CN107007615A - 使用岩藻糖类似物在体内抑制蛋白质岩藻糖基化的方法 - Google Patents
使用岩藻糖类似物在体内抑制蛋白质岩藻糖基化的方法 Download PDFInfo
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Abstract
本发明提供通过给予岩藻糖类似物在体内抑制蛋白质包括抗体的岩藻糖基化的方法与组合物。
Description
相关申请的交叉引用
本申请要求于2010年8月5日提交的美国临时专利申请号61/371,116,的优先权,该临时申请的公开内容通过引用纳入本文。
背景技术
L-岩藻糖是一种单糖,又名6-脱氧-L-半乳糖,是动物中的一些N-连接型与O-连接型多聚糖与糖脂的组分。(见Becker与Lowe,Glycobiology 13:41R-51R(2003).)岩藻糖通常作为末端修饰添加至多聚糖,包括血型抗原,选择素与抗体所接多聚糖。岩藻糖可以通过特异性岩藻糖基转移酶经α(1,2)-、α(1,3)-、α(1,4)-与α(1,6)-连接结合到多聚糖上。α(1,2)-岩藻糖连接通常与H血型抗原相关联。α(1,3)-与α(1,4)-岩藻糖连接与LewisX抗原的修饰相关联。α(1,6)-岩藻糖连接与N-连接的N-乙酰葡萄糖胺(GlcNac)分子如在抗体中的那些分子相关联。
据信蛋白质的岩藻糖基化在哺乳动物的发育过程中发挥作用。将FX基因靶向突变的小鼠纯合子表现出多种异常,包括致死表型。也报道过小鼠自杂合体杂交种的恢复减弱。(Becker等人,Mammalian Genome 14:130-139(2003))。已提出异常的蛋白质岩藻糖基化与人类疾病相关联,包括在癌症中的唾液酸化LewisX与唾液酸化Lewisy的上调。这些多聚糖是E-型和P-型选择素分子的配体。据推测癌细胞上唾液酸化LewisX与唾液酸化Lewisy多聚糖的提高通过与内皮上的E-型和P-型选择素的相互作用来促进转移。在风湿性关节炎的患者中也观察到岩藻糖基化多聚糖增多。然而,目前还没有已批准的针对蛋白岩藻糖基化水平的治疗手段。
发明内容
本文所述方法和组合物部分基于实施例中所示的出乎意料的结果,显示出施用岩藻糖类似物的动物中蛋白质岩藻糖基化减少。抗体与其他蛋白质的岩藻糖基化可以使用本文所述的岩藻糖类似物来调节。
一方面,本发明提供在体内产生去岩藻糖基化蛋白质的方法和组合物。施用产岩藻糖类似物(如化学式Ⅰ,Ⅱ,Ⅲ,Ⅳ,Ⅴ或Ⅵ)的蛋白质如细胞表面蛋白质于动物如哺乳动物,该动物的岩藻糖基化降低。岩藻糖基化的降低分别相对于未经具有化学式Ⅰ,Ⅱ,Ⅲ,Ⅳ,Ⅴ或Ⅵ的岩藻糖类似物处理的动物而言。
在一相关方面,本发明提供在体内产生核心岩藻糖基化降低的抗体和抗体衍生物的方法和组合物。施用岩藻糖类似物(如化学式Ⅰ,Ⅱ,Ⅲ,Ⅳ,Ⅴ或Ⅵ)于动物,该动物产生出核心岩藻糖基化降低的抗体和抗体衍生物(即,N-糖苷连接型复合糖链的N-乙酰葡萄糖胺的岩藻糖基化降低,所述糖链通过糖链还原性末端的N-乙酰葡萄糖胺结合于Fc区)。核心岩藻糖基化的降低分别相对于未经具有化学式Ⅰ,Ⅱ,Ⅲ,Ⅳ,Ⅴ或Ⅵ的岩藻糖类似物处理的动物而言。
另一方面,本发明提供包含岩藻糖类似物并配制供施用于目标动物的药物组合物。所述岩藻糖类似物可以配制供施用于目标动物以在体内抑制或降低岩藻糖基化。
本发明的上述与其他方面可通过参考以下详细叙述、具体实施方式的非限制性实施例和附图得以更全面地理解。
附图简要说明
图1显示使用施用岩藻糖类似物(通过腹腔注射)对抗体岩藻糖基化的影响。左图显示斑点印迹图而右图显示坐标图。斑点印迹蛋白点样水平(左上图)与岩藻糖特异性生物发光(左下图)显示抗体cAC10标准(下方的斑点印迹最左侧虚线框与上方斑点印迹的对应列),未经处理的对照(下方的斑点印迹左起第二个虚线框与上方斑点印迹的对应列),以及炔基岩藻糖(SGD-1887;下方的斑点印迹居中的虚线框长方形与上方斑点印迹的对应列),过乙酸炔基岩藻糖(SGD-1890;下方的斑点印迹右起第二个虚线框与上方斑点印迹的对应列),以及2-氟岩藻糖(SGD-2083;下方的斑点印迹最右侧的虚线框与上方斑点印迹的对应列)。在校正点样水平后,岩藻糖基化的百分率显示在右侧坐标图中。
图2显示通过饮用水给予岩藻糖类似物对于抗体核心岩藻糖基化的影响。坐标图显示由气相色谱(GC)测定的抗体岩藻糖基化的百分率:图A与B显示分离自处理组的抗KLH-抗体(Ab)的岩藻糖基化水平,而图C与D则显示其余IgG抗体(非-KLH-特异性)的岩藻糖基化的水平。图A与C显示使用纯化抗体的标准曲线(0-100%岩藻糖基化)确定的各动物的岩藻糖基化百分率。图B与D以相对未经处理的对照组均值的百分率显示处理组的岩藻糖基化水平。
图3显示通过饮用水给予岩藻糖类似物对于抗体核心岩藻糖基化的影响。图中显示非-KLH-特异性抗体的岩藻糖基化水平。显示蛋白点样水平(左上图)与岩藻糖特异性生物发光(左下图)的斑点印迹,分别为抗体cAC10标准(上方与下方的斑点印迹,最左侧框),未经处理的对照组(上方与下方的斑点印迹,左起第二个(上方)及右侧框),以及2-氟岩藻糖(上方与下方的斑点印迹,左起第二个(下方)以及右起第二个框(上方与下方的))。在校正点样水平后,岩藻糖化的百分率显示在右侧坐标图中。
图4显示通过饮用水给予不同剂量2-氟岩藻糖对抗体核心岩藻糖基化的影响。斑点印迹显示蛋白点样水平(左)与岩藻糖特异性生物发光(中),分别是未经处理的对照组和1,10,与100毫摩尔SGD-2083(如图所示)。与未经处理组相比的岩藻糖化的百分率显示在右侧坐标图中。
图5显示给予2-氟岩藻糖对循环白细胞与嗜中性粒细胞的影响。图A,从个体小鼠采集血样,在血细胞计数器上使用Turk溶液排除红细胞来计数确定白细胞数。图B,为确定嗜中性粒细胞数,通过流式细胞术来测定Gr-1+的白细胞百分率,并用于(A)中测定的细胞总数。图C,从个体小鼠采集了淋巴结库,制备单细胞悬液,并用血细胞计数器计数。符号代表个体小鼠(每组n=3;菱形,未经处理;方形,1毫摩尔2-氟岩藻糖(SGD-2083);三角形,10毫摩尔2-氟岩藻糖;圆形,100毫摩尔2-氟岩藻糖)。
图6显示给予2-氟岩藻糖对于E-选择素结合嗜中性粒细胞的影响。图A,使用流式细胞术鉴定嗜中性粒细胞的示例。细胞根据前向角散射和侧向角散射来门控以纳入活的白细胞,然后将结果用描述Gr-1染色的直方图表示以鉴定嗜中性粒细胞。门控选出阳性细胞,确定阳性细胞的百分比(用于图5B中的细胞计数),此门控应用于(B)的直方图中。图B,E-选择素结合来自未经处理的动物(左)和口服给予100毫摩尔2-氟岩藻糖(SGD-2803)的动物(右)的嗜中性粒细胞的示例。灰色的直方图显示E-选择素的结合而虚线显示仅二级试剂的结合。针对E-选择素的结合测定荧光强度的几何平均值。图C,对(B)中各动物测定E-选择素结合的几何平均荧光强度,并在组间比较(每组n=3;误差线表示标准差)。
图7显示用某些岩藻糖类似物培养细胞系对蛋白质岩藻糖基化的影响。检测了细胞系LS174T,PC-3,Ramos,HL-60cy与Caki-1。
图8显示给予岩藻糖类似物对小鼠肿瘤异种移植模型的影响。图A-E分别显示使用LS174T,PC-3,Ramos,HL-60cy与Caki-1细胞系(经过2-氟岩藻糖(SGD-2803)预处理)的小鼠肿瘤异种移植模型中的结果。图F显示使用未经处理LS174T细胞系的小鼠肿瘤异种移植模型中的结果。
图9显示肿瘤疫苗模型的研究计划(图A)与结果(图B),该模型基于使用灭活的A20鼠淋巴瘤细胞进行预免疫,然后在给予或不给予岩藻糖类似物(2-氟岩藻糖)的情况下使用活性A20细胞进行攻击。
具体实施方式
定义
术语“抗体”指(a)免疫球蛋白多肽和免疫球蛋白多肽的免疫活性部分,即,免疫球蛋白家族的多肽,或其片段,它们包含能免疫特异性结合特定抗原的抗原结合位点,并具有含复合N-糖苷连接型糖链的Fc结构域,或(b)这些免疫球蛋白多肽多肽或片段能免疫特异性结合所述抗原的保守取代衍生物。抗体概述于,例如,Harlow与Lane,Antibodies:ALaboratory Manual(抗体:实验室手册)(冷泉港实验室出版社(Cold Spring HarborLaboratory Press),1988年)。
“抗体衍生物”指上文所定义的抗体(包括抗体片段)或抗体的包含复合N-糖苷连接型糖链的Fc结构域或区域,通过共价结合通常不与抗体或Fc结构域或区域相关联的异源分子而被修饰,例如,通过结合异源多肽(例如,异源蛋白的配体结合域),或通过糖基化(核心岩藻糖基化除外),去糖基化(非核心岩藻糖基化除外),乙酰化,磷酸化,或其他修饰。
术语“单克隆抗体”指抗体源于单一细胞克隆,包含任何真核或原核细胞克隆,或噬菌体克隆,而并非指其产生方法。因此,术语“单克隆抗体”不仅限于通过杂交瘤技术生产的抗体。
术语“Fc区”指抗体的恒定区,例如,CH1-铰链-CH2-CH3结构域,可选具有CH4结构域,或是此类Fc区的保守取代衍生物。
术语“Fc结构域”指抗体的恒定结构域,例如,CH1,铰链,CH2,CH3,或CH4域,或此类Fc结构域的保守取代衍生物。
“抗原”是某种抗体或抗体衍生物特异性结合的分子。
术语“特异性结合”与“特异性结合于”指抗体或抗体衍生物将以高度选择性方式结合其相应的靶抗原而不结合众多其它抗原。通常,抗体或抗体衍生物结合的亲和力至少1×10-7M,并优选1×10-8M到1×10-9M,1×10-10M,1×10-11,或1×10-12M,并且与预定抗原结合的亲和力至少两倍于其结合预定抗原以外的非特异性抗原或密切相关抗原(例如,BSA,酪蛋白)的亲和力。
术语“抑制”或“对……的抑制”指以可检测量减弱,或完全阻止。
