CN111760025A - 用于诱导免疫耐受的具有特定药效学有效持续期之免疫抑制剂与抗原的递送 - Google Patents
用于诱导免疫耐受的具有特定药效学有效持续期之免疫抑制剂与抗原的递送 Download PDFInfo
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Abstract
本发明涉及用于诱导免疫耐受的具有特定药效学有效持续期之免疫抑制剂与抗原的递送。本发明涉及提供免疫抑制剂和在所述免疫抑制剂的药效学有效窗内施用的治疗性大分子以诱导针对所述治疗性大分子的免疫耐受的方法。所述方法允许转变免疫应答以有利于治疗性大分子特异性的致耐受性免疫应答发生。
Description
本申请是申请日为2014年5月2日、申请号为“201480032224.9”、发明名称为“用于诱导免疫耐受的具有特定药效学有效持续期之免疫抑制剂与抗原的递送”的中国专利申请的分案申请,原申请是国际申请PCT/US2014/036697的中国国家阶段申请。
相关申请
本申请依据35 U.S.C.§119要求于2013年5月3日提交的美国临时申请61/819517、于2013年9月24日提交的美国临时申请61/881851、于2013年9月24日提交的美国临时申请61/881913、于2013年9月24日提交的美国临时申请61/881921、于2013年11月21日提交的美国临时申请61/907177、于2014年3月5日提交的美国临时申请61/948313、以及于2014年3月5日提交的美国临时申请61/948384的权益,其每一个的全部内容均通过引用并入本文。
技术领域
本发明涉及方法,所述方法提供了免疫抑制剂和在免疫抑制剂的药效学有效窗(pharmacodynamically effective window)内施用的治疗性大分子以诱导针对治疗性大分子的免疫耐受。所述方法允许转变(shifting)免疫应答以有利于治疗性大分子特异性的致耐受性免疫应答发生。本文中提供的方法可用于在其中施用治疗性大分子会导致或预期会导致不期望免疫应答的对象中产生致耐受性免疫应答。
背景技术
治疗性治疗(例如蛋白质或酶替代治疗)通常导致针对具体治疗的不期望免疫应答。可通过使用免疫抑制药物来降低此类不期望免疫应答。然而,常规的免疫抑制药物作用广泛。另外,为了维持免疫抑制作用,免疫抑制药物治疗一般是终生议题。不幸的是,作用广泛的免疫抑制剂的使用与严重副作用的风险相关,所述副作用例如肿瘤、感染、肾毒性和代谢紊乱。因此,新的致耐受性治疗将是有益的。
发明内容
在一个方面,提供了一种方法,其包括以提供相对于治疗性大分子的施用药效学有效持续期(administration pharmacodynamic effective-life)的施用剂量向第一类对象中的对象施用免疫抑制剂;以及在免疫抑制剂的施用药效学有效持续期的持续时间内向对象施用治疗性大分子。在一个实施方案中,所述药效学有效持续期的持续时间为最短20小时至最长1个月。在一个实施方案中,治疗性大分子与免疫抑制剂彼此未连接。在一个实施方案中,治疗性大分子未与合成纳米载体连接。
在本文中提供的任一种方法的一个实施方案中,所述方法还包括基于免疫抑制剂的测试剂量来确定免疫抑制剂的施用剂量。在本文中提供的任一种方法的一个实施方案中,所述测试剂量具有相对于治疗性大分子的测试药效学有效持续期,其持续时间在第二类对象中为最短20小时至最长1个月。
在另一个方面,提供了本文中提供的任一种免疫抑制剂组合物以用于诱导针对治疗性大分子之耐受的方法中。在本文中提供的任一种方法的一个实施方案中,所述方法包括:(a)以足以引起药效学有效持续期的剂量向对象施用免疫抑制剂,所述药效学有效持续期的持续时间为20小时至1个月;以及(b)在所述药效学有效持续期的持续时间内向所述对象施用治疗性大分子。在本文中提供的任一种方法的一个实施方案中,治疗性大分子与免疫抑制剂彼此未连接。在本文中提供的任一种方法的一个实施方案中,治疗性大分子未与合成纳米载体连接。
在另一个方面,提供了本文中提供的任一种免疫抑制剂组合物用于制备用于本文中提供的任一种方法中的药物的用途,所述方法例如在对象中诱导针对治疗性大分子之耐受的方法。在一个实施方案中,所述方法包括(a)以足以引起药效学有效持续期的剂量向对象施用免疫抑制剂,所述药效学有效持续期的持续时间为20小时至1个月;以及(b)在所述药效学有效持续期的持续时间内向所述对象施用治疗性大分子。在本文中提供的任一种方法的一个实施方案中,治疗性大分子与免疫抑制剂彼此未连接。在本文中提供的任一种方法的另一个实施方案中,治疗性大分子未与合成纳米载体连接。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述免疫抑制剂包含合成纳米载体,所述合成纳米载体包含与合成纳米载体连接的免疫抑制剂、可植入渗透泵、双特异性抗体或可植入聚合物储库材料(implantable polymeric depotmaterial)。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述免疫抑制剂包括与合成纳米载体连接的免疫抑制剂。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述合成纳米载体包含脂质纳米颗粒、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳剂、树状聚体、巴基球(buckyball)、纳米线(nanowire)、病毒样颗粒、蛋白质颗粒或包含纳米材料之组合的纳米颗粒,任选地,其中所述纳米颗粒为脂质-聚合物纳米颗粒。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述免疫抑制剂包含他汀类(statins);mTOR抑制剂;TGF-β信号传导剂(TGF-β signaling agent);TGF-β受体激动剂;组蛋白去乙酰化酶抑制剂;皮质类固醇;线粒体功能的抑制剂;P38抑制剂;NF-κβ抑制剂、地塞米松;TCPA-1;IKK VII;腺苷受体激动剂;前列腺素E2激动剂;磷酸二酯酶抑制剂;蛋白酶体抑制剂;激酶抑制剂;G蛋白偶联受体激动剂;G蛋白偶联受体拮抗剂;糖皮质激素;类视黄醇;细胞因子抑制剂;细胞因子受体抑制剂;细胞因子受体激活剂;过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor)拮抗剂;过氧化物酶体增殖物激活受体激动剂;组蛋白去乙酰化酶抑制剂;钙调神经磷酸酶(calcineurin)抑制剂;磷酸酶抑制剂;PI3KB抑制剂;自噬抑制剂;芳基烃受体抑制剂;蛋白酶体抑制剂I(proteasome inhibitor I,PSI);氧化的ATP;1DO、维生素D3;环孢素;芳基烃受体抑制剂;白藜芦醇;硫唑嘌呤;6-巯基嘌呤;6-硫鸟嘌呤;FK506;萨菲菌素A(sanglifehrin A);沙美特罗;吗替麦考酚酯(mycophenolate mofetil);阿司匹林及其他COX抑制剂;尼氟灭酸(niflumic acid);雌三醇;或雷公藤内酯(triptolide)。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述免疫抑制剂包含mTOR抑制剂。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述mTOR抑制剂包含雷帕霉素。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,基于合成纳米载体中材料的配方总干重(total dry recipe weight),合成纳米载体中免疫抑制剂的载量(loading)为0.0001wt%至50wt%(重量/重量)。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,基于合成纳米载体中材料的配方总干重,合成纳米载体中免疫抑制剂的载量为0.1wt%至10wt%(重量/重量)。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述治疗性大分子包含治疗性蛋白质或治疗性多核苷酸。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述治疗性蛋白质包含酶、酶辅因子、激素、凝血因子、细胞因子、生长因子、单克隆抗体或多克隆抗体。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述施用药效学有效持续期的持续时间为最短20小时至最长2周。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述施用药效学有效持续期的持续时间为最短20小时至最长1周。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述施用药效学有效持续期的持续时间为最短24小时至最长2天。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述测试药效学有效持续期的持续时间为最短20小时至最长2周。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述测试药效学有效持续期的持续时间为最短20小时至最长1周。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述测试药效学有效持续期的持续时间为最短24小时至最长2天。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,基于免疫抑制剂的测试剂量并使用异速缩放(allometric scaling)或等速缩放(isometric scaling)技术来确定免疫抑制剂的施用剂量。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,第一类对象和第二类对象为同一类对象。在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,第一类对象和第二类对象为不同类对象。
在本文中提供的任一种方法、免疫抑制剂或用途的一个实施方案中,所述合成纳米载体包含脂质纳米颗粒。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述合成纳米载体包含脂质体。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述合成纳米载体包含金属纳米颗粒。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述金属纳米颗粒包含金纳米颗粒。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述合成纳米载体包含聚合物纳米颗粒。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述聚合物纳米颗粒包含聚合物,其为非甲氧基封端的普朗尼克聚合物。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述聚合物纳米颗粒包含聚酯、与聚醚连接的聚酯、聚氨基酸、聚碳酸酯、聚缩醛、聚缩酮、多糖、聚乙基唑啉或聚乙烯亚胺。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述聚酯包含聚(乳酸)、聚(乙醇酸)、聚乳酸-乙醇酸共聚物或聚己内酯。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述聚合物纳米颗粒包含聚酯和与聚醚连接的聚酯。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述聚醚包含聚乙二醇或聚丙二醇。
在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,使用合成纳米载体的动态光散射获得的颗粒大小分布的平均值为大于100nm的直径。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述直径大于150nm。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述直径大于200nm。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述直径大于250nm。在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述直径大于300nm。
在本文中提供的任一种方法、免疫抑制剂或用途的另一个实施方案中,所述合成纳米载体的纵横比(aspect ratio)大于1∶1、1∶1.2、1∶1.5、1∶2、1∶3、1∶5、1∶7或1∶10。
在另一个方面,提供了制备本文中提供的任一种免疫抑制剂和/或治疗性大分子组合物的方法。在一个实施方案中,制备方法包括产生治疗性大分子的剂量或剂型和产生免疫抑制剂的剂量或剂型。在所提供之任一种制备方法的另一个实施方案中,产生免疫抑制剂的剂量或剂型的步骤包括使免疫抑制剂与合成纳米载体连接。在所提供之任一种制备方法的另一个实施方案中,所述方法还包括将免疫抑制剂的剂量或剂型与治疗性大分子的剂量或剂型在药盒(kit)中组合。
在另一个方面,任一种所述制备方法均可用于制备用于进行本文中提供的任一种方法的药物,并且还提供了这样的制备方法。在一个实施方案中,所述制备方法用于制备用于诱导针对治疗性大分子之耐受的药物。在另一个实施方案中,所述制备方法用于制备用于施用免疫抑制剂和治疗性大分子使得在免疫抑制剂的药效学有效持续期内施用治疗性大分子的药物。在本文中提供的任一种制备方法的另一个实施方案中,免疫抑制剂未与合成纳米载体连接。
附图说明
图1示出了针对与OVA和KLH一起施用的经包封雷帕霉素的IgG应答。
图2示出了方案和多种雷帕霉素剂量的结果。
图3证明了在与雷帕霉素连接的合成纳米载体的药效学有效持续期内进行施用的效果。
图4证明了与经包封蛋白质伴随施用之与雷帕霉素连接的合成纳米载体或与GSK1059615连接的纳米载体的效果。
具体实施方式
在对本发明进行详细描述之前,应当理解,本发明不限于具体举例说明的材料或工艺参数,因为其当然可以变化。还应理解的是,本文中使用的术语仅是为了描述本发明的一些具体实施方案,并非旨在对描述本发明的替代术语的用途进行限制。
出于所有目的,本文中引用的所有出版物、专利和专利申请(无论上文或下文)均在此通过引用整体并入。
除非所述内容另有明确指出,否则本说明书及所附权利要求书中使用的没有数量词修饰的名词表示一个/种或更多个/种。例如,提及的“聚合物”包括两种或更多种此类分子的混合物或不同分子量的单一聚合物种类的混合物,提及的“合成纳米载体”包括两种或更多种此类合成纳米载体的混合物或多种这样的合成纳米载体,提及的“RNA分子”包括两种或更多种此类RNA分子的混合物或多种这样的RNA分子,提及的“免疫抑制剂”包括两种或更多种此类材料的混合物或多种这样的免疫抑制剂分子等。
本文中使用的术语“包含/包括”或其变化形式应理解为指包括引用的任何整体(例如特点、要素、特征、特性、方法/处理步骤或限制)或整体(例如特点、要素、特征、特性、方法/处理步骤或限制)的组,但不排除任何其他整体或整体的组。因此,本文中使用的术语“包含/包括”是包括性的并且不排除另外的未引用整体或方法/处理步骤。
在本文中提供任一种组合物和方法的一些实施方案中,可用“基本由...组成”或“由...组成”来替代“包含/包括”。本文中使用的短语“基本由...组成”要求指定的整体或步骤以及不显著影响所要求保护之发明的特征或功能的那些。本文中使用的术语“由...组成”仅用于指所引用的整体(例如特点、要素、特征、特性、方法/处理步骤或限制)或整体(例如特点、要素、特征、特性、方法/处理步骤或限制)的组的存在。
A.引言
作为在免疫抑制剂的药效学有效窗(或药效学有效持续期)内施用治疗性大分子的结果,本文中提供的方法可允许提高治疗效果。在一些实施方案中,通过与合成纳米载体连接的方式来施用免疫抑制剂。当向对象施用治疗性大分子时,本文中提供的方法和组合物有助于使免疫抑制剂治疗的益处最大化。
本发明人已出乎意料且令人惊讶地发现,上述问题和限制可通过实施本文中公开的发明来克服。特别地,本发明人已出乎意料地发现,可提供这样的方法,其包括以提供相对于治疗性大分子的施用药效学有效持续期的施用剂量向对象施用免疫抑制剂,所述施用药效学有效持续期的持续时间为最短20小时至最长1个月;以及在免疫抑制剂的施用药效学有效持续期的持续时间内向对象施用治疗性大分子,其中免疫抑制剂和治疗性大分子彼此未偶联,并且治疗性大分子未与合成纳米载体偶联。本文中还提供了相关组合物。
在下文中的实施例中对本发明进行举例说明,这些实施例对可用于实施本发明的多种组合物进行了举例说明并且在本发明的某些实施方案中还提供了对药效学有效持续期隐含的概念进行举例说明的数据。
现在,将在下文对本发明进行更详细的描述。
B.定义
“施用剂量”或“免疫抑制剂的施用剂量”意指适合进行施用的免疫抑制剂的剂量。在一些实施方案中,施用剂量基于免疫抑制剂的测试剂量。在一些实施方案中,可基于来自免疫抑制剂的测试剂量的信息并应用异速缩放技术来确定施用剂量。参见,例如,I.Mahmood,“Interspecies Pharmacokinetic Scaling:Principles and Application ofAllometric Scaling”,Pine House Publishers 2005。在一些实施方案中,可基于来自免疫抑制剂的测试剂量的信息并应用等速缩放技术来确定施用剂量,特别是如果第一类对象和第二类对象来自同一物种的话。在一些实施方案中,除上述使用异速缩放或等速缩放简单预测之外,还可基于测试剂量通过在第二类对象中进行直接实验来确定施用剂量。
“施用”意指以在药理学上可用的方式向对象提供物质。在一些实施方案中,“施用”包括“引起施用”。“引起施用”意指直接或间接地引起、促使、鼓励、帮助、诱导或指导另一方施用物质。
“施用药效学有效持续期”意指在免疫抑制剂的施用剂量下和在第一类对象中相对于治疗性大分子确定的免疫抑制剂的药效学有效持续期。在一些实施方案中,所述免疫抑制剂可具有相对于治疗性大分子的施用药效学有效持续期,其持续时间的范围为最短20小时至最长1个月,优选最短20小时至最长2周,优选最短20小时至最长1周,优选最短20小时至最长5天,优选最短20小时至最长3天,优选最短24小时至最长2天。优选地,在药效学有效持续期内施用治疗性大分子,因此,在一些实施方案中,可在施用免疫抑制剂的同一时间或稍后施用治疗性大分子,只要治疗性大分子的施用发生在药效学有效持续期的持续时间结束之前即可。
在用于向对象施用之组合物或剂量的情况下,“有效量”指该组合物或剂量在对象中产生一种或更多种期望应答的量,所述期望应答例如产生致耐受性免疫应答(例如,治疗性大分子特异性B细胞之增殖、活化、诱导、存活、募集的降低或者治疗性大分子特异性抗体之产生的降低)。在一些实施方案中,有效量为治疗有效量。因此,在一些实施方案中,有效量为本文中提供的组合物或剂量之产生本文中提供的一种或更多种期望免疫效应和/或治疗效果的任意量。该量可用于体外或体内目的。对于体内目的,所述量可以是临床医生认为可对需要治疗性大分子施用和/或针对它的抗原特异性免疫耐受的对象具有临床益处的量。
有效量可涉及降低不期望免疫应答的水平,但是在一些实施方案中,其涉及完全阻止不期望的免疫应答。有效量还可涉及延迟不期望免疫应答的发生。有效量还可以为产生期望治疗终点或期望治疗结果的量。在另一些实施方案中,有效量可涉及增强期望应答(例如治疗终点或结果)的水平。优选地,有效量在对象中产生针对抗原(例如治疗性大分子)的致耐受性免疫应答。可通过常规方法来监测上述任一项的实现。
在所提供之任一种方法的一些实施方案中,有效量为其中期望应答在对象中持续存在的量。在所提供之任一种组合物或方法的另一些实施方案中,有效量为在一段时间内产生可测量的期望应答的量。
