CN115531609A - 重塑造血巢以重建免疫 - Google Patents
重塑造血巢以重建免疫 Download PDFInfo
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Abstract
本发明涉及重塑造血巢以重建免疫。具体地,本发明公开了使用支架材料(例如多孔海藻酸盐水凝胶支架)重塑骨髓基质的组合物和相关方法,所述支架材料含有一种或多种细胞分化因子和一种或多种生长因子。这些方法和组合物促进可以改善移植细胞植入的异位结节或位点的形成,并选择性地驱动造血干细胞移植后淋巴细胞的发育和适应性免疫的重建。
Description
本申请是国际申请日2017年2月6日、国际申请号PCT/US2017/016729于2018年8月3日进入中国国家阶段、申请号201780009851.4、发明名称“重塑造血巢以重建免疫”的申请的分案申请。
相关申请
本申请要求2016年2月6日提交的美国临时申请序列号62/292,288的权益,该美国临时申请的全部教导通过引用并入本文。
政府资助
本发明是以国立卫生研究院(National Institutes of Health)颁发的许可号NIH HL129903、NIH EB015498和NIH EB014703以及国家科学基金会(National ScienceFoundation)颁发的NSF 1000099416在政府支持下完成的。政府拥有本发明的某些权利。
背景技术
接受造血干细胞移植(HSCT)的患者的长期免疫缺陷仍然是控制威胁生命的血液或骨髓疾病如多发性骨髓瘤和白血病的最严重障碍之一。在移植之前,受体经历调理性细胞毒性放射和化疗方案来破坏患病细胞。所述调理方法的副作用是由于适应性免疫***的T细胞和B细胞破坏导致的严重淋巴细胞减少。特征是T细胞和B细胞数量急剧减少和其多样性减少的严重移植后免疫缺陷可持续一至两年。免疫缺陷相关的严重机会性感染(约30%)、癌症复发(急性骨髓性白血病>50%)和移植物抗宿主病(GVHD)(约40%)是接受HSCT的患者最常见的并发症以及发病和死亡的原因。
需要可用于改善HSCT后免疫***的重建的新组合物和方法。还需要能够降低与HSCT相关的风险并改善患者结果的组合物和方法。
发明内容
本文公开可用于例如在干细胞移植后帮助重建受试者的免疫***的新组合物和相关方法。可以将这些组合物施用于受试者来增加移植的干细胞和祖细胞的植入,从而帮助重建受试者的免疫***。
在某些实施方式中,本文公开的组合物包含一种或多种支架材料(例如多孔可植入支架材料),所述材料可以施用于受试者或以其它方式植入受试者中(例如皮下植入受试者的淋巴中或周围的一个或多个位点)。这些组合物还可以包含一种或多种生长因子、一种或多种归巢因子和一种或多种分化因子。
在某些方面,所述支架材料是或包含水凝胶(例如冷冻凝胶)。在某些实施方式中,所述支架材料是骨诱导性的。在某些实施方式中,所述支架材料包含海藻酸盐(例如阴离子海藻酸盐)。在一些实施方式中,所述支架材料选自:聚乳酸、聚乙醇酸、PLGA聚合物、海藻酸盐和海藻酸盐衍生物、聚己内酯、基于磷酸钙的材料、明胶、胶原、纤维蛋白、透明质酸、富含层粘连蛋白的凝胶、琼脂糖、天然和合成多糖、聚氨基酸、多肽、聚酯、聚酐、聚磷嗪(polyphosphazine)、聚(乙烯醇)、聚(环氧烷)、聚(烯丙胺)(PAM)、聚(丙烯酸酯)、改性苯乙烯聚合物、普卢兰尼克多元醇(pluronic polyol)、泊洛沙姆(polyoxamer)、聚(糖醛酸)、聚(乙烯基吡咯烷酮)以及其任何组合或共聚物。
本文公开的组合物和支架材料可用作传递一种或多种生长因子(例如在体内传递一种或多种生长因子)的载体或媒剂。在施用或植入所述组合物后,这种组合物中含有的一种或多种生长因子促进所施用的支架材料上或周围的组织(例如骨组织)的形成,从而形成结节。在某些方面,一种或多种生长因子包含骨形态发生蛋白(BMP)(例如BMP-2)。例如一种或多种生长因子可以选自:BMP-2、BMP-4、BMP-6、BMP-7、BMP-12、BMP-14、TGF-β、IGF-1、FGF-2和PDGF。在一些实施方式中,可以将一种或多种生长因子包封在支架材料中(例如被包封并且在约7-14天内从支架材料释放)。在一些实施方式中,这样的一种或多种生长因子(例如BMP-2)在延长的时间段(例如约7-30天或更长,约17-18天)内从支架材料释放。
本文公开的组合物和支架材料还可以用作一种或多种分化因子的载体或媒剂。在某些方面,考虑的分化因子诱导或促进干细胞或祖细胞(例如移植的HSC)向一种或多种所需细胞类型分化。例如可以将一种或多种分化因子并入本文公开的组合物中,以促进移植的干细胞或祖细胞向淋巴谱系细胞分化。在一些实施方式中,一种或多种分化因子结合于Notch受体(例如一种或多种分化因子可以结合于选自Notch-1、Notch-2、Notch-3和Notch-4的Notch受体)。在某些方面,一种或多种分化因子选自δ样1、δ样3、δ样4、Jagged1和Jagged2。
在一些实施方式中,一种或多种分化因子包含细胞因子(例如选自白细胞介素-7(IL-7)和白细胞介素-15(IL-15)的细胞因子)。在一些实施方式中,可以将一种或多种细胞因子包封在支架材料中。在某些方面,一种或多种细胞因子在延长的时间段(例如约7-30天或更长,约17-18天)内从支架材料释放。