除非上下文另有说明,本文所用“炔基岩藻糖过乙酸酯”指在R1-4位(参见下文式Ⅰ与Ⅱ)带有乙酸基团的炔基岩藻糖(5-乙炔基阿拉伯糖)的任意或所有形式,包括6-乙炔基-四氢-2H-吡喃-2,3,4,5-四基-四乙酸酯,包含(2S,3S,4R,5R,6S)与(2R,3S,4R,5R,6S)异构体,和5-((S)-1-羟丙基-2-炔基)-四氢呋喃-2,3,4-三基-四乙酸酯,包含(2S,3S,4R,5R)和(2R,3S,4R,5R)异构体,以及醛糖形式。术语“炔基岩藻糖三乙酸酯”“炔基岩藻糖二乙酸酯”及“炔基岩藻糖单乙酸酯”分别表示炔基岩藻糖的三-,二-,和单-乙酸酯形式。
除非上下文另有说明,术语“烷基”指具有1至20个碳原子(以及其间的碳原子数范围和具体数量的所有组合与再组合)的未取代的饱和直链或支链烃类,除非另有特指。优选1至3个,1至8个或1至10个碳原子的烷基基团。烷基基团的示例有甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,正戊基,2-戊基,3-戊基,2-甲基-2-丁基,正己基,正庚基,正辛基,正壬基,正癸基,3-甲基-2-丁基,3-甲基-1-丁基,2-甲基-1-丁基,1-己基,2-己基,3-己基,2-甲基-2-戊基,3-甲基-2-戊基,4-甲基-2-戊基,3-甲基-3-戊基,2-甲基-3-戊基,2,3-二甲基-2-丁基,和3,3-二甲基-2-丁基。
烷基基团,无论是单独还是作为另一基团的一部分,在被取代时可被一个或多个基团取代,优选1至3个基团(以及选自卤族的任何附加取代)包括但不限于:卤素,-O-(C1-C8烷基),-O-(C2-C8烯基),-O-(C2-C8炔基),-芳基,-C(O)R’,-OC(O)R’,-C(O)OR’,-C(O)NH2,-C(O)NHR’,-C(O)N(R’)2,-NHC(O)R’,-SR’,-SO3R’,-S(O)2R’,-S(O)R’,-OH,=O,-NH2,-NH(R’),-N(R’)2和-CN;其中各R’独立地选自-H,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基或芳基。
除非本文另有说明,术语“烯基”与“炔基”指具有2至20个碳原子(以及其间的碳原子数范围和具体数量的所有组合与再组合)的未取代或可选被取代(有标明)的直链或支链碳链,优选碳原子数从2至3个,2至4个,2至8个,或2至10个。烯基链在链中具有至少一个双键而炔基链在链中具有至少一个三键。烯基基团的示例包括但不限于,亚烷基或乙烯基,烯丙基,-1烯丁基,-2烯丁基,-异丁烯基,-1戊烯基,-2戊烯基,-3-甲基-1-丁烯基,-2甲基2丁烯基,和-2,3二甲基2丁烯基。炔基基团的示例包括但不限于,炔类,炔丙基,乙炔基,丙炔基,-1丁炔基,-2丁炔基,-1戊炔基,-2戊炔基,和-3甲基1丁炔基。
烯基与炔基基团,无论是单独还是作为另一基团的一部分,在被取代时可被一个或多个基团取代,优选1至3个基团(以及选自卤族的任何附加取代),包括但不限于:卤素,-O-(C1-C8烷基),-O-(C2-C8烯基),-O-(C2-C8炔基),-芳基,-C(O)R’,-OC(O)R’,-C(O)OR’,-C(O)NH2,-C(O)NHR’,-C(O)N(R’)2,-NHC(O)R’,-SR’,-SO3R’,-S(O)2R’,-S(O)R’,-OH,=O,-NH2,-NH(R’),-N(R’)2与-CN;其中各R’独立地选自-H,-C1-C8烷基,-C2-C烯基,-C2-C8炔基或芳基。
除非本文另有说明,术语“亚烷基”指具有1至20个碳原子(以及其间的碳原子数范围和具体数量的所有组合与再组合),优选具有1至8或1至10个碳原子,并具有通过除去母体乙烯的同一碳原子或两个不同碳原子上的两个氢原子而获得两个单价基团中心的未被取代的饱和的支链或直链烃基。典型亚烷基包括但不限于,亚甲基,亚乙基,亚丙基,亚丁基,亚戊基,亚己基,亚庚基,亚辛基,亚壬基,亚癸基,1,4-环亚己基等。
亚烷基基团,无论是单独还是作为另一基团的一部分,在被取代时可被一个或多个基团取代,优选1至3个基团(以及选自卤素的任何附加取代),包括但不限于:卤素,-O-(C1-C8烷基),-O-(C2-C8烯基),-O-(C2-C8炔基),-芳基,-C(O)R’,-OC(O)R’,-C(O)OR’,-C(O)NH2,-C(O)NHR’,-C(O)N(R’)2,-NHC(O)R’,-SR’,-SO3R’,-S(O)2R’,-S(O)R’,-OH,=O,-NH2,-NH(R’),-N(R’)2与-CN;其中各R’独立地选自H,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基或-芳基。
术语“亚烯基”指烯基(如上所述)的不饱和的支链或直链或环状的烃类基团,且具有通过除去母体烯烃的同一碳原子或两个不同碳原子上的两个氢原子而获得两个单价的基团中心。如上文针对烯基所述,“亚烯基”基团可以指未取代的或可选被取代的(有标明)。在一些实施方式中,“亚烯基”基团未被取代。
术语“亚炔基”指炔基(如上所述)的不饱和的支链或直链或环状的烃类基团,且具有通过除去母体炔烃的同一碳原子或两个不同碳原子的两个氢原子而获得两个单价的基团中心。如上文针对炔基所述,“亚炔基”基团可以指未取代的或可选被取代的(有标明)。在一些实施方式中,“亚炔基”基团未被取代。
除非本文另有说明,术语“芳基”指6至20个碳原子(以及其间的碳原子数范围和具体数量的所有组合与再组合)的被取代的或未被取代的单价芳香族烃基团,通过除去母体芳香族环系统的单个碳原子上的一个氢原子而获得。一些芳基基团在示例性结构中表示为“Ar”。典型芳基基团包括但不限于,源自苯,被取代的苯,苯基,萘,蒽,联苯等。
芳基基团,无论是单独还是作为另一基团的一部分,在被取代时可被一个或多个基团取代,优选1至5个基团,甚至1至2个基团,包括但不限于:卤素,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基,-O-(C1-C8烷基),-O-(C2-C8烯基),-O-(C2-C8炔基),-芳基,-C(O)R’,-OC(O)R’,-C(O)OR’,-C(O)NH2,-C(O)NHR’,-C(O)N(R’)2,-NHC(O)R’,-SR’,-SO3R’,-S(O)2R’,-S(O)R’,-OH,-NO2,-NH2,-NH(R’),-N(R’)2与-CN;其中各R’独立地选自H,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基或芳基。
除非本文另有说明,术语“杂环”指具有从3至7,或3至10个环原子(也称为环成员)的被取代的或未被取代的单环的环系统,其中至少一个环原子是选自N,O,P或S的杂原子(以及其间的碳原子和杂原子的范围和具体数量的所有组合与再组合)。所述杂合可以具有独立选自N,O,P或S的1-4个杂原子。杂环中的一个或多个N,O或S原子可被氧化。单环的杂环优选具有3-7个环成员(例如,2-6个碳原子和独立选自N,O,P或S的1-3个杂原子)。包含杂原子的环可以是芳环或非芳环。除非另外指出,杂环在能产生稳定结构的任何杂原子或碳原子上连接其侧基。
杂环的描述见Paquette“Principles of Modern Heterocyclic Chemistry”(现代杂环化学原理)(W.A.Benjamin,纽约,1968),特别是第1,3,4,6,7和9章;“The Chemistryof Heterocyclic Compounds,A series of Monographs”(杂环化合物化学丛书)(纽约约翰韦利森出版社(John Wiley&Sons),1950至今),特别是第13,14,16,19和28卷;和J.Am.Chem.Soc.82:5566(1960)。“杂环”基团的示例包括但不限于吡啶基,二氢吡啶基,四氢吡啶基(哌啶基),噻唑基,嘧啶基,呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,四唑基,岩藻糖基,氮丙啶基(azirdinyl),氮杂环丁基(azetidinyl),环氧乙基,环氧丙基和四氢呋喃基。
杂环基团,无论是单独还是作为另一基团的一部分,在被取代时可被一个或多个基团取代,优选1至2个基团,包括但不限于:-C1-C8烷基,-C2-C8烯基,-C2-C8炔基,卤素,-O-(C1-C8烷基),-O-(C2-C8烯基),-O-(C2-C8炔基),-芳基,-C(O)R’,-OC(O)R’,-C(O)OR’,-C(O)NH2,-C(O)NHR’,-C(O)N(R’)2,-NHC(O)R’,-SR’,-SO3R’,-S(O)2R’,-S(O)R’,-OH,-NH2,-NH(R’),-N(R’)2与-CN;其中各R’独立地选自H,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基或-芳基。
示例性但非限制性的,碳键杂环可以在以下位置成键:吡啶的2、3、4、5或6号位;哒嗪的3、4、5或6号位;嘧啶的2、4、5或6号位;吡嗪的2、3、5或6号位;呋喃、四氢呋喃、硫代呋喃、噻吩、吡咯、或四氢吡咯的2、3、4或5号位;唑、咪唑、噻唑的2、4或5号位;异唑、吡唑或异噻唑的3、4或5号位;氮丙啶的2或3号位;或氮杂环丁烷的2、3或4号位。示例性的碳键合杂环可包括2-吡啶基,3-吡啶基,4-吡啶基,5-吡啶基,6-吡啶基,3-哒嗪基,4-哒嗪基,5-哒嗪基,6-哒嗪基,2-嘧啶基,4-嘧啶基,5-嘧啶基,6-嘧啶基,2-吡嗪基,3-吡嗪基,5-吡嗪基,6-吡嗪基,2-噻唑基,4-噻唑基或5-噻唑基。
示例性但非限制性的,氮键杂环可以在以下位置成键:氮丙环、氮杂环丁烷、吡咯、吡咯啶、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、或1氢-吲唑的1号位;异吲哚或异吲哚啉的2号位;和吗啉的4号位。更典型地,氮键杂环包括1-氮丙环基,1-氮杂环丁基,1-吡咯基,1-咪唑基,1-吡唑基,和1-哌啶基。