当然,有效量将取决于所治疗的具体对象;病症、疾病或紊乱的严重程度;个体患者的参数,包括年龄、身体状况、身材和体重;治疗的持续时间;同时治疗(如果有的话)的性质;具体的施用途径以及在健康从业者的知识和经验范围内的类似因素。这些因素是本领域普通技术人员公知的并且可仅用常规实验就可解决。一般优选使用最大剂量,即根据合理医疗判断的最高安全剂量。然而,本领域普通技术人员将理解,患者可由于医学原因、心理原因或实际上任何其他原因而坚持使用较低剂量或可耐受剂量。
一般来说,本发明组合物中免疫抑制剂和/或治疗性大分子的剂量指免疫抑制剂和/或治疗性大分子的量。或者,可基于提供期望量的免疫抑制剂的合成纳米载体的数量来施用所述剂量。
“抗原”意指B细胞抗原或T细胞抗原。“抗原的类型”意指共有相同或基本相同的抗原性特征的分子。在一些实施方案中,抗原可以是蛋白质、多肽、肽、脂蛋白、糖脂、多核苷酸、多糖或者包含在细胞中或在细胞内表达。在一些实施方案中,例如当抗原是未经充分定义或表征时,抗原可包含在细胞或组织制备物、细胞碎片、细胞外来体、条件化培养基等中。
“抗原特异性的”指由于该抗原或其一部分的存在而产生的任何免疫应答或产生特异性地识别或结合该抗原之分子的任何免疫应答。在一些实施方案中,当抗原包含治疗性大分子时,抗原特异性的可意指治疗性大分子特异性的。例如,当免疫应答是抗原特异性抗体产生时,产生特异性地与该抗原(例如治疗性大分子)结合的抗体。作为另一个实例,当免疫应答是抗原特异性B细胞或CD4+ T细胞增殖和/或活性时,增殖和/或活性由识别单独或在与MHC分子、B细胞等的复合物中的抗原或其一部分引起。
“评估免疫应答”指对体外或体内免疫应答的水平、存在或不存在、降低、升高等的任何测量或确定。可对从对象获得的一份或更多份样品进行这样的测量或确定。这样的评估可用本文中提供的或本领域中另外已知的任何方法来进行。本文中提供的任一种方法均可包括评估免疫应答的步骤。
“连接”或“连接的”或者“偶联”或“偶联的”(等)意指使一个实体(例如一个部分)与另一个实体化学缔合。在一些实施方案中,连接是共价的,意指连接发生在两个实体之间存在共价键的情况下。在一些非共价实施方案中,非共价连接由非共价相互作用介导,所述非共价相互作用包括但不限于:电荷相互作用、亲和性相互作用、金属配位、物理吸附、主体-客体相互作用、疏水性相互作用、TT堆积相互作用、氢键合相互作用、范德华相互作用、磁性相互作用、静电相互作用、偶极-偶极相互作用和/或其组合。在一些实施方案中,包封是连接的一种形式。在一些实施方案中,治疗性大分子与免疫抑制剂彼此未连接,意指治疗性大分子和免疫抑制剂未经历特异性地意图使彼此化学缔合的过程。在一些实施方案中,治疗性大分子和/或免疫抑制剂未与合成纳米载体连接,意指治疗性大分子(和/或免疫抑制剂)和合成纳米载体未经历特异性地使彼此化学缔合的过程。
除非另有指出,否则本文中使用的“平均值”指算术平均值。
“对象的类别”意指对共有一个或更多个共同特征(例如生物分类学、饮食习惯、睡眠习惯、免疫系统生物学、某一位置中的有形存在等)的对象的分组。类别无需仅遵循标准的生物分类学。确定在某一类对象中的结果可用于预测在另一类对象中可实现的结果(例如在预测或探索人疾病中使用动物模型)。
“确定”意指确知实际关系。确定可以以多种方式实现,包括但不限于进行实验或者作出预测。例如,可如下确定免疫抑制剂或治疗性大分子的剂量:以测试剂量开始并使用已知的缩放技术(例如异速缩放或等速缩放)来确定施用剂量。这还可用于确定如本文中提供的方案。在另一个实施方案中,可通过在对象中测试多种剂量来确定所述剂量,即通过以经验和指导数据为基础进行直接实验。在一些实施方案中,“确定”包括“引起确定”。“引起确定”意指引起、促使、鼓励、帮助、诱导或指导实体确知实际关系或者与实体协同作用以使其确知实际关系;包括直接或间接地,或者明确或隐含地。
“剂型”意指在适合向对象施用的介质、载体、载剂或装置中的药理学和/或免疫学活性材料。本文中提供的任一种组合物或剂量均可以是剂型形式。
“剂量”指在给定时间内向对象施用的药理学和/或免疫学活性材料的具体量。
“包封”意指将至少一部分物质封装在合成纳米载体内。在一些实施方案中,将物质全部封装在合成纳米载体内。在另一些实施方案中,大部分或全部的经包封物质不暴露于合成载体外部的局部环境。在另一些实施方案中,不超过50%、40%、30%、20%、10%或5%(重量/重量)暴露于局部环境。包封与吸附不同,吸附将大部分或全部的物质置于合成纳米载体的表面上并使物质暴露于合成纳米载体外部的局部环境。
“产生”意指自身直接或间接地引起作用例如发生生理学或免疫学应答(例如,致耐受性免疫应答)。
“鉴定对象”为这样的任何活动或活动集合,其允许临床医生将对象识别为可受益于本文中提供的方法、组合物或药盒的对象。优选地,经鉴定的对象为本文中提供的这样的对象,其需要来自治疗性大分子的治疗益处和/或其中已发生或预期发生抗治疗性大分子特异性抗体应答(或正处于发生抗治疗性大分子特异性抗体应答的风险之中)。所述活动或活动集合可以本身直接采取或者间接采取。在本文中提供之任一种方法的一个实施方案中,所述方法还包括鉴定需要本文中提供的方法、组合物或药盒的对象。
“免疫抑制剂”意指这样的化合物,其导致APC具有免疫抑制作用(例如,致耐受性作用)或者T细胞或B细胞被抑制。免疫抑制作用一般指APC产生或表达降低、抑制或预防不期望的免疫应答或促进期望免疫应答(例如,调节性免疫应答)的细胞因子或其他因子。当APC在识别由该APC呈递之抗原的免疫细胞上获取免疫抑制功能(属于免疫抑制作用)时,认为该免疫抑制作用对所呈递的抗原具有特异性。不受任何特定理论的限制,认为:免疫抑制作用是免疫抑制剂被递送至APC的结果,优选在抗原存在下。在一个实施方案中,免疫抑制剂致使APC促进一个或更多个免疫效应细胞中的调节性表型。例如,调节性表型的特征可在于:抑制抗原特异性CD4+ T细胞或B细胞的产生、诱导、刺激或募集,抑制抗原特异性抗体的产生,Treg细胞(例如CD4+CD25高FoxP3+Treg细胞)的产生、诱导、刺激或募集等。这可以是CD4+ T细胞或B细胞转化成调节性表型的结果。这也可以是其他免疫细胞(例如CD8+ T细胞、巨噬细胞和iNKT细胞)中诱导FoxP3的结果。在一个实施方案中,免疫抑制剂在其对抗原进行加工之后影响APC的应答。在另一个实施方案中,免疫抑制剂不干涉对抗原的加工。在另一个实施方案中,免疫抑制剂不是细胞凋亡信号传导分子。在另一个实施方案中,免疫抑制剂不是磷脂。
免疫抑制剂包括但不限于:他汀类;mTOR抑制剂,例如雷帕霉素或雷帕霉素类似物;TGF-β信号传导剂;TGF-β受体激动剂;组蛋白去乙酰化酶抑制剂,例如曲古抑菌素A;皮质类固醇;线粒体功能的抑制剂,例如鱼藤酮;P38抑制剂;NF-κβ抑制剂,例如6Bio、地塞米松、TCPA-1、IKK VII;腺苷受体激动剂;前列腺素E2激动剂(prostaglandin E2 agonist,PGE2),例如米索前列醇;磷酸二酯酶抑制剂,例如磷酸二酯酶4抑制剂(phosphodiesterase4 inhibitor,PDE4),例如咯利普兰;蛋白酶体抑制剂;激酶抑制剂;G蛋白偶联受体激动剂;G蛋白偶联受体拮抗剂;糖皮质激素;类视黄醇;细胞因子抑制剂;细胞因子受体抑制剂;细胞因子受体激活剂;过氧化物酶体增殖物激活受体拮抗剂;过氧化物酶体增殖物激活受体激动剂;组蛋白去乙酰化酶抑制剂;钙调神经磷酸酶抑制剂;磷酸酶抑制剂;PI3KB抑制剂,例如TGX-221;自噬抑制剂,例如3-甲基腺嘌呤;芳基烃受体抑制剂;蛋白酶体抑制剂I(PSI);以及氧化的ATP,例如P2X受体阻断剂。免疫抑制剂还包括:IDO、维生素D3、环孢素(例如环孢素A)、芳基烃受体抑制剂、白藜芦醇、硫唑嘌呤(azathiopurine,Aza)、6-巯基嘌呤(6-mercaptopurine,6-MP)、6-硫鸟嘌呤(6-thioguanine,6-TG)、FK506、萨菲菌素A、沙美特罗、吗替麦考酚酯(mycophenolate mofetil,MMF)、阿司匹林以及其他COX抑制剂、尼氟灭酸、雌三醇、甲氨喋呤和雷公藤内酯。在一些实施方案中,免疫抑制剂可包括本文中提供的药剂中的任一种。
免疫抑制剂可以是直接提供对APC的免疫抑制作用或者其可以是间接提供免疫抑制作用的化合物(即,在施用后以某种方式进行加工)。因此,免疫抑制剂包括本文中提供的任何化合物的前药形式。
在本文中提供之任一种方法、组合物或药盒的一些实施方案中,本文中提供的免疫抑制剂与合成纳米载体连接。在一些优选实施方案中,免疫抑制剂是除构成合成纳米载体之结构的材料之外的组分。例如,在一个实施方案中,当合成纳米载体由一种或更多种聚合物构成时,免疫抑制剂为除所述一种或更多种聚合物之外并与其连接的化合物。作为另一个实例,在一个实施方案中,当合成纳米载体由一种或更多种脂质构成时,免疫抑制剂仍为除所述一种或更多种脂质之外并与其连接。在一些实施方案中,例如当合成纳米载体的材料也引起免疫抑制作用时,免疫抑制剂为除合成纳米载体的材料之外存在的引起免疫抑制作用的组分。
在本文中提供之任一种方法、组合物或药盒的一些实施方案中,免疫抑制剂是例如纳米结晶形式的形式,由此免疫抑制剂的形式本身是颗粒或颗粒样。在一些实施方案中,这样的形式模拟病毒或其他外来病原体。很多药物是已被纳米化的并且本领域普通技术人员知晓用于产生这样的药物形式的合适方法。药物纳米晶体(例如纳米结晶雷帕霉素)是本领域普通技术人员已知的(Katteboinaa,等2009,International Journal of PharmTechResesarch;第1卷,第3期;第682-694页)。本文中使用的“药物纳米晶体”指不包含载体或基质材料的药物(例如,免疫抑制剂)的形式。在一些实施方案中,药物纳米晶体包含90%、95%、98%或99%或更多药物。用于产生药物纳米晶体的方法包括但不限于:研磨、高压均质化、沉淀、喷雾干燥、超临界溶液的迅速膨胀(rapid expansion of supercriticalsolution,RESS)、技术(Baxter Healthcare)和Nanocrystal TechnologyTM(Elan Corporation)。在一些实施方案中,表面活性剂或稳定剂可用于药物纳米晶体的空间或静电稳定性。在一些实施方案中,免疫抑制剂的纳米晶体或纳米结晶形式可用于提高免疫抑制剂(特别是不溶性或不稳定的免疫抑制剂)的溶解度、稳定性和/或生物利用度。在一些实施方案中,施用纳米结晶形式的免疫抑制剂诱导针对治疗性大分子的耐受。
其他示例性的免疫抑制剂包括但不限于:小分子药物、天然产品、抗体(例如针对CD20、CD3、CD4的抗体)、基于生物制品的药物、基于碳水化合物的药物、纳米颗粒、脂质体、RNAi、反义核酸、适配体、甲氨蝶呤、NSAID;芬戈莫德;那他珠单抗;阿仑单抗;抗-CD3;他克莫司(FK506);细胞因子和生长因子,例如TGF-β和IL-10;等。在本文中提供的任一个方面或实施方案中,免疫抑制剂可与合成纳米载体连接或者以可植入渗透泵(例如可植入渗透泵)、可植入储库材料或双特异性抗体(抗CD22+Ag、抗GITR+Ag或抗LAG3+Ag)的形式递送。另一些免疫抑制剂是本领域技术人员已知的并且本发明在此方面不受限制。
当与合成纳米载体连接时,免疫抑制剂的“载量”为基于合成纳米载体中材料的配方总干重之与合成纳米载体连接的免疫抑制剂的量(重量/重量)。一般来说,将所述载量计算为整个合成纳米载体群的平均值。在一个实施方案中,基于所有合成纳米载体的平均值,免疫抑制剂的载量为0.0001wt%至99wt%。在另一个实施方案中,免疫抑制剂的载量为0.01wt%至50wt%。在另一个实施方案中,所述载量为0.1wt%至20wt%。在另一个实施方案中,免疫抑制剂的载量为0.1wt%至10wt%。在又一个实施方案中,免疫抑制剂的载量为1wt%至10wt%。在又一个实施方案中,所述载量为7wt%至20wt%。在又一个实施方案中,基于整个合成纳米载体群的平均值,免疫抑制剂的载量为至少0.1wt%、至少0.2wt%、至少0.3wt%、至少0.4wt%、至少0.5wt%、至少0.6wt%、至少0.7wt%、至少0.8wt%、至少0.9wt%、至少1wt%、至少2wt%、至少3wt%、至少4wt%、至少5wt%、至少6wt%、至少7wt%、至少8wt%、至少9wt%、至少10wt%、至少11wt%、至少12wt%、至少13wt%、至少14wt%、至少15wt%、至少16wt%、至少17wt%、至少18wt%、至少19wt%或至少20wt%、至少25wt%、至少30wt%、至少40wt%、至少50wt%、至少60wt%、至少70wt%、至少80wt%、至少90wt%、至少95wt%、至少96wt%、至少97wt%、至少98wt%或至少99wt%。在又一个实施方案中,基于整个合成纳米载体群的平均值,免疫抑制剂的载量为0.1wt%、0.2wt%、0.3wt%、0.4wt%、0.5wt%、0.6wt%、0.7wt%、0.8wt%、0.9wt%、1wt%、2wt%、3wt%、4wt%、5wt%、6wt%、7wt%、8wt%、9wt%、10wt%、11wt%、12wt%、13wt%、14wt%、15wt%、16wt%、17wt%、18wt%、19wt%或20wt%。在上述实施方案的一些实施方案中,基于整个合成纳米载体群的平均值,免疫抑制剂的载量为不超过25wt%。在一些实施方案中,可如实施例中所述或者如本领域中另外已知的计算载量。
在一些实施方案中,当免疫抑制剂的形式本身是颗粒或颗粒样(例如纳米结晶免疫抑制剂)时,免疫抑制剂的载量为颗粒等中免疫抑制剂的量(重量/重量)。在这样的一些实施方案中,载量可接近97%、98%、99%或更多。
“合成纳米载体的最大尺寸”意指沿合成纳米载体之任意轴测量的该纳米载体的最大尺寸。“合成纳米载体的最小尺寸”意指沿合成纳米载体之任意轴测量的该合成纳米载体的最小尺寸。例如,对于球形合成纳米载体,合成纳米载体的最大尺寸和最小尺寸基本相同并且是其直径的尺寸。类似地,对于立方形合成纳米载体,合成纳米载体的最小尺寸是其高度、宽度或长度中的最小者,而合成纳米载体的最大尺寸是其高度、宽度或长度中的最大者。在一个实施方案中,基于样品中合成纳米载体的总数,该样品中至少75%,优选至少80%,更优选至少90%的合成纳米载体的最小尺寸等于或大于100nm。在一个实施方案中,基于样品中合成纳米载体的总数,该样品中至少75%,优选至少80%,更优选至少90%的合成纳米载体的最大尺寸等于或小于5μm。优选地,基于样品中合成纳米载体的总数,该样品中至少75%,优选至少80%,更优选至少90%的合成纳米载体的最小尺寸大于110nm,更优选大于120nm,更优选大于130nm,并且更优选还大于150nm。合成纳米载体的最大尺寸和最小尺寸的纵横比可根据实施方案而不同。例如,合成纳米载体的最大尺寸:最小尺寸的纵横比可以是1∶1至1,000,000∶1,优选1∶1至100,000∶1,更优选1∶1至10,000∶1,更优选1∶1至1000∶1,仍更优选1∶1至100∶1并且还更优选1∶1至10∶1。优选地,基于样品中合成纳米载体的总数,该样品中至少75%,优选至少80%,更优选至少90%的合成纳米载体的最大尺寸等于或小于3μm,更优选等于或小于2μm,更优选等于或小于1μm,更优选等于或小于800nm,更优选等于或小于600nm,并且更优选还等于或小于500nm。在一些优选实施方案中,基于样品中合成纳米载体的总数,该样品中至少75%,优选至少80%,更优选至少90%的合成纳米载体的最小尺寸等于或大于100nm,更优选地等于或大于120nm,更优选等于或大于130nm,更优选等于或大于140nm,并且更优选还等于或大于150nm。在一些实施方案中,可如下获得合成纳米载体尺寸(例如,有效直径)的测量:使合成纳米载体混悬于液体介质(通常为水性介质)中并使用动态光散射(dynamic light scattering,DLS)(例如使用BrookhavenZetaPALS仪器)。例如,可将合成纳米载体的混悬液从水性缓冲液稀释到纯化水中以获得约0.01mg/mL至0.1mg/mL的最终合成纳米载体混悬液浓度。可在用于DLS分析的合适比色皿内直接制备经稀释的混悬液或者可将经稀释的混悬液转移至用于DLS分析的合适比色皿。然后,可将比色皿放置在DLS中,允许平衡至受控温度,随后基于针对介质之黏度和样品之折射指数的合适输入,扫描足够的时间以获取稳定且可重现的分布。然后,报道有效直径或分布的平均值。确定高纵横比或非球形合成纳米载体的有效尺寸可需要放大技术(例如电子显微术)以获得更精确的测量。合成纳米载体的“尺寸”或“大小”或“直径”意指例如使用动态光散射获得的颗粒大小分布的平均值。
“非甲氧基封端的聚合物”意指至少一个末端以不同于甲氧基的部分结尾的聚合物。在一些实施方案中,所述聚合物具有至少两个以不同于甲氧基的部分结尾的末端。在另一些实施方案中,所述聚合物没有以甲氧基结尾的末端。“非甲氧基封端的普朗尼克聚合物”意指不同于两端都具有甲氧基的线性普朗尼克聚合物的聚合物。本文中提供的聚合物纳米颗粒可包含非甲氧基封端的聚合物或非甲氧基封端的普朗尼克聚合物。
“可药用赋形剂”或“可药用载体”意指与药理学活性材料一起使用以配制组合物的药理学惰性材料。可药用赋形剂包括本领域中已知的多种材料,包括但不限于:糖类(例如葡萄糖、乳糖等)、防腐剂(例如抗微生物剂)、重构助剂(reconstitution aid)、着色剂、盐水(例如磷酸缓冲盐水)和缓冲剂。
“药效学有效持续期”意指在向对象施用免疫抑制剂后的第一剂量依赖期,在所述第一剂量依赖期内施用抗原在对象中产生在第二时期内可测量的抗原特异性耐受,所述第二时期从施用抗原后5天至3个月的时间开始。在一些实施方案中,可将药效学有效持续期测量为在一个或更多个对象(例如第一类对象)中测量的个体药效学有效持续期的平均值,并且可在每个被测量对象中测量一次或更多次。
“提供”意指个体进行的供给用于实施本发明的所需项目或项目组或方法的活动或活动集合。所述活动或活动集合可本身直接采取或者间接采取。
“提供对象”为这样的任何活动或活动集合,其促使临床医生与对象接触并向其施用本文中提供的组合物或者对其进行本文中提供的方法。优选地,所述对象是需要治疗性大分子施用和针对它的抗原特异性免疫耐受的对象。所述活动或活动集合可本身直接采取或者间接采取。本文中提供的任一种方法的一个实施方案中,所述方法还包括提供对象。
“对象”意指动物,包括温血哺乳动物,例如人和灵长类动物;禽类;驯养的家养或农场动物,例如猫、狗、绵羊、山羊、牛、马和猪;实验室动物,例如小鼠、大鼠和豚鼠;鱼;爬行动物;动物园动物和野生动物;等。
“合成纳米载体”意指不存在于自然界中并且至少一个维度的尺寸小于或等于5微米的离散物体。白蛋白纳米颗粒一般作为合成纳米载体包括在内,然而在某些实施方案中,合成纳米载体不包括白蛋白纳米颗粒。在一些实施方案中,合成纳米载体不包含壳聚糖。在另一些实施方案中,合成纳米载体不是基于脂质的纳米颗粒。在另一些实施方案中,合成纳米载体不包含磷脂。
