架,其中所述微图案化金属薄膜支架是TFN微网格支架。
50.如权利要求47所述的淋巴细胞支架,其中所述支架基质是藻酸盐支架。
51.如权利要求47所述的淋巴细胞支架,其中所述支架基质是聚合的钙交联的藻酸盐支架。
52.如权利要求47所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是遗传重编程的T细胞和/或天然杀伤细胞。
53.如权利要求47所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是CD8+T细胞。
54.如权利要求47所述的淋巴细胞支架,其包括至少2x106个遗传重编程的淋巴细胞。
55.如权利要求47所述的淋巴细胞支架,其包括至少7x106个遗传重编程的淋巴细胞。
56.如权利要求47所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括对CD3、CD28和CD137具特异性的抗体。
57.如权利要求47所述的淋巴细胞支架,其中所述淋巴细胞激活部分连接到所述支架。
58.如权利要求47所述的淋巴细胞支架,其中所述淋巴细胞激活部分包埋在所述支架内。
59.一种淋巴细胞支架,其包括:支架基质、遗传重编程的淋巴细胞和淋巴细胞激活部分。
60.如权利要求59所述的淋巴细胞支架,其还包括STING激动剂。
61.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
62.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP。
63.如权利要求59所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是遗传重编程的T细胞和/或天然杀伤细胞。
64.如权利要求59所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是CD8+T细胞。
65.如权利要求59所述的淋巴细胞支架,其包括至少7x106个遗传重编程的淋巴细胞。
66.如权利要求59所述的淋巴细胞支架,其中所述淋巴细胞激活部分包括对CD3、CD28和/或CD137具特异性的抗体。
67.如权利要求59所述的淋巴细胞支架,其还包括免疫刺激剂。
68.如权利要求67所述的淋巴细胞支架,其中所述免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
69.如权利要求67所述的淋巴细胞支架,其中所述免疫刺激剂选自(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
70.如权利要求59所述的淋巴细胞支架,其还包括淋巴细胞粘附部分。
71.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括纤维蛋白。
72.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
73.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括GFOGER(SEQID NO:1)肽。
74.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
75.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括ICAM-1肽。
76.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
77.如任何权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
78.如权利要求70所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
79.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到所述支架基质。
80.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分包埋在所述支架基质内。
81.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分在覆盖所述支架基质表面的至少一部分的生物活性涂层内。
82.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到颗粒。
83.如权利要求82所述的淋巴细胞支架,其中所述颗粒连接到所述支架基质连接和/或包埋在所述支架基质内。