除非本文另有说明,术语“碳环”指具有3至6个环原子(以及其间的碳原子数范围和具体数量的所有组合与再组合)的被取代的或未被取代的,饱和的或不饱和的非芳香族单环的环系统,其中所有的环原子都是碳原子。
碳环基团,无论是单独还是作为另一基团的一部分,在被取代时,举例而言可被以下的一个或多个基团,优选1或2个基团(以及选自卤素的任何附加取代基)取代,包括但不限于:卤素,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基,-O-(C1-C8烷基),-O-(C2-C8烯基),-O-(C2-C8炔基),芳基,-C(O)R’,-OC(O)R’,-C(O)OR’,-C(O)NH2,-C(O)NHR’,-C(O)N(R’)2,-NHC(O)R’,-SR’,-SO3R’,-S(O)2R’,-S(O)R’,-OH,=O,-NH2,-NH(R’),-N(R’)2与-CN;其中各R’独立地选自-H,-C1-C8烷基,-C2-C8烯基,-C2-C8炔基或芳基。
单环的碳环取代基的示例包括环丙基,环丁基,环戊基,1-环戊-1-烯基,1-环戊-2-烯基,1-环戊-3-烯基,环己基,1-环己-1-烯基,1-环己-2-烯基,1-环己-3-烯基,环庚基,环辛基,-1,3-环己基二烯基,-1,4-环己基二烯基,-1,3-环庚基二烯基,-1,3,5-环庚基三烯基,和-环辛基二烯基。
在任何组成部分或任何分子式中,当任何变量出现多次时,它每次出现时的定义相互独立。取代基和/或变量的组合只有在这种组合产生稳定化合物时才是可容许的。
除非本文另有说明,连字符(-)标明与侧基分子的连接点。因此,术语“-(C1-C10亚烷基)芳基”或“-C1-C10亚烷基(芳基)”指如本文定义的C1-C10亚烷基基团,其中所述亚烷基基团通过其任意一个碳原子连接侧基分子并且与所述亚烷基基团中的碳原子成键的一个氢原子被如本文所定义的芳基替换。
当特定基团“被取代”时,所述基团可具有独立选自取代基列表的一个或多个取代基,优选一至五个取代基,更优选一至三个取代基,最优选一至二个取代基。然而,所述基团通常可以具有选自卤素的任意数量的取代基。
根据发明人意图,对分子的特定位置的任意取代基或变量的定义应独立于它在该分子其它位置的定义。应理解,本领域技术人员能选择本发明所述化合物上的取代基和取代方式,以提供有活性且化学稳定并易于用本领域中已知技术和本文所述方法合成的化合物。
术语“药学上可接受的”指经联邦政府或州政府监管机构批准或列入美国药典或其他被公认的药典中的,用于动物,或具体是用于人的。术语“药学相容成分”指岩藻糖可与之一同给予的药学上可接受的稀释剂、辅料、赋形剂,或载剂。
“小的吸电子基团”指在取代基连接位点处,相比例如氢原子或羟基或相对位于岩藻糖中该位点的取代基而言具有更强的电负性的任意取代基。通常,所述小的吸电子基团具有10个或更少的原子(氢原子除外)并且包含基团如硝基;氰基与氰烷基(例如,-CH2CH2CN);卤素;乙炔或其他炔烃或卤代炔烃(例如(-C≡CCF3);烯烃或卤代烯烃;丙二烯类;羧酸酯、酯类、酰胺类及其卤代形式;磺酸盐或酯和膦酸盐或酯、酯类、酰胺类及其卤代形式;卤代烷基基团(例如,-CF3,-CHF2,-CH2CF3),酰基和卤代酰基基团(例如,-C(O)CH3与-C(O)CF3);烷基磺酰基与卤代烷基磺酰基(例如,-S(O)2烷基与-S(O)2卤代烷基);芳氧基(例如,苯氧基和被取代的苯氧基);芳烷氧基(例如,苄氧基和被取代的苄氧基);和环氧乙烷。小的吸电子基团优选具有8个、7个、6个或更少的原子(氢原子除外)。
岩藻糖类似物通常实质上不含不需要的污染物。这意味着所述类似物通常纯度至少约50%w/w(重量/重量),同时还实质上不含干扰蛋白与其他污染物。试剂纯度有时至少约80%w/w,更优选至少90%w/w或约95%w/w。使用常规纯化技术,可以获得至少99%w/w的均质产物。
概述
本发明提供在动物个体内降低蛋白质岩藻糖基化的方法与组合物。所述方法的提出部分是基于实施例中显示的意外结果,即,将岩藻糖类似物给予对象(例如,哺乳动物)导致抗体或者抗体衍生物的核心岩藻糖基化降低,且其他蛋白的岩藻糖基化也降低。就蛋白质而言的“岩藻糖基化降低”通常指降低多聚糖上通过α(1,2)-、α(1,3)-、α(1,4)-、α(1,6)-连接的岩藻糖加成。就抗体而言的“核心岩藻糖基化”指将岩藻糖加成(“岩藻糖基化”)到抗体的N-连接型多聚糖的还原性末端处的N-乙酰葡萄糖胺(“GlcNAc”)上。就抗体而言的“核心岩藻糖基化降低”指连接于抗体的N-连接型多聚糖的还原性末端处N-乙酰葡萄糖胺(“GlcNAc”)上的岩藻糖比未经处理的动物减少。
本文所述的多个方面中,接受岩藻糖类似物给予的动物通常是哺乳动物,优选为人类。因此,本发明还提供用于降低哺乳动物如人类中的蛋白质岩藻糖基化的方法和组合物。
在其他方面,提供岩藻糖类似物和药学赋形剂的适于给予动物的药物组合物,其中将有效量的岩藻糖类似物与所述赋形剂混合在一起。在一些实施方式中,所述岩藻糖类似物为干燥形式(例如,冻干的),可选地带有能提高所述组合物的稳定性以供长期贮存的稳定剂。在一些实施方式中,岩藻糖类似物与药学赋形剂的药物组合物配制成供动物给药。在一些进一步实施方式中,岩藻糖类似物与药学赋形剂的药物组合物配制成供人类给药。
在一些实施方式中,结合于抗体的Fc区(或结构域)的复合N-糖苷连接型糖链的岩藻糖基化被降低。如本文所用,“复合N-糖苷连接型糖链”通常结合于天冬酰胺297(按Kabat编号系统编号)结合,尽管复合N-糖苷连接型糖链也可连接于其它天冬酰胺残基上。如本文所述,复合N-糖苷连接型糖链具有双触角型复合糖链,主要具有如下结构:
其中±指可以含有也可以缺失该糖分子,而数字表明了糖分子之间的连接的位置。在上述结构中,糖链与天冬酰胺结合的末端叫做还原性末端(右侧),而另一侧叫做非还原性末端。岩藻糖通常结合于还原性末端的N-乙酰葡萄糖胺(“GlcNAc”),通常通过α1,6键(GlcNAc的6-位结合岩藻糖的1-位)。“Gal”指半乳糖,而“Man”指甘露糖。
“复合N-糖苷连接型糖链”排除在核心结构的非还原性末端处仅纳入甘露糖的高甘露糖型糖链,但包括1)复合型糖链,其核心结构的非还原性末端一侧具有一个或者多个半乳糖-N-乙酰葡萄糖胺(也称为“gal-GlcNAc)分支,并且Gal-GlcNAc的非还原性末端一侧可选具有唾液酸、截开型N-乙酰葡萄糖胺或者类似结构;或者2)杂合型,其核心结构的非还原性末端一侧同时具有高甘露糖N-糖苷连接型糖链和复合N-糖苷连接型糖链。
在一些实施方式中,“复合N-糖苷连接型糖链”包含复合型,其核心结构的非还原性末端具有零个,一个或者多个半乳糖-N-乙酰葡萄糖胺(也称为“gal-GlcNAc)的分支并且Gal-GlcNAc的非还原性末端一侧可选还具有唾液酸、截开型N-乙酰葡萄糖胺或者类似结构,但是排除具有高甘露糖成分的糖链。
根据本发明的方法,在给予岩藻糖类似物后,通常只有少量岩藻糖会被纳入糖链(例如,多聚糖或者复合N-糖苷连接型糖链)。例如,在不同实施方式中,与未接受岩藻糖类似物的动物相比,所述动物(例如,哺乳动物如人类)血清中,低于约60%,低于约50%、低于约40%、低于约30%、低于约20%、低于约15%、低于约10%、低于约5%或者低于约1%的抗体被核心岩藻糖基化。在一些实施方式中,与未经岩藻糖类似物处理的动物相比,动物血清中的抗体实质上未被(例如,低于0.5%)核心岩藻糖基化。
在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)中就岩藻糖基化细胞表面蛋白质而言,蛋白质岩藻糖基化降低,程度约60%、约50%、约40%、约30%、约20%、约15%、约10%、约5%或者约1%。在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)中就岩藻糖基化细胞表面蛋白而言,通过α(1,2)-连接的蛋白质岩藻糖基化降低,程度约60%、约50%、约40%、约30%、约20%、约15%、约10%、约5%或者约1%。
在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)中就岩藻糖基化细胞表面蛋白而言,通过α(1,3)-连接的蛋白质岩藻糖基化降低,程度约60%、约50%、约40%、约30%、约20%、约15%、约10%、约5%或者约1%。在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)中就岩藻糖基化的细胞表面蛋白而言,通过α(1,4)-连接的蛋白质岩藻糖基化降低,程度约60%、约50%、约40%、约30%、约20%、约15%、约10%、约5%或者约1%。
在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)中就岩藻糖基化的细胞表面蛋白而言,通过α(1,6)-连接的蛋白质岩藻糖基化降低,程度约60%、约50%、约40%、约30%、约20%、约15%、约10%、约5%或者约1%。
在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)血清中白细胞的岩藻糖基化降低,程度至少约60%、至少约50%、至少约40%、至少约30%、至少约20%、至少约15%、至少约10%或者至少约5%。在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)血清中白细胞通过α(1,3)-连接的岩藻糖基化降低,程度至少约60%、至少约50%、至少约40%、至少约30%、至少约20%、至少约15%、至少约10%或者至少约5%。在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)血清中白细胞通过α(1,4)-连接的岩藻糖基化降低,程度至少约60%、至少约50%、至少约40%、至少约30%、至少约20%、至少约15%、至少约10%或者至少约5%。