合成纳米载体可以是但不限于以下中的一种或多种:基于脂质的纳米颗粒(在本文中也称为脂质纳米颗粒,即构成其结构的大部分材料为脂质的纳米颗粒)、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳剂、树状聚体、巴基球、纳米线、病毒样颗粒(即,主要由非感染性或具有低感染性的病毒结构蛋白构成的颗粒)、基于肽或蛋白质的颗粒(在本文中也称为蛋白质颗粒,即,构成其结构的大部分材料是肽或蛋白质的颗粒)(例如白蛋白纳米颗粒)和/或使用纳米材料之组合开发的纳米颗粒(例如脂质-聚合物纳米颗粒)。合成纳米载体可以是多种不同的形状,包括但不限于球形、立方形、棱锥形、长方形、圆柱形、环形等。根据本发明的合成纳米载体包括一个或更多个表面。适用于实施本发明的示例性合成纳米载体包括:(1)Gref等的美国专利5,543,158中公开的生物可降解纳米颗粒,(2)Saltzman等的公开的美国专利申请20060002852中的聚合物纳米颗粒,(3)DeSimone等的公开的美国专利申请20090028910中以平版印刷方式构建的纳米颗粒,(4)von Andrian等的WO 2009/051837的公开内容,(5)Penades等的公开的美国专利申请2008/0145441中公开的纳米颗粒,(6)de los Rios等的公开的美国专利申请20090226525中公开的蛋白质纳米颗粒,(7)Sebbel等的公开的美国专利申请20060222652中公开的病毒样颗粒,(8)Bachmann等的公开的美国专利申请20060251677中公开的核酸连接的病毒样颗粒,(9)WO2010047839A1或WO2009106999A2中公开的病毒样颗粒,(10)P.Paolicelli等,“Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-likeParticles”Nanomedicine.5(6):843-853(2010)中公开的经纳米沉淀的纳米颗粒,(11)美国公开2002/0086049中公开的凋亡细胞、凋亡体或者合成或半合成模拟物,或者(12)Look等,Nanogel-based delivery of mycophenolic acid ameliorates systemic lupuserythematosus in mice”J.Clinical Investigation 123(4):1741-1749(2013)中的那些。在一些实施方案中,合成纳米载体的纵横比可大于1∶1、1∶1.2、1∶1.5、1∶2、1∶3、1∶5、1∶7,或大于1∶10。
最小尺寸等于或小于约100nm、优选等于或小于100nm之根据本发明的合成纳米载体不包含具有激活补体的羟基的表面,或者作为替代地包含基本由不是激活补体之羟基的部分组成的表面。在一个优选实施方案中,最小尺寸等于或小于约100nm、优选等于或小于100nm之根据本发明的合成纳米载体不包含显著激活补体的表面,或者作为替代地包含基本由不显著激活补体的部分组成的表面。在一个更优选的实施方案中,最小尺寸等于或小于约100nm、优选等于或小于100nm之根据本发明的合成纳米载体不包含激活补体的表面,或者作为替代地包含基本由不激活补体的部分组成的表面。在一些实施方案中,合成纳米载体不包含病毒样颗粒。在一些实施方案中,合成纳米载体的纵横比可大于1∶1、1∶1.2、1∶1.5、1∶2、1∶3、1∶5、1∶7,或大于1∶10。
“测试剂量”或“免疫抑制剂的测试剂量”意指用于进行测试的免疫抑制剂的剂量。
“测试药效学有效持续期”意指在免疫抑制剂的测试剂量下和在第二类对象中相对于治疗性大分子确定的免疫抑制剂的药效学有效持续期。在一些实施方案中,所述免疫抑制剂可具有相对于治疗性大分子的测试药效学有效持续期,其持续时间的范围可以是最短20小时至最长1个月,优选最短20小时至最长2周,最短20小时至最长1周,优选最短20小时至最长5天,优选最短20小时至最长3天,优选最短24小时至最长2天。
“治疗性大分子”指可向对象施用并且具有治疗效果的任何蛋白质、碳水化合物、脂质或核酸。在一些实施方案中,向对象施用治疗性大分子可引起不期望的免疫应答,包括抗治疗性大分子特异性抗体的产生。如本文中所述,在一些实施方案中,施用如本文中提供的治疗性大分子可增强该治疗性大分子的治疗有效性,例如通过降低针对它的不期望免疫应答。在一些实施方案中,治疗性大分子可以是治疗性多核苷酸或治疗性蛋白质。
“治疗性多核苷酸”意指可向对象施用并且具有治疗效果的任何多核苷酸或基于多核苷酸的治疗。这样的治疗包括基因沉默。这样的治疗的实例在本领域中是已知的并且包括但不限于:裸RNA(包括信使RNA、经修饰的信使RNA以及RNAi的形式)。本文中的其他部分还提供了其他治疗性多核苷酸的实例。治疗性多核苷酸可在细胞中产生、在细胞上产生或者由细胞产生,并且还可使用无细胞体外方法获得或者由完全体外合成方法获得。因此,对象包括需要前述任何治疗性多核苷酸进行治疗的任何对象。这样的对象包括将接受前述任何治疗性多核苷酸的那些。
“治疗性蛋白质”意指可向对象施用并且具有治疗效果的任何蛋白质或基于蛋白质的治疗。这样的治疗包括蛋白质替代治疗和蛋白质补充治疗。这样的治疗还包括施用外源或外来蛋白质、抗体治疗和细胞治疗或基于细胞的治疗。治疗性蛋白质包括但不限于:酶、酶辅因子、激素、凝血因子、细胞因子、生长因子、单克隆抗体、抗体-药物缀合物和多克隆抗体。本文中的其他部分还提供了其他治疗性蛋白质的实例。治疗性蛋白质可在细胞中产生、在细胞上产生或者由细胞产生,并且可从这样的细胞获得或者以这样的细胞的形式施用。在一些实施方案中,治疗性蛋白质在哺乳动物细胞、昆虫细胞、酵母细胞、细菌细胞、植物细胞、转基因动物细胞、转基因植物细胞等中产生、在其上产生或者由其产生。治疗性蛋白质可在这样的细胞中重组产生。治疗性蛋白质可在经病毒转化的细胞中产生、在其上产生或者由其产生。因此,对象可包括需要前述任何治疗性蛋白质进行治疗的任何对象。这样的对象包括将接受前述任何治疗性蛋白质的那些。
C.可用于实施所述方法的组合物
本文中提供了可用于降低不期望免疫应答的产生和促进治疗性大分子特异性致耐受性免疫应答的产生的方法及相关组合物。通过在免疫抑制剂之相对于治疗性大分子的药效学有效持续期内施用治疗性大分子,所述方法和组合物有助于使施用免疫抑制剂的益处最大化。可用其中期望针对治疗性大分子的致耐受性免疫应答的对象来实施本发明的方法。这样的对象包括将施用治疗性大分子的那些。特别可用于实施本发明的是相对于治疗性大分子之药效学有效持续期的持续时间的范围最短20小时至最长1个月的免疫抑制剂。多种免疫抑制剂可用于实施本发明。
在某些实施方案中,所述免疫抑制剂可以是装置(例如可植入渗透泵)的形式。可用于实施本发明的一种此类可植入渗透泵为牌可植入渗透泵(可获自DurectCorporation,Cupertino CA)。牌渗透泵为在可以以受控速率连续递送药物、激素及其他测试药剂1天至4周而无需外部连接、频繁操作或重复给药的微型可植入渗透泵。这些输注泵在被植入皮下或体内时可用于全身施用。当药物或测试剂的作用定位于特定组织或器官中时,可将它们与用于静脉内、脑内或动脉内输注或者用于靶向递送的导管连接。这些泵由泵和动物的体液之间的渗透压差提供动力,因此无需外部能源。ALZET泵已被用于靶向递送至多种部位,包括脊髓、脾、肝、器官或组织移植部位和伤口愈合部位。参见,例如S.M.Stepkowski等,“Inhibition of host-versus-graft and graft-versus-hostresponses after small bowel transplantation in rats by rapamycin.”Transplantation(1992)53(-2-):258-264。有关牌渗透泵的其他信息可在alzet.com获得。
在一些实施方案中,所述免疫抑制剂可以是双特异性抗体(BsAb)的形式,其中一个可变区设计成靶向选择性地结合免疫细胞上之目的大分子的抗原受体(例如BCR),而另一个可变区设计成结合参与刺激耐受之免疫细胞上的靶标(例如细胞表面受体)。在另一个实施方案中,BsAb由设计成靶向与目的大分子结合之另一抗体的可变区的一个可变区(抗独特型区或抗体)和设计成结合参与刺激耐受之免疫细胞上的靶标(例如细胞表面受体)的另一可变区组成。通过将两种结合特异性组合,可提高BsAb免疫抑制剂的选择性和效力并且可诱导目的大分子的免疫耐受。在一些实施方案中,免疫抑制剂BsAb靶标包括但不限于B细胞上的CD-19、CD-20、CD-21、CD-22(参考:M.R.Clatworthy,American Journal ofTransplantation 2011;11:1359-1367),和GITR(糖皮质激素诱导的肿瘤坏死因子(Glucocorticoid-induced tumor necrosis factor)(tumor necrosis factor,TNF))受体家族相关基因。GITR为与TNF受体家族成员同源的I型跨膜蛋白。GITR在静息CD4+和CD8+T细胞上以低水平表达并且在T细胞活化后上调。GITR的连接提供了增强CD4+和CD8+T细胞增殖和效应功能的共刺激信号,特别是在次最佳T细胞受体(T-cell receptor,TCR)刺激的情况下。另外,GITR在调节性T细胞(Treg)上以高水平组成型表达并且已被探索作为用于克服Treg抑制的潜在靶标。使用GITR配体通过GITR的信号传导消除Treg的抑制作用、增强自体反应性和同种异体反应性T细胞应答并加强自身免疫)。另一BsAb靶标可包含LAG3(akaCD223)。与CD4相比,CD223以更高亲和力与II类MHC结合,并且认为这种相互作用参与T细胞活化和稳态增殖的负调节。此外,CD223由CD4+CD25+调节性T细胞表达,并且已表明CD223可参与其调节功能,除此之外还有本领域中已知的其他这样的靶标。
在某些实施方案中,所述免疫抑制剂可以是可植入聚合物储库材料的形式。在一些实施方案中,可植入聚合物储库材料包含生物相容性的生物可降解热塑性聚合物、速率调节剂和生物活性材料的微多孔固体基质。所述基质在溶液或悬浮液中形成以形成可注射的液体。基质控制生物活性剂从基质的释放速率和释放程度。形成储库的过程部分地负责速率和释放控制的发生。液体组合物与体内原位或身体外部之水性介质的使聚合物体系凝固的相互作用至少部分地引起期望的受控释放谱,其为多种组合物的组分和浓度的变化的函数。示例性的可植入聚合物储库材料可见于Dunn等之标题为“Polymeric compositionsuseful as controlled release implants”的美国专利5,702,716;和Brodbeck等之标题为“Gel composition and methods”的美国专利6,130,200中。
所述免疫抑制剂还可以以包含免疫抑制剂的合成纳米载体的形式施用。根据本发明,可使用多种合成纳米载体。在一些实施方案中,合成纳米载体为球体或球状体。在一些实施方案中,合成纳米载体是平的或板状的。在一些实施方案中,合成纳米载体为立方体物或者是立方体的。在一些实施方案中,合成纳米载体为卵形或椭圆形。在一些实施方案中,合成纳米载体为圆柱体、圆锥体或棱锥体。
在一些实施方案中,期望使用在尺寸或形状方面相对均一的合成纳米载体群使得每个合成纳米载体具有类似的特性。例如,基于合成纳米载体的总数,至少80%、至少90%或至少95%的合成纳米载体的最小尺寸或最大尺寸可落入合成纳米载体之平均直径或平均尺寸的5%、10%或20%内。
合成纳米载体可以是实心的或中空的并且可包含一个或更多个层。在一些实施方案中,相对于其他层,每个层均具有独特的组合物和独特的特性。仅为了给出一个实例,合成纳米载体可具有芯/壳结构,其中芯为一个层(例如聚合物芯)而壳为第二层(例如脂质双层或单层)。合成纳米载体可包含多个不同的层。
在一些实施方案中,合成纳米载体可任选地包含一种或更多种脂质。在一些实施方案中,合成纳米载体可包含脂质体。在一些实施方案中,合成纳米载体可包含脂质双层。在一些实施方案中,合成纳米载体可包含脂质单层。在一些实施方案中,合成纳米载体可包含胶束。在一些实施方案中,合成纳米载体可包含由脂质层(例如,脂质双层、脂质单层等)包围的包含聚合物基质的芯。在一些实施方案中,合成纳米载体可包含由脂质层(例如,脂质双层、脂质单层等)包围的非聚合物芯(例如,金属颗粒、量子点、陶瓷颗粒、骨颗粒、病毒颗粒、蛋白质、核酸、碳水化合物等)。
在另一些实施方案中,合成纳米载体可包含金属颗粒、量子点、陶瓷颗粒等。在一些实施方案中,非聚合物合成纳米载体是非聚合物组分的聚集体,例如金属原子(例如,金原子)的聚集体。
在一些实施方案中,合成纳米载体可任选地包含一种或更多种两亲性实体。在一些实施方案中,两亲性实体可促进产生稳定性提高、均匀性提高或黏度提高的合成纳米载体。在一些实施方案中,两亲性实体可与脂质膜(例如,脂质双层、脂质单层等)的内表面相缔合。本领域中已知的很多两亲性实体均适用于制备根据本发明的合成纳米载体。这样的两亲性实体包括但不限于:磷酸甘油酯;磷脂酰胆碱;二棕榈酰磷脂酰胆碱(DPPC);二油烯基磷脂酰乙醇胺(DOPE);二油烯氧基丙基三乙铵(DOTMA);二油酰磷脂酰胆碱;胆固醇;胆固醇酯;二酰甘油;琥珀酸二酰甘油酯;二磷脂酰甘油(DPPG);十六烷醇(hexanedecanol);脂肪醇,例如聚乙二醇(PEG);聚氧乙烯-9-月桂基醚;表面活性脂肪酸,例如棕榈酸或油酸;脂肪酸;脂肪酸单甘油酯;脂肪酸二甘油酯;脂肪酸酰胺;去水山梨糖醇三油酸酯(85)甘氨胆酸盐;去水山梨糖醇单月桂酸酯(20);聚山梨醇酯20(20);聚山梨醇酯60(60);聚山梨醇酯65(65);聚山梨醇酯80(80);聚山梨醇酯85(85);聚氧乙烯单硬脂酸酯;表面活性素;泊洛沙姆;去水山梨糖醇脂肪酸酯,例如去水山梨糖醇三油酸酯;卵磷脂;溶血卵磷脂;磷脂酰丝氨酸;磷脂酰肌醇;鞘磷脂;磷脂酰乙醇胺(脑磷脂);心磷脂;磷脂酸;脑苷脂;磷酸二鲸蜡酯;二棕榈酰磷脂酰甘油;硬脂酰胺;十二烷胺;十六烷胺;乙酰棕榈酸酯;蓖麻醇酸甘油酯;硬脂酸十六烷酯;肉豆蔻酸异丙酯;泰洛沙泊;聚(乙二醇)5000-磷脂酰乙醇胺;聚(乙二醇)400-单硬脂酸酯;磷脂;具有高表面活性剂特性的合成和/或天然洗涤剂;脱氧胆酸盐;环糊精;离液盐;离子配对剂;及其组合。两亲性实体组分可以是不同两亲性实体的混合物。本领域技术人员将认识到:这是具有表面活性剂活性之物质的示例性的非全面性列表。任何两亲性实体均可用于产生根据本发明使用的合成纳米载体。
在一些实施方案中,合成纳米载体可任选地包含一种或更多种碳水化合物。碳水化合物可以是天然的或合成的。碳水化合物可以是衍生化的天然碳水化合物。在某些实施方案中,碳水化合物包含单糖或二糖,包括但不限于:葡萄糖、果糖、半乳糖、核糖、乳糖、蔗糖、麦芽糖、海藻糖、纤维二糖、甘露糖、木糖、阿拉伯糖、葡萄糖醛酸、半乳糖醛酸、甘露糖醛酸、葡糖胺、半乳糖胺和神经氨酸。在某些实施方案中,碳水化合物为多糖,包括但不限于:普鲁兰多糖、纤维素、微晶纤维素、羟丙基甲基纤维素(HPMC)、羟基纤维素(HC)、甲基纤维素(MC)、葡聚糖、环葡聚糖、糖原、羟乙基淀粉、角叉菜胶、糖苷配糖基(glycon)、直链淀粉、壳聚糖、N,O-羧甲基壳聚糖、藻胶和藻酸、淀粉、甲壳质、菊粉、魔芋、葡甘露聚糖、石耳素(pustulan)、肝素、透明质酸、凝胶多糖(curdlan)和黄原胶。在一些实施方案中,合成纳米载体不包含(或者特别排除)碳水化合物,例如多糖。在某些实施方案中,碳水化合物可包含碳水化合物衍生物,例如糖醇,包括但不限于:甘露糖醇、山梨糖醇、木糖醇、赤藓糖醇、麦芽糖醇和乳糖醇。
在一些实施方案中,合成纳米载体可包含一种或更多种聚合物。在一些实施方案中,合成纳米载体可包含一种或更多种这样的聚合物,其为非甲氧基封端的普朗尼克聚合物。在一些实施方案中,构成合成纳米载体的至少1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、97%或99%(重量/重量)聚合物为非甲氧基封端的普朗尼克聚合物。在一些实施方案中,构成合成纳米载体的所有聚合物均为非甲氧基封端的普朗尼克聚合物。在一些实施方案中,合成纳米载体包含一种或更多种这样的聚合物,其为非甲氧基封端的聚合物。在一些实施方案中,构成合成纳米载体的至少1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、97%或99%(重量/重量)聚合物为非甲氧基封端的聚合物。在一些实施方案中,构成合成纳米载体的所有聚合物均为非甲氧基封端的聚合物。在一些实施方案中,合成纳米载体包含一种或更多种不含普朗尼克聚合物的聚合物。在一些实施方案中,构成合成纳米载体的至少1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、97%或99%(重量/重量)聚合物不包含普朗尼克聚合物。在一些实施方案中,构成合成纳米载体的所有聚合物均不包含普朗尼克聚合物。在一些实施方案中,这样的聚合物可由包被层(例如,脂质体、脂质单层、胶束等)包围。在一些实施方案中,合成纳米载体中的多种组分可与聚合物连接。
可通过多种方法中的任一种来使免疫抑制剂与合成纳米载体连接。一般来说,连接可以是免疫抑制剂与合成纳米载体之间键合的结果。这种键合可导致免疫抑制剂与合成纳米载体的表面连接和/或包含(包封)在合成纳米载体中。然而,在一些实施方案中,由于合成纳米载体的结构的原因,免疫抑制剂被合成纳米载体包封而不是与合成纳米载体键合。在一些优选实施方案中,合成纳米载体包含本文中提供的聚合物,并且免疫抑制剂与聚合物连接。
当由于免疫抑制剂与合成纳米载体之间的键合而发生连接时,所述连接可经由偶联部分发生。偶联部分可以是免疫抑制剂通过它与合成纳米载体键合的任何部分。这样的部分包括共价键(例如酰胺键或酯键)以及使免疫抑制剂与合成纳米载体(共价或非共价)键合的独立分子。这样的分子包含接头或聚合物或其单元。例如,偶联部分可包含与免疫抑制剂静电结合的带电聚合物。作为另一个实例,偶联部分可包含与免疫抑制剂共价键合的聚合物或其单元。
在一些优选实施方案中,合成纳米载体包含本文中提供的聚合物。这些合成纳米载体可以是完全聚合物的或者其可以是聚合物与其他材料的混合物。
在一些实施方案中,合成纳米载体中的聚合物缔合以形成聚合物基质。在这些实施方案中的一些中,组分如免疫抑制剂可与聚合物基质中的一种或更多种聚合物共价缔合。在一些实施方案中,共价缔合由接头介导。在一些实施方案中,组分可与聚合物基质中的一种或更多种聚合物非共价缔合。例如,在一些实施方案中,组分可包封在聚合物基质内、被聚合物基质包围和/或分散在聚合物基质中。作为替代或补充,组分与聚合物基质中的一种或更多种聚合物可通过疏水性相互作用、电荷相互作用、范德华力等缔合。多种聚合物以及用于由其形成聚合物基质的方法均是常规已知的。
聚合物可以是天然聚合物或非天然(合成)聚合物。聚合物可以是含有两个或更多个单体的均聚物或共聚物。就序列而言,共聚物可以是随机的、嵌段的,或者包含随机序列和嵌段序列的组合。通常来说,根据本发明的聚合物是有机聚合物。
在一些实施方案中,聚合物包含聚酯、聚碳酸酯、聚酰胺或聚醚或其单元。在另一些实施方案中,聚合物包含聚(乙二醇)(PEG)、聚丙二醇、聚(乳酸)、聚(乙醇酸)、聚乳酸-乙醇酸共聚物或聚己内酯或其单元。在一些实施方案中,优选地,聚合物是生物可降解的。因此,在这些实施方案中,优选地,如果聚合物包含聚醚(例如聚(乙二醇)、聚丙二醇或其单元),则该聚合物包含聚醚和生物可降解聚合物的嵌段共聚物,使得该聚合物是生物可降解的。在另一些实施方案中,聚合物不仅包含聚醚或其单元,例如聚(乙二醇)或聚丙二醇或其单元。
适用于本发明中的聚合物的其他实例包括但不限于:聚乙烯、聚碳酸酯(例如聚(1,3-二烷-2酮))、聚酐(例如聚(癸二酐))、聚丙基富马酸酯、聚酰胺(例如聚己内酰胺)、聚缩醛、聚醚、聚酯(例如,聚丙交酯、聚乙交酯、聚丙交酯-乙交酯共聚物、聚己内酯、聚羟基酸(例如聚(β-羟基烷酸酯)))、聚(原酸酯)、聚氰基丙烯酸酯、聚乙烯醇、聚氨酯、聚磷腈、聚丙烯酸酯、聚甲基丙烯酸酯、聚脲、聚苯乙烯以及聚胺、聚赖氨酸、聚赖氨酸-PEG共聚物和聚(乙烯亚胺)、聚(乙烯亚胺)-PEG共聚物。
在一些实施方案中,根据本发明的聚合物包括已由美国食品药品管理局(U.S.Food and Drug Administration,FDA)根据21C.F.R.§177.2600批准用于人的聚合物,包括但不限于:聚酯(例如,聚乳酸、聚乳酸-乙醇酸共聚物、聚己内酯、聚戊内酯、聚(1,3-二烷-2酮));聚酐(例如,聚(癸二酐));聚醚(例如,聚乙二醇);聚氨酯;聚甲基丙烯酸酯;聚丙烯酸酯;和聚氰基丙烯酸酯。
在一些实施方案中,聚合物可以是亲水性的。例如,聚合物可包含阴离子基团(例如,磷酸根基团、硫酸根基团、羧酸根基团);阳离子基团(例如,季胺基团);或极性基团(例如,羟基、巯基、胺基)。在一些实施方案中,包含亲水性聚合物基质的合成纳米载体在合成纳米载体内产生亲水性环境。在一些实施方案中,聚合物可以是疏水性的。在一些实施方案中,包含疏水性聚合物基质的合成纳米载体在合成纳米载体内产生疏水性环境。对聚合物之亲水性或疏水性的选择可影响合成纳米载体中掺入(例如连接)的材料的性质。
在一些实施方案中,可用一个或更多个部分和/或官能团对聚合物进行修饰。根据本发明可使用多种部分或官能团。在一些实施方案中,可用聚乙二醇(PEG)、碳水化合物和/或由多糖衍生的无环聚缩醛(Papisov,2001,ACS Symposium Series,786:301)对聚合物进行修饰。某些实施方案可使用Gref等的美国专利No.5543158或Von Andrian等的WO公开WO2009/051837的一般性教导来进行。