84.如权利要求60所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分与原始细胞的脂质体结合。
85.如权利要求84所述的淋巴细胞支架,其中所述支架基质内的所述原始细胞与所述淋巴细胞的比率为0.5∶1;1∶1;5∶1;或10∶1。
86.如权利要求59所述的淋巴细胞支架,其中所述淋巴细胞支架包括7x106至1x1010个原始细胞。
87.如权利要求59所述的淋巴细胞支架,其中所述支架基质是藻酸盐支架、胶原蛋白/藻酸盐支架、壳聚糖支架、自组装肽支架、中孔二氧化硅支架、微图案化金属薄膜支架或PLGA支架。
88.如权利要求87所述的淋巴细胞支架,其中所述微图案化金属薄膜支架是TFN微网格支架。
89.如权利要求59所述的淋巴细胞支架,其中所述支架基质是藻酸盐支架。
90.如权利要求59所述的淋巴细胞支架,其中所述支架基质是聚合的钙交联的藻酸盐支架。
91.一种淋巴细胞支架,其包括:
(i)支架基质,其包括藻酸盐支架;
(ii)遗传重编程的淋巴细胞;
(iii)淋巴细胞粘附部分,其包括GFOGER(SEQ ID NO:1)肽;
(iv)淋巴细胞激活部分,其包括对CD3、CD28和CD137具特异性的抗体;以及
(v)STING激动剂。
92.如权利要求91所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
93.如权利要求92所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP。
94.如权利要求91所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是遗传重编程的T细胞和/或天然杀伤细胞。
95.如权利要求91所述的淋巴细胞支架,其中所述遗传重编程的淋巴细胞是CD8+T细胞。
96.如权利要求91所述的淋巴细胞支架,其包括至少7x106个遗传重编程的淋巴细胞。
97.如权利要求91所述的淋巴细胞支架,其还包括免疫刺激剂。
98.如权利要求97所述的淋巴细胞支架,其中所述免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
99.如权利要求97所述的淋巴细胞支架,其中所述免疫刺激剂选自(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
100.如权利要求91所述的淋巴细胞支架,其中所述GFOGER(SEQ ID NO:1)肽包括SEQID NO:1或SEQ ID NO:2的肽。
101.如权利要求91所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到所述支架基质。
102.如权利要求91所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分包埋在所述支架基质内。
103.如权利要求91所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分在覆盖所述支架基质表面的至少一部分的生物活性涂层内。
104.如权利要求91所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分连接到颗粒。
105.如权利要求104所述的淋巴细胞支架,其中所述颗粒连接到所述支架基质和/或包埋在所述支架基质内。
106.如权利要求91所述的淋巴细胞支架,其中所述STING激动剂和/或所述淋巴细胞激活部分与原始细胞的脂质体结合。
107.如权利要求106所述的淋巴细胞支架,其中所述支架基质内的所述原始细胞与所述淋巴细胞的比率为0.5∶1;1∶1;5∶1;或10∶1。
108.如权利要求91所述的淋巴细胞支架,其中所述淋巴细胞支架包括7x106至1x1010个原始细胞。
109.如权利要求91所述的淋巴细胞支架,其中所述藻酸盐支架是聚合的钙交联的藻酸盐支架。
110.一种淋巴细胞支架,其包括:(i)支架基质材料,(ii)具有抗癌活性的天然杀伤细胞,和(iii)淋巴细胞激活部分,其包括IL-15和对CD137具特异性的抗体。
111.如权利要求110所述的淋巴细胞支架,其中所述支架基质材料包括微图案化金属薄膜。
112.如权利要求111所述的淋巴细胞支架,其中所述微图案化金属薄膜包括TFN微网格。
113.如权利要求110所述的淋巴细胞支架,其还包括STING激动剂。
114.如权利要求112所述的淋巴细胞支架,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
115.如权利要求113所述的淋巴细胞支架,其还包括药物洗脱聚合物。
116.如权利要求115所述的淋巴细胞支架,其中所述药物洗脱聚合物包括PLGA。