在一些实施方式中,与未接受岩藻糖类似物的动物相比,动物(例如,哺乳动物如人)血清中抗体的岩藻糖基化降低,程度至少约60%、至少约50%、至少约40%、至少约30%、至少约20%、至少约15%、至少约10%或者至少约5%。
在某些实施方式中,只有少量的岩藻糖类似物(或所述岩藻糖类似物的代谢物或者产物)被纳入所述抗体、抗体衍生物的多聚糖(例如所述复合N-糖苷连接型糖链)或者其他蛋白质的多聚糖。例如,在不同实施方式中,与未接受岩藻糖类似物的动物相比,低于约60%,低于约40%,低于约30%,低于约20%,低于约15%,低于约10%,低于约5%或者低于约1%的岩藻糖类似物(或所述岩藻糖类似物的代谢物或者产物)被纳入所述动物血清中抗体的多聚糖上。在一些实施方式中,与未接受岩藻糖类似物的动物相比,低于约60%,低于约40%,低于约30%,低于约20%,低于约15%,低于约10%,低于约5%或者低于约1%的岩藻糖类似物(或所述岩藻糖类似物的代谢物或者产物)被纳入动物的细胞表面蛋白的多聚糖上。
在一些实施方式中,与未接受岩藻糖类似物的动物相比,低于约60%,低于约40%,低于约30%,低于约20%,低于约15%,低于约10%,低于约5%或者低于约1%的岩藻糖类似物(或所述岩藻糖类似物的代谢物或者产物)被纳入动物血清中白细胞的多聚糖上。
岩藻糖类似物
本发明所述方法的合适岩藻糖类似物(下文分别定为化学式Ⅰ、II、III、IV、V和VI)是能以有效量安全给予动物来抑制抗体或者抗体衍生物的复合N-糖苷连接型糖链的核心岩藻糖基化的那些岩藻糖类似物。岩藻糖类似物在已出版的美国专利申请2009-0317869中有描述,其在体外降低宿主细胞所产生的抗体或者抗体衍生物的复合N-糖苷连接型糖链的岩藻糖纳入。岩藻糖类似物可以通过胃肠道外、口服或其它合适的给药方式给予动物(例如,哺乳动物)。
在一些实施方式中,岩藻糖类似物(或者所述岩藻糖类似物的胞内代谢物或产物)抑制岩藻糖补救中的酶。(如本文所述,胞内代谢物可以是例如GDP-修饰的类似物或者完全或部分脱酯的类似物。产物可以是例如完全或部分脱酯的类似物。)例如,岩藻糖类似物(或者所述岩藻糖类似物的胞内代谢物或产物)可以抑制岩藻糖激酶或GDP-岩藻糖-焦磷酸化酶的活性。在一些实施方式中,岩藻糖类似物(或者所述岩藻糖类似物的胞内代谢物或产物)抑制岩藻糖基转移酶(例如,1,2-岩藻糖基转移酶,1,3-岩藻糖基转移酶,1,4-岩藻糖基转移酶,或者1,6-岩藻糖基转移酶(例如,FUT8蛋白))。在一些实施方式中,岩藻糖类似物(或者所述岩藻糖类似物的胞内代谢物或产物)可抑制岩藻糖从头合成通路中的酶的活性。例如,岩藻糖类似物(或者所述岩藻糖类似物的胞内代谢物或产物)可抑制GDP-甘露糖4,6-脱水酶或/或GDP-岩藻糖合成酶的活性。在一些实施例中,岩藻糖类似物(或者所述岩藻糖类似物的胞内代谢物或产物)可抑制岩藻糖转运蛋白(例如,GDP-岩藻糖转运蛋白)。
在一些实施方式中,所述岩藻糖类似物具有以下化学式(Ⅰ)或(Ⅱ):
或者所述类似物的生物学上可接受的盐类或溶剂化物,其中化学式(Ⅰ)或(Ⅱ)各自可以是α或者β异头物或是对应的醛糖形式。在上述化学式中,R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3烷基甲硅烷基,-OC1-C10烷基,-OCH2OC(O)烷基,-OCH2OC(O)烯基,-OCH2OC(O)炔基,-OCH2OC(O)芳基,-OCH2OC(O)杂环,-OCH2OC(O)O烷基,-OCH2OC(O)O烯基,-OCH2OC(O)O炔基,-OCH2OC(O)O芳基,-OCH2OC(O)O杂环,其中各n是独立选自0-5的整数;并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F,Br,Cl或者I),-CHX2(其中各X是F,Br或者Cl)和甲基环氧乙烷(methoxiran)。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中,R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3甲硅烷基,-OC1-C10烷基,-OCH2OC(O)烷基,-OCH2OC(O)O烷基,-OCH2OC(O)芳基,和-OCH2OC(O)O芳基,其中各n是独立选自0-5的整数;并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F,Br,Cl或者I),-CHX2(其中各X是F,Br或者Cl)和甲基环氧乙烷。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F,Br,Cl或者I),-CHX2(其中各X是F,Br或者Cl)和甲基环氧乙烷。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-O-三-C1-C3甲硅烷基,-OC1-C10烷基;并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是Br,Cl或者I),和甲基环氧乙烷。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OCH2OC(O)烷基,-OCH2OC(O)烯基,-OCH2OC(O)炔基,-OCH2OC(O)芳基,-OCH2OC(O)杂环,-OCH2OC(O)O烷基,-OCH2OC(O)O烯基,-OCH2OC(O)O炔基,-OCH2OC(O)O芳基,-OCH2OC(O)O杂环;并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F,Br,Cl或者I),-CHX2(其中各X是F,Br或者Cl)和甲基环氧乙烷。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,和甲基环氧乙烷。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-CH2F,-CH2I,-CH2Br,和-CH2Cl。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-CHF2,-CHBr2,和-CHCl2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-C≡CH,-C≡CCH3,和-CH2C≡CH。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组-C≡CH,-C≡CCH3,-(CH2)n(CN)(其中n=0或1)和-C(O)OCH3。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-C≡CH,-C≡CCH3,-CH2CN和-C(O)OCH3。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环);并且R5选自下组:-C≡CH,-C≡CCH3,-CH(OAc)CH3,-CH2CN,和-C(O)OCH3。
在异些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R5如本文中所定义,并且R1至R4各自为羟基或者-OC(O)C1-C10烷基。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R5如本文中所定义,并且R1至R4各自为羟基或者-OAc。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OC(O)C1-C10烷基;并且R5选自下组:-C≡CH,-C≡CCH3,-CH(OAc)CH3,-CH2CN,-C(O)OCH3,-CH2F与-CHF2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OAc;并且R5选自下组:-C≡CH,-C≡CCH3,-CH(OAc)CH3,-CH2CN,-C(O)OCH3,-CH2F与-CHF2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OC(O)C1-C10烷基;并且R5选自下组:-C≡CH,-CH2F与-CHF2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OAc;并且R5选自下组:-C≡CH,-CH2F与-CHF2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OC(O)C1-C10烷基;并且R5为-C≡CH。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OAc;并且R5为-C≡CH。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OC(O)C1-C10烷基;并且R5为-CHF2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OAc;并且R5为-CHF2。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自为-OH或是选自下组的酯,包括:-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OC(O)CH2O(CH2CH2O)nCH3(其中n为0-5),-OC(O)CH2CH2O(CH2CH2O)nCH3(其中n为0-5);并且R5选自下组:-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F,Br,Cl或者I),-CHX2(其中各X是F,Br或者Cl)和甲基环氧乙烷。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OC(O)C1-C10烷基;并且R5为-CH2X(其中X是F,Br,Cl或者I)。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OAc;并且R5为-CH2X(其中X是F,Br,Cl或者I)。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OC(O)C1-C10烷基;并且R5为-CH2Br。