在一些实施方案中,可用脂质或脂肪酸基团来对聚合物进行修饰。在一些实施方案中,脂肪酸基团可以是以下中的一种或更多种:丁酸、己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山嵛酸或二十四烷酸。在一些实施方案中,脂肪酸基团可以是以下中的一种或更多种:棕榈油酸、油酸、异油酸、亚油酸、α-亚油酸、γ-亚油酸、花生四烯酸、鳕油酸、花生四烯酸、二十碳五烯酸、二十二碳六烯酸或芥酸。
在一些实施方案中,聚合物可以是聚酯,包含含有乳酸和乙醇酸单元的共聚物,例如聚乳酸-乙醇酸共聚物和聚丙交酯-乙交酯共聚物,在本文中将其统称为“PLGA”;以及含有乙醇酸单元的均聚物(在本文中称为“PGA”)和含有乳酸单元的均聚物,例如聚-L-乳酸、聚-D-乳酸、聚-D,L-乳酸、聚-L-丙交酯、聚-D-丙交酯和聚-D,L-丙交酯(在本文中统称为“PLA”)。在一些实施方案中,示例性的聚酯包括例如:聚羟基酸;PEG共聚物及丙交酯和乙交酯的共聚物(例如,PLA-PEG共聚物、PGA-PEG共聚物、PLGA-PEG共聚物,及其衍生物。在一些实施方案中,聚酯包括例如:聚(己内酯)、聚(己内酯)-PEG共聚物、聚L-丙交酯-L-赖氨酸共聚物、聚(丝氨酸酯)、聚(4-羟基-L-脯氨酸酯)、聚[α-(4-氨基丁基)-L-乙醇酸],及其衍生物。
在一些实施方案中,聚合物可以是PLGA。PLGA是乳酸和乙醇酸的生物相容性的生物可降解共聚物,并且多种PLGA形式通过乳酸:乙醇酸之比来表征。乳酸可以是L-乳酸、D-乳酸或D,L-乳酸。可通过改变乳酸:乙醇酸之比来调节PLGA的降解速率。在一些实施方案中,根据本发明使用的PLGA的特征在于:乳酸:乙醇酸之比为约85∶15、约75∶25、约60∶40、约50∶50、约40∶60、约25∶75或约15∶85。
在一些实施方案中,聚合物可以是一种或更多种丙烯酸类聚合物。在某些实施方案中,丙烯酸类聚合物包括例如:丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、甲基丙烯酸氰基乙酯、甲基丙烯酸氨基烷酯共聚物、聚(丙烯酸)、聚(甲基丙烯酸)、甲基丙烯酸烷基酰胺共聚物、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸酐)、甲基丙烯酸甲酯、聚甲基丙烯酸酯、聚(甲基丙烯酸甲酯)共聚物、聚丙烯酰胺、甲基丙烯酸氨基烷酯共聚物、甲基丙烯酸缩水甘油酯共聚物、聚氰基丙烯酸酯以及包含前述聚合物中一种或更多种的组合。丙烯酸类聚合物可包括丙烯酸酯和甲基丙烯酸酯的具有低含量季铵基团的完全聚合的共聚物。
在一些实施方案中,聚合物可以是阳离子聚合物。一般来说,阳离子聚合物能够缩合和/或保护核酸的带负电链。含胺聚合物例如聚(赖氨酸)(Zauner等,1998,Adv.DrugDel.Rev.,30:97;和Kabanov等,1995,Bioconjugate Chem.,6:7)、聚(乙烯亚胺)(PEI;Boussif等,1995,Proc.Natl.Acad.Sci.,USA,1995,92:7297)和聚(酰胺胺)树状聚体(Kukowska-Latallo等,1996,Proc.Natl.Acad.Sci.,USA,93:4897;Tang等,1996,Bioconjugate Chem.,7:703;和Haensler等,1993,Bioconjugate Chem.,4:372)在生理pH下带正电并且与核酸形成离子对。在一些实施方案中,合成纳米载体可不包含(或者可排除)阳离子聚合物。
在一些实施方案中,聚合物可以是携带阳离子侧链的可降解聚酯(Putnam等,1999,Macromolecules,32:3658;Barrera等,1993,J.Am.Chem.Soc.,115:11010;Kwon等,1989,Macromolecules,22:3250;Lim等,1999,J.Am.Chem.Soc.,121:5633;和Zhou等,1990,Macromolecules,23:3399)。这些聚酯的实例包括聚L-丙交酯-L-赖氨酸共聚物(Barrera等,1993,J.Am.Chem.Soc.,115:11010)、聚(丝氨酸酯)(Zhou等,1990,Macromolecules,23:3399)、聚(4-羟基-L-脯氨酸酯)(Putnam等,1999,Macromolecules,32:3658;和Lim等,1999,J.Am.Chem.Soc.,121:5633)和聚(4-羟基-L-脯氨酸酯)(Putnam等,1999,Macromolecules,32:3658;和Lim等,1999,J.Am.Chem.Soc.,121:5633)。
这些和其他聚合物的特性及其制备方法在本领域中是公知的(参见,例如,美国专利6,123,727;5,804,178;5,770,417;5,736,372;5,716,404;6,095,148;5,837,752;5,902,599;5,696,175;5,514,378;5,512,600;5,399,665;5,019,379;5,010,167;4,806,621;4,638,045;和4,946,929;Wang等,2001,J.Am.Chem.Soc.,123:9480;Lim等.,2001,J.Am.Chem.Soc.,123:2460;Langer,2000,Acc.Chem.Res.,33:94;Langer,1999,J.Control.Release,62:7;和Uhrich等,1999,Chem.Rev.,99:3181)。更一般地,用于合成某些合适聚合物的多种方法在以下中进行了描述:Concise Encyclopedia of PolymerScience and Polymeric Amines and Ammonium Salts,由Goethals编辑,PergamonPress,1980;Principles of Polymerization,Odian,John Wiley&Sons,第四版,2004;Contemporary Polymer Chemistry,Allcock等,Prentice-Hall,1981;Deming等,1997,Nature,390:386;以及美国专利6,506,577、6,632,922、6,686,446和6,818,732。
在一些实施方案中,聚合物可以是直链聚合物或支链聚合物。在一些实施方案中,聚合物可以是树状聚体。在一些实施方案中,聚合物可彼此基本交联。在一些实施方案中,聚合物可基本无交联。在一些实施方案中,可根据本发明在不经历交联步骤的情况下使用聚合物。还应当理解的是,合成纳米载体可包含前述及其他聚合物的嵌段共聚物、接枝共聚物、共混物、混合物和/或加合物。本领域技术人员将认识到,本文中所列举的聚合物代表可根据本发明使用之聚合物的示例性的非全面性列表。
在一些实施方案中,合成纳米载体不包含聚合物组分。在一些实施方案中,合成纳米载体可包含金属颗粒、量子点、陶瓷颗粒等。在一些实施方案中,非聚合物合成纳米载体为非聚合物组分的聚集体,例如金属原子(例如,金原子)的聚集体。
根据本发明的组合物可包含与可药用赋形剂(例如防腐剂、缓冲剂、盐水和磷酸缓冲盐水)组合的组分。所述组合物可使用常规的药物制备和配合技术制成以实现可用的剂型。在一个实施方案中,将组合物(例如包含合成纳米载体的那些)与防腐剂一起混悬于无菌盐水溶液中以用于注射。
在一些实施方案中,当制备合成纳米载体用作载体时,用于使组分与合成纳米载体连接方法是可用的。如果组分是小分子,有利地可在组装合成纳米载体之前使该组分与聚合物连接。在一些实施方案中,还有利的是,可制备具有表面基团的合成纳米载体,其可用于通过使用这些表面基团来使组分与合成纳米载体连接,而非使组分与聚合物连接并然后在构建合成纳米载体中使用该聚合物缀合物。
在某些实施方案中,连接可以是共价接头。在一些实施方案中,根据本发明的组分可与外表面经由1,2,3-三唑接头共价连接,所述接头通过纳米载体之表面上的叠氮基与含有炔基之组分的1,3-偶极环加成反应形成或者通过纳米载体之表面上的炔与含有叠氮基之组分的1,3-偶极环加成反应形成。优选在Cu(I)催化剂以及合适Cu(I)配体和还原剂存在下进行这样的环加成反应以将Cu(II)化合物还原成催化活性的Cu(I)化合物。还可将这种Cu(I)催化的叠氮化物-炔环加成(CuAAC)称为点击反应。
另外,共价连接可包含共价接头,其包括酰胺接头、二硫接头、硫醚接头、腙接头、酰肼接头、亚胺或肟接头、脲或硫脲接头、脒接头、胺接头和磺酰胺接头。
酰胺接头通过一种组分(例如免疫抑制剂)上的胺与第二组分(例如纳米载体)的羧酸基团之间的酰胺键形成。接头中的酰胺键可使用经适当保护的氨基酸和活化羧酸(例如N-羟基琥珀酰亚胺活化的酯)利用任何常规的酰胺键形成反应形成。
二硫接头通过在形式为例如R1-S-S-R2的两个硫原子之间形成二硫(S-S)键构成。二硫键可通过使含有巯基/硫醇基(-SH)的组分与聚合物或纳米载体上的另一个活化巯基进行巯基交换形成,或者通过使含有巯基/硫醇基的纳米载体与含有活化巯基的组分进行巯基交换形成。
三唑接头,特别是其中R1和R2可以是任何化学实体之形式的1,2,3-三唑,通过与第一组分(例如纳米载体)连接之叠氮化物和与第二组分(例如免疫抑制剂)连接之末端炔的1,3-偶极环加成反应形成。在存在或无催化剂,优选Cu(I)催化剂的情况下进行1,3-偶极环加成反应,其通过1,2,3-三唑功能将两种组分连接。Sharpless等,Angew.Chem.Int.第41(14)版,2596,(2002)和Meldal,等,Chem.Rev.,2008,108(8),2952-3015对这一化学进行了详细描述,并且通常将其称为“点击”反应或CuAAC。
在一些实施方案中,制备聚合物链末端包含叠氮化合物或炔基团的聚合物。然后,使用这种聚合物以使得多个炔或叠氮化物基团位于合成纳米载体之表面的方式制备合成纳米载体。或者,可通过另一途径制备合成纳米载体并随后用炔或叠氮化物进行官能化。在炔(如果聚合物包含叠氮化物)基团或叠氮化物(如果聚合物包含炔)基团存在下制备该组分。然后,在催化剂存在或不存在下使该组分与纳米载体经由1,3-偶极环加成反应而反应,所述催化剂使该组分与颗粒通过1,4-二取代的1,2,3-三唑接头连接。
硫醚接头通过以例如R1-S-R2的形式形成硫-碳(硫醚)键构成。硫醚可通过一种组分上的巯基/硫醇基(-SH)与第二组分上的烷基化基团(例如卤化物或环氧化物)的烷基化形成。硫醚接头还可通过将一种组分上的巯基/硫醇基Michael加成到含有马来酰亚胺基团或乙烯砜基团作为Michael接受体之第二组分上的缺电子烯基团形成。在另一种方式中,硫醚接头可通过一种组分上的巯基/硫醇基与第二组分上的烯基团的自由基巯基-烯反应制备。
腙接头通过使一种组分上的酰肼基团与第二组分上的醛/酮基团反应形成。
酰肼接头通过使一种组分上的肼基团与第二组分上的羧酸基团反应形成。这样的反应一般使用与其中羧酸经活化试剂激活的酰胺键形成类似的化学来进行。
亚胺接头或肟接头通过使一种组分上的胺或N-烷氧基胺(或氨基氧基)基团与第二组分上的醛或酮基团反应形成。
脲或硫脲接头通过使一种组分上的胺基团与第二组分上的异腈酸酯或硫代异腈酸酯基团反应制备。
脒接头通过使一种组分上的胺基团与第二组分上的亚氨酸酯基团反应制备。
胺接头通过一种组分上的胺基团与第二组分上的烷基化基团(例如卤化物、环氧化物或磺酸酯基团)的烷基化反应形成。或者,胺接头还可通过使一种组分上的胺基团与第二组分上的醛或酮基团在合适还原剂(例如氰基硼氢化钠或三乙酰氧基硼氢化钠)存在下进行还原胺化形成。
磺酰胺接头通过使一种组分上的胺基团与第二组分上的磺酰卤(例如磺酰氯)基团反应形成。
砜接头通过将亲核体Michael加成到乙烯砜形成。乙烯砜或亲核体可以在纳米载体的表面上或者与组分连接。
组分与纳米载体缀合还可通过非共价缀合方法缀合。例如,带负电的免疫抑制剂可与带正电的纳米载体通过静电吸附缀合。含有金属配体的组分可与含有金属复合物的纳米载体经由金属-配体复合物缀合。
在一些实施方案中,可在组装合成纳米载体之前使组分与聚合物(例如聚乳酸-乙二醇嵌段共聚物)连接,或者合成纳米载体可形成为在其表面上具有反应性或可活化基团。在后一种情况下,组分可使用与通过合成纳米载体之表面呈现的连接化学相容的基团制备。在另一些实施方案中,可使用合适的接头使肽组分与VLP或脂质体连接。接头为能够将两个分子连接在一起的化合物或试剂。在一个实施方案中,接头可以是Hermanson 2008中所述的同双功能试剂或异双功能试剂。例如,可在EDC存在下用同双功能接头己二酸二酰肼(adipic dihydrazide,ADH)处理表面上包含羧基的VLP或脂质体合成纳米载体以形成具有ADH接头的相应合成纳米载体。然后,使所得ADH连接的合成纳米载体经由该纳米载体上ADH接头的另一端与含有酸基团的肽组分缀合以产生相应的VLP或脂质体肽缀合物。
有关可用缀合方法的详细描述,参见Hermanson G T“BioconjugateTechniques”,第2版,由Academic Press出版,Inc.,2008。除共价连接之外,组分可与预先形成的合成纳米载体通过吸附连接或者其可在形成合成纳米载体期间通过包封连接。
本文中提供的任何免疫抑制剂均可用于所提供的方法或组合物中,并且在一些实施方案中,可与合成纳米载体连接。免疫抑制剂包括但不限于:他汀类;mTOR抑制剂,例如雷帕霉素或雷帕霉素类似物;TGF-β信号传导剂;TGF-β受体激动剂;组蛋白去乙酰化酶(HDAC)抑制剂;皮质类固醇;线粒体功能的抑制剂,例如鱼藤酮;P38抑制剂;NF-κβ抑制剂;腺苷受体激动剂;前列腺素E2激动剂;磷酸二酯酶抑制剂,例如磷酸二酯酶4抑制剂;蛋白酶体抑制剂;激酶抑制剂;G蛋白偶联受体激动剂;G蛋白偶联受体拮抗剂;糖皮质激素;类视黄醇;细胞因子抑制剂;细胞因子受体抑制剂;细胞因子受体激活剂;过氧化物酶体增殖物激活受体拮抗剂;过氧化物酶体增殖物激活受体激动剂;组蛋白去乙酰化酶抑制剂;钙调神经磷酸酶抑制剂;磷酸酶抑制剂和氧化的ATP。免疫抑制剂还包括IDO、维生素D3、环孢素A、芳基烃受体抑制剂、白藜芦醇、硫唑嘌呤、6-巯基嘌呤、阿司匹林、尼氟灭酸、雌三醇、雷公藤内酯、白介素(例如,IL-1、IL-10)、环孢素A、靶向细胞因子或细胞因子受体的siRNA等。
mTOR抑制剂的实例包括雷帕霉素及其类似物(例如,CCL-779、RAD001、AP23573、C20-甲基烯丙基雷帕霉素(C20-Mavap)、C16-(S)-丁基磺酰氨基雷帕霉素(C16-Bsrap)、C16-(S)-3-甲基吲哚雷帕霉素(C16-iRap)(Bayle等Chemistry&Biology 2006,13:99-107))、AZD8055、BEZ235(NVP-BEZ235)、大黄根酸(大黄酚)、地磷莫司(deforolimus,MK-8669)、依维莫司(RAD0001)、KU-0063794、PI-103、PP242、坦罗莫司和WYE-354(可获自Selleck,Houston,TX,USA)。
TGF-β信号传导剂的实例包括TGF-β配体(例如,活化素A、GDF1、GDF11、骨形态生成蛋白、nodal、TGF-β)及其受体(例如,ACVR1B、ACVR1C、ACVR2A、ACVR2B、BMPR2、BMPR1A、BMPR1B、TGFβRI、TGFβRII)、R-SMADS/co-SMADS(例如,SMAD1、SMAD2、SMAD3、SMAD4、SMAD5、SMAD8)和配体抑制剂(例如,卵泡抑素、头蛋白(noggin)、脊索蛋白(chordin)、DAN、lefty、LTBP1、THBS1、Decorin)。
线粒体功能的抑制剂的实例包括苍术苷(二钾盐)、米醇菌酸(三铵盐)、羰基氰化物间氯苯腙、羧基苍术苷(例如,来自欧苍术(Atractylis gummifera))、CGP-37157、(-)-鱼藤素(例如,来自绢毛萌豆(Mundulea sericea))、F16、己糖激酶II VDAC结合结构域肽、寡霉素、鱼藤酮、Ru360、SFK1和缬氨霉素(例如,来自极暗黄链霉菌(Streptomycesfulvissimus)(EMD4Biosciences,USA)。
P38抑制剂的实例包括SB-203580(4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)1H-咪唑)、SB-239063(反式-1-(4羟基环己基)-4-(氟苯基)-5-(2-甲氧基-嘧啶-4-基)咪唑)、SB-220025(5-(2氨基-4-嘧啶基)-4-(4-氟苯基)-1-(4-哌啶基)咪唑))和ARRY-797。
NF(例如,NK-κβ)抑制剂的实例包括IFRD1、2-(1,8-萘啶-2-基)苯酚、5-氨基水杨酸、BAY 11-7082、BAY 11-7085、CAPE(咖啡酸苯乙酯)、马来酸二乙酯、IKK-2抑制剂IV、IMD0354、乳胞素、MG-132[Z-Leu-Leu-Leu-CHO]、NFκB激活抑制剂III、NF-κB激活抑制剂II、JSH-23、小白菊内酯、氧化苯胂(PAO)、PPM-18、吡咯烷二硫代氨基甲酸铵盐、QNZ、RO 106-9920、楝酰胺、楝酰胺AL、楝酰胺C、楝酰胺I、楝酰胺J、洛克米兰醇(rocaglaol)、(R)-MG-132、水杨酸钠、雷公藤内酯(PG490)和蟛蜞菊内酯(wedelolactone)。
腺苷受体激动剂的实例包括CGS-21680和ATL-146e。
前列腺素E2激动剂的实例包括E-Prostanoid 2和E-Prostanoid 4。
磷酸二酯酶抑制剂(非选择性和选择性抑制剂)的实例包括咖啡因、氨茶碱、IBMX(3-异丁基-1-甲基黄嘌呤)、副黄嘌呤、己酮可可碱、可可碱、茶碱、甲基化黄嘌呤、长春西汀、EHNA(赤型-9-(2-羟基-3-壬基)腺嘌呤)、阿那格雷、依诺昔酮(PERFANTM)、米立农、左西孟旦、日中花碱(mesembrine)、异丁司特、吡拉米司特、木犀草素、屈他维林、罗氟司特(DAXASTM、DALIRESPTM)、西地那非 他达拉非伐地那非 乌地那非、阿伐那非、淫羊藿苷(icariin)、4-甲基哌嗪和吡唑并嘧啶-7-1。
蛋白酶体抑制剂的实例包括硼替佐米、双硫仑、表没食子儿茶素-3-没食子酸酯和salinosporamide A。
激酶抑制剂的实例包括贝伐单抗、BIBW 2992、西妥昔单抗伊马替尼曲妥珠单抗吉非替尼雷珠单抗哌加他尼、索拉非尼、达沙替尼、舒尼替尼、埃罗替尼、尼洛替尼、拉帕替尼、帕尼单抗、凡德他尼、E7080、帕唑帕尼(pazopanib)和木利替尼(mubritinib)。
糖皮质激素的实例包括氢化可的松(皮质醇)、醋酸可的松、泼尼松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、曲安西龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮(DOCA)和醛固酮。
过氧化物酶体增殖物激活受体拮抗剂的实例包括GW9662、PPARγ拮抗剂III、G335和T0070907(EMD4Biosciences,USA)。
过氧化物酶体增殖物激活受体激动剂的实例包括吡格列酮、环格列酮、氯贝丁酯、GW1929、GW7647、L-165,041、LY 171883、PPARγ激活剂、Fmoc-Leu、曲格列酮和WY-14643(EMD4Biosciences,USA)。
组蛋白去乙酰化酶抑制剂的实例包括异羟肟酸(或氧肟酸盐)例如曲古抑菌素A、环四肽(例如trapoxin B)和缩酚酸肽、苯甲酰胺、亲电性酮类、脂族酸化合物(例如苯丁酸和丙戊酸)、异羟肟酸(例如伏立诺他(SAHA)、贝利司他(PXD101)、LAQ824和帕比司他(LBH589))、苯甲酰胺例如恩替诺特(MS-275)、CI994和mocetinostat(MGCD0103),烟酰胺、NAD衍生物、二氢香豆素类、萘并吡喃酮类、以及2-羟基萘醛。
钙调神经磷酸酶抑制剂的实例包括环孢素、吡美莫司、伏环孢素(voclosporin)和他克莫司。