117.如权利要求115所述的淋巴细胞支架,其中所述STING激动剂包埋在药物洗脱聚合物内。
118.如权利要求110所述的淋巴细胞支架,其还包括淋巴细胞粘附部分。
119.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括纤维蛋白。
120.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
121.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括GFOGER(SEQ ID NO:1)肽。
122.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ IDNO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
123.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括ICAM-1肽。
124.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ IDNO:3的ICAM-1肽。
125.如任何权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
126.如权利要求118所述的淋巴细胞支架,其中所述淋巴细胞粘附部分包括SEQ IDNO:4的FNIII7-10肽。
127.一种治疗受试者中包括逃避变体肿瘤细胞的异质实体瘤的方法,其包括将如权利要求59所述的淋巴细胞支架在足以导致破坏所述受试者中的所述异质实体瘤的所述异质实体瘤细胞附近植入所述受试者中,从而治疗包括逃避变体肿瘤细胞的所述异质实体瘤。
128.一种对受试者接种疫苗以防止癌症复发的发展的方法,其包括将如权利要求59所述的淋巴细胞支架在异质实体瘤附近或在所述受试者中的实体瘤切除床内植入所述受试者中,从而对所述受试者接种疫苗以防止癌症复发的发展。
129.一种治疗有需要的受试者中的肿瘤细胞的方法,其包括将如权利要求59所述的淋巴细胞支架在肿瘤切除床内植入所述受试者中,从而治疗所述受试者中的所述肿瘤细胞。
130.如权利要求127所述的方法,其中所治疗的肿瘤细胞是肾上腺癌细胞、脑癌细胞、乳腺癌细胞、宫颈癌细胞、结肠癌细胞、结肠直肠癌细胞、耳、鼻和咽喉(ENT)癌细胞、子宫内膜癌细胞、食道癌细胞、胃肠癌细胞、神经胶质瘤细胞、头颈癌细胞、肠癌细胞、肾癌细胞、肝癌细胞、肺癌细胞、淋巴结癌细胞、黑素瘤细胞、神经母细胞瘤细胞、卵巢癌细胞、胰腺癌细胞、前列腺癌细胞、直肠癌细胞、精原细胞瘤细胞、皮肤癌细胞、胃癌细胞、畸胎瘤细胞、甲状腺癌细胞或子宫癌细胞。
131.如权利要求127所述的方法,其中所治疗的肿瘤细胞是胶质母细胞瘤细胞、胰腺癌细胞或卵巢癌细胞。
132.一种减少原发性肿瘤切除后转移性复发引起的手术治疗失败的方法,其包括将如权利要求59所述的淋巴细胞支架施用于受试者的肿瘤切除床,从而减少原发性肿瘤切除后转移性复发引起的手术治疗失败。
133.如权利要求132所述的方法,其中所述原发性肿瘤包括精原细胞瘤细胞、黑素瘤细胞、畸胎瘤细胞、神经母细胞瘤细胞、神经胶质瘤细胞、直肠癌细胞、子宫内膜癌细胞、肾癌细胞、肾上腺癌细胞、甲状腺癌细胞、皮肤癌细胞、脑癌细胞、宫颈癌细胞、肠癌细胞、肝癌细胞、结肠癌细胞、胃癌细胞、头颈癌细胞、胃肠癌细胞、淋巴结癌细胞、食道癌细胞、结肠直肠癌细胞、胰腺癌细胞、耳、鼻和咽喉(ENT)癌细胞、乳腺癌细胞、前列腺癌细胞、子宫癌细胞、卵巢癌细胞或肺癌细胞。
134.一种治疗癌症受试者的方法,其包括将涂覆有包括TFN微网格、遗传修饰的淋巴细胞和淋巴细胞激活部分的淋巴细胞支架的医疗装置植入所述受试者中。
135.如权利要求134所述的方法,其中所述植入包括微创手术。
136.如权利要求134所述的方法,其中所述医疗装置包括支架。
137.一种形成淋巴细胞支架以治疗受试者中的实体瘤的试剂盒,其包括(i)支架基质;和(ii)淋巴细胞激活部分,其包括对CD3、CD28和CD137具特异性的抗体。
138.如权利要求137所述的试剂盒,其还包括多孔颗粒。
139.如权利要求137所述的试剂盒,其还包括脂质体。
140.如权利要求137所述的试剂盒,其还包括原始细胞。
141.如权利要求137所述的试剂盒,其还包括STING激动剂。
142.如权利要求141所述的试剂盒,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
143.如权利要求141所述的试剂盒,其中所述STING激动剂包括c-diGMP。
144.如权利要求137所述的试剂盒,其还包括免疫刺激剂。
145.如权利要求144所述的试剂盒,其中所述免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