在某些实施方式中,一种或多种分化因子共价结合于支架材料。例如分化因子可以共价结合于海藻酸盐主链并保留在受试者中植入所述组合物后形成的结节中而不是从海藻酸盐支架材料释放。通过将分化因子共价结合或偶联于支架材料,这种分化因子将保留在向受试者施用组合物后形成的结节内,因此可用于促进移植的干细胞或祖细胞的分化,如本文所预期。在某些实施方式中,使用N-羟基丁二酰亚胺(NHS)和1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)化学法使一种或多种分化因子与支架材料结合。可以使用本领域已知的任何共价结合或偶联分化因子的方法,并且不受限制。参见“生物缀合技术(Bioconjugate Techniques Bioconjugate Techniques)(Third Addition)”,GregT.Hermanson,Academic,Greg T.Hermanson,Academic Press,2013Press,2013。
在某些实施方式中,本文公开的组合物和支架材料包含一种或多种归巢因子。在某些方面,在本文公开的组合物中包括这些归巢因子促进移植的干细胞和/或祖细胞(例如HSC)归巢到植入的组合物或结节中。在某些方面,这些归巢因子促进移植的干细胞或祖细胞(例如HSC)向植入的组合物或结节浸润。在一些实施方式中,一种或多种归巢因子包含干细胞分化因子(SDF-1)。在某些实施方式中,将一种或多种归巢因子包封在所述材料中。在某些实施方式中,一种或多种归巢因子在延长的时间段(例如约7-30天或更长,约17-18天)内从所述材料释放。
在一些实施方式中,将约0.01nmol至1000nmol、约0.1nmol至100nmol或1nmol至约10nmol的一种或多种生长因子、一种或多种归巢因子和一种或多种分化因子与支架材料结合。
在一些实施方式中,本发明涉及帮助或支持重建有需要的受试者的免疫***的方法,这些方法包含向受试者施用包含支架材料的组合物的步骤,所述组合物包含:一种或多种生长因子,其促进在施用的支架材料上或周围形成组织以形成结节;一种或多种归巢因子,其促进移植的干细胞或祖细胞向结节浸润;和一种或多种分化因子,其促进移植的干细胞或祖细胞向淋巴谱系细胞分化,从而帮助或支持重建受试者的免疫***。在一些实施方式中,受试者已经经历细胞毒性放射和/或化疗以治疗血液病症。
在某些实施方式中,本文公开的发明涉及在有需要的受试者中形成异位造血干细胞巢(stem cell niche)的方法,这些方法包含向受试者施用包含支架材料的组合物的步骤,所述组合物包含:一种或多种生长因子,其促进在施用的支架材料上或周围形成组织以形成结节;一种或多种归巢因子,其促进移植的造血干细胞向结节浸润;和一种或多种分化因子,其促进移植的干细胞或祖细胞向一种或多种淋巴或骨髓谱系细胞分化,从而在受试者中形成异位造血干细胞巢。
在其它实施方式中,本发明涉及改善移植的造血干细胞在有需要的受试者的干细胞巢中的植入的方法,所述方法包含向受试者施用包含支架材料的组合物,所述组合物包含:一种或多种生长因子,其促进在施用的支架材料上或周围形成组织以形成结节;一种或多种归巢因子,其促进移植的造血干细胞向结节浸润;和一种或多种分化因子,其促进移植的干细胞或祖细胞向一种或多种淋巴或骨髓谱系细胞(例如CD4+、CD8+和Mac-1+/GR-1+淋巴或骨髓谱系细胞中的一种或多种)分化,从而改善移植的造血干细胞在受试者的干细胞巢中的植入。
在某些实施方式中,本文公开的发明涉及在有需要的受试者中增加移植的干细胞和祖细胞的植入位点(例如增加一个或多个位点的数量或体积)的方法,这些方法包含向受试者施用包含支架材料的组合物,这些组合物包含:一种或多种生长因子,其促进在施用的支架材料上或周围形成组织以形成结节;一种或多种归巢因子,其促进移植的干细胞和祖细胞向结节浸润;和一种或多种分化因子,其促进移植的干细胞或祖细胞向一种或多种淋巴或骨髓谱系细胞(例如CD4+、CD8+和Mac-1+/GR-1+淋巴或骨髓谱系细胞中的一种或多种)分化,从而在受试者中增加移植的干细胞和祖细胞的植入位点。
在某些方面,根据本发明方法使用的考虑的支架材料包含水凝胶材料(例如冷冻凝胶材料)。在一些实施方式中,支架材料包含海藻酸盐(例如包含阴离子海藻酸盐的支架材料)。在一些实施方式中,支架材料是骨诱导性的。在某些实施方式中,支架材料选自:聚乳酸、聚乙醇酸、PLGA聚合物、海藻酸盐和海藻酸盐衍生物、聚己内酯、基于磷酸钙的材料、明胶、胶原、纤维蛋白、透明质酸、富含层粘连蛋白的凝胶、琼脂糖、天然和合成多糖、聚氨基酸、多肽、聚酯、聚酐、聚磷嗪、聚(乙烯醇)、聚(环氧烷)、聚(烯丙胺)(PAM)、聚(丙烯酸酯)、改性苯乙烯聚合物、普卢兰尼克多元醇、泊洛沙姆、聚(糖醛酸)、聚(乙烯基吡咯烷酮)以及其任何组合或共聚物。
本文公开的组合物和方法通常涵盖向受试者施用组合物的步骤。在某些方面,这样的施用步骤包含将组合物植入受试者中(例如组合物可以被皮下植入)。例如在一些实施方式中,可以在干细胞移植之前(例如在干细胞移植前约5天、7天、10天、14天、18天、21天、24天、28天、30天、35天、42天或更长时间)在***中或周围的一个或多个位点处向受试者皮下施用本文公开的组合物。