磷酸酶抑制剂的实例包括BN82002盐酸盐、CP-91149、花萼海绵诱癌素A(calyculin A)、斑蝥酸、斑蝥素、氯氰菊酯、乙基-3,4-迪磷他汀、福司曲星钠盐、MAZ51、甲基-3,4-迪磷他汀、NSC 95397、去甲斑蝥素、来自凹形原甲藻(prorocentrum concavum)的冈田酸铵盐、冈田酸、冈田酸钾盐、冈田酸钠盐、氧化苯胂、多种磷酸酶抑制剂混合物、蛋白质磷酸酶1C、蛋白质磷酸酶2A抑制剂蛋白、蛋白质磷酸酶2A1、蛋白质磷酸酶2A2和正钒酸钠。
在一些实施方案中,治疗性大分子可以以治疗性大分子自身的形式递送或者以其片段或衍生物的形式递送。治疗性大分子可包括治疗性蛋白质和治疗性多核苷酸。治疗性蛋白质包括但不限于:可输注的治疗性蛋白质、酶、酶辅因子、激素、凝血因子、细胞因子和干扰素、生长因子、单克隆抗体和多克隆抗体(例如作为替代治疗施用于对象)以及与庞皮病(Pompe’s disease)相关的蛋白质(例如,酸性葡糖苷酶α,rhGAA)(例如,Myozyme和Lumizyme(Genzyme))。治疗性蛋白质还包括参与凝血级联的蛋白质。治疗性蛋白质包括但不限于:因子VIII、因子VII、因子IX、因子V、冯·维勒布兰德因子(von Willebrandfactor)、von Heldebrant因子、组织纤溶酶原激活物、胰岛素、生长激素、红细胞生成素α、VEGF、血小板生成素、溶菌酶、抗凝血酶等。治疗性蛋白质还包括脂肪素(adipokine),例如瘦素和脂联素。治疗性蛋白质的其他实例如下文及本文中的其他部分所述。
用于患有溶酶体贮积症之对象的酶替代治疗中的治疗性蛋白质的实例包括但不限于:用于治疗戈谢病(Gaucher’s disease)的伊米苷酶(例如,CEREZYMETM),用于治疗法布里病(Fabry disease)的a-半乳糖苷酶A(a-gal A)(例如,阿加糖酶β、FABRYZYMETM),用于治疗庞皮病的酸性α-葡糖苷酶(GAA(例如,酸性葡糖苷酶α、LUMIZYMETM、MYOZYMETM),和用于治疗黏多醣贮积症(Mucopolysaccharidose)的芳基硫酸酯酶B(例如,拉罗尼酶、ALDURAZYMETM、艾杜硫酶、ELAPRASETM、芳基硫酸酯酶B、NAGLAZYMETM)、聚乙二醇化重组尿酸酶(pegloticase)(KRYSTEXXA)和聚乙二醇化重组假丝酵母尿酸酶(pegsiticase)。
酶的实例包括:氧化还原酶、转移酶、水解酶、裂合酶、异构酶、天冬酰胺酶、尿酸酶、糖苷酶、天冬酰胺酶、尿酸酶、蛋白酶、核酸酶、胶原酶、透明质酸酶、肝素酶、类肝素酶、细胞溶素(lysin)和连接酶。
治疗性蛋白质还可包括分离自或来源于细菌、真菌或病毒来源的任何酶、毒素或其他蛋白质或肽。
激素的实例包括:褪黑激素(N-乙酰基-5-甲氧基色胺)、血清素、甲状腺素(或四碘甲腺原氨酸)(甲状腺激素)、三碘甲腺氨酸(甲状腺激素)、肾上腺素(或肾上腺激素)、去甲肾上腺素(或去甲肾上腺激素)、多巴胺(或催乳素抑制激素)、抗米勒管激素(或米勒管抑制因子或激素)、脂连蛋白、促肾上腺皮质激素(或促皮质素)、血管紧张素原和血管紧张素、抗利尿激素(或加压素、精氨酸加压素)、心房钠尿肽(或心钠素)、降钙素、胆囊收缩素、促皮质素释放激素、红细胞生成素、促卵泡激素、胃泌素、生长素释放肽、胰高血糖素、胰高血糖素样肽(GLP-1)、GIP、促性腺素释放激素、生长激素释放激素、人绒毛膜促性腺素、人胎盘催乳素、生长激素、抑制素、胰岛素、胰岛素样生长因子(或生长调节素)、瘦素、黄体化激素、黑素细胞刺激激素、食欲素、催产素、甲状旁腺激素、催乳素、松弛素、分泌素、生长激素抑制素、血小板生成素、甲状腺刺激激素(或促甲状腺素)、促甲状腺素释放激素、皮质醇、醛固酮、睾酮、去氢表雄酮、雄烯二酮、二氢睾酮、雌二醇、雌酮、雌三醇、黄体酮、骨化三醇(1,25-二羟基维生素D3)、骨化二醇(25-羟基维生素D3)、前列腺素类、白三烯类、前列环素、血栓烷类、催乳素释放激素、促脂解素、脑钠尿肽、神经肽Y、组胺、内皮素、胰多肽、肾素和脑啡肽。
血液因子或凝血因子的实例包括因子I(纤维蛋白原)、因子II(凝血酶原)、组织因子、因子V(前加速素,不稳定因子)、因子VII(稳定因子、前转化素)、因子VIII(抗血友病球蛋白)、因子IX(克雷司马斯因子(Christmas factor)或血浆促凝血酶原激酶组分)、因子X(斯图尔特因子(Stuart-Prower factor))、因子Xa、因子XI、因子XII(哈格曼因子(Hagemanfactor))、因子XIII(纤维蛋白稳定因子)、冯·维勒布兰德因子、前激肽释放酶(弗莱彻因子(Fletcher factor))、高分子量激肽原(HMWK)(菲兹杰拉尔德因子(Fitzgeraldfactor))、纤连蛋白、纤维蛋白、凝血酶、抗凝血酶III、肝素辅因子II、蛋白C、蛋白S、蛋白Z、蛋白Z相关蛋白酶抑制剂(ZPI)、纤溶酶原、α2-抗纤溶酶、组织纤溶酶原激活物(tPA)、尿激酶、纤溶酶原激活物抑制剂-1(PAI1)、纤溶酶原激活物抑制剂-2(PAI2)、癌促凝物质或阿法依伯汀(Epogen,Procrit)。
细胞因子的实例包括淋巴因子、白介素、以及趋化因子、1型细胞因子(例如IFN-γ、TGF-β)和2型细胞因子(例如IL-4、IL-10和IL-13)。
生长因子的实例包括肾上腺髓质素(AM)、血管生成素(Ang)、自分泌运动因子、骨形态生成蛋白(Bone morphogenetic protein,BMP)、脑源性神经营养因子(Brain-derivedneurotrophic factor,BDNF)、表皮生长因子(Epidermal growth factor,EGF)、红细胞生成素(EPO)、成纤维细胞生长因子(Fibroblast growth factor,FGF)、神经胶质细胞系源性神经营养因子(Glial cell line-derived neurotrophic factor,GDNF)、粒细胞集落刺激因子(Granulocyte colony-stimulating factor,G-CSF)、粒细胞-巨噬细胞集落刺激因子(Granulocyte macrophage colony-stimulating factor,GM-CSF)、生长分化因子-9(Growth differentiation factor-9,GDF9)、肝细胞生长因子(Hepatocyte growthfactor,HGF)、肝癌源性生长因子(Hepatoma-derived growth factor,HDGF)、胰岛素样生长因子(Insulin-like growth factor,IGF)、促移行因子、肌生长抑制素(GDF-8)、神经生长因子(Nerve growth factor,NGF)及其他神经营养因子、血小板源性生长因子(Platelet-derived growth factor,PDGF)、血小板生成素(TPO)、转化生长因子α(Transforming growth factor alpha,TGF-α)、转化生长因子β(Transforming growthfactor beta,TGF-β)、肿瘤坏死因子α(Tumour_necrosis_factor-alpha,TNF-α)、血管内皮生长因子(Vascular endothelial growth factor,VEGF)、Wnt信号传导途径、胎盘生长因子(placental growth factor,P1GF)、(胎牛促生长素,Foetal Bovine Somatotrophin)(FBS)、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6和IL-7。
单克隆抗体的实例包括阿巴伏单抗、阿昔单抗、阿达木单抗、阿德木单抗、阿非莫单抗、阿夫土珠单抗(Afutuzumab)、培化阿珠单抗、ALD、阿仑单抗、阿妥莫单抗喷替酸盐、麻安莫单抗、安芦珠单抗、抗胸腺细胞珠蛋白、阿泊珠单抗、阿西莫单抗、阿塞珠单抗、Atlizumab(托珠单抗)、阿托木单抗、Bapineuzumab、巴利昔单抗、巴维昔单抗、贝妥莫单抗、贝利木单抗、Benralizumab、柏替木单抗、贝索单抗、贝伐单抗、比西单抗、莫比伐珠单抗、二Blinatumomab、Brentuximab vedotin、Briakinumab、卡那单抗、莫坎妥珠单抗、卡罗单抗喷地肽、卡妥索单抗、西利珠单抗、赛妥珠单抗、西妥昔单抗、泊西他珠单抗、Cixutumumab、克立昔单抗、Clivatuzumab tetraxetan、Conatumumab、Dacetuzumab、达珠单抗、Daratumumab、狄迪诺塞麦、地莫单抗、阿托度单抗、Dorlixizumab、依美昔单抗、依库珠单抗、埃巴单抗、依决可单抗、依法利珠单抗、依芬古单抗、埃罗妥珠单抗、艾西莫单抗、培戈赖莫单抗、西依匹莫单抗、依帕珠单抗、Erlizumab、厄妥索单抗、Etaracizumab、艾韦单抗、Fanolesomab、法拉莫单抗、Farletuzumab、非维珠单抗、非扎奴单抗、Figitumumab、芳妥珠单抗、Foravirumab、Fresolimumab、Galiximab、Gantenerumab、加维莫单抗、吉妥单抗、GC1008、Girentuximab、Glembatumumab vedotin、戈利木单抗、Gomiliximab、Ibalizumab、替伊莫单抗、伊戈伏单抗、英西单抗、英夫利昔单抗、Intetumumab、伊诺莫单抗、奥英妥珠单抗、依匹木单抗、Iratumumab、凯利昔单抗、拉贝珠单抗、Lebrikizumab、来马索单抗、乐地单抗、来沙木单抗、利韦单抗、林妥珠单抗、Lorvotuzumab mertansine、Lucatumumab、鲁昔单抗、马帕木单抗、马司莫单抗、马妥珠单抗、美泊利单抗、美替木单抗、Milatuzumab、明瑞莫单抗、米妥莫单抗、莫罗木单抗、Motavizumab、鼠单克隆抗体-CD3、他那可单抗、Naptumomabestafenatox、那他珠单抗、奈巴库单抗、Necitumumab、奈瑞莫单抗、尼妥珠单抗、巯诺莫单抗、Ocrelizumab、奥度莫单抗、奥法木单抗、Olaratumab、奥马珠单抗、莫奥珠单抗、奥戈伏单抗、Otelixizumab、Pagibaximab、帕利珠单抗、帕尼单抗、Panobacumab、帕考珠单抗、Pemtumomab、帕妥珠单抗、Pexelizumab、平妥莫单抗、普立昔单抗、Pritumumab、雷韦单抗、雷莫芦单抗、雷珠单抗、Raxibacumab、瑞加韦单抗、瑞利珠单抗、Rilotumumab、利妥昔单抗、Robatumumab、Rontalizumab、罗维珠单抗、鲁利单抗、沙妥莫单抗喷地肽、司韦单抗西罗珠单抗、西法木单抗、Siltuximab、西利珠单抗、Solanezumab、Sonepcizumab、Sontuzumab、Stamulumab、硫索单抗、Tacatuzumab tetraxetan、他度珠单抗、Talizumab、尼珠单抗、帕他普莫单抗、替非珠单抗、阿替莫单抗、Tenatumomab、替奈昔单抗、Teplizumab、Ticilimumab(替西木单抗)、替加珠单抗、托珠单抗(atlizumab)、托利珠单抗、托西莫单抗、曲妥珠单抗、替西木单抗、Tucotuzumab celmoleukin、妥韦单抗、乌珠单抗、Ustekinumab、伐利昔单抗、维多珠单抗、维妥珠单抗、维帕莫单抗、Visilizumab、伏洛昔单抗、伏妥莫单抗、Zalutumumab、扎木单抗、齐拉木单抗和阿佐莫单抗。单克隆抗体还包括抗-TNF-a抗体。
输注治疗或可注射的治疗性蛋白质的实例包括例如:托珠单抗α-1抗胰蛋白酶(Kamada/AAT)、(Affymax和Takeda,合成肽)、白蛋白干扰素α-2b(albinterferon alfa-2b)(Novartis/ZalbinTM)、(Pharming Group,C1抑制剂替代治疗)、替莫瑞林(Theratechnologies/Egrifta,合成生长激素释放因子)、奥瑞珠单抗(Genentech、Roche和Biogen)、贝利木单抗聚乙二醇化重组尿酸酶(SavientPharmaceuticals/KrystexxaTM)、聚乙二醇化重组假丝酵母尿酸酶、他利苷酶α(Protalix/Uplyso)、阿加糖酶α葡糖脑苷脂酶α(Shire)和钥孔林普贝血蓝蛋白(Keyhole Limpet Hemocyanin,KLH)。
另外的治疗性蛋白质包括例如:工程化蛋白质,例如Fc融合蛋白、双特异性抗体、多特异性抗体、纳米体、抗原结合蛋白、抗体片段和蛋白质缀合物,例如抗体药物缀合物。
治疗性多核苷酸包括但不限于:核酸适配体例如哌加他尼(Macugen,一种聚乙二醇化抗VEGF适配体)、反义治疗性多核苷酸例如反义多核苷酸或反义寡核苷酸(例如,抗病毒药福米韦生,或米泊美生,靶向载脂蛋白B的信使RNA以降低胆固醇水平的反义治疗剂);小干扰RNA(siRNA)(例如,dicer底物siRNA分子(DsiRNA),其为以极高效力介导RNAi的25-30个碱基对的不对称双链RNA);或经修饰的信使RNA(mmRNA)例如Fougerolles等的美国专利申请2013/0115272和Schrum等的公开的美国专利申请2012/0251618中所述的那些。
可根据本发明的一些方面使用的其他治疗性大分子对本领域技术人员是显而易见的,并且本发明在此方面不受限制。
在一些实施方案中,组分(例如治疗性大分子或免疫抑制剂)可以是经分离的。“经分离的”指组分与其天然环境分离并且以足够量存在以允许其鉴定或使用。这意味着,例如,组分可(i)通过表达克隆选择性地产生或者(ii)通过色谱或电泳进行纯化。经分离的组分可以但不需要是基本纯的。由于可将经分离的组分与可药用赋形剂一起混合在药物制剂中,所述组分可仅占制剂的小重量百分比。组分仍是经分离的,只要其已与在活系统中与其相关的物质分离,即与其他脂质或蛋白质分离。本文中提供的任一种组分均可以是经分离的并且以经分离形式包含在组合物中或者用于方法中。
D.制备和使用所述方法及相关组合物的方法
在所述免疫抑制剂包括可植入渗透泵的实施方案中,可使用含有免疫抑制剂的溶液的可植入渗透泵制备免疫抑制剂。这样的可植入泵可皮下植入以使免疫抑制剂受控地释放到局部皮下空间中从而使化合物被局部毛细管吸收,产生全身施用,或者可腹膜内植入在腹膜腔内以使免疫抑制剂受控地释放到肝门静脉循环中。还可经由导管使用可植入泵以使免疫抑制剂受控地静脉内递送到静脉或动脉循环中。当药物或测试剂的作用定位于特定组织或器官中时,可将它们与用于静脉内、脑内或动脉内输注或者用于靶向递送的导管连接。参见,例如,S.M.Stepkowski等,“Inhibition of host-versus-graft andgraft-versus-host responses after small bowel transplantation in rats byrapamycin.”Transplantation(1992)53(-2-):258-264。有关牌渗透泵的设置和使用的更多信息(包括丰富的文献数据库)可在alzet.com获得。
在所述免疫抑制剂包括双特异性抗体(BsAb)的实施方案中,可根据本领域中已知的方法通过遗传学或生物学方法(例如使两种不同的杂交瘤细胞系融合)或者通过化学方法(例如使两个抗体分子经由合适的接头交联)来制备双特异性抗体。已开发了用于产生BsAb的数种方法。可通过使两种杂交瘤系融合,产生能够分泌BsAb的四体瘤(quadroma)来生物学产生BsAb。还可遗传学产生BsAb,并且多种遗传技术已用于产生双特异性分子。产生BsAb的第三种方法是通过化学手段使用多种同双功能和异双功能化学接头(参考:Bispecific Antibodies,由Roland E.Kontermann编辑,Springer,2011)。有关形成的更多信息可见于文献中,所述文献包括但不限于M.Peipp等,“Bispecific antibodiestargeting cancer cells”Biochemical Society Transaction第507-511页第30卷第4章(2002)。与使用单克隆抗体的方法类似,可通过皮下或静脉内注射来向患者施用BsAb。
在某些实施方案中,所述免疫抑制剂可以是可植入聚合物储库材料的形式。可根据见于例如Dunn等之标题为“Polymeric compositions useful as controlled releaseimplants”的美国专利5,702,716;和Brodbeck等之标题为“Gel composition andmethods”的美国专利6,130,200中的常规实践来配制和施用可植入聚合物储库材料。
在一些实施方案中,免疫抑制剂是与合成纳米载体连接的。可使用本领域中已知的多种方法来制备合成纳米载体。例如,可通过以下方法及本领域普通技术人员公知的其他方法来形成合成纳米载体:例如,纳米沉淀、使用流体通道的流体聚焦、喷雾干燥、单乳化溶剂蒸发和复乳化溶剂蒸发、溶剂萃取、相分离、研磨、微乳化法、微制造、纳米制造、牺牲层、简单凝聚和复合凝聚。作为替代或补充,用于单分散半导体纳米材料、电导性纳米材料、磁性纳米材料、有机纳米材料及其他纳米材料的水性溶剂和有机溶剂合成已有描述(Pellegrino等,2005,Small,1:48;Murray等,2000,Ann.Rev.Mat.Sci.,30:545;和Trindade等,2001,Chem.Mat.,13:3843)。另外的方法已在以下文献中进行了描述(参见,例如,Doubrow,编辑,“Microcapsules and Nanoparticles in Medicine and Pharmacy,”CRC Press,Boca Raton,1992;Mathiowitz等,1987,J.Control.Release,5:13;Mathiowitz等,1987,Reactive Polymers,6:275;和Mathiowitz等,1988,J.Appl.Polymer Sci.,35:755;美国专利5578325和6007845;P.Paolicelli等,“Surface-modified PLGA-basedNanoparticles that can Efficiently Associate and Deliver Virus-likeParticles”Nanomedicine.5(6):843-853(2010))。
如果期望的话,可使用多种方法将多种材料包封在合成纳米载体内,所述方法包括但不限于C.Astete等,“Synthesis and characterization of PLGA nanoparticles”J.Biomater.Sci.Polymer Edn,第17卷,第3期,第247-289页(2006);K.Avgoustakis“Pegylated Poly(Lactide)and Poly(Lactide-Co-Glycolide)Nanoparticles:Preparation,Properties and Possible Applications in Drug Delivery”CurrentDrug Delivery 1:321-333(2004);C.Reis等,“Nanoencapsulation I.Methods forpreparation of drug-loaded polymeric nanoparticles”Nanomedicine 2:8-21(2006);P.Paolicelli等,“Surface-modified PLGA-based Nanoparticles that canEfficiently Associate and Deliver Virus-like Particles”Nanomedicine.5(6):843-853(2010)。也可使用适合将材料包封在合成纳米载体内的其他方法,包括但不限于于2003年10月14日授权之Unger的美国专利6,632,671中所公开的方法。