在一些实施方式中,所述岩藻糖类似物具有化学式(Ⅰ)或(Ⅱ),其中R1至R4各自独立地选自:-OH和-OAc;并且R5为-CH2Br。
在一些实施方式中,所述岩藻糖类似物的分子量低于2000道尔顿。在一些实施方式中,所述岩藻糖类似物的分子量低于1000道尔顿。
在一些实施方式中,R5未被取代。
在一些实施方式中,各R1至R4未被取代。
在一些实施方式中,R5不是酮(-C(O)烷基)。
在一些实施方式中,R5不是-CH(CH3)OAc。
在一些实施方式中,当各R1至R4是-OAc时,R5不是-CH(CH3)OAc。
在一些实施方式中,R5不是-C≡CH。
在一些实施方式中,当任何R1至R4是-OAc的时候,R5不是-C≡CH。
在一些实施方式中,当任何R1至R4是-OC(O)烷基的时候,R5不是-C≡CH。
在一些实施方式中,各R1至R4是-OC(O)烷基的时候,R5不是-C≡CH。
在一些实施方式中,当各R1至R4是-OH的时候,R5不是-C≡CH。
在一些实施方式中,所述岩藻糖类似物是炔基岩藻糖过乙酸酯。在一些实施方式中,所述岩藻糖类似物是炔基岩藻糖三乙酸酯。在一些实施方式中,所述岩藻糖类似物是炔基岩藻糖二乙酸酯。在一些实施方式中,所述岩藻糖类似物是炔基岩藻糖过乙酸酯,炔基岩藻糖三乙酸酯与炔基岩藻糖二乙酸酯的混合物。
在一些实施方式中,所述岩藻糖类似物是炔基岩藻糖过乙酸酯,炔基岩藻糖三乙酸酯,炔基岩藻糖二乙酸酯与炔基岩藻糖单乙酸酯的混合物。
在一些实施方式中,所述岩藻糖类似物不是岩藻糖。在一些实施方式中,所述岩藻糖类似物不是炔基岩藻糖过乙酸酯。在一些实施方式中,岩藻糖类似物不是半乳糖或者L-半乳糖。
在另一组实施方式中,所述岩藻糖类似物具有以下化学式(Ⅲ)或(Ⅳ):
或者其生物学上可接受的盐或溶剂化物,其中各化学式(Ⅲ)或(Ⅳ)可以是α或者β异头物或是相应的醛糖形式;并且式中,
R1至R4各自独立地选自下组:氟,氯,-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OCH2OC(O)烷基,-OCH2OC(O)O烷基,-OCH2OC(O)芳基,-OCH2OC(O)O芳基,-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3烷基甲硅烷基与-OC1-C10烷基,其中各n是独立选自0-5的整数;并且
各R2a至R3a独立地选自下组:H,F与Cl;
R5选自下组:-CH3,-CHF2,-CH=C=CH2,-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F,Br,Cl或者I),和甲基环氧乙烷;
其中,R5不是-CH=C=CH2、-CH2F、-CHF2时,R1,R2,R3,R2a与R3a其中至少一个是氟或者氯。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1为F。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R2为F。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R3为F。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1与R2各为F。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R2与R2a各为F。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R3与R4各自独立地选自:-OH与-OC(O)C1-C10烷基;R2为F;并且R5为-CH3。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R3与R4各自独立地选自:-OH与-OAc;R2为F;并且R5为-CH3。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R3与R4各自独立地选自:-OH与-OC(O)C1-C10烷基;R2为F;R2a与R3a各为H;并且R5为-CH3。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R3与R4各自独立地选自:-OH与-OAc;R2为F;R2a与R3a各为H;并且R5为-CH3。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R2,R3与R4各自独立地选自:-OH与-OC(O)C1-C10烷基;R2a与R3a分别为H;并且R5为-CHF2。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R2,R3与R4各自独立地选自:-OH与-OAc;R2a与R3a各为H;并且R5为-CHF2。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R2,R3与R4各自独立地选自:-OH与-OC(O)C1-C10烷基;R2a与R3a各为H;并且R5为-CH2F。
在化学式(Ⅲ)或(Ⅳ)的一些实施方式中,R1,R2,R3与R4各自独立地选自:-OH与-OAc;R2a与R3a各为H;并且R5为-CH2F。
在另一组实施方式中,所述岩藻糖类似物具有以下化学式(Ⅴ)或(Ⅵ):
或是其生物学上可接受的盐或溶剂化物,其中各化学式(Ⅴ)或(Ⅵ)可以是α或者β异头物或是相应的醛糖形式;并且式中,
每个R1,R2,R2a,R3,R3a,R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OCH2OC(O)烷基,-OCH2OC(O)O烷基,-OCH2OC(O)芳基,-OCH2OC(O)O芳基,-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3烷基甲硅烷基,-OC1-C10烷基,和小的吸电子基团,其中各n是独立地选自0-5的整数;
R5选自下组:-CH3,-CHX2-CH2X,被卤素取代的或者未被取代的-CH(X’)-C1-C4烷基,被卤素取代的或者未被取代的-CH(X’)-C2-C4烯基,被卤素取代的或者未被取代的-CH(X’)-C2-C4炔基,-CH=C(R10)(R11),-C(CH3)=C(R12)(R13),-C(R14)=C=C(R15)(R16),被甲基或卤素取代的或者未被取代的-C3碳环,被甲基或卤素取代的或者未被取代的-CH(X’)-C3碳环,被甲基或卤素取代的或者未被取代的C3杂环,被甲基或卤素取代的或者未被取代的-CH(X’)-C3杂环,-CH2N3,-CH2CH2N3,和苄氧甲基,或者R5是一个小的吸电子基团;其中R10是氢或者未被取代或者被卤素取代的C1-C3烷基;R11是未被取代或者被卤素取代的C1-C3烷基;R12是氢,卤素或者未被取代或者被卤素取代的C1-C3烷基;R13是氢,或者未被取代或者被卤素取代的C1-C3烷基;R14是氢或者甲基;R15与R16独立地选自氢,甲基和卤素;X为卤素;X’为卤素或者氢;并且
此外,个R1,R2,R2a,R3与R3a可选为氢;位于邻近的碳原子上的两个R1,R2,R2a,R3与R3a可选结合形成所述邻近碳原子之间的双键;并且
前提是R1,R2,R2a,R3,R3a,R4与R5中至少一个是小的吸电子基团,或者R5包含卤素、不饱和位点、碳环、杂环或者叠氮化物,除非(ⅰ)R2与R2a均为氢,(ⅱ)R3与R3a均为氢,(ⅲ)R1为氢,(ⅳ)上述邻近的碳原子之间存在双键,或者(ⅴ)R5为苄氧甲基;并且
其中体内生成的蛋白质、抗体或者抗体衍生物的岩藻糖基化低于缺乏岩藻糖类似物的情况下在体内生成的蛋白质、抗体或者抗体衍生物。
在化学式(Ⅴ)与(Ⅵ)的一些实施方式中,R2a,R3a分别为氢。
在化学式(Ⅴ)与(Ⅵ)的一些实施方式中,R5选自下组:-CH3,-CH2CH3,-CH2C≡CH,-CH=CHCH3,-环丙基,-环氧乙烷,甲基取代的-环氧乙烷,-CH2F,-CH2Cl,-CH2Br,-CH2I,-CHF2,-CH=C=CH2,-CH2N3与-CH2CH2N3。
在化学式(Ⅴ)与(Ⅵ)的一些实施方式中,所述小的吸电子基团选自下组:氟、氯、溴、-CHF2、-CH=C=CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-CO2H、-C(O)OC1-C4烷基、-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是Br,Cl或者I),和甲基环氧乙烷。
在化学式(Ⅴ)与(Ⅵ)的一些实施方式中,R5选自下组:-CH3,-C≡CH,-CH2F,-CH2Br与-CHF2。在一些进一步的实施方式中,R1,R2,R2a,R3,R3a,R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基。
在化学式(Ⅴ)与(Ⅵ)的一些实施方式中,所述小的吸电子基团选自下组:氟,氯,溴,-CHF2,-CH=C=CH2,-C≡CH,-C≡CCH3,-CH2C≡CH,-CO2H,-C(O)OC1-C4烷基,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X为Br,Cl或者I)和甲基环氧乙烷。