146.如权利要求144所述的试剂盒,其中所述免疫刺激剂选自(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
147.如权利要求137所述的试剂盒,其还包括淋巴细胞粘附部分。
148.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括纤维蛋白。
149.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括结合α1β1整联蛋白、α2β1整联蛋白、α4β1整联蛋白、α5β1整联蛋白或淋巴细胞功能相关抗原(LFA-1)的肽。
150.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括GFOGER(SEQ IDNO:1)肽。
151.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括SEQ ID NO:1或SEQ ID NO:2的GFOGER(SEQ ID NO:1)肽。
152.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括ICAM-1肽。
153.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括SEQ ID NO:3的ICAM-1肽。
154.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括FNIII7-10肽。
155.如权利要求147所述的试剂盒,其中所述淋巴细胞粘附部分包括SEQ ID NO:4的FNIII7-10肽。
156.如权利要求137所述的试剂盒,其中所述试剂盒包括7x106至1x1010个颗粒、脂质体或原始细胞。
157.如权利要求137所述的试剂盒,其还包括遗传重编程的淋巴细胞。
158.如权利要求157所述的试剂盒,其中所述遗传重编程的淋巴细胞是T细胞和/或天然杀伤细胞。
159.如权利要求157所述的试剂盒,其中所述遗传重编程的淋巴细胞是CD8+T细胞。
160.如权利要求157所述的试剂盒,其中所述淋巴细胞包括至少7x106个淋巴细胞。
161.如权利要求137所述的试剂盒,其中所述支架基质包括藻酸盐、胶原蛋白、壳聚糖、自组装肽、中孔二氧化硅、TFN微网格或PLGA。
162.如权利要求161所述的试剂盒,其中所述支架基质包括藻酸盐。
163.如权利要求137所述的试剂盒,其还包括钙。
164.如权利要求137所述的试剂盒,其还包括药物洗脱聚合物。
165.如权利要求164所述的试剂盒,其中所述药物洗脱聚合物涂覆在所述支架基质上。
166.如权利要求164所述的试剂盒,其中STING激动剂或免疫刺激剂包埋在所述药物洗脱聚合物内。
167.如权利要求164所述的试剂盒,其中所述药物洗脱聚合物包括PLGA。
168.一种形成淋巴细胞支架的试剂盒,其包括:(i)支架基质,其包括TFN微网格;(ii)淋巴细胞粘附部分,其包括纤维蛋白;以及(iii)淋巴细胞激活部分,其包括对CD3、CD28和CD137具特异性的抗体。
169.如权利要求168所述的试剂盒,其还包括用于遗传重编程淋巴细胞的载体。
170.如权利要求168所述的试剂盒,其中所述纤维蛋白和所述淋巴细胞激活部分共价连接。
171.如权利要求168所述的试剂盒,其还包括遗传重编程的淋巴细胞。
172.如权利要求171所述的试剂盒,其中所述遗传重编程的淋巴细胞是T细胞和/或天然杀伤细胞。
173.如权利要求171所述的试剂盒,其中所述遗传重编程的淋巴细胞是CD8+T细胞。
174.如权利要求171所述的试剂盒,其中所述淋巴细胞包括至少7x106个淋巴细胞。
175.如权利要求168所述的试剂盒,其还包括STING激动剂和/或免疫刺激剂。
176.如权利要求175所述的试剂盒,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
177.如权利要求175所述的试剂盒,其中所述STING激动剂包括c-diGMP。
178.如权利要求175所述的试剂盒,其中所述免疫刺激剂包括细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
179.如权利要求175所述的试剂盒,其还包括药物洗脱聚合物,其中所述STING激动剂和/或所述免疫刺激剂包埋在所述药物洗脱聚合物内。
180.一种形成淋巴细胞支架的试剂盒,其包括:(i)支架基质,其包括藻酸盐支架,(ii)淋巴细胞粘附部分,其包括GFOGER(SEQ ID NO:1)肽,(iii)淋巴细胞激活部分,其包括对CD3、CD28和CD137具特异性的抗体,和(iv)STING激动剂。