在某些实施方案中,通过纳米沉淀法或喷雾干燥来制备合成纳米载体。可对用于制备合成纳米载体的条件进行改变以产生具有期望尺寸或特性(例如,疏水性、亲水性、外部形态、“黏性”、形状等)的颗粒。制备合成纳米载体的方法及所使用的条件(例如,溶剂、温度、浓度、空气流速等)可取决于待与合成纳米载体连接的材料和/或聚合物基质的组成。
如果通过上述任一种方法制备的合成纳米载体的尺寸范围在期望范围之外,则可例如使用筛对此类合成纳米载体进行尺寸选择。
合成纳米载体的成分(即,组分)可与整个合成纳米载体例如通过一个或更多个共价键连接,或者可借助一个或更多个接头连接。官能化合成纳米载体的另外方法可改编自Saltzman等的公开的美国专利申请2006/0002852、DeSimone等的公开的美国专利申请2009/0028910或Murthy等的公开的国际专利申请WO/2008/127532 A1。
作为替代或补充,合成纳米载体与组分可直接地或间接地经由非共价相互作用连接。在一些非共价实施方案中,非共价偶联由非共价相互作用介导,所述非共价相互作用包括但不限于:电荷相互作用、亲和性相互作用、金属配位、物理吸附、主体-客体相互作用、疏水性相互作用、TT堆积相互作用、氢键合相互作用、范德华相互作用、磁性相互作用、静电相互作用、偶极-偶极相互作用和/或其组合。这样的偶联可布置成在合成纳米载体的外表面或内表面上。在一些实施方案中,包封和/或吸附是偶联的形式。在一些实施方案中,可将合成纳米载体与免疫抑制剂或治疗性大分子通过混合在同一载剂或递送系统中而组合。
所提供的组合物可包含无机或有机缓冲剂(例如,磷酸、碳酸、醋酸或柠檬酸的钠盐或钾盐)和pH调节剂(例如,盐酸、氢氧化钠或氢氧化钾、柠檬酸或醋酸的盐、氨基酸及其盐)、抗氧化剂(例如,抗坏血酸、α-生育酚)、表面活性剂(例如,聚山梨醇酯20、聚山梨醇酯80、聚氧乙烯9-10壬基苯酚、去氧胆酸钠)、溶液剂和/或冷冻/冻干稳定剂(例如,蔗糖、乳糖、甘露醇、海藻糖)、渗透调节剂(例如,盐或糖)、抗菌剂(例如,苯甲酸、苯酚、庆大霉素)、消泡剂(例如,聚二甲基硅氧烷)、防腐剂(例如,硫柳汞、2-苯氧基乙醇、EDTA)、聚合物稳定剂和黏度调节剂(例如,聚乙烯吡咯烷酮、泊洛沙姆488、羧甲基纤维素)和潜溶剂(例如甘油、聚乙二醇、乙醇)。
根据本发明的组合物可包含可药用赋形剂。所述组合物可使用常规的药物制备和配合技术制成以实现可用的剂型,或者可使用专业技术制成(例如在泵或双特异性抗体的情况下)。适用于实施本发明的技术可见于Handbook of Industrial Mixing:Science and Practice,由Edward L.Paul,Victor A.Atiemo-Obeng和Suzanne M.Kresta编辑,2004John Wiley&Sons,Inc.;和Pharmaceutics:The Science of Dosage FormDesign,第2版.由M.E.Auten编辑,2001,Churchill Livingstone中。在一个实施方案中,组合物与防腐剂一起存在于无菌盐水溶液中以用于注射。
应当理解,本发明的组合物可以以任何合适的方式制备,并且本发明不以任何方式局限于可使用本文中所述的方法制备的组合物。对合适制备方法的选择可需要注意所缔合的具体部分的特性。
在一些实施方案中,免疫治疗剂、治疗性大分子或包含此类材料的组合物是在无菌条件下制备的,或者是经最终灭菌的。这可确保所得材料或组合物是无菌的和非感染性的,从而当与非无菌材料或组合物相比时,安全性提高。这提供了有价值的安全措施,尤其是当接受所述材料或组合物的对象有免疫缺陷,患有感染和/或易受感染时。在一些实施方案中,可将所述材料或组合物冷冻干燥并悬浮储存或者作为冻干粉末储存,这取决于不丧失活性的长期配制策略。
根据本发明的施用可通过多种途径,包括但不限于:皮下、静脉内、腹膜内、肌内、经粘膜、经皮、经皮肤或皮内途径。在一个优选实施方案中,施用经由皮下施用途径。可使用常规方法将本文中提及的组合物配制和制备成用于施用,在一些实施方案中用于伴随施用。
可以以有效量(例如本文中其他部分所述的有效量)施用本发明的组合物。根据本发明,剂型的剂量可包含不同量的免疫抑制剂或治疗性大分子。剂型中存在的免疫抑制剂或治疗性大分子的量可根据以下方面而不同:治疗性大分子、免疫抑制剂的性质、需达到的治疗益处、及其他这样的参数。在一些实施方案中,可进行剂量范围研究以建立任何剂型中存在的免疫抑制剂或治疗性大分子的最佳治疗量。在一些实施方案中,免疫抑制剂或治疗性大分子以在施用于对象后有效产生针对治疗性大分子的致耐受性免疫应答的量存在于剂型中。可使用常规的剂量范围研究和技术来确定免疫抑制剂或治疗性大分子之在对象中有效产生致耐受性免疫应答的量。免疫抑制剂或治疗性大分子的施用可以以多种频率发生。
本公开内容的另一个方面涉及药盒。在一些实施方案中,所述药盒包含提供药效学有效持续期的免疫抑制剂剂量。在一些实施方案中,所述药盒还包含治疗性大分子的剂量。免疫抑制剂剂量和治疗性大分子剂量可包含在药盒中的独立容器中或者包含在药盒中的同一容器中。在一些实施方案中,所述容器为小瓶或安瓿。在一些实施方案中,治疗性大分子剂量和/或免疫抑制剂剂量包含在与容器分开的溶液中,使得可随后将治疗性大分子剂量和/或免疫抑制剂剂量添加至容器。在一些实施方案中,治疗性大分子剂量和/或免疫抑制剂剂量以冻干形式各自存在于独立容器中或同一容器中,使得它们可随后重构。在一些实施方案中,所述药盒还包含用于重构、混合、施用等的说明书。在一些实施方案中,所述说明书包含对本文中所述的方法的说明。说明书可以是任何合适的形式,例如,作为印刷插入物或标签。在一些实施方案中,所述药盒还包含一个或更多个注射器。
实施例
实施例1:含雷帕霉素的纳米载体
材料
雷帕霉素购自TSZ CHEM(185Wilson Street,Framingham,MA01702;产品目录#R1017)。约25,000Da的PLGA购自Lakeshore Biochemicals(756 Tom Martin Drive,Birmingham,AL 35211)。产品代码5050 DLG 2.5A。甲基醚封端的PEG嵌段为约5,000Da并且PLA嵌段为约48,000Da的PLA-PEG-OMe嵌段共聚物购自Lakeshore Biochemicals(756 TomMartin Drive,Birmingham,AL 35211)。产品代码100 DLmPEG 5000 5CE。聚乙烯醇4-88,USP(85%至89%水解的,黏度为3.4mPa·s至4.6mPa·s)购自EMDChemicals Inc.(480 South Democrat Road Gibbstown,NJ 08027.型号1.41354)。
方法
如下制备溶液:
溶液1:二氯甲烷中的75mg/mL PLGA、25mg/mL PLA-PEG-OMe和12.5mg/mL的雷帕霉素。该溶液通过将PLGA、PLA-PEG-OMe和雷帕霉素溶解于纯二氯甲烷中制备。
溶液2:100mM pH 8磷酸盐缓冲液中的50mg/mL聚乙烯醇。
溶液3:70mM磷酸盐缓冲液,pH 8。
如下制备水包油型乳剂:将溶液1(1mL)和溶液2(3mL)混合在小玻璃压力管中并使用Branson Digital Sonifier 250以30%振幅进行超声处理60秒。将乳剂添加至含有溶液3(30mL)的50mL敞开烧杯并在室温下搅拌2小时以使二氯甲烷蒸发并混悬形成纳米载体。然后,将一部分的混悬纳米载体经如下洗涤:将纳米载体混悬液转移至离心管并在75,600rcf旋转40分钟,除去上清液并将沉淀物重悬于磷酸缓冲盐水中。重复该洗涤操作并随后将沉淀物重悬于PBS 1X中以获得基于聚合物的标称浓度为10mg/mL的纳米载体混悬液。将混悬液冷冻储存在-20℃下直至使用。
通过动态光散射确定纳米载体的尺寸。通过HPLC分析确定纳米载体中的雷帕霉素量。通过重量法确定总干纳米载体质量/mL混悬液。
实施例2:包含聚合物-雷帕霉素缀合物的聚合物纳米载体(预示性的)
步骤1:制备PLGA-雷帕霉素缀合物:
将具有酸端基的PLGA聚合物(7525 DLG1A,酸值0.46mmol/g,LakeshoreBiomaterials;5g,2.3mmol,1.0当量)溶解于30mL二氯甲烷(dichloromethane,DCM)中。添加N,N-二氯环己基碳二亚胺(1.2当量,2.8mmol,0.57g),之后添加雷帕霉素(1.0当量,2.3mmol,2.1g)和4-二甲基氨基吡啶(4-dimethylaminopyridine,DMAP)(2.0当量,4.6mmol,0.56g)。将混合物在室温下搅拌2天。然后,过滤混合物以除去不溶性二环己基脲。将滤液浓缩至体积为约10mL并添加至100mL异丙醇(isopropyl alcohol,IPA)以沉淀出PLGA-雷帕霉素缀合物。移出IPA层并随后用50mL IPA和50mL甲基叔丁基醚(methyl t-butyl ether,MTBE)洗涤聚合物。然后,将聚合物在35℃下真空干燥2天以得到作为白色固体的PLGA-雷帕霉素(约6.5g)。
步骤2:根据实施例1中所述的操作如下制备包含PLGA-雷帕霉素的纳米载体:
如下制备用于纳米载体形成的溶液:
溶液1:二氯甲烷中的100mg/mL PLGA-雷帕霉素。该溶液通过将PLGA-雷帕霉素溶解于纯二氯甲烷中制备。溶液2:二氯甲烷中的100mg/mL PLA-PEG。该溶液通过将PLA-PEG溶解于纯二氯甲烷中制备。溶液3:100mM pH 8磷酸盐缓冲液中的50mg/mL聚乙烯醇。
首先制备初级的油包水乳剂。如下制备W1/O1:将溶液1(0.75mL)和溶液2(0.25mL)合并在小压力管中并使用Branson Digital Sonifier 250以50%振幅进行超声处理40秒。然后,如下制备次级乳剂(W1/O1/W2):将溶液3(3.0mL)与初级W1/O1乳剂组合,涡旋10秒并使用Branson Digital Sonifier 250以30%振幅进行超声处理60秒。然后,将W1/O1/W2乳剂添加至含有70mM pH 8磷酸盐缓冲溶液(30mL)的烧杯并在室温下搅拌2小时以使二氯甲烷蒸发并形成纳米载体。将一部分的纳米载体经如下洗涤:将纳米载体混悬液转移至离心管并在75,600×g和4℃下离心35分钟,除去上清液并将沉淀物重悬于磷酸缓冲盐水中。重复洗涤操作并将沉淀物重悬于磷酸缓冲盐水中以获得约10mg/mL的最终纳米载体分散体。
实施例3:制备包含雷帕霉素的金纳米载体(AuNC)(预示性的)
步骤1.制备HS-PEG-雷帕霉素:
将PEG酸二硫化物(1.0当量)、雷帕霉素(2.0至2.5当量)、DCC(2.5当量)和DMAP(3.0当量)在无水DMF中的溶液在室温下搅拌过夜。通过过滤除去不溶性二环己基脲并将滤液添加至异丙醇(IPA)以沉淀出PEG-二硫化物-二-雷帕霉素酯,用IPA洗涤并干燥。然后,用DMF中的三(2-羧基乙基)膦盐酸盐处理聚合物以将PEG二硫化物还原成巯基PEG雷帕霉素酯(HS-PEG-雷帕霉素)。通过从IPA中沉淀出回收所得聚合物,如前所述进行干燥并通过H NMR和GPC分析。
步骤2.金NC(AuNC)的形成:
在剧烈搅拌下,将500mL 1mM HAuCl4的水溶液在装备有冷凝器的1L圆底瓶中加热回流10分钟。然后,向搅拌中的溶液迅速添加50mL40mM柠檬酸三钠的溶液。将所得的深酒红色溶液在回流下保持25至30分钟并输出热量,将溶液冷却至室温。然后,通过0.8μm膜过滤器过滤溶液以得到AuNC溶液。使用可见光谱和透射电子显微术对AuNC进行表征。经柠檬酸盐包被的AuNC的直径为约20nm,并且在520nm下具有峰吸光度。
步骤3.具有HS-PEG-雷帕霉素的AuNC缀合物:
向1mL直径为20nm的经柠檬酸盐包被金纳米载体(1.16nM)添加150μl HS-PEG-雷帕霉素(在10mM pH 9.0碳酸盐缓冲液中10μM)的溶液以产生巯基∶金为2500∶1的摩尔比。将混合物在氩气下在室温下搅拌1小时以使巯基与金纳米载体上的柠檬酸盐完全交换。然后,通过在12,000g下离心30分钟纯化表面上具有PEG-雷帕霉素的AuNC。将上清液倒出并随后用1x PBS缓冲液洗涤含有AuNC-S-PEG-雷帕霉素的沉淀物。然后,将经纯化的金-PEG-雷帕霉素纳米载体重悬于合适的缓冲液中以进行进一步的分析和生物测定。
实施例4:经包封雷帕霉素对引发抗体应答的影响
I.IgG的测量
一般如下测量IgG抗体的水平。使用PBS中的封闭剂酪蛋白(Thermo Fisher,目录#37528)作为稀释剂。使用PBS中的0.05%Tween-20作为洗涤缓冲液,其通过将10ml Tween-20((Sigma,目录#P9416-100mL)添加至2升10x PBS贮存液(PBS:10X PBS液体浓缩物,4L,EMD Chemicals,目录#6505)和18升去离子水制备而成。
使用贮存液浓度为10mg/ml的钥孔林普贝血蓝蛋白(KLH)或贮存液浓度为5mg/ml的卵清蛋白(Ovalbumin,OVA)作为包被材料。将两种材料稀释至5μg/ml,并将其用作工作浓度。用100μl经稀释KLH或OVA/孔包被测定板的每个孔,将板用密封膜(VWR目录#60941-120)密封并在4℃下孵育过夜。使用Costar 901796孔平底板作为测定板(Costar 9017)。
使用低结合聚丙烯96孔板或管作为在转移至测定板之前在其中制备样品的制备板(set-up plate)。制备板不含任何抗原,因此在制备样品期间血清抗体不与该板结合。如果使用经抗原包被的板来制备样品,使用制备板进行样品制备以最小化在制备或用移液管吸移样品期间可发生的结合。在于制备板中制备样品之前,将孔用稀释剂覆盖以封闭任何非特异性结合,将板密封并在4℃下孵育过夜。
将测定板用洗涤缓冲液洗涤三次,并在最后一次洗涤之后完全吸出孔中的洗涤缓冲液。在洗涤之后,向测定板的每个孔添加300μl稀释剂以封闭非特异性结合并将板在室温下孵育至少2小时。在制备板的合适孔中以1∶40稀释血清样品。使用标准物作为阳性对照。对于KLH,以1μg/mL起始稀释物使用小鼠抗KLH IgG抗体,然后在整个板中稀释3倍。对于OVA,以0.5μg/mL起始稀释物使用小鼠抗OVA IgG抗体,然后在整个板中稀释3倍
一旦在制备板中制备完所有的样品,将板密封并储存在4℃下,直至测定板的封闭完成。将测定板用洗涤缓冲液洗涤三次,并在最后一次洗涤之后完全吸出洗涤缓冲液。在洗涤之后,向测定板的柱2至柱12添加100μL稀释剂。使用移液管将样品从制备板转移至测定板。在转移之前通过将150μl经稀释的血清用移液管上下吸移3次来混合样品。在混合之后,将每份样品中的150μl从制备板转移并添加至各自的测定板。
一旦将每份样品的起始稀释物从制备板转移至测定板,如下在测定板上用移液管吸移连续稀释物:使用移液管取出每份血清样品中的50μl并将其与之前添加的100μl稀释剂混合。在整个板中重复该步骤。在用移液管吸移最后柱的稀释物之后,从最后柱的孔中取出50μl流体并弃掉,在测定板的每个孔中产生100μl的终体积。一旦在测定板中制备完样品稀释物,将板在室温下孵育至少2小时。
在孵育之后,将板用洗涤缓冲液洗涤三次。在稀释剂中以1∶1500(0.33μg/mL)稀释检测抗体(山羊抗小鼠抗IgG,HRP缀合的)并向每个孔添加100μl经稀释的抗体。将板在室温下孵育1小时并随后用洗涤缓冲液洗涤5次,在最后一次洗涤之后完全吸出洗涤缓冲液。在洗涤之后,向孔添加检测底物。在即将添加至测定板之前,将等份的底物A和底物B(BDBiosciences TMB Substrate Reagent Set,目录#555214)合并,向每个孔添加100μl的经混合底物溶液并在暗处孵育10分钟。10分钟时间后,通过向每个孔添加50μl终止溶液(2NH2SO4)终止反应。在添加终止溶液之后,立即通过450nm下的板读数与570nm下的板读数相减评估孔的光密度(optical density,OD)。使用Molecular Device软件SoftMax Prov6.2.2进行数据分析。以稀释度为x轴(log刻度)并以OD值为y轴(线性刻度)制作四参数逻辑曲线拟合图(logistic vurve-fit graph),并确定每份样品的半最大值(EC50)。调整布局顶部的板模板以反映每份样品的稀释度(1/排)。
II.制备颗粒卵清蛋白(Particulate Ovalbumin Protein,pOVA)
材料
鸡卵卵清蛋白(OVA)购自Worthington Biochemical Corporation(730 VassarAvenue,Lakewood,NJ 08701;产品代码LS003054)。磷酸缓冲盐水(Phosphate bufferedsaline,PBS)购自Mediatech(9345 Discovery Boulevard,Manassas,VA 20109;产品代码21-040-CV)。氢氧化钠(NaOH,产品代码367176)和三氟乙酸(trifluoroacetic acid,TFA;产品代码T62200)购自Sigma-Aldrich Corp.(3050 Spruce Street,St.Louis,MO 63103)。
方法
如下制备溶液:
溶液1:PBS中的15mg/mL OVA。该溶液通过将卵清蛋白直接溶解于PBS中制备。溶液2:水中的1M NaOH。该溶液通过将NaOH直接溶解于无内毒素的水中制备。
通过重复升降卵清蛋白溶液的pH使OVA凝聚。将溶液1(10mL)添加至含有磁力搅拌棒的20-mL玻璃小瓶。在搅拌的同时,向瓶逐滴添加溶液2,直至溶液达到pH 12。然后,向小瓶逐滴添加TFA,直至溶液达到pH 2。将pH的这种升降再重复3次。然后,向小瓶逐滴添加溶液2,直至溶液达到pH 7。
然后,通过高压均质化减小凝聚OVA颗粒的尺寸。将凝聚OVA混悬液上样到具有G10Z相互作用室的Microfluidics LV1中,并随后在20,000psi下使用3程进行均质化。将尺寸为190至240nm的所得颗粒OVA(pOVA)储存在-20C下。
III.对经包封雷帕霉素对引发抗体应答的体内测试
在第0、3和7天,使C57BL/6动物的组(n=5)保持未处理且未免疫(未免疫)、未处理但进行免疫(未处理)或者用来自实施例1之含雷帕霉素的纳米载体进行处理并进行免疫(Rapa-NC)。免疫由注射卵清蛋白的颗粒形式(pOVA)组成。注射发生在后肢内皮下。每次注射的颗粒剂量为100μg雷帕霉素的当量,在三次注射之后总共300μg。从第14天开始,使未经处理和经处理的动物(未处理和Rapa-NC)两周一次地接受以下免疫(第14、28和42天):在前肢内注射如上制备的10μg pOVA(每个30μl),并在尾根部内注射50μg钥孔林普贝血蓝蛋白(KLH,Sigma Aldrich)(每侧50μl)。在图1中的指定的日子对所有动物采血并通过ELISA确定抗OVA应答。
数据证明,当在本文中提供的药效学有效持续期范围内在施用抗原前7天注射时,经包封的雷帕霉素有效地抑制抗OVA应答。
实施例5:在经包封雷帕霉素存在下对T细胞活化的剂量依赖性抑制
为了测试T细胞活化之雷帕霉素介导的抑制的剂量依赖性,以不同剂量对CD45.1+动物(B6.SJL)静脉内注射经包封的雷帕霉素(NP[Rapa],如实施例1中所公开的)(10至50μg雷帕霉素和一个PBS对照)。这些动物与C57BL/6小鼠具有相同的遗传背景,但表达CD45分子的不同同工型(CD45.1,而非CD45.2)。6天后,将通过磁性细胞分选(magnetic cellsorting,MACS;Miltenyi)从OTII小鼠品系的脾和淋巴结分离的T细胞过继转移到经CD45.1+-处理的动物中,所述T细胞表达CD45.2和识别来自在MHC CLII背景下存在的鸡卵清蛋白的肽(OVA323-339或OPII.323)的转基因TCR。还用CFSE(Invitrogen)标记这些细胞以追踪它们的增殖状态。次日(第7天),在后肢内向所有动物皮下注射免疫原性剂量的与TLR7/8激动剂R4848混合的OPII.323。在第11天,将所有动物处死,切除引流注射部位的淋巴结(腘)并通过流式细胞术分析细胞以鉴定经转移的CD45.2+TCRb+CD4+7AAD-T细胞(抗体来自Biolegend)。如图2中所示,注射低至20μg的雷帕霉素甚至在在本文中提供的药效学有效持续期范围内注射纳米载体后6天仍在这些T细胞的活化和存活方面具有抑制作用。提高雷帕霉素的给药产生降低的细胞数量和增殖。