根据任何前述方法使用的组合物可以包含一种或多种生长因子。例如这些生长因子(例如BMP-2)可以被支架材料包封,并促进在施用的组合物中或周围形成结节(例如骨结节)。在某些方面,一种或多种生长因子包含骨形态发生蛋白(BMP)。在一些实施方式中,一种或多种生长因子选自BMP-2、BMP-4、BMP-6、BMP-7、BMP-12和BMP-14。在某些方面,将一种或多种生长因子包封在材料中。在某些方面,一种或多种生长因子在延长的时间段(例如约7-30天或更长)内从材料释放。
根据任何前述方法使用的组合物还可以包含一种或多种分化因子。这些分化因子可用于促进体内移植的干细胞和祖细胞(例如移植的HSC)的分化。例如在一些方面,一种或多种分化因子促进体内移植的干细胞和祖细胞(例如移植的HSC)的淋巴细胞增殖(lymphopoiesis)。
在某些方面,一种或多种分化因子包含结合于Notch受体的组合物。在某些方面,Notch受体选自Notch-1、Notch-2、Notch-3和Notch-4。在一些实施方式中,一种或多种分化因子选自δ样1、δ样3、δ样4、Jagged1和Jagged2。
在一些实施方式中,一种或多种分化因子包含细胞因子。例如一种或多种分化因子可以选自由IL7和IL-15组成的细胞因子的组。
在一些实施方式中,将一种或多种分化因子(例如细胞因子)包封在材料中。在一些实施方式中,一种或多种分化因子(例如细胞因子)在约7-30天内从材料释放。或者,在一些实施方式中,一种或多种分化因子共价结合于所述材料。
根据任何前述方法使用的组合物还可以包含一种或多种归巢因子。在一些实施方式中,一种或多种归巢因子包含干细胞分化因子(SDF-1)。在某些实施方式中,将一种或多种归巢因子包封在材料中。在一些实施方式中,一种或多种归巢因子在约7-30天内从材料释放。
本文公开的组合物和方法适用于在受试者(例如有需要的受试者)中施用或植入。例如这些组合物和方法可用于治疗已经经历干细胞移植的受试者和/或免疫受损的受试者。
本发明的上述以及许多其它特征和伴随的优点将通过参考本发明的以下详细描述而变得更好地理解。
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图1描绘了本发明的一种实施方式的一般总体方法。如图1中所描绘,形成骨结节的可注射蛋白质-聚合物水凝胶在体内募集移植的造血干细胞(HSC)。募集的细胞HSC获得存在于水凝胶中的分化因子来驱动其向淋巴细胞的分化。
图2A-2E描绘根据本发明形成的异位骨结节。图2A说明了包封在水凝胶内的生长因子(BMP-2)的释放,而图2B(上)以图解方式说明包封在水凝胶内并且在约一至两周内释放的生长因子(BMP-2)的释放,图2B(中)显示在约一至两周内BMP-2和分化因子δ样4(DLL-4)两者从水凝胶的释放,并且图2B(下)显示在约一至两周内从水凝胶释放的BMP-2和分化因子白细胞介素-7(IL-7)的累积量。图2C描绘了皮下骨结节(红色箭头)。图2D描绘了骨结节的三维微计算机断层扫描图像。图2E描绘了切除的骨结节的番红-O染色的组织学切片,其展示了骨海藻酸盐和骨髓。
图3A和3B描绘根据本发明的水凝胶介导的淋巴细胞增殖。图3A展示在骨结节形成水凝胶存在的情况下,体外培养的分离的LKS细胞在固定的系拴DLL-4存在下展示出分化(n=9,***P<0.001,**P<0.01,ns=不显著)。图3B说明在体内,异位骨结节加快亚致死照射的小鼠中T细胞(CD3+)和B细胞(B220+)的重建。骨髓细胞(Mac-1+Gr-1+)群的重建动力学没有变化。
图4A和4B描绘造血干细胞移植(HSCT)后的表征免疫重建。如图4A所示,使用T细胞和B细胞贫化的移植物的情况下,含有BMP-2/DLL-4的水凝胶显著加快了HSCT后T细胞和B细胞的恢复。图4B描绘了HSCT后2周免疫库的分析结果,并且指示在具有BMP-2/DLL-4水凝胶的CD3+T细胞中发生了较大的VJ重组事件。
图5显示用于包括白血病和骨髓瘤的血液病症的常规HBSC治疗。上排显示患有血液病症的患者接受放射治疗来根除宿主血细胞,接着用血液干细胞移植物重建血液和免疫***。下排显示来自血液病症患者的血液样本;正常和照射的骨髓;以及血液干细胞移植数周内骨髓细胞的再增殖和移植后数月至数年T细胞和B细胞的再增殖。
图6说明了一种示意图,其中将HSC和本文所述的具有DLL-4的水凝胶植入小鼠中以加快免疫重建。
图7显示如本文所述的水凝胶的组分。上排显示DLL4-PEG2k-MA和BMP-2。中间一排说明使用EDC/NHS化学法和甲基丙烯酸2-氨基乙酯(AEMA)进行的海藻酸盐和PEG的甲基化。下排说明通过冷聚合(cryo-polymerization)形成如本文所述的大孔冷冻凝胶。
图8A显示了体外培养和分析血液干细胞的示意图。图8B说明了用COOH官能化的程度和T细胞、B细胞、骨髓细胞、CLP和CMP的相对细胞丰度。
图9显示体外不同的CLP/T细胞动力学是DLL-4依赖性的。左侧图提供了与具有BMP-2和DLL-4的水凝胶接触的细胞的数据。右侧图提供了与具有BMP-2的水凝胶接触的细胞的数据。
图10显示使用GFP+细胞在照射的小鼠中进行细胞移植的示意图。
图11显示BMP-2释放增加了冷冻凝胶中的移植细胞数。
图12显示BMP-2和DLL-4增加了冷冻凝胶中的CLP细胞数。
图13A显示BMP-2诱导异位骨髓结节。图13B是通过本文公开的方法生长的异位骨髓结节的图片。图13C是通过本文公开的方法生长的皮下组织中的骨结节的照片。