在化学式(Ⅴ)或(Ⅵ)的一些实施方式中,R1,R2,R2a,R3,R3a与R4中的至少两个各自独立地选自小的吸电子基团。
在化学式(Ⅴ)或(Ⅵ)的一些实施方式中,所述岩藻糖类似物选自表1,2或3的化合物。
药物组合物
分子式Ⅰ、II、III、IV、V和VI的岩藻糖类似物(下文称‘岩藻糖类似物’)可配制用于治疗性应用。所述岩藻糖类似物可配制为包含治疗或预防有效量的岩藻糖类似物以及一种或多种药学相容(可接受)成份的药物组合物。例如,药物或非药物的组合物通常包括一种或多种载体(例如,无菌液体,例如水和油类,包括石油、动物、植物或合成来源的那些油,例如花生油、大豆油、矿物油、芝麻油等)。在所述药物组合物为静脉内给药的时候,水是更典型的载体。盐水溶液与葡萄糖水溶液与甘油溶液也可以用作液体载体,特别是用于注射用溶液。适宜的赋形剂包括,例如,氨基酸、淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙二醇、乙二醇、水、乙醇等。需要时,所述组合物还可以包括少量的湿润剂或者乳化剂,或者pH缓冲试剂。这些组合物可以具有溶液、悬浮剂、乳剂、片剂、丸剂、胶囊、粉末缓释剂型等形式。适宜的药学载体的示例见E.W.Martin编著的“Remington’s Pharmaceutical Sciences”(《雷明顿药物科学》)中的描述。这些组合物通常含有在治疗有效量的所述岩藻糖类似物和适当含量的载体来提供适宜给药于病人的方式,所含岩藻糖类似物通常为纯化形式。所述制剂对于有给药方式。
本文中描述的药物组合物可以是允许将此组合物给予动物(例如,哺乳动物)的任何形式。本文中描述的药学组合物可以是允许将此组合物给予哺乳动物的任何形式。本文中描述的药物组合物可以是允许将此组合物给予人的任何形式。
所述组合物可以是固体或者液体的形态。典型的给药途径包括但不限于,口服、胃肠外、舌下和眼部。胃肠外给药包括皮下注射、静脉注射、肌肉注射、胸腔内注射或者输液技术。所述组合物优选胃肠外或口服给予。这些药物组合物可以配制成使得在将所述组合物给予动物时岩藻糖类似物是生物可利用的。组合物也可以采用一个或多个剂量单位的形式,例如,片剂可以是单个剂量单位,而固体形式岩藻糖类似物的容器可以容纳多个剂量单位。
用于制备所述药物组合物的材料在其使用量上可以是无毒的。本领域中的普通技术人员显然了解药物组合物中的活性成份的最佳剂量取决于多种因素。相关因素包括但不限于,动物的种类(例如,人类),岩藻糖类似物的特定形式,给药方式,所用组合物,以及待处理疾病或状况的严重程度。
药学上可接受的载体或者载剂可以是颗粒状的,以使所述组合物可以是例如片剂或者粉剂的形式。载体可以是液体,从而所述组合物是例如口服糖浆或者注射液。
当计划口服给药时,所述组合物优选为固体或者液体形式,此处半固体,半液体,悬浮剂,以及凝胶形式包括在本文所认为的固体或者液体范围内。
作为用于口服给药的固体组合物,所述组合物配制成粉剂,颗粒剂,压缩片剂,丸剂,胶囊剂,咀嚼胶,扁胶剂(wafer)等形式。这些固体的组合物通常包含一种或多种惰性的稀释剂。另外,可能存在一种或多种以下物质:粘合剂例如羧甲基纤维素、乙基纤维素、微晶纤维素或者明胶;赋形剂例如淀粉、乳糖或者糊精,崩解剂例如褐藻酸、藻酸钠、羟基乙酸淀粉钠(Primogel)、玉米淀粉等;润滑剂例如硬脂酸镁或者氢化植物油(Sterotex);助流剂例如胶状二氧化硅;甜味剂例如蔗糖或者糖精;调味剂例如薄荷,水杨酸甲酯或者橘子味调味剂,以及着色剂。
当所述组合物是胶囊形式如明胶胶囊时,在上述类型材料外,它还可以含有液体载体,例如聚乙二醇,环状糊精或者脂肪油类。
所述组合物可以是液体形态,例如,酏剂,糖浆,溶液,乳剂或者悬浮剂。所述液体可以用于口服给药或者通过注射来递送。当用于口服给药的时候,组合物可以包含一种或多种甜味剂、防腐剂、染料/色素以及增味剂。在用于注射给药的组合物中(如上所述),还可包含一种或多种表面活性剂、防腐剂、湿润剂、分散剂、悬浮剂、缓冲剂、稳定剂以及等渗剂。
液体组合物,无论是溶液、悬浮液或者其他类似形式,还可以包括以下一种或多种:注射用无菌稀释剂例如水,盐溶液,优选生理盐水,任氏(Ringer)溶液,等渗氯化钠,可用作溶剂或悬浮介质的不挥发性油如合成的单或双甘油酯,聚乙二醇,甘油,环状糊精,丙二醇或者其他溶剂;抗菌剂如苯甲醇,或者对羟基苯甲酸甲酯;抗氧化剂例如抗坏血酸,亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲剂例如醋酸盐、柠檬酸盐或者磷酸盐,以及张力调节剂如氯化钠或者右旋葡萄糖。生理盐水是优选的佐剂。注射用的组合物优选是无菌的。
如上所述,能有效治疗特定紊乱或状况的岩藻糖类似物的用量将取决于所述紊乱或状况的性质,而这可以通过标准的临床技术来确定。另外,可以可选地采用体外或者体内试验来协助鉴定最优的剂量范围。所述组合物中使用的精确剂量还取决于给药途径和所述疾病或者紊乱的严重程度,而且应该依照医生的判断与每个病人的情况来决定。
所述组合物含有有效量的岩藻糖类似物使得能获得适宜的剂量。通常,该用量是岩藻糖类似物占所述组合物重量的至少约0.01%。当用于口服给药的时候,该用量可以在所述组合物重量的约0.1%至约80%范围内。优选的口服组合物可含有占所述组合物重量约4%至约50%的岩藻糖类似物。本发明的优选组合物制备为使得胃肠外剂量单位含有占约0.01%至2%重量的岩藻糖类似物。
对于静脉给药,所述组合物可含有每公斤动物体重约1至约250mg的岩藻糖类似物。在一些实施方式中,岩藻糖类似物给药剂量的范围在约1-25毫克/公斤体重。优选岩藻糖类似物给药剂量的范围在约4至约25毫克/公斤体重。
总体上,给予动物的岩藻糖类似物的剂量通常相对于所述动物的体重为约0.1mg/kg至约250mg/kg。优选的,给予动物的剂量相对于所述动物的体重为约0.1mg/kg至约25mg/kg,更优选相对于所述动物的体重为约1mg/kg至约10mg/kg。
所述组合物含有有效量的岩藻糖类似物使得能获得适宜的剂量。通常,该用量是岩藻糖类似物占所述组合物重量的至少约0.01%。当用于口服给药的时候,该用量可以在所述组合物重量的约0.1%至约80%范围内。优选的口服组合物可含有占所述组合物重量约4%至约50%的岩藻糖类似物。本发明的优选组合物制备为使得胃肠外剂量单位含有约0.01%至2%重量的岩藻糖类似物。
对于静脉注射给药,所述组合物可包含每公斤动物体重约1至250mg的岩藻糖类似物。在一些实施方式中,岩藻糖类似物给药剂量的范围在约1至约25毫克/公斤体重。优选岩藻糖类似物给药剂量的范围在约4至约25毫克/公斤体重。
总体上,根据所需效果,岩藻糖类似物或其药物组合物的给药方案可以是每日一次,每周一次,两周一次或者一月一次。岩藻糖类似物或其药物组合物的给药可以从约1至5个,约1至约10个,约1至约15个,或更多疗程,其中每个疗程持续一个月。每个疗程用药的给予可以每日一次,隔日一次,一周两次,每周一次,两周一次,三周一次或者一月一次。疗程可以可选地包括休息期,期间蛋白质(例如抗体或者其他蛋白质)的岩藻糖基化上升。替代地,休息期可以包括在疗程之间。这种休息期可以使参与重要功能的蛋白质的岩藻糖基化得到回复。
岩藻糖类似物或其药物组合物的优选给药方式由医生裁量,并将部分取决于所述医学状况的位点(例如癌症或者自体免疫性疾病的位点)。在一个实施方式中,所述岩藻糖类似物或者组合物为胃肠外给药。在另一实施方式中,所述岩藻糖类似物或组合物为口服给药。
在具体实施方式中,可能会要求将一种或多种岩藻糖类似物或者组合物局部给予到需要治疗的区域。这是可以实现的,例如,但并不限于,手术中通过局部灌注;局部施用;通过注射;或者通过植入手段,所述植入体是多孔的、非多孔的、或者胶状材料,包括膜,例如硅橡胶膜,或者纤维。在一个实施方式中,可以通过直接注射在癌症、肿瘤、肿瘤性或者肿瘤前的组织位点(或其过去的位点)来进行给药。
在另一实施方式中,可以直接注射在自体免疫性疾病的发病位点(或其过去的位点)来进行给药。
在另一实施方式中,岩藻糖类似物可以在载体,特别是在脂质体中来递送(见Langer,Science249:1527-1533(1990);Treat等人,在LIPOSOMES IN THE THERAPY OFINFECTIOUS DISEASE AND CANCER,(感染性疾病和癌症治疗中的脂质体),Lopez-Berestein与Fidler编著,Liss出版时,纽约,353-365页(1989);Lopez-Berestein,同上,317-327页;一般参见同上)。
在另一实施方式中,岩藻糖类似物或者组合物可以通过控释系统给药。在一个实施方式中,可以使用泵(参见Langer,同前;Sefton,CRC Cirt.Ref.Biomed.Eng.14:201(1987);Buchwald等人,Surgery 88:507(1980);Saudek等人,N.Engl.J.Med.321:574(1989))。在另一实施方式中,可使用聚合材料(参见MEDICAL APPLICATIONS OFCONTROLLED RELEASE,(《控释的医学应用》)Langer和Wise编著,CRC出版社,弗罗里达博卡拉顿(1974);CONTROLLED DRUG BIOAVAILABILITY,DRUG PRODUCT DESIGN ANDPERFORMANCE,(《受控的药品生物可利用性,药品的设计与性能》)Smolen与Ball编著,Wiley出版社,纽约(1984);Ranger与Peppas,J.Macromol.Sci.Rev.Macromol.Chem.23:61(1983);还可参见Levy等人,Science 228:190(1985);During等人,Ann.Neurol.25:351(1989);Howard等人,J.Neurosurg.71:105(1989))。也可以使用Langer的综述中讨论的其他控释系统(Science 249:1527-1533(1990))。