实施例6:使用可植入渗透泵的免疫抑制剂及对其体内致耐受性免疫应答的评价
(预示性的)
步骤1:
将雷帕霉素溶解于由甲基亚砜(dimethyl sulfoxide,DMSO)/聚乙二醇400组成的载剂中并装载在可植入渗透泵(体积0.2mL,模型2001,Durect Corp.,Cupertino,CA)中。然后,根据泵操作步骤将泵皮下(s.c.)植入在小鼠的右侧下腹部内。借助泵,以2.5mg/kg/天的剂量连续皮下施用雷帕霉素2天。
步骤2:
在第0、3和7天,使C57BL/6动物的组(n=5)保持未处理且未免疫(无免疫)、未处理但进行免疫(未处理)或者用上述皮下植入在小鼠右侧下腹部内之雷帕霉素装载的渗透泵进行处理并进行免疫。免疫由注射卵清蛋白的颗粒形式(pOVA)组成。借助泵,以2.5mg/kg/天的剂量连续皮下施用雷帕霉素2天。每次注射的雷帕霉素剂量为100μg雷帕霉素的当量,在三次注射之后总共300μg。从第14天开始,使未经处理和经处理的动物(未处理和雷帕霉素装载的泵)两周一次地接受以下免疫(第14、28和42天):在前肢内注射100μg治疗性蛋白质,例如酸性α-葡糖苷酶,或组织纤溶酶原激活物,或红细胞生成素α,或Dorlixizumab,或利妥昔单抗。在第40天和第54天,对所有动物采血并通过ELISA确定抗蛋白质应答。预期,当在本文中提供的药效学有效持续期内注射时,经由植入的渗透泵施用的雷帕霉素有效地抑制抗蛋白质应答,并且预期这些作用甚至在用蛋白质引发并进行两次加强后仍是明显的。
实施例7:使用可植入渗透泵的免疫抑制剂及对其体内致耐受性免疫应答的评价
(预示性的)
步骤1:
将雷帕霉素(Rapa)在N,N-二甲基乙酰胺(N,N-dimethylacetamide,DMAC)中的贮存液(19mg/ml)储存在4℃下并保护防止暴露于光。为了获得基于大鼠体重的合适Rapa浓度,在10%Tween-80、20%DMAC和70%聚乙二醇400(polyethylene glycol 400,PEG400)的混合物中对贮存液进行稀释。将经适当稀释的Rapa装载到已通过在37℃下在无菌盐水中孵育而准备4至6小时的牌可植入渗透泵(模型2002;Durect Corp.,Cupertino,CA)中。此后,将递送套管插入到鼠的腰静脉内以用于静脉内递送雷帕霉素。
步骤2:
在第0、3和7天,使C57BL/6动物的组(n=5)保持未处理且未免疫(未免疫)、未处理但进行免疫(未处理)或者用上述雷帕霉素装载的渗透泵进行处理并进行免疫。免疫由注射卵清蛋白的颗粒形式(pOVA)组成。借助泵,以2.5mg/kg/天的剂量通过静脉内输注施用雷帕霉素2天。每次输注的雷帕霉素剂量为100μg雷帕霉素的当量,在三次输注之后总共300μg。从第14天开始,使未经处理和经处理的动物(未处理和雷帕霉素装载的泵)两周一次地接受50至100μg治疗性多核苷酸如哌加他尼(Pegaptanib)、米泊美生(Mipomersen)、经修饰信使RNA(mmRNA)(例如de Fougerolles等的美国专利申请2013/0115272中公开的那些)的免疫(第14、28和42天)。
在第40天和第54天,对所有动物采血并通过ELISA确定抗蛋白质应答。预期,当在本文中提供的药效学有效持续期内注射时,经由植入的渗透泵施用的雷帕霉素有效地抑制抗多核苷酸应答,并且预期这些作用甚至在用多核苷酸引发并进行两次加强后仍是明显的。
实施例8:用于因子VIII蛋白的耐受诱导之使用化学交联的抗GITR抗体和针对抑
制性因子VIII的抗体的抗独特型抗体的双特异性抗体免疫抑制剂(预示性的)
步骤1:制备双特异性抗体
使用ImmunoPure F(ab’)2制备试剂盒(Pierce)根据生产商的说明书制备抗GITR抗体(例如依帕珠单抗)和针对抑制性因子VIII抗体的抗独特型抗体(根据美国专利8071094制备)的F(ab’)2片段。将含有F(ab’)2的级分合并,并使用10,000MWCO离心过滤器(Millipore)进行浓缩。通过在30℃下添加2-巯基乙醇直至20mM的终浓度20至40分钟来将每个F(ab’)2还原成F(ab)-硫醇。将样品在冰上冷却并随后通过在50mM乙酸钠/0.5mM EDTApH 5.3中平衡的经冷却Sephadex G25柱。将含蛋白质的级分合并。然后,通过添加1/2体积经预冷却的12mM交联剂,邻亚苯基二马来酰亚胺(o-phenylenedimaleimide,o-PDM)(溶解于DMF中)在冰浴中使抗GITR Fab-硫醇马来酰亚胺化30分钟。然后,使抗GITR-马来酰亚胺化-Fab通过在50mM乙酸钠/0.5mM EDTA pH 5.3中平衡的经冷却Sephadex G25柱。将含蛋白质的级分合并,并立即以1∶1的摩尔比添加至针对抑制性因子VIII抗体-硫醇-Fab的抗独特型抗体。将反应置于氮气下并在4℃下缓慢搅拌15至20小时。使用1M Tris-HCl pH 8.0将pH调节至pH 8.0,之后添加2-巯基乙醇直至20mM的终浓度。将反应在30℃下孵育20至40分钟,然后通过添加碘乙酰胺直至25mM的终浓度进行烷基化。然后,使混合物通过在PBS pH 7.4中平衡的Superdex 200柱,并收集级分。在非还原条件下,使各个级分在10%SDS-PAGE凝胶上运行并用考马斯亮蓝(Coomassie Brilliant Blue,Sigma)或Silver Snap II试剂盒(Pierce)染色。对双特异性抗体(抗GITR/针对抑制性因子VIII抗体的抗独特型抗体)进行鉴定,将其合并并储存以用作抑制剂(剂量:10μg/天)
步骤2:因子VIII的耐受诱导
在第0、3和7天,使C57BL/6动物的组(n=5)保持未处理且未免疫(未免疫)、未处理但进行免疫(未处理)或者以10μg/天用上述双特异性抗体进行处理并进行免疫。免疫由注射卵清蛋白的颗粒形式(pOVA)组成。从第14天开始,使未经处理和经处理的动物(未处理和双特异性抗体处理)两周一次地接受150IU/kg重组人抗血友病因子VIII(因子VIII)的免疫(第14、28和42天)。
在第40天和第54天,对所有动物采血并通过ELISA确定抗蛋白质应答。预期,当在本文中提供的药效学有效持续期内注射时,双特异性抗体(抗GITR/针对抑制性因子VIII抗体的抗独特型抗体)有效地抑制抗因子VIII应答,并且预期这些作用甚至在用因子VIII蛋白引发并进行两次加强后仍是明显的。
实施例9:使用可植入聚合物储库材料的免疫抑制剂及对其体内致耐受性免疫的
评价(预示性的)
步骤1:凝胶载体的制备
在Mettler PJ3000顶部装载式天平上量取玻璃容器的皮重。将聚(D,L-丙交酯-乙交酯)共聚物50∶50 RESOMER.RTM.RG502(PLGA-502)称重到玻璃容器中。量取含有PLGA-502的玻璃容器的皮重并添加对应的溶剂(如表2中所示)。多种聚合物/溶剂组合之以百分比表示的量示于下文的表1中。用不锈钢方尖铲人工搅拌聚合物/溶剂混合物,产生含有白色聚合物颗粒的粘性琥珀色糊剂样物质。将含有聚合物/溶剂混合物的容器密封并置于平衡至39℃的控温培养箱中。当聚合物/溶剂混合物似乎变成透明的琥珀色均质凝胶时,将其从培养箱中取出。基于溶剂和聚合物的类型以及溶剂和聚合物的比例,孵育时间间隔的范围可以为1天至4天。用以下聚合物制备另外的储库凝胶载剂:聚(D,L-丙交酯-乙交酯)共聚物50∶50 RESOMER.RTM.L104,PLGA-L104,代码号33007,聚(D,L-丙交酯-乙交酯)共聚物50∶50RESOMER.RTM.RG206,PLGA-206,代码号8815,聚(D,L-丙交酯-乙交酯)共聚物50∶50RESOMER.RTM.RG502,PLGA-502,代码0000366,聚(D,L-丙交酯-乙交酯)共聚物50∶50RESOMER.RTM.RG502H,PLGA-502H,代码号260187,聚(D,L-丙交酯-乙交酯)共聚物50∶50RESOMER.RTM.RG503,PLGA-503,代码号0080765,聚(D,L-丙交酯-乙交酯)共聚物50∶50RESOMER.RTM.RG506,PLGA-506,代码号95051,聚(D,L-丙交酯-乙交酯)共聚物50∶50RESOMER.RTM.RG755,PLGA-755,代码号95037,(Boehringer Ingelheim Chemicals,Inc.,Petersburg,Va.),及以下溶剂或混合物:三乙酸甘油酯(Eastman Chemical Co.,Kingsport,Tenn.)、苯甲酸苄酯(benzyl benzoate,“BB”)、苯甲酸乙酯(ethyl benzoate,“EB”)、苯甲酸甲酯(methyl benzoate,“MB”)、三醋精(triacetin,“TA”)和柠檬酸三乙酯(triethyl citrate,“TC”)(Aldrich Chemical Co.,St Louis,Mo.)。当使用溶剂组合(例如20%三醋精和80%苯甲酸苄酯)时,将溶剂混合物直接添加至经预称重的干聚合物。典型的聚合物分子量为14,400(Mw)至39,700(Mw)[6,400(Mn)至12,200(Mn)]。代表性的凝胶载剂在下文的表1中进行了描述。
表1:凝胶载剂
表2:免疫抑制剂
阿托伐他汀
雷帕霉素
C16-(S)-丁基磺酰氨基雷帕霉素(C16-Bsrap)
替西罗莫司
活化素A
苍术苷(二钾盐)
2-(1,8-萘啶-2-基)-苯酚
E-前列腺素类2
茶碱
硼替佐米
甲泼尼龙
环孢素A
匹格列酮
吡美莫司
斑蝥素
将根据上文表2(10%w/w至20%w/w)的多种免疫抑制剂添加至指定的透明琥珀色储库凝胶载剂,并人工混合直至干粉末完全湿润。然后,使用具有连接的方尖金属铲的Caframo机械搅拌器通过常规混合来使混合彻底共混。将最终的均质凝胶免疫抑制剂可植入聚合物储库材料转移至3、10或30cc的一次性注射器以用于储存或分配。
步骤2:评价体内致耐受性免疫应答
在第0、3和7天,使C57BL/6动物的组(n=5)保持未处理且未免疫(无免疫)、未处理但进行免疫(未处理)或者用上述含有100μg雷帕霉素的可植入聚合物储库材料进行处理并进行免疫。免疫由注射颗粒卵清蛋白(pOVA)组成。将聚合物储库-雷帕霉素植入在后肢内。聚合物储库-雷帕霉素的剂量为100μg雷帕霉素的当量,在三次处理之后总共300μg。从第14天开始,使未经处理和经处理的动物(未处理和Rapa-储库)两周一次地接受以下免疫(第14、28和42天):在前肢内注射2mg/kg治疗性蛋白质,例如重组组织纤溶酶原激活物(recombinant tissue plasminogen activator,rtPA)。在指定的日子对所有动物采血并通过ELISA确定抗rtPA应答。预期,当在本文中提供的药效学有效持续期内注射时,含雷帕霉素的凝胶植入物有效地抑制抗rtPA应答,并且预期这些作用甚至在用rtPA引发并进行两次加强后仍是明显的。
实施例10:在与合成纳米载体连接的雷帕霉素的药效学有效持续期内的施用
材料
雷帕霉素购自TSZ CHEM(185 Wilson Street,Framingham,MA 01702;产品代码R1017)。丙交酯∶乙交酯之比为3∶1并且特性黏度为0.69dL/g的PLGA购自SurModicsPharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;产品代码7525 DLG7A)。甲基醚封端的PEG嵌段为约5,000Da并且整体特性黏度为0.5DL/g的PLA-PEG-OMe嵌段共聚物购自Lakeshore Biochemicals(756 Tom Martin Drive,Birmingham,AL 35211;产品代码100 DL mPEG 5000 5CE)。聚乙烯醇4-88,USP(85%至89%水解的,黏度为3.4mPa·s至4.6mPa·s)购自EMD Chemicals Inc.(480 South Democrat RoadGibbstown.NJ 08027.产品代码1.41350)。
方法
如下制备溶液:
溶液1:二氯甲烷中的75mg/mL PLGA、25mg/mL PLA-PEG-OMe和12.5mg/mL的雷帕霉素。该溶液通过将PLGA、PLA-PEG-OMe和雷帕霉素溶解于纯二氯甲烷中制备。溶液2:100mMpH 8磷酸盐缓冲液中的50mg/mL聚乙烯醇。
使用水包油型乳剂制备纳米载体。如下制备O/W乳剂:将溶液1(1.0mL)和溶液2(3.0mL)合并在小压力管中并使用Branson Digital Sonifier 250以30%振幅进行超声处理60秒。将O/W乳剂添加至含有70mM pH 8磷酸盐缓冲溶液的烧杯。形成三份相同的乳剂并添加至与第一乳剂相同的烧杯。然后,将这些乳剂在室温下搅拌2小时以使二氯甲烷蒸发并形成纳米载体。将一部分的纳米载体经如下洗涤:将纳米载体混悬液转移至离心管并在75,600×g和4℃下离心35分钟,除去上清液并将沉淀物重悬于磷酸缓冲盐水中。重复洗涤操作并将沉淀物重悬于磷酸缓冲盐水中以获得约10mg/mL的最终纳米载体分散体。来自Pall型号4656的1.2μm PES膜注射器式过滤器过滤经洗涤的纳米载体溶液。
通过动态光散射确定纳米载体的尺寸。通过HPLC分析确定纳米载体中雷帕霉素的量。通过重量法确定总干纳米载体质量/mL混悬液。
确定雷帕霉素装载的纳米载体的免疫抑制窗(药效学有效持续期)
从在注射钥孔林普贝血蓝蛋白(d0,200μg,KLH)的当天前14、10、7、4、2和1天(分别为d-14、-10、-7、-4、-2和-1)开始,在不同时间点(如图3中所示)在尾静脉内向C57BL/6年龄匹配(5至6周)的雌性静脉内注射0.9mg纳米载体。在第0、7和14天,使所有动物每周接受KLH的注射(200μg,KLH)。在第19天,确定这些动物的血液中的抗体效价。
图3中的结果表明,甚至在免疫前14天注射含雷帕霉素的纳米载体就可改变针对KLH的抗体应答,并且致耐受性纳米载体提供了显著的免疫抑制窗,在该免疫抑制窗内免疫应答的引发被抑制。结果证明,能够在免疫抑制剂的药效学有效持续期内施用免疫抑制剂和抗原来降低抗原特异性免疫应答。
实施例11:针对具有经包封雷帕霉素的鸡卵清蛋白的抗体特异性致耐受性应答
NP[Rapa]材料和方法
材料
雷帕霉素购自TSZ CHEM(185 Wilson Street,Framingham,MA 01702),产品代码R1017。丙交酯∶乙交酯之比为1∶1并且特性黏度为0.24dL/g的PLGA购自LakeshoreBiomaterials(756 Tom Martin Drive,Birmingham,AL 35211),产品代码5050 DLG 2.5A。甲基醚封端的PEG嵌段为约5,000Da并且整体特性黏度为0.50DL/g的PLA-PEG-OMe嵌段共聚物购自Lakeshore Biomaterials(756 Tom Martin Drive,Birmingham,AL 35211),产品代码100 DL mPEG 5000 5CE。聚乙烯醇4-88,USP(85%至89%水解的,黏度为3.4mPa·s至4.6mPa·s)购自EMD Chemicals Inc.(480 South Democrat RoadGibbstown,NJ 08027),产品代码1.41350。Cellgro磷酸缓冲盐水1X(PBS 1X)购自Corning(9345 Discovery Blvd.Manassas,VA 20109),产品代码21-040-CV。
方法
如下制备溶液:
溶液1:聚合物和雷帕霉素混合物通过将75mg/mL PLGA、25mg/mL PLA-PEG-OMe和12.5mg/mL雷帕霉素溶解于二氯甲烷中制备。溶液2:在100mM pH 8磷酸盐缓冲液中以50mg/mL制备聚乙烯醇。
如下制备O/W乳剂:将溶液1(1.0mL)和溶液2(3.0mL)合并在小玻璃压力管中并使用Branson Digital Sonifier 250以30%振幅进行超声处理60秒。将O/W乳剂添加至含有70mM pH 8磷酸盐缓冲溶液(60mL)的敞开烧杯。制备另外三份相同的O/W乳剂,并添加至与第一乳剂相同的烧杯。然后,将这些乳剂在室温下搅拌2小时以使二氯甲烷蒸发并形成纳米载体。将一部分的纳米载体经如下洗涤:将纳米载体混悬液转移至离心管并在75,600×g和4℃下离心35分钟,除去上清液并将沉淀物重悬于PBS 1X中。重复洗涤操作并将沉淀物重悬于PBS 1X中以获得基于聚合物的标称浓度为10mg/mL的纳米载体混悬液。在独立的烧杯中如上制备相同的配制物并在洗涤步骤之后与第一配制物合并。使用来自Pall型号4656的1.2μm PES膜注射器式过滤器过滤经混合的纳米载体溶液并将其储存在-20℃下。
通过动态光散射确定纳米载体的尺寸。通过HPLC分析确定纳米载体中雷帕霉素的量。通过重量法确定总干纳米载体质量/mL混悬液。
NP[OVA]材料和方法
材料
卵清蛋白购自Worthington Biochemical Corporation(730 Vassar Avenue,Lakewood,NJ 08701),产品代码LS003054)。具有54%丙交酯和46%乙交酯含量并且特性黏度为0.24dL/g的PLGA购自Lakeshore Biomaterials(756 Tom Martin Drive,Birmingham,AL 35211),产品代码5050 DLG 2.5A)。甲基醚封端的PEG嵌段为约5,000Da并且Mw为28,000Da,特性黏度为0.38dL/g的PLA-PEG嵌段共聚物购自Lakeshore Biomaterials(756 TomMartin Drive,Birmingham,AL 35211),产品代码100 DL mPEG 5000 4CE。聚乙烯醇4-88,USP(85%至89%水解的,黏度为3.4mPa.s至4.6mPa.s)购自EMD Chemicals Inc.(480South Democrat Road Gibbstown,NJ 08027),产品代码1.41350.1001。Cellgro磷酸缓冲盐水IX(PBS 1X)购自Corning(9345 DiscoveryBlvd.Manassas,VA 20109),产品代码21-040-CV。
方法
如下制备溶液:
溶液1:在具有10重量%蔗糖的10mM磷酸盐缓冲液pH 8中制备50mg/mL卵清蛋白。溶液2:PLGA通过在化学通风橱中以100mg/1mL二氯甲烷溶解PLGA制备。溶液3:PLA-PEG-OMe通过在化学通风橱中以100mg/mL二氯甲烷溶解PLA-PEG-OMe制备。溶液4:100mM磷酸盐缓冲液,pH 8中的65mg/mL聚乙烯醇。
首先,通过将溶液1至溶液3混合产生初级(W1/O)乳剂。将溶液1(0.2mL)、溶液2(0.75mL)和溶液3(0.25mL)合并在经在冰水浴中预冷却>4分钟的小玻璃压力管中并使用Branson Digital Sonifier 250在冰浴上以50%振幅进行超声处理40秒。然后,如下形成次级(W1/O/W2)乳剂:向初级乳剂添加溶液4(3mL),涡旋混合以产生乳状分散体并随后使用Branson Digital Sonifier 250在冰浴上以30%振幅进行超声处理60秒。将次级乳剂添加至含有PBS 1X(30mL)的50mL敞开烧杯。如上所述制备第二相同的双乳剂配制物并添加至与第一乳剂配制物相同的50mL烧杯。将两份制备物在室温下搅拌2小时以使二氯甲烷蒸发并混悬形成合成纳米载体。将一部分的混悬纳米载体经如下洗涤:将纳米载体混悬液转移至离心管,在75,600rcf下旋转50分钟,除去上清液并将沉淀物重悬于PBS 1X中。重复洗涤操作并将沉淀物重悬于PBS 1X中以获得基于聚合物的标称浓度为10mg/mL的纳米载体混悬液。将混悬液冷冻储存在-20℃下直至使用。
NP[GSK1059615]材料和方法
材料