图14显示照射后0-60天如下小鼠中的T细胞、B细胞和骨髓细胞的数量:仅具有移植物的小鼠(左图)、具有移植物加上含BMP-2的水凝胶的小鼠(中图)以及具有移植物加上含BMP-2和DLL-4的水凝胶的小鼠(右图)。
图15说明TCRβ中CDR 1-3的测序可以提供细胞多样性的快照。
图16显示未照射、仅使用移植物、使用移植物加上具有BMP-2的水凝胶以及使用移植物加上具有BMP-2和DLL-4的水凝胶的情况下的TCR库分析。
图17A显示了用于测量胸腺输出的sjTREC分析的示意图。图17B显示未照射、仅使用移植物、使用移植物加上具有BMP-2的水凝胶以及使用移植物加上具有BMP-2和DLL-4的水凝胶的情况下的每毫克胸腺的sjTREC。
图18A显示免疫重建1个月后亚致死病毒注射攻击的示意图。图18B显示未照射、仅使用移植物、使用移植物加上具有BMP-2的水凝胶以及使用移植物加上具有BMP-2和DLL-4的水凝胶的小鼠的病毒攻击后存活率。
具体实施方式
造血干细胞移植(HSCT)后的一个基本挑战涉及产生新的免疫反应,同时避免可能导致自身免疫疾病的过度旺盛的反应。在干细胞水平,免疫***来自造血干细胞(HSC),造血干细胞存在于骨髓巢中并且包含细胞和周围基质。骨髓除了通过支持淋巴发育而作为主要的淋巴器官的作用之外,还充当各种成熟淋巴细胞类型的宿主。骨髓影响HSC的再生能力和分化成免疫细胞的能力,并为新T细胞和B细胞提供祖细胞群。
造血干细胞移植(HSCT)调理过程损害骨髓巢和其支持供体细胞植入的能力,从而直接影响免疫***的重建。因此,免疫调节小分子、治疗性蛋白质和输注纯化的供体T细胞有时用于暂时增加移植受体的免疫细胞绝对数;然而,这些方法依赖于克隆扩增和供体细胞的活化,并且不能恢复T细胞和B细胞库的多样性。
与内源性骨髓相比,本发明通常涉及参与异位骨髓巢或结节产生的组合物和方法,所述异位骨髓巢或结节在将本文公开的组合物施用于或植入受试者(例如有需要的哺乳动物受试者)后形成。例如在某些方面,本发明涉及包含多孔可植入支架材料和一种或多种分化因子的组合物,所述分化因子具体化淋巴细胞增殖并促进移植的HSC向淋巴谱系细胞(CLP)分化,从而帮助重建受试者的免疫***。因此,能够产生针对适当抗原的免疫反应的原初免疫细胞(immune cell)的内源性生成提供广泛的长期免疫。
本文公开的组合物包含一种或多种支架材料(例如多孔可植入支架材料),所述支架材料可以施用于受试者或以其它方式植入受试者中。例如在某些实施方式中,本文公开的组合物包含一种或多种生长因子,所述生长因子可以被载入支架材料中或被支架材料包封,并且在将这种组合物施用于受试者(例如免疫受损的受试者)之后,所述组合物促进在施用的支架材料上或周围形成组织(例如骨组织)以形成作为异位骨髓巢的结节。因此,在某些方面,本文公开的支架材料为一种或多种生长因子、分化因子、归巢因子、细胞因子、趋化因子和任何其它试剂提供递送媒剂。
在某些实施方式中,支架材料包含聚合物(例如三维聚合物***)。在某些实施方式中,支架材料是骨诱导性的。在某些方面,支架材料是或包含海藻酸盐(例如阴离子海藻酸盐)。在一些实施方式中,支架材料为水凝胶形式。
在一些实施方式中,支架材料为冷冻凝胶形式。冷冻凝胶是一类具有高度多孔互连结构的材料,其使用冷冻凝胶化(cryotropic gelation/cryogelation)技术产生。冷冻凝胶化是一种在准冷冻反应溶液中进行聚合-交联反应的技术。在大分子(例如MA-海藻酸盐)溶液冷冻期间,大分子单体和引发剂***(例如APS/TEMED)从冰晶之间的通道内的冰浓缩物中排出,使得反应仅在这些未冷冻的液体通道中发生。在聚合之后并且在冰融化之后,产生多孔材料,其微观结构是形成的冰的负像复制品。冰晶用作成孔剂(porogen)。通过改变冷冻凝胶化过程的温度来调节孔径。例如冷冻凝胶化过程通常通过在-20℃下快速冷冻溶液来进行。将温度降至例如-80℃将产生更多的冰晶并产生更小的孔。在一些实施方式中,通过至少甲基丙烯酸化(MA)-海藻酸盐和MA-PEG的冷聚合来制备冷冻凝胶。在一些实施方式中,通过至少MA-海藻酸盐、分化因子和MA-PEG的冷聚合来制备冷冻凝胶。在一些实施方式中,分化因子还包含系链(例如PEG、PEG2k)和MA基团。在一些实施方式中,分化因子是DLL4-PEG2k-MA。在一些实施方式中,冷聚合在待包封于冷冻凝胶中的试剂存在下进行。在一些实施方式中,所述试剂是一种或多种生长因子、分化因子、归巢因子、细胞因子和趋化因子。在一些实施方式中,所述试剂是BMP(例如BMP-2)。
冷冻凝胶可以包含至少75%的孔,例如80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%或更多的孔。所述孔是互连的。孔的互连性允许水(和其它组合物,如细胞和化合物)进入和离开结构。在完全水合状态下,组合物包含至少90%水(例如90-99%、至少92%、95%、97%、99%或更多)水。例如冷冻凝胶体积的至少90%(例如至少92%、95%、97%、99%或更多)由孔中含有的液体(例如水)构成。在压缩或脱水的水凝胶中,所述水的高达50%、60%、70%不存在,例如冷冻凝胶包含少于25%(20%、15%、10%、5%或更少)的水。
本发明的冷冻凝胶可以包含足够大的孔以使细胞穿过。例如冷冻凝胶含有直径为20-500μm(例如20-300μm、30-150μm、50-500μm、50-450μm、100-400μm、200-500μm)的孔。在一些情况下,水合孔径为1-500μm(例如10-400μm、20-300μm、50-250μm)。