术语“载体”指稀释剂、佐剂或者赋形剂,岩藻糖类似物与之一同给予。这谢药物载体可以是液体,例如水与油类,包括石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、芝麻油等。载体可以是盐水、阿拉伯树胶、明胶、淀粉糊、滑石粉、角蛋白、硅胶、尿素等。另外,可使用辅剂、稳定剂、增稠剂、润滑剂与着色剂。在一种实施方式中,在给予动物的时候,岩藻糖类似物或者组合物以及药学可接受的载体是无菌的。在静脉给药的时候水是优选载体。盐溶液与右旋葡萄糖水溶液以及丙三醇溶液也可用作为液体载体,尤其是用于注射液。适宜的药学载体还包括赋形剂,例如淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、丙三醇、丙烯、乙二醇、水、乙醇等。需要时,本发明的组合物还可含有少量的湿润剂或者乳化剂,或者pH缓冲剂。
使用岩藻糖类似物来在体内降低抗体与其他蛋白岩藻糖基化的治疗方法本文所提供的分子式Ⅰ、II、III、IV、V和VI的岩藻糖类似物(下文称‘岩藻糖类似物’)可用于治疗动物的癌症、自体免疫性疾病或感染性疾病。
癌症的治疗
岩藻糖类似物可用于治疗患者的癌症。向有需要的动物(例如,哺乳动物如人类)给予岩藻糖类似物可以导致对肿瘤细胞或者癌细胞的增殖的抑制,或是所述动物(例如,人类患者)中癌症的治疗。岩藻糖类似物可按多种设定用于治疗动物癌症。
岩藻糖类似物还可用于提高缺乏核心岩藻糖基化的抗体的体内生成。患者中针对癌靶标的这类抗体所占的比例的提高可以导致对肿瘤细胞或者癌细胞的增殖的抑制,或是动物(例如,人类患者)中癌症的治疗。岩藻糖类似物可按多种设定用于治疗动物癌症。
可以使用岩藻糖类似物来治疗的癌症的具体类型包括实体肿瘤与恶性血液病。这些癌症包括但不限于:(1)实体肿瘤,包括但不限于:纤维肉瘤,黏液肉瘤,脂肪肉瘤,软骨肉瘤,骨肉瘤,脊索癌,血管肉瘤,血管内皮肉瘤,淋巴管肉瘤,淋巴管内皮肉瘤,滑膜瘤,间皮瘤,骨尤文肉瘤,平滑肌肉瘤,横纹肌肉瘤,结肠癌,大肠癌,肾癌,胰脏癌,骨癌,乳腺癌,卵巢癌,前列腺癌,食道癌,胃癌,口腔癌,鼻癌,喉癌,鳞状细胞癌,基底细胞癌,腺癌,汗腺癌,皮脂腺癌,乳头状癌,乳头状腺癌,囊腺癌,骨髓癌,支气管癌,肾细胞癌,肝癌胆管癌,绒毛膜癌,精原细胞癌,胚胎癌,Wilm氏瘤,宫颈癌,尿道癌,睾丸癌,小细胞肺癌,膀胱癌,肺癌,上皮细胞癌,神经胶质瘤,胶质母细胞瘤,多形性星形细胞瘤,髓母细胞瘤,颅咽管瘤,室鼓膜瘤,松果体瘤,成血管细胞瘤,听觉神经瘤,少突神经胶质瘤,脑膜瘤,皮肤癌,黑色素瘤,成神经细胞瘤,以及视网膜母细胞瘤;(2)血源性癌症,包括但不限于:急性淋巴细胞性白血病“ALL”,急性淋巴细胞B细胞白血病,急性淋巴细胞T细胞白血病,急性骨髓细胞性白血病“AML”,急性原髓细胞白血病“APL”,急性单核细胞性白血病,急性红白血病,急性巨核细胞性白血病,急性骨髓单核细胞性白血病,急性非淋巴细胞性白血病,急性未分化型白血病,慢性骨髓细胞性白血病“CML”,慢性淋巴细胞性白血病“CLL”,毛细胞白血病,多发性骨髓瘤,急性与慢性白血病,例如,成淋巴细胞髓性白血病以及淋巴细胞性骨髓细胞白血病,以及(3)淋巴瘤例如霍奇金氏病,非霍奇金氏淋巴瘤,多发性骨髓瘤,华氏(Waldenstrom)巨球蛋白血症,重链病以及真性红细胞增多症。
癌症的多模态治疗
癌症,包括但不限于:肿瘤,转移癌,或者以非受控细胞增殖为特征的任何疾病或紊乱,都可以通过将上述化学式I,II,III,IV,V或VI任一种的岩藻糖类似物给予有需要的动物(例如,哺乳动物如人)来治疗或预防。在一些实施方式中,本发明提供方法来治疗或者预防癌症,所述方法包括将有效量的岩藻糖类似物与可选的化疗剂给予有需要的动物。在一个实施方式中,所述化疗剂是用于治疗未发现是难治的癌症。在另一实施方式中,所述化疗剂是用于治疗已被认为是难治的癌症。可将岩藻糖类似物给予已经为了治疗所述癌症经历过手术的动物。
在一个实施方式中,附加的治疗方法是放射性治疗。
在一个具体实施方式中,岩藻糖类似物与化疗剂或者与放射性治疗同时给予。在另一具体实施方式中,化疗剂或者放射性治疗的给予在岩藻糖类似物的给予之前或之后实施,优选在岩藻糖类似物的给药之前或之后至少1小时,5小时,12小时,一天,一周,两周,三周,一个月或者若干月(例如,最长达三个月)进行。
化疗剂的给药可以持续一系列期段(session),并且可以是任一种或者是本文提供的化疗剂的组合。关于放射,可以根据待治疗的癌症类型使用任何放射性治疗方案。例如,但并不限于,可以给予X射线放射;具体地,高能兆伏(大于1兆伏能量的放射)可用于深部肿瘤,而电子束和中电压X射线放射可用于皮肤癌。也可以给予伽马射线发射型放射性同位素,例如镭、钴或者其他元素的发射型同位素。
另外,本发明提供使用岩藻糖类似物作为化疗或者放疗的替代物来治疗癌症的方法,应用于已经证明或者能够证明化疗或者放疗对于待治疗的对象而言毒性过大,例如,导致不可接受的或者无法忍受的副作用的场合。可选地,接受治疗的动物可以用另一种癌症疗法例如手术,放疗或者化疗来治疗,这取决于哪一种疗法被认为是可接受的或者可以忍受的。
癌症的多药物疗法
本发明包含治疗癌症的方法,该方法包括向有需要的动物给予有效量的岩藻糖类似物和治疗剂,该治疗剂是抗癌剂。适宜的抗癌剂包括但不限于:甲氨蝶呤,紫杉醇,左旋门冬酰胺酶,巯基嘌呤,硫代鸟嘌呤,羟基脲,阿糖胞苷,环磷酰胺,异环磷酰胺,亚硝基脲,
顺铂,卡铂,丝裂霉素,达卡巴嗪,甲基苄肼(procarbizine),托泊替康,氮芥,环磷酰胺,依托泊苷,5-氟尿嘧啶,BCNU,伊立替康,喜树碱,博莱霉素,多柔比星,伊达比星(idarubicin),柔红霉素,放线菌素,普卡霉素,米托蒽醌,天冬酰胺酶,长春碱,长春新碱,长春瑞滨,紫杉醇和多西他赛。在优选实施方式中,所述抗癌剂包括但不限于:烷化剂,氮芥(环磷酰胺,异环磷酰胺,氯乙环磷酰胺,苯丁酸氮芥),亚硝基脲(卡莫司汀(BCNU),洛莫司汀(CCNU)),烷基磺酸盐(白消安(busulfan),苏消安(Treosulfan)),三氮烯类(达卡巴嗪),含铂化合物(顺铂,奥沙利铂,卡铂),植物生物碱(长春花生物碱类-长春新碱,长春碱,长春地辛,长春瑞滨),紫杉烷类(紫杉醇,多西他赛),DNA拓扑异构酶抑制剂,表鬼臼毒素类(依托泊苷,替尼泊苷,托泊替康,9-氨基喜树碱,喜树碱),克立那托(Crisnatol),丝裂霉素(丝裂霉素C);抗代谢物如抗叶酸:二氢叶酸还原酶(DHFR)抑制剂:甲氨蝶呤,三甲曲沙(Trimetrexate);IMP脱氢酶抑制剂:霉酚酸,噻唑呋啉(Tiazofurin),利巴韦林,EICAR;核糖核苷酸还原酶抑制剂:羟基脲去铁胺;嘧啶类似物:尿嘧啶类似物:5-氟尿嘧啶,氟尿苷,去氧氟尿苷,雷替曲塞(ratitrexed);胞嘧啶类似物:阿糖胞苷(araC),胞嘧啶阿拉伯糖苷,氟达拉滨;嘌呤类似物:巯基嘌呤,硫代鸟嘌呤;激素疗法:受体拮抗剂:抗雌激素类:他莫昔芬,雷洛昔芬,甲地孕酮;促性腺激素释放激素(LHRH)激动剂:格斯克林(goscrclin),醋酸亮丙瑞林;抗雄激素类:氟他胺(flutamide),比卡鲁胺;维甲酸类(Retinoid/Deltoid):维生素D3类似物:EB1089,CB1093,KH1060;光动力治疗剂:维替泊芬(BPD-MA),酞菁,光敏剂Pc4,去甲氧竹红菌素A(2BA-2-DMHA);细胞因子类:干扰素-α、干扰素-γ;肿瘤坏死因子:其他:异戊二烯化抑制剂,洛伐他汀;多巴胺能神经毒素:1-甲基-4-苯基吡啶离子;细胞周期抑制剂:星形孢菌素;放线菌素:放线菌素D,更生霉素;博莱霉素类:博莱霉素A2,博莱霉素B2,培洛霉素;蒽环类:柔红霉素,多柔比星(阿霉素),伊达比星,表柔比星,吡柔比星,佐柔比星,米托蒽醌;MDR抑制剂类:维拉帕米(Verapamil);以及Ca2+ATP酶抑制剂类:毒胡萝卜素。
癌症的辅助疗法
岩藻糖类似物可用作佐剂,与癌症疫苗联用。本文使用的术语“癌症疫苗”指通过诱导和/或增强针对肿瘤细胞的特异性免疫反应来选择性破坏肿瘤细胞的复合物。例如,癌症疫苗可以是包含TAA或TSA的蛋白质或者肽、多肽的药物,和包含TAA或TSA的蛋白质或者肽、多肽的药物组合物。如本文所述,TSA指一种“肿瘤-特异性抗原”而TAA指肿瘤相关抗原。TSA是癌细胞独有的分子。TAA是癌细胞和正常细胞中共有但差异表达的分子。
癌症疫苗的剂量可以根据针对疫苗激活的免疫反应的程度经适当调整后确定。通常,作为活性成分,它介于0.01到100mg/天/成人,或者优选介于0.1与10mg/天/成人。癌症疫苗的给予可以从数天一次到数月一次。可以根据医用肽、多肽或者蛋白质的熟知给药方法来进行给药,例如皮下的静脉内或肌肉内。为了诱导和/或增强给药时的免疫反应,所述肽、多肽或者蛋白质使用时可以有或者没有适当佐剂,带或不带与载体的连接。载体没有限制,只要它本身不对人体施加有害作用,并且能够增强抗原性;纤维素,多聚氨基酸,白蛋白等可以作为载体的示例。佐剂可以是通常用于肽疫苗接种的那些,弗氏不完全佐剂,(FIA),铝佐剂(ALUM),百日咳疫苗,矿物油等可以作为示例。另外,所述制剂可以通过应用合适的用于配制肽、多肽或者蛋白质的熟知方法来适当选择。
另外,还可以通过从患者的外周血中采集部分单核细胞,将这些细胞与本发明的肽、多肽或者蛋白质一起孵育,再将其中已观察到CTL的诱导和/或CTL的激活的该部分单核细胞碎片输回患者的血液中。岩藻糖类似物可以在重给予所述单核细胞的同时或其后联合给予。培养条件,例如单核细胞的浓度,所述肽、多肽或蛋白质的浓度,培养时间等可以由简单的重复研究确定。培养过程中可添加能够增强淋巴细胞生长的物质,例如白介素-2。
自体免疫性疾病的治疗
岩藻糖类似物可用于调控自体免疫性疾病或者用于治疗自体免疫性疾病,以便减轻症状和/或自体免疫性反应。岩藻糖类似物可按多种设定用于治疗动物的自体免疫性疾病。