GSK1059615购自MedChem Express(11Deer Park Drive,Suite 102D MonmouthJunction,NJ 08852),产品代码HY-12036。丙交酯∶乙交酯之比为1∶1并且特性黏度为0.24dL/g的PLGA购自Lakeshore Biomaterials(756 Tom Martin Drive,Birmingham,AL35211),产品代码5050 DLG 2.5A。甲基醚封端的PEG嵌段为约5,000Da并且整体特性黏度为0.26DL/g的PLA-PEG-OMe嵌段共聚物购自Lakeshore Biomaterials(756 Tom MartinDrive,Birmingham,AL 35211;产品代码100DL mPEG 5000 5K-E)。Cellgro磷酸缓冲盐水IXpH 7.4(PBS 1X)购自Corning(9345 Discovery Blvd.Manassas,VA 20109),产品代码21-040-CV。
方法
如下制备溶液:
溶液1:将PLGA(125mg)和PLA-PEG-OMe(125mg)溶解于10mL丙酮中。溶液2:以1mLN-甲基-2-吡咯烷酮(NMP)中制备10mg GSK1059615。
如下制备纳米载体:将溶液1(4mL)和溶液2(0.25mL)合并在小玻璃压力管中并在搅拌下将混合物逐滴添加至含有20mL超纯化水的250mL圆底瓶。将该瓶安装在旋转式蒸发装置上,并在减压下除去丙酮。将一部分的纳米载体经如下洗涤:将纳米载体混悬液转移至离心管并在75,600rcf和4℃下离心50分钟,除去上清液并将沉淀物重悬于PBS 1X中。重复洗涤操作并将沉淀物重悬于PBS 1X中以获得基于聚合物的标称浓度为10mg/mL的纳米载体混悬液。然后,使用来自Pall,型号4656的1.2μm PES膜注射器式过滤器过滤经洗涤的纳米载体溶液。如上制备相同的纳米载体溶液并在过滤步骤之后与第一纳米载体溶液合并。将均质混悬液冷冻储存在-20℃下。
通过动态光散射确定纳米载体的尺寸。通过351nm下的UV吸收确定纳米载体中GSK1059615的量。通过重量法确定总干纳米载体质量/mL混悬液。
在第-21天和第-14天,在尾静脉内对C57BL/6年龄匹配(5至6周)的雌性小鼠静脉内注射盐水(未处理),与1.2mg含雷帕霉素之纳米载体(NP[Rapa])或8mg含GSK1059615之纳米载体(NP[GSK1059615])组合的1.1mg全卵清蛋白装载的纳米载体(NP[OVA])。
在第0天,在后肢内对所有动物皮下注射与2μgCpG混合的25μg颗粒OVA(pOVA),随后在第7天和第14天仅注射25μg pOVA。在第21天,测量抗体效价。在不存在任何处理的情况下,动物发生针对OVA的稳健免疫应答,其可通过抗OVA IgG抗体效价进行测量。图4中所示之第21天的抗体效价证明:在相同溶液(NP[OVA]+NP[Rapa]或NP[GSK1059615])中与经包封OVA伴随施用的合成致耐受性纳米载体的2个剂量甚至在单独注射1次OVA+CpG1次和注射2次OVA后有效地降低针对OVA的抗体形成。这些结果表明:经包封的免疫抑制剂(例如,雷帕霉素和GSK1059615)当与蛋白质伴随递送时可预防针对该蛋白质的抗体形成。
实施例12.使用合成纳米载体的施用药效学有效持续期(预示性的)
使用可溶性因子VIII和实施例1的合成纳米载体对非人灵长类动物对象进行试验性试验。将50个非人灵长类动物对象随机分成5组:安慰剂,以及针对剂量范围选择的4个合成纳米载体剂量水平。剂量范围是为了建立20小时至1个月的药效学有效持续期,其中一个优选的药效学有效持续期目标为1天。在第0天,向各个活动组中的所有对象皮下施用一定剂量的合成纳米载体,并且在合成纳米载体剂量的24小时内输注标准输注剂量的因子VIII。两周后,用标准剂量的可溶性因子VIII攻击每个动物并使用标准ELISA技术测量抗因子VIII IgG抗体的水平。选择4个活动组中表现出抗因子VIII IgG抗体的显著降低的最低合成纳米载体剂量作为测试剂量。
然后,对合成纳米载体的测试剂量进行异速缩放以施用于人对象,并用于人临床试验中以确定与标准剂量之可溶性因子VIII一起使用的合成纳米载体的施用剂量水平的范围。然后,确定合成纳米载体和因子VIII的施用剂量以用于常规临床实践。
实施例13.使用合成渗透泵的施用药效学有效持续期(预示性的)
使用可溶性因子VIII和渗透泵(一般根据实施例6制备,但在实施例6中用GSKl059615替代雷帕霉素)对非人灵长类动物对象进行试验性试验。将50个非人灵长类动物对象随机分成5组:安慰剂,以及由渗透泵递送并针对剂量范围选择的4个GSK1059615剂量水平。剂量范围是为了建立20小时至1个月的药效学有效持续期,其中一个优选的药效学有效持续期目标为1天。在第0天,向各个活动组中的所有对象皮下施用一定剂量的合成纳米载体,并且在合成纳米载体剂量的24小时内输注标准输注剂量的因子VIII。两周后,用标准剂量的可溶性因子VIII攻击每个动物并使用标准ELISA技术测量抗因子VIII IgG抗体的水平。选择4个活动组中表现出抗因子VIII IgG抗体的显著降低的由渗透泵递送的最低GSK1059615剂量作为测试剂量。
然后,对由渗透泵递送之GSK1059615的测试剂量进行异速缩放以施用于人对象,并用于人临床试验中以确定与标准剂量之可溶性因子VIII一起使用的由渗透泵递送之GSK1059615的施用剂量水平的范围。然后,确定由渗透泵递送的GSK1059615以及因子VIII的施用剂量以用于常规临床实践。
实施例14:使用治疗性多核苷酸的施用药效学有效持续期(预示性的)
使用编码天冬酰胺酶的mmRNA(一般根据de Fougerolles等的美国专利申请2013/0115272制备,(“mmRNA”))和实施例1的合成纳米载体对非人灵长类动物对象进行试验性试验。将50个非人灵长类对象随机分成5组:安慰剂,以及然后针对剂量范围选择的4个合成纳米载体剂量。剂量范围是为了建立20小时至1个月的药效学有效持续期,其中一个优选的药效学有效持续期目标为1天。在第0天,向各个活动组中的所有对象皮下施用所述剂量的合成纳米载体,并且在合成纳米载体剂量的24小时内输注标准输注剂量的因子VIII。两周后,用标准剂量的mmRNA攻击每个动物并使用标准ELISA技术测量抗mmRNA抗体的水平。选择4个活动组中表现出抗mmRNA抗体的显著降低的最低合成纳米载体剂量作为测试剂量。
然后,对合成纳米载体的测试剂量进行异速缩放以施用于人对象,并用于人临床试验中以确定与标准剂量水平之mmRNA一起使用的合成纳米载体的施用剂量范围。然后,确定合成纳米载体和mmRNA的施用剂量以用于常规临床实践。
实施例15.使用纳米结晶免疫抑制剂的施用药效学有效持续期(预示性的)
使用可溶性因子VIII和实施例1的合成纳米载体对非人灵长类动物对象进行试验性试验。将50个非人灵长类动物对象随机分成5组:安慰剂,以及然后针对剂量范围选择的4个纳米结晶雷帕霉素剂量水平。剂量范围是为了建立20小时至1个月的药效学有效持续期,其中一个优选的药效学有效持续期目标为1天。在第0天,向各个活动组中的所有对象皮下施用所述剂量的纳米结晶雷帕霉素,并且在结晶雷帕霉素剂量的24小时内输注标准输注剂量的因子VIII。两周后,用标准剂量的可溶性因子VIII攻击每个动物并使用标准ELISA技术测量抗因子VIII IgG抗体的水平。选择4个活动组中表现出抗因子VIII IgG抗体的显著降低的最低纳米结晶雷帕霉素剂量作为测试剂量。
然后,对纳米结晶雷帕霉素的测试剂量进行异速缩放以施用于人对象,并用于人临床试验中以确定与标准剂量之可溶性因子VIII一起使用的纳米结晶雷帕霉素的施用剂量水平的范围。然后,确定纳米结晶雷帕霉素和因子VIII的施用剂量以用于常规临床实践。
实施例16:使用纳米结晶免疫抑制剂的施用药效学有效持续期(预示性的)
使用编码天冬酰胺酶的mmRNA(一般根据de Fougerolles等的美国专利申请2013/0115272制备,(“mmRNA”))和纳米结晶雷帕霉素在非人灵长类动物对象中进行试验性试验。将50个非人灵长类对象随机分成5组:安慰剂,以及然后针对剂量范围选择的4个纳米结晶雷帕霉素剂量。剂量范围是为了建立20小时至1个月的药效学有效持续期,其中一个优选的药效学有效持续期目标为1天。在第0天,向各个活动组中的所有对象皮下施用一定剂量的纳米结晶雷帕霉素,并且在纳米结晶雷帕霉素剂量的24小时内输注标准输注剂量的因子VIII。两周后,用标准剂量的mmRNA攻击每个动物并使用标准ELISA技术测量抗mmRNA抗体的水平。选择4个活动组中表现出抗mmRNA抗体的显著降低的最低纳米结晶雷帕霉素剂量作为测试剂量。
然后,对纳米结晶雷帕霉素的测试剂量进行异速缩放以施用于人对象,并用于人临床试验中以确定与标准剂量水平之mmRNA一起使用的纳米结晶雷帕霉素的施用剂量范围。然后,确定纳米结晶雷帕霉素和mmRNA的施用剂量以用于常规临床实践。
本发明还涉及以下实施方案:
1.一种方法,其包括:
以相对于治疗性大分子而言提供施用药效学有效持续期的施用剂量向第一类对象中的对象施用免疫抑制剂,所述药效学有效持续期的持续时间为最短20小时至最长1个月;以及
在所述免疫抑制剂的施用药效学有效持续期的持续时间内向所述对象施用所述治疗性大分子;
其中所述治疗性大分子与免疫抑制剂彼此未连接,并且所述治疗性大分子未与合成纳米载体连接。
2.实施方案1所述的方法,其中所述方法还包括:
基于所述免疫抑制剂的测试剂量确定所述免疫抑制剂的施用剂量;
其中所述测试剂量具有相对于所述治疗性大分子的测试药效学有效持续期,所述药效学有效持续期的持续时间在第二类对象中为最短20小时至最长1个月。
3.一种免疫抑制剂,其用于诱导针对治疗性大分子之耐受的方法,所述方法包括:(a)以足以引起药效学有效持续期的剂量向对象施用所述免疫抑制剂,所述药效学有效持续期的持续时间为20小时至1个月;以及(b)在所述药效学有效持续期的持续时间内向所述对象施用所述治疗性大分子,其中所述治疗性大分子与免疫抑制剂彼此未连接,并且所述治疗性大分子未与合成纳米载体连接。
4.免疫抑制剂用于制备用于以下方法的药物的用途,所述方法包括:(a)以足以引起药效学有效持续期的剂量向对象施用所述免疫抑制剂,所述药效学有效持续期的持续时间为20小时至1个月;以及(b)在所述药效学有效持续期的持续时间内向所述对象施用治疗性大分子,其中所述治疗性大分子与所述免疫抑制剂彼此未连接,并且所述治疗性大分子未与合成纳米载体连接。
5.实施方案1或2所述的方法、实施方案3所述的免疫抑制剂或实施方案4所述的用途,其中所述免疫抑制剂包含含有与合成纳米载体连接的免疫抑制剂的合成纳米载体、可植入渗透泵、双特异性抗体或可植入聚合物储库材料。
6.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述免疫抑制剂包含与合成纳米载体连接的免疫抑制剂。
7.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述合成纳米载体包含脂质纳米颗粒、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳剂、树状聚体、巴基球、纳米线、病毒样颗粒、蛋白质颗粒或包含纳米材料之组合的纳米颗粒,任选地,其中所述纳米颗粒为脂质-聚合物纳米颗粒。
8.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述免疫抑制剂包含:他汀类;mTOR抑制剂;TGF-β信号传导剂;TGF-β受体激动剂;组蛋白去乙酰化酶抑制剂;皮质类固醇;线粒体功能的抑制剂;P38抑制剂;NF-κβ抑制剂、地塞米松;TCPA-1;IKKVII;腺苷受体激动剂;前列腺素E2激动剂;磷酸二酯酶抑制剂;蛋白酶体抑制剂;激酶抑制剂;G蛋白偶联受体激动剂;G蛋白偶联受体拮抗剂;糖皮质激素;类视黄醇;细胞因子抑制剂;细胞因子受体抑制剂;细胞因子受体激活剂;过氧化物酶体增殖物激活受体拮抗剂;过氧化物酶体增殖物激活受体激动剂;组蛋白去乙酰化酶抑制剂;钙调神经磷酸酶抑制剂;磷酸酶抑制剂;PI3KB抑制剂;自噬抑制剂;芳基烃受体抑制剂;蛋白酶体抑制剂I(PSI);氧化的ATP;IDO、维生素D3;环孢素;芳基烃受体抑制剂;白藜芦醇;硫唑嘌呤;6-巯基嘌呤;6-硫鸟嘌呤;FK506;萨菲菌素A;沙美特罗;吗替麦考酚酯;阿司匹林及其他COX抑制剂;尼氟灭酸;雌三醇;或雷公藤内酯。
9.实施方案8所述的方法、免疫抑制剂或用途,其中所述免疫抑制剂包含mTOR抑制剂。
10.实施方案9所述的方法、免疫抑制剂或用途,其中所述mTOR抑制剂包含雷帕霉素。
11.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中基于所述合成纳米载体中材料的配方总干重,所述合成纳米载体中所述免疫抑制剂的载量为0.0001wt%至50wt%(重量/重量)。
12.实施方案11中所述的方法、免疫抑制剂或用途,其中基于所述合成纳米载体中材料的配方总干重,所述合成纳米载体中所述免疫抑制剂的载量为0.1wt%至10wt%(重量/重量)。
13.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述治疗性大分子包含治疗性蛋白质或治疗性多核苷酸。
14.实施方案13所述的方法、免疫抑制剂或用途,其中所述治疗性蛋白质包含酶、酶辅因子、激素、凝血因子、细胞因子、生长因子、单克隆抗体或多克隆抗体。
15.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述施用药效学有效持续期的持续时间为最短20小时至最长2周。
16.实施方案15所述的方法、免疫抑制剂或用途,其中所述施用药效学有效持续期的持续时间为最短20小时至最长1周。
17.实施方案16所述的方法、免疫抑制剂或用途,其中所述施用药效学有效持续期的持续时间为最短24小时至最长2天。
18.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述测试药效学有效持续期的持续时间为最短20小时至最长2周。
19.实施方案18所述的方法、免疫抑制剂或用途,其中所述测试药效学有效持续期的持续时间为最短20小时至最长1周。
20.实施方案19所述的方法、免疫抑制剂或用途,其中所述测试药效学有效持续期的持续时间为最短24小时至最长2天。
21.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中基于所述免疫抑制剂的测试剂量并使用异速缩放或等速缩放技术来确定所述免疫抑制剂的施用剂量。
22.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述第一类对象和所述第二类对象为同一类对象。
23.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述第一类对象和所述第二类对象为不同类对象。
24.实施方案7所述的方法、免疫抑制剂或用途,其中所述合成纳米载体包含脂质纳米颗粒。
25.实施方案7所述的方法、免疫抑制剂或用途,其中所述合成纳米载体包含脂质体。
26.实施方案7所述的方法、免疫抑制剂或用途,其中所述合成纳米载体包含金属纳米颗粒。
27.实施方案26所述的方法、免疫抑制剂或用途,其中所述金属纳米颗粒包含金纳米颗粒。
28.实施方案7所述的方法、免疫抑制剂或用途,其中所述合成纳米载体包含聚合物纳米颗粒。
29.实施方案28所述的方法、免疫抑制剂或用途,其中所述聚合物纳米颗粒包含聚合物,所述聚合物为非甲氧基封端的普朗尼克聚合物。
31.实施方案30所述的方法、免疫抑制剂或用途,其中所述聚酯包含聚(乳酸)、聚(乙醇酸)、聚乳酸-乙醇酸共聚物或聚己内酯。
32.实施方案30或31所述的方法、免疫抑制剂或用途,其中所述聚合物纳米颗粒包含聚酯和与聚醚连接的聚酯。
33.实施方案30至32中任一项所述的方法、免疫抑制剂或用途,其中所述聚醚包含聚乙二醇或聚丙二醇。
34.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中使用所述合成纳米载体的动态光散射获得的颗粒大小分布的平均值为大于100nm的直径。
35.实施方案34所述的方法、免疫抑制剂或用途,其中所述直径大于150nm。
36.实施方案35所述的方法、免疫抑制剂或用途,其中所述直径大于200nm。
37.实施方案36所述的方法、免疫抑制剂或用途,其中所述直径大于250nm。
38.实施方案37所述的方法、免疫抑制剂或用途,其中所述直径大于300nm。
39.前述实施方案中任一项所述的方法、免疫抑制剂或用途,其中所述合成纳米载体的纵横比大于1∶1、1∶1.2、1∶1.5、1∶2、1∶3、1∶5、1∶7或1∶10。
Claims (10)
1.一种方法,其包括:
以相对于治疗性大分子而言提供施用药效学有效持续期的施用剂量向第一类对象中的对象施用免疫抑制剂,所述药效学有效持续期的持续时间为最短20小时至最长1个月;以及
在所述免疫抑制剂的施用药效学有效持续期的持续时间内向所述对象施用所述治疗性大分子;
其中所述治疗性大分子与免疫抑制剂彼此未连接,并且所述治疗性大分子未与合成纳米载体连接。
2.权利要求1所述的方法,其中所述方法还包括:
基于所述免疫抑制剂的测试剂量确定所述免疫抑制剂的施用剂量;
其中所述测试剂量具有相对于所述治疗性大分子的测试药效学有效持续期,所述药效学有效持续期的持续时间在第二类对象中为最短20小时至最长1个月。
3.一种免疫抑制剂,其用于诱导针对治疗性大分子之耐受的方法,所述方法包括:(a)以足以引起药效学有效持续期的剂量向对象施用所述免疫抑制剂,所述药效学有效持续期的持续时间为20小时至1个月;以及(b)在所述药效学有效持续期的持续时间内向所述对象施用所述治疗性大分子,其中所述治疗性大分子与免疫抑制剂彼此未连接,并且所述治疗性大分子未与合成纳米载体连接。
4.免疫抑制剂用于制备用于以下方法的药物的用途,所述方法包括:(a)以足以引起药效学有效持续期的剂量向对象施用所述免疫抑制剂,所述药效学有效持续期的持续时间为20小时至1个月;以及(b)在所述药效学有效持续期的持续时间内向所述对象施用治疗性大分子,其中所述治疗性大分子与所述免疫抑制剂彼此未连接,并且所述治疗性大分子未与合成纳米载体连接。
5.权利要求1或2所述的方法、权利要求3所述的免疫抑制剂或权利要求4所述的用途,其中所述免疫抑制剂包含含有与合成纳米载体连接的免疫抑制剂的合成纳米载体、可植入渗透泵、双特异性抗体或可植入聚合物储库材料。
6.前述权利要求中任一项所述的方法、免疫抑制剂或用途,其中所述免疫抑制剂包含与合成纳米载体连接的免疫抑制剂。
7.前述权利要求中任一项所述的方法、免疫抑制剂或用途,其中所述合成纳米载体包含脂质纳米颗粒、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳剂、树状聚体、巴基球、纳米线、病毒样颗粒、蛋白质颗粒或包含纳米材料之组合的纳米颗粒,任选地,其中所述纳米颗粒为脂质-聚合物纳米颗粒。
8.前述权利要求中任一项所述的方法、免疫抑制剂或用途,其中所述免疫抑制剂包含:他汀类;mTOR抑制剂;TGF-β信号传导剂;TGF-β受体激动剂;组蛋白去乙酰化酶抑制剂;皮质类固醇;线粒体功能的抑制剂;P38抑制剂;NF-κβ抑制剂、地塞米松;TCPA-1;IKK VII;腺苷受体激动剂;前列腺素E2激动剂;磷酸二酯酶抑制剂;蛋白酶体抑制剂;激酶抑制剂;G蛋白偶联受体激动剂;G蛋白偶联受体拮抗剂;糖皮质激素;类视黄醇;细胞因子抑制剂;细胞因子受体抑制剂;细胞因子受体激活剂;过氧化物酶体增殖物激活受体拮抗剂;过氧化物酶体增殖物激活受体激动剂;组蛋白去乙酰化酶抑制剂;钙调神经磷酸酶抑制剂;磷酸酶抑制剂;PI3KB抑制剂;自噬抑制剂;芳基烃受体抑制剂;蛋白酶体抑制剂I(PSI);氧化的ATP;IDO、维生素D3;环孢素;芳基烃受体抑制剂;白藜芦醇;硫唑嘌呤;6-巯基嘌呤;6-硫鸟嘌呤;FK506;萨菲菌素A;沙美特罗;吗替麦考酚酯;阿司匹林及其他COX抑制剂;尼氟灭酸;雌三醇;或雷公藤内酯。
9.权利要求8所述的方法、免疫抑制剂或用途,其中所述免疫抑制剂包含mTOR抑制剂。
10.权利要求9所述的方法、免疫抑制剂或用途,其中所述mTOR抑制剂包含雷帕霉素。
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