在一些实施方式中,通过添加选自以下各项的官能团进一步官能化冷冻凝胶:氨基、乙烯基、醛、硫醇、硅烷、羧基、叠氮化物、炔烃。或者,通过添加另一种交联剂(例如多臂聚合物、盐、醛等)进一步官能化冷冻凝胶。溶剂可以是水性的,并且特别是酸性或碱性的。水性溶剂可以包含与水混溶的溶剂(例如甲醇、乙醇、DMF、DMSO、丙酮、二噁烷等)。在一些实施方式中,在冷冻凝胶化之前,将一种或多种官能团添加到冷冻凝胶的组分(例如海藻酸盐、PEG)中。冷冻交联在模具中进行,并且可注射的冷冻凝胶可以是可降解的。孔径可以通过选择使用的主要溶剂、并入成孔剂、所应用的冷冻温度和速率、交联条件(例如聚合物浓度)以及所用聚合物的类型和分子量来控制。
在一些实施方式中,本文公开的支架材料和组合物在其施用于或植入受试者之前未接种或以其它方式装载细胞。或者,在其它实施方式中,本文公开的支架材料和组合物在其施用于或植入受试者之前已经接种或以其它方式装载细胞(例如HSC)。在其它实施方式中,支架材料选自:聚乳酸、聚乙醇酸、PLGA聚合物、海藻酸盐和海藻酸盐衍生物、聚己内酯、基于磷酸钙的材料、明胶、胶原、纤维蛋白、透明质酸、富含层粘连蛋白的凝胶、琼脂糖、天然和合成多糖、聚氨基酸、多肽、聚酯、聚酐、聚磷嗪、聚(乙烯醇)、聚(环氧烷)、聚(烯丙胺)(PAM)、聚(丙烯酸酯)、改性苯乙烯聚合物、普卢兰尼克多元醇、泊洛沙姆、聚(糖醛酸)、聚(乙烯基吡咯烷酮)以及其任何组合或共聚物。其它示例性支架材料、组合物以及其使用和制备方法描述于美国专利公开号2008/0044900、2013/0331343、2015/0366956、2014/0112990、2014/0227327和2015/0359928中,所述专利通过全文引用的方式并入本文中。
本文公开的支架材料可以进一步修饰,例如包括化合物或赋形剂来使这些支架材料具有骨诱导性(例如磷酸钙)。类似地,化合物或赋形剂可以包括在支架材料中来影响其机械特性。例如为了调节支架材料的机械特性,聚合物如硬聚己内酯(PCL)和软聚乙二醇(PEG)可以与海藻酸盐组合使用。
支架材料可以用于控制例如施用或植入支架材料或组合物后一种或多种生长因子、分化因子和/或归巢因子的体内呈递或释放。例如可以使用EDC/NHS化学法,使用海藻酸盐骨架上的羧酸基团使DLL-4与支架材料结合。一种或多种生长因子、分化因子和/或归巢因子的这种呈递或释放可以通过将这些分子包封或偶联(例如共价结合或偶联)在支架材料中或上(例如将分子与海藻酸盐骨架偶联)来实现。通过微调用于偶联这些分子的化学反应以及通过选择或改变支架材料的物理和化学特性,可以精确地控制这些分子的空间和时间呈递。因此,这些支架材料尤其可用于控制一种或多种分子(例如生长因子)的体内递送和/或呈递,所述分子可以包封在支架材料中或与其偶联。因此,基于一种或多种生长因子、分化因子和/或归巢因子的选择,可以优化这些分子从支架材料中的释放来实现并精确控制体内移植的干细胞和祖细胞的行为(例如增殖、迁移和/或分化)。
在某些方面,施用或植入本文公开的组合物后,这种组合物中含有的一种或多种生长因子促进所施用的组合物上或周围的组织(例如骨组织)的形成,从而形成用作异位骨髓巢的结节。如本文所用,术语“生长因子”通常是指引起或以其它方式促进细胞增殖的任何生物活性剂、多肽、激素、细胞因子、趋化因子或化合物,并且在某些方面包括成骨生长因子及其类似物。示例性生长因子包括骨形态发生蛋白,如BMP-2、BMP-4、BMP-6、BMP-7、BMP-12和BMP-14。可以将一种或多种生长因子包封在支架材料中并且在延长的时间段内(例如在约7-14天内)从支架材料释放。可以将一种或多种生长因子包封在支架材料中并且在约1-50、5-25、10-20或17-18天内从支架材料释放。在一些实施方式中,这一种或多种生长因子(例如BMP-2)在足够的时间段内释放,以允许在植入的组合物上或周围形成组织(例如骨组织)而形成结节。
本文公开的组合物还包含一种或多种分化因子。如本文所用,术语“分化因子”泛指任何促进细胞分化的分子。例如促进干细胞或祖细胞分化成一种或多种淋巴谱系细胞的任何分化因子。在某些方面,分化因子促进移植的细胞(例如HSC)迁移至一个或多个二级位点,如胸腺和/或***,然后这些细胞在所述位点成熟。例如移植的干细胞可以归巢到或以其它方式渗入结节,在结节中这些细胞接触分化因子(例如Notch配体,如DLL-2和/或DLL-4),接着进一步迁移至胸腺,在胸腺中其将成熟为T细胞。在某些方面,分化因子促进移植细胞在结节内的分化和成熟。例如移植的干细胞可以归巢到或以其它方式渗入结节,在结节中这些细胞接触分化因子(例如IL-7或IL-15),然后在结节内分化成成熟的B细胞。
在某些方面,本文公开的分化因子可以根据需要进行修饰,以例如优化本文公开的组合物的性能。在一些实施方式中,可以使用DLL-1或DLL-4的Notch结合肽片段(约2kDa)代替完整蛋白质(约70kDa)以允许海藻酸盐支架材料的更大功能化。在一些实施方式中,为了进一步提高支架材料的效果,可以并入血管生成血管内皮生长因子(VEGF)和/或趋化性SDF-1。