181.如权利要求180所述的试剂盒,其还包括多孔颗粒。
182.如权利要求180所述的试剂盒,其还包括脂质体。
183.如权利要求180所述的试剂盒,其还包括原始细胞。
184.如权利要求180所述的试剂盒,其中所述STING激动剂包括c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2和/或DMXAA。
185.如权利要求180所述的试剂盒,其中所述STING激动剂包括c-diGMP。
186.如权利要求180所述的试剂盒,其还包括免疫刺激剂。
187.如权利要求186所述的试剂盒,其中所述免疫刺激剂是细胞因子、抗体、小分子、siRNA、质粒DNA和/或疫苗佐剂。
188.如权利要求186所述的试剂盒,其中所述免疫刺激剂选自(i)选自CpG、Cpg-28、聚(I:C)、α-半乳糖神经酰胺、MPLA、VTX-2337、EMD1201081)咪喹莫特、MGN1703、G100、CBLB502、Hiltonol和咪喹莫特的Toll样受体配体,和/或(ii)17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素)。
189.如权利要求180所述的试剂盒,其中所述试剂盒包括7x106至1x1010个颗粒、脂质体或原始细胞。
190.如权利要求180所述的试剂盒,其还包括用于遗传重编程的淋巴细胞的载体。
191.如权利要求180所述的试剂盒,其还包括遗传重编程的淋巴细胞。
192.如权利要求191所述的试剂盒,其中所述遗传重编程的淋巴细胞是T细胞和/或天然杀伤细胞。
193.如权利要求191所述的试剂盒,其中所述遗传重编程的淋巴细胞是CD8+T细胞。
194.如权利要求191所述的试剂盒,其中所述淋巴细胞包括至少7x106个淋巴细胞。
195.如权利要求180所述的试剂盒,其还包括钙。
196.一种可植入医疗装置,其包括:(i)微图案化金属薄膜支架,(ii)遗传重编程的淋巴细胞,和(iii)淋巴细胞激活部分。
197.如权利要求196所述的可植入医疗装置,其还包括STING激动剂和/或免疫刺激剂。
198.如权利要求196所述的可植入医疗装置,其还包括药物洗脱聚合物,其中所述STING激动剂和/或所述免疫刺激剂包埋在所述药物洗脱聚合物内。
199.如权利要求196所述的可植入医疗装置,其中所述微图案化金属薄膜支架具有三维形状。
200.如权利要求199所述的可植入医疗装置,其中所述三维形状是圆柱形。
201.如权利要求196所述的可植入医疗装置,其包括支架。
202.如权利要求1967所述的可植入医疗装置,其包括微创医疗装置。
203.如权利要求196所述的可植入医疗装置,其中所述微图案化金属薄膜支架堆叠成层。
204.如权利要求196所述的可植入医疗装置,其中所述微图案化金属薄膜包括TFN微网格。
205.如权利要求196所述的可植入医疗装置,其中所述遗传重编程的淋巴细胞的浓度为至少7X106个细胞/cm3。
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WO2014110591A1 (en) | 2013-01-14 | 2014-07-17 | Fred Hutchinson Cancer Research Center | Compositions and methods for delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse |
JP7311514B2 (ja) * | 2017-08-30 | 2023-07-19 | ベイジン シュエンイー ファーマサイエンシズ カンパニー, リミテッド | インターフェロン遺伝子刺激因子調節薬としての環状ジヌクレオチド |
JP2022531899A (ja) | 2019-05-09 | 2022-07-12 | アリゴス セラピューティクス インコーポレイテッド | Stingモジュレータとしての修飾環状ジヌクレオシド化合物 |
CN113456810A (zh) * | 2020-03-30 | 2021-10-01 | 杭州星鳌生物科技有限公司 | 一种新型抗新冠病毒治疗性疫苗及其制备方法和应用 |
WO2021231350A1 (en) * | 2020-05-13 | 2021-11-18 | Massachusetts Institute Of Technology | Compositions of polymeric microdevices and their use in cancer immunotherapy |
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