在一些实施方式中,本文公开的组合物还包含一种或多种“归巢因子”,该术语通常是指促进移植的干细胞迁移或归巢到在施用或植入本文公开的组合物后形成的结节的任何组合物。干细胞移植很可能是因为造血干细胞在输注入受试者后具有从血流“归巢”到骨髓的先天能力。通过将一种或多种归巢因子并入、包封或系拴到包含本文公开的组合物的支架材料中,增强了移植的干细胞(例如HSC)向结节的归巢。例如本文公开的方法和组合物可用于提高(例如增加)输注的HSC从移植期间输注这些HSC的组织(例如血液)归巢到由结节形成的异位骨髓巢的能力。如本文所用,术语“归巢”是指移植的干细胞(例如HSC或祖细胞)从输注其的第一特定组织或区域(例如血液)迁移、移动或以其它方式集中到需要其的第二组织或区域(例如受试者中植入组合物后形成的结节)。内源性干细胞巢内的各种因子调节HSC向骨髓干细胞巢的归巢,并且一种或多种这些因子可以并入到本文公开的组合物中。促进HSC在内源性骨髓内保留和归巢的一种这样的因子是干细胞分化因子(SDF-1)。因此,在某些方面,本文公开的组合物包含SDF-1,SDF-1促进移植的干细胞归巢到结节,以及随后这些细胞在由这种结节形成的异位骨髓巢中的植入。
本文公开的方法和组合物可用于干细胞移植(例如HSC移植)。如本文所用,术语“造血干细胞”或“HSC”是指可以分化成造血谱系并产生所有血球类型如白血球和红血球的干细胞,所述造血谱系包括骨髓谱系(例如单核细胞和巨噬细胞、嗜中性粒细胞、嗜碱性粒细胞、嗜酸性粒细胞、红细胞、巨核细胞/血小板、树突细胞)和淋巴谱系(例如T细胞、B细胞、NK细胞)。干细胞由其形成多种细胞类型的能力(多能性)和其自我更新的能力来定义。造血干细胞可以例如通过细胞表面标志物如CD34-、CD133+、CD48-、CD150+、CD244-、cKit+、Sca1+和缺乏谱系标志物(尤其B220、CD3、CD4、CD8、Mac1、Gr1和Ter119阴性)来鉴定。
如本文所用,术语“祖细胞”涵盖多能细胞,其定向于造血细胞谱系,通常不自我更新,并且能够分化成造血***的数种细胞类型,如粒细胞、单核细胞、红细胞、巨核细胞、B细胞和T细胞,所述祖细胞包括但不限于短期造血干细胞(ST-HSC)、多能祖细胞(MPP)、常见骨髓祖细胞(CMP)、粒细胞-单核细胞祖细胞(GMP)、巨核细胞-红细胞祖细胞(MEP)和定向淋巴祖细胞(CLP)。造血祖细胞的存在可以在完全甲基纤维素分析中作为集落形成单位细胞(CFU-C)进行功能测定,或使用本领域技术人员已知的分析通过检测细胞表面标志物(例如CD45-、CD34+、Ter119-、CD16/32、CD127、cKit、Sca1)来进行表型确定。
本文公开的方法的某些方面包含向有需要的受试者施用或以其它方式移植干细胞,使得施用的干细胞植入在向受体受试者施用本文公开的组合物后形成的结节(例如骨结节)的异位骨髓巢中。如本文所用,“植入”干细胞包括造血干细胞是指将干细胞例如通过注射置于动物中,其中干细胞在体内持续存在。这可以通过干细胞的能力容易地测量,所述能力例如促进正在进行的免疫细胞和/或血细胞形成的能力。成功的干细胞移植取决于在受试者的组织中植入足够量的移植干细胞的能力,因此本文公开的组合物和方法增加了这些移植干细胞可以植入的位点和组织的数量或体积。
如本文所用,术语“施用”通常是指通过使移植的干细胞迁移或归巢到结节的异位骨髓巢的方法或途径将本文所述的组合物置于受试者中(例如将这些组合物肠胃外放置或植入受试者中)。在某些方面,例如在进行干细胞移植之前,将本文公开的组合物施用或植入受试者的多个位点中。在某些实施方式中,在受试者淋巴***附近的位点(例如接近受试者的颈部、腹股沟和腋下中的一个或多个)施用本文公开的组合物。在某些方面,重建受试者的免疫***后,将本文公开的结节去除(例如通过手术切除)。
在某些实施方式中,本文公开的组合物和方法可用于治疗任何需要移植造血干细胞和/或祖细胞的病症、疾病、病状或并发症。这些病症的实例包括血液恶性病和非恶性血液病。本文公开的组合物和方法也可用于重建T细胞和B细胞,因此可以广泛地应用于涉及免疫缺陷的其它疾病,如年龄相关的疫苗失败、自身免疫病症(例如类风湿性关节炎和糖尿病)、传染性疾病等。
如本文所用,术语“受试者”指任何人或动物。在某些方面,动物是脊椎动物,如灵长类动物、啮齿动物、家养动物或狩猎动物(game animal)。灵长类动物包括黑猩猩、食蟹猴、蜘蛛猴和猕猴,例如恒河猴(Rhesus)。啮齿动物包括小鼠、大鼠、土拨鼠、雪貂、兔子和仓鼠。家养和狩猎动物包括牛、马、猪、鹿、野牛、水牛、猫科物种如家猫、犬科物种如狗、狐狸、狼、鸟类物种如鸡、鸸鹋、鸵鸟和鱼如鳟鱼、鲶鱼和鲑鱼。患者或受试者包括前述类别的任何子集,例如上述所有类别但不包括一个或多个组或物种如人、灵长类动物或啮齿动物,在某些实施方式中,受试者是哺乳动物(例如灵长类动物或人)。在一些实施方式中,哺乳动物是人、非人灵长类动物、小鼠、大鼠、狗、猫、马或牛,并且不限于这些实例。可以有利地使用人以外的哺乳动物例如作为代表例如血液恶性病的动物模型的受试者。另外,本文所述的方法可用于治疗驯养动物和/或宠物。受试者可以是雄性或雌性的。
在某些实施方式中,受试者可以是先前已被诊断为或以其它方式被鉴定为罹患或患有病状、疾病或干细胞病症者。“需要”治疗特定病状(例如干细胞病症)的“受试者”可以是患有该病状、诊断为患有该病状或相对于给定参考群体产生该病状的风险增加的受试者。在一些实施方式中,本文所述的治疗方法包含选择被诊断患有、怀疑患有或具有产生血液恶性病或免疫受损的风险的受试者。在一些实施方式中,本文所述的方法包含选择诊断患有、怀疑患有或具有产生非恶性病如本文所述的非恶性病的风险的受试者。
在一些实施方式中,本文公开的方法加快了从内源性祖细胞HSC重建受试者免疫***。在一些实施方式中,本文公开的方法使从内源性祖细胞HSC进行的重建加快约1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、3或4个数量级或更多。在一些实施方式中,本文公开的方法使从内源性祖细胞HSC进行的重建加快超过2个数量级。
在一些实施方式中,本文公开的方法加快了从移植的祖细胞HSC重建受试者免疫***。在一些实施方式中,本文公开的方法使从移植的祖细胞HSC进行的重建加快约1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、3或4个数量级或更多。在一些实施方式中,本文公开的方法使从移植的祖细胞HSC进行的重建加快超过2个数量级。
应理解,本发明的应用并不限于说明书中阐述或示例的细节。本发明涵盖其它实施方式并且能够以各种方式实践或进行。此外,应理解,本文采用的措辞和术语是为了描述的目的,并且不应该被认为是限制性的。
虽然已经根据某些实施方式具体描述了本发明的某些试剂、化合物、组合物和方法,但以下实施例仅用于说明本发明的方法和组合物,并不意图限制本发明。
除非明确相反地指示,否则本说明书和权利要求书中使用的量词“一”应理解为包括多个指示物。除非上下文相反地指示或明显相反,否则如果组成员中的一个、多于一个或所有在给定产品或过程中存在、用于给定产品或过程中或以其它方式与给定产品或过程相关,则认为满足在组中一个或多个成员之间包括“或”的权利要求或描述。本发明包括如下实施方式,其中该组的恰好一个成员在给定产品或过程中存在、用于给定产品或过程中或以其它方式与给定产品或过程相关。本发明还包括如下实施方式,其中超过一个组成员或全部组成员在给定产品或过程中存在、用于给定产品或过程中或以其它方式与给定产品或过程相关。此外,应理解,除非另外指示或除非对于本领域普通技术人员显然会出现矛盾或不一致,否则本发明涵盖所有变化、组合和变换,其中一个或多个所列权利要求中的一个或多个限制、要素、条款、描述性术语等被引入另一个依附于同一个基础权利要求的权利要求(或相关的任何其它权利要求)中。在将要素以清单形式(例如以马库什组或类似格式)呈现的情况下,应理解,还公开了要素的每个子组,并且可以从组中去除任何要素。应理解,通常,在本发明或本发明的方面被称为包含特定要素、特征等的情况下,本发明的某些实施方式或本发明的方面由这些要素、特征等组成或基本上由其组成。出于简化的目的,在本文中,在每一种情况下,这些实施方式都不会以如此多的词语具体阐述。还应理解,无论是否在本说明书中对特定排除进行了叙述,本发明的任何实施方式或方面都可以明确地从权利要求书中排除。本文提及来描述本发明的背景并且提供有关其实践的其它细节的出版物和其它参考材料在此通过引用并入。
实施例
实施例1-诱导骨结节形成的合成材料
本发明人使用天然阴离子多糖——海藻酸盐作为水凝胶支架材料,并且海藻酸盐适合于并入阳离子性有效骨形成生长因子——骨形态发生蛋白(BMP-2)来产生骨结节,如图2A-2E所说明。优化了BMP-2生长因子装载于海藻酸盐和从海藻酸盐释放的性能(例如注射时的总量和海藻酸盐的交联密度来控制释放),目的是在小鼠体内皮下注射后1-2周内产生功能性活性骨结节。
T细胞和B细胞两者都来自特定类型的HSC祖细胞,即常见的淋巴祖细胞(CLP)。在骨髓内,Notch路径对于淋巴细胞的特化至关重要。暴露于Notch配体δ样配体1或4(DLL-1/4)的CLP通往胸腺并分化成T细胞。暴露于白细胞介素-7(IL-7)的骨髓中的CLP分化成B细胞。为了具体化归巢到异位骨髓的移植的HSC的淋巴细胞分化,本发明人评定了将Notch配体DLL-4并入异位骨髓中的效果。使用EDC/NHS化学法,使用海藻酸盐骨架上的羧酸基团结合DLL-4以引导HSC的T细胞分化。
使用Lin-c-kit+Sca-1+(LKS)细胞——推定的造血干细胞和祖细胞测试含有生长因子BMP-2和分化因子DLL-4的水凝胶的体外分化潜力。本发明人分析了向CD4+和CD8+T细胞的分化,并比较了并入DLL-4的不同策略(图3A)。观察到DLL-4的结合和系拴是生物学活性所必需的。接着,本发明人测试了亚致死照射的小鼠中表现最佳的凝胶的子集,并且如图3B中所说明,观察到与未处理组相比,T细胞和B细胞产生的速率加快。
除了上述研究之外,本发明人将得到的异位骨髓结节均质化并切片来确定细胞群。还将测量HSC趋化性的基质细胞衍生因子-1(SDF-1)的水平,并且将异位骨髓结节的血管分布和细胞构成的组织学评定与健康骨髓进行比较。本发明人将通过在一定摩尔比范围内(例如10-9至10-6)将DLL-4与海藻酸盐骨架结合来进一步优化该***。此外,为了专门驱动骨髓中的B细胞产生,本发明人将在水凝胶中并入一定剂量范围内(100-500ng)的可溶性IL-7而不是DLL-4,目的是持续释放可溶性IL-7至少1周。将使用流式细胞术在淋巴祖细胞分化、成熟并迁移通过骨髓、外周淋巴器官、血液和脾时跟踪淋巴祖细胞。
实施例2-表征HSTC后的淋巴细胞重建和免疫库
原初T细胞和B细胞分别是通过细胞介导的免疫和体液免疫对不熟悉的病原体的连续反应所必需的。检查了HSCT后来自供体细胞的原初淋巴细胞的重建。从供体小鼠收获骨髓,将T细胞和B细胞贫化(>95%)的骨髓移植到致死照射的同类受体小鼠中,并且跟踪T细胞和B细胞的重建,如图4A所说明。通过测序CD3+细胞的T细胞受体(TCR)并检查TCR基因的可变区(V)和连接区(J)的频率和分布,确定TCR的多样性,如图4B所说明。
本发明人将模拟在临床中进行的移植操作,并使用全骨髓或来自骨髓的纯化的LKS细胞进行检查。将从实施例1中描述的研究中鉴定的表现最佳的水凝胶支架材料与移植的细胞一起测试。使用流式细胞术和全血细胞计数分析造血区室中的T细胞和B细胞。另外,本发明人将使用T细胞受体切除环(TREC)分析来测量来自胸腺的原初T细胞的输出并评定原初CD3+CD4+/CD8+CD62Lhi群。类似地,本发明人将评定骨髓中原初B细胞(B220+CD40+CD84+)的重建和B细胞受体库。
实施例3具有DLL-4、SDF-1和BMP-2的大孔水凝胶
用甲基丙烯酸酯基官能化UP海藻酸钠(ProNova Biomedical)以制备甲基丙烯酸化的海藻酸盐(MA-Alg)。使用EDC-NHS偶联使1-10nmol的δ样配体4(DLL-4,R&D systems)与MA-Alg结合。通过使MA-海藻酸盐和4臂甲基丙烯酸化聚乙二醇(MA-PEG)进行低温氧化还原诱导的自由基聚合来合成可注射的大孔水凝胶,制得2.5重量%水凝胶。将骨形态发生蛋白-2(BMP-2,R&D systems)和干细胞分化因子-1(SDF-1,R&D systems)添加到混合物中,随后进行冷聚合。使用骨髓分离的Lin-c-kit+Sca-1+(LKS)细胞向CD4+和CD8+T细胞的分化来评定DLL-4的生物活性。分别使用C57BL/6小鼠中的亚致死和致死照射来模拟免疫缺陷和清髓性移植调理。在CD45.2+小鼠品系中进行移植并监测来自同类CD45.1+B6.SJL小鼠的供体产生的细胞。皮下注射水凝胶,并且分别使用微型计算机断层扫描(μCT)和组织学监测骨结节的产生和相关的造血巢环境。使用FACS分析定期监测外周血中免疫细胞的恢复。使用T细胞受体(TCR)的测序来确定T细胞库的多样性。
在MA-Alg/MA-PEG水凝胶中,DLL-4仍与支架系拴,而BMP-2和SDF-1在2.5周的时间内共同释放。在体外,水凝胶系拴的DLL-4将Lin-c-kit+Sca-1+(LKS)细胞分化成原初CD4+和CD8+细胞,并且与吸收在TCPS上的天然DLL-4相当。在体内,支架诱导小鼠中皮下骨结节的形成。注射的水凝胶的组织学分析显示具有骨髓的骨结节的形成,所述骨结节在注射后2周内充满淋巴祖细胞。在亚致死照射的小鼠中,BMP-2/DLL-4水凝胶通过募集和驱动内源性祖细胞HSC的淋巴细胞分化,在3周内使T-淋巴细胞和B-淋巴细胞的重建加快超过两个数量级。在移植的致死照射的小鼠中,水凝胶充当移植的祖细胞HSC植入的优先位点并诱导其分化成T细胞和B细胞。适应性免疫***的恢复遵循与亚致死照射的小鼠类似的趋势。水凝胶介导的T-感受态祖细胞库的扩增使移植小鼠的胸腺输出增加,并且对应于原初T细胞库的增加。TCR的测序显示频率和多样性增加,如通过水凝胶介导的T细胞库的TCR基因的可变区(V)和连接区(J)的重组所测量。
结果指示,具有生物学线索的可编程生物材料可以重塑骨髓基质的各方面。通过增加供体细胞植入的可用位点并提供淋巴细胞增殖的线索,可以加快HSCT后适应性免疫的重建,从而可以潜在地降低HSCT相关的免疫并发症并改善血液病症的治疗。
Claims (5)
1.一种组合物,其包含多孔可植入支架材料、一种或多种生长因子和一种或多种分化因子以及任选的一种或多种归巢因子。
2.一种帮助重建有需要的受试者的免疫***的方法,所述方法包含向所述受试者施用包含支架材料的组合物,所述组合物包含:
一种或多种生长因子,其促进在所施用的支架材料上或周围形成组织以形成结节;
一种或多种分化因子,其促进移植的干细胞向淋巴谱系细胞分化;和任选的
一种或多种归巢因子,其促进移植的干细胞向所述结节浸润,
从而帮助重建所述受试者的免疫***。
3.一种在有需要的受试者中形成异位造血干细胞巢的方法,所述方法包含向所述受试者施用包含支架材料的组合物,所述组合物包含:
一种或多种生长因子,其促进在所施用的支架材料上或周围形成组织以形成结节;
一种或多种分化因子,其促进移植的干细胞向一种或多种淋巴或骨髓谱系细胞分化;和任选的
一种或多种归巢因子,其促进移植的造血干细胞向所述结节浸润,
从而在所述受试者中形成异位造血干细胞巢。
4.一种改善移植的造血干细胞在有需要的受试者的干细胞巢中的植入的方法,所述方法包含向所述受试者施用包含支架材料的组合物,所述组合物包含:
一种或多种生长因子,其促进在所施用的支架材料上或周围形成组织以形成结节;
一种或多种分化因子,其促进移植的干细胞向一种或多种淋巴或骨髓谱系细胞分化;和任选的
一种或多种归巢因子,其促进移植的造血干细胞向所述结节浸润,
从而改善所述移植的造血干细胞在所述受试者的干细胞巢中的植入。
5.一种在有需要的受试者中增加移植的干细胞的植入位点的方法,所述方法包含向所述受试者施用包含支架材料的组合物,所述组合物包含:
一种或多种生长因子,其促进在所施用的支架材料上或周围形成组织以形成结节;
一种或多种分化因子,其促进移植的干细胞向一种或多种淋巴或骨髓谱系细胞分化;和任选的
一种或多种归巢因子,其促进移植的干细胞向所述结节浸润,
从而在所述受试者中增加所述移植的干细胞的植入位点。
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