在一个实施方式中,岩藻糖类似物向下调节或者向下调控与特定的自体免疫性疾病相关联的自体免疫抗体。
可以使用岩藻糖类似物来治疗的自体免疫性疾病的具体类型包括但不限于:Th2-淋巴细胞相关疾病(例如,特应性(atopic)皮炎,特应性哮喘,鼻结膜炎,过敏性鼻炎,欧门氏(Omenn)综合征,系统性硬化症,和移植物抗宿主病);Th1淋巴细胞相关疾病(例如,类风湿关节炎,多发性硬化症,牛皮癣,干燥(Sjorgren)综合征,桥本氏甲状腺炎,格雷夫斯(Grave)病,原发性胆汁性肝硬化,韦格纳肉芽肿病,和肺结核);活化B-淋巴细胞相关疾病(例如,全身性红斑性狼疮,肺出血肾炎综合征(Goodpasture's syndrome),类风湿关节炎,和Ⅰ型糖尿病);以及下述疾病。
慢性活动性肝炎,艾迪生病,过敏性肺泡炎,过敏反应,过敏性鼻炎,奥尔波特综合征,过敏性反应,强直性脊柱炎,抗磷脂综合征,关节炎,蛔虫病,曲霉病,特应性过敏,萎缩性(atropic)皮炎,萎缩性鼻炎,白塞氏病,养鸟人肺病,支气管哮喘,卡普兰综合征,心肌病,乳糜泻,南美锥虫病,慢性肾小球性肾炎,科甘综合征,冷凝集素病,先天性风疹感染,CREST综合征,克罗恩病,冷球蛋白血症,库欣综合征,皮肌炎,盘状红斑狼疮,德雷斯勒综合征,重症肌无力综合征(Eaton-Lambert Syndrome),埃可病毒感染,脑脊髓炎,内分泌眼病,Epstein-Barr病毒感染,马气喘病,斑狼疮,伊文氏综合征,费尔蒂综合征,纤维性肌痛,富克斯(Fuch)睫状体炎,胃萎缩,胃肠道过敏,巨细胞动脉炎,肾小球性肾炎,肺出血肾炎综合征,移植物抗宿主病,格雷夫斯病,格林巴利病,桥本氏甲状腺炎,溶血性贫血,过敏性紫癜,特发性肾上腺萎缩,特发性肺纤维化,IgA肾病,炎症性肠病,胰岛素依赖型糖尿病,幼年性关节炎,青少年糖尿病(Ⅰ型),重症肌无力综合征,蹄叶炎,扁平苔癣,狼疮样肝炎,狼疮性淋巴细胞减少,美尼尔氏病,混合性结缔组织疾病,多发性硬化症,重症肌无力,恶性贫血,多腺体综合征,早老性痴呆症,原发性无丙种球蛋白血症,原发性胆汁性肝硬化,牛皮癣,牛皮癣性关节炎,雷诺氏现象,复发性流产,赖特综合征,风湿热,类风湿关节炎,山特氏(Sampter)综合征,血吸虫病,施密特综合征,硬皮病,舒尔曼综合征,舍格林氏(Sjorgen)综合征,僵人综合征,交感性眼炎,系统性红斑狼疮,大动脉炎,颞动脉炎,甲状腺炎,血小板减少症,甲状腺毒症,中毒性表皮坏死松解B型,胰岛素抵抗型Ⅰ型糖尿病,溃疡性结肠炎,葡萄膜炎白癜风,华氏巨球蛋白血症,和韦格纳肉芽肿。
自体免疫性疾病的多药物疗法
本发明还提供自体免疫性疾病的治疗方法,该方法包括向有需要的动物(例如,哺乳动物)给予有效量的岩藻糖类似物和可选的已知用于治疗自体免疫性疾病的治疗剂。在一个实施方式中,该抗自体免疫性疾病药剂包括但不限于:环孢霉素,环孢霉素A,吗替麦考酚酯(mycophenylate,mofetil),西罗莫司,他克莫司,依那西普,强的松,硫唑嘌呤,甲氨蝶呤,环磷酰胺,强的松,氨基己酸,氯喹,羟化氯喹,氢化可的松,地塞米松,苯丁酸氮芥,脱氢表雄酮,达那唑,溴麦角环肽,美洛昔康或英夫利昔单抗。
感染性疾病的治疗
岩藻糖类似物可用于增强免疫反应或用于治疗感染性疾病,所述免疫反应可导致对能造成感染性疾病的细胞的增殖抑制或杀死的提高。岩藻糖类似物按多种设定用于治疗动物的感染性疾病用。
在一个实施方式中,岩藻糖类似物增强免疫反应,导致能造成感染性疾病的细胞增殖的杀死或抑制,或者提高其杀死或抑制。
可用岩藻糖类似物治疗的感染性疾病的具体类型包括但不限于,(1)细菌性疾病:白喉,百日咳,隐性菌血症,尿道感染,肠胃炎,蜂窝组织炎,会厌炎,气管炎,腺样体肥大,咽后脓肿,脓疱,深脓疱,肺炎,心内膜炎,化脓性关节炎,肺炎,腹膜炎,细菌性脑膜炎,急性化脓性脑膜炎,尿道炎,宫颈炎,直肠炎,咽炎,输卵管炎,附睾炎,淋病,梅毒,李斯特菌病,炭疽,诺卡菌病,沙门氏菌感染,伤寒,痢疾,结膜炎,鼻窦炎,布鲁氏菌病,兔热病,霍乱,鼠疫,破伤风,坏死性肠炎,放线菌混合厌氧菌感染,梅毒,回归热,钩端螺旋体病,莱姆病,鼠咬热,结核,淋巴结炎,麻风病,衣原体,衣原体肺炎,沙眼,包涵体结膜炎,全身感染;(2)真菌感染:组织胞浆菌病,球孢子菌病,芽生菌,孢子丝菌病,隐球菌病,系统性念珠菌病,曲霉菌病,毛霉菌病,足分支菌病,着色霉菌病;(3)立克次氏体病:斑疹伤寒,落基山斑疹热,埃立克体病,东方蜱传立克次体痘,立克次氏体病,Q热,和巴尔通氏体病;(4)寄生虫病:疟疾,巴贝斯虫病,非洲昏睡病,南美锥虫病,利什曼病,黑热病,弓形虫病,脑膜脑炎,角膜炎,阿米巴病,贾第虫病,隐孢子虫病,等孢子球虫病,圆孢子虫病,微孢子虫病,蛔虫,鞭虫感染,钩虫感染,蛲虫感染,眼幼虫移行,旋毛虫病,几内亚龙线虫病,淋巴丝虫病,罗阿丝虫病,盘尾丝虫病,犬心丝虫感染,血吸虫病,血吸虫皮炎,东方肺吸虫病,东方肝吸虫病,肝片吸虫病,姜片虫病,后睾吸虫病,绦虫感染,棘球蚴病,泡状棘球蚴病;(5)病毒性疾病:麻疹,亚急性硬化性全脑炎,普通感冒,腮腺炎,风疹,红疹,传染性红斑,水痘,呼吸道合胞体病毒感染,哮吼(Croup),细支气管炎,传染性单核细胞增多症,小儿麻痹症,疱疹性咽峡炎,手足口病,博恩霍尔姆疾病,生殖器疱疹,生殖器疣,无菌性脑膜炎,心肌炎,心包炎,胃肠炎,获得性免疫缺陷综合症(艾滋病),雷依氏综合征,川崎综合征,流感,支气管炎,病毒性行动性肺炎(Viral"Walking"Pneumonia),急性发热性呼吸道疾病,急性咽结膜热,流行性角膜结膜炎,单纯疱疹病毒1型(HSV-1),单纯疱疹病毒2型(HSV-2),带状疱疹,巨细胞包涵体病,狂犬病,渐进多灶性白质脑病,库鲁病,致命性家族性失眠症,克雅氏疾病,GSS氏病,热带痉挛性瘫痪,西部马脑炎,加利福尼亚脑炎,圣路易斯脑炎,黄热病,登革热,淋巴细胞性脉络丛脑膜炎,拉沙热,出血热,汉坦病毒,肺综合征,马尔堡病毒感染,埃博拉病毒病毒感染以及天花。
感染性疾病的多药物治疗
本发明还提供治疗感染性疾病的方法,包括向有需要的动物(例如,哺乳动物)给予有效量的岩藻糖类似物和可选的治疗剂,该治疗剂是用于抗感染性疾病的药剂。在一个实施方式中,抗感染性疾病的药剂包括但不限于:(1)抗菌剂:β-内酰胺类抗生素:青霉素G,青霉素V,氯唑西林,双氯青霉素,甲氧西林,奈夫西林,苯唑西林,氨苄西林,阿莫西林,巴氨西林,阿洛西林,羧苄青霉素,美洛西林,哌拉西林,替卡西林;氨基糖苷类:丁胺卡那霉素,庆大霉素,卡那霉素,新霉素,奈替米星,链霉素,妥布霉素;大环内酯类:阿奇霉素,克拉霉素,红霉素,林可霉素,克林霉素;四环类:地美环素,强力霉素,米诺环素,土霉素,四环素;喹诺酮类:西诺沙星,萘啶酸,氟喹诺酮类:环丙沙星,依诺沙星,格帕沙星,左氧氟沙星,洛美沙星,诺氟沙星,氧氟沙星,司帕沙星,曲伐沙星;多肽类:杆菌素,黏菌素,多粘菌素B;磺胺类:磺胺异唑,磺胺甲唑,磺胺嘧啶,磺胺甲二唑,乙酰磺胺;其它抗菌剂:甲氧苄氨嘧啶,磺胺二甲唑,氯霉素,万古霉素,甲硝唑,奎奴普丁,达福普汀,利福平,大观霉素,呋喃妥;抗病毒剂:普通抗病毒剂:碘去氧脲嘧啶,阿拉伯糖腺苷,三氟尿苷,阿昔洛韦,泛昔洛韦,泮昔洛韦(pencicyclovir),伐昔洛韦,甘昔洛韦(gancicyclovir),膦甲酸,利巴韦林,金刚烷胺,金刚乙胺,西多福韦;反义寡核苷酸类;免疫球蛋白类;干扰素类;艾滋病毒感染用药:齐多夫定,地达诺新,扎西它滨,司他夫定,拉米夫定,奈韦拉平,地拉夫定,沙奎那韦,利托那韦,茚地那韦和奈非那韦。
其他治疗性剂
本发明的方法还可包括给予岩藻糖类似物和治疗剂或者其药学可接受的盐或溶剂化物。岩藻糖类似物以及治疗剂可以起到累加作用,或者更优选起到协同作用。在优选的实施方式中,含有岩藻糖的组合物的给予与一种或多种治疗剂的给予同时进行,这些治疗剂可以在含有岩藻糖类似物的同一组合物中,或是在另一组合物中。在另一实施方式中,岩藻糖类似物的给予在所述治疗剂的给药之前或之后进行。
在本发明的治疗癌症、自体免疫疾病或者感染性疾病的方法中,治疗剂还可以是止吐剂。适宜的止吐剂包括但不限于:胃复安(metoclopromide),多潘立酮,甲哌氯丙嗪,异丙嗪,氯丙嗪,曲美苄胺,昂丹司琼,格拉司琼,羟嗪,乙酰亮氨酸单乙醇胺,阿立必利,阿扎司琼,苯喹胺,氨醇醋茶碱,溴必利,布克利嗪,氯波必利,赛克利嗪,乘晕宁,地芬尼多,多拉司琼,美其敏,美沙拉妥,美托哌丙嗪,大麻隆,奥西喷地,匹哌马嗪,东莨菪碱,舒必利,四氢大麻酚,硫乙拉嗪,硫丙拉嗪,和托烷司琼。
在另一实施方式中,所述治疗剂可以是造血细胞集落刺激因子。适宜的造血细胞集落刺激因子包括但不限于:非格司亭(filgrastim),沙格司亭(sargramostim),莫拉司亭和促红细胞生成素α。
在另一实施方式中,所述治疗剂可以是阿片类或者非阿片类镇痛剂。适宜的阿片类镇痛剂包括但不限于:吗啡,海洛因,氢化吗啡酮,氢化可待因酮,羟吗啡酮,羟可待因酮,麦脱朋,阿朴吗啡,去甲吗啡,埃托啡,丁丙诺啡,度冷丁,洛哌丁胺,氨苄度冷丁,依索庚嗪,匹米尼定(piminidine),倍他罗定,地芬诺酯,芬太尼,舒芬太尼,阿芬太尼,瑞芬太尼,羟甲左吗喃,右美沙芬,苯唑星,喷他佐辛,环唑辛,美沙酮,异美沙酮和丙氧吩。适宜的非阿片类镇痛剂包括但不限于:阿司匹林,塞来昔布,罗非昔布,双氯芬酸钠,二氟尼柳(diflusinal),依托度酸,非诺洛芬,氟比洛芬,布洛芬,酮洛芬,吲哚美辛,酮咯酸,甲氧胺苯酸钠,甲芬那酸,萘丁美酮,萘普生,吡罗昔康和舒林酸。
本发明在如下实施例中有详细描述,但这些实施例并不意味着限制本发明的范围。
实施例
实施例1:非-岩藻糖基化抗体的体内生成
方法:
在开始本研究之前30-60天,用钥孔血蓝蛋白(KLH)免疫雌性BALB/c小鼠。在第一项研究中,小鼠持续7天每天一次被ip给予150mg/kg的炔基岩藻糖(SGD-1887),过乙酸炔基岩藻糖(SGD-1890),2-氟岩藻糖(SGD-2083),或者2-氟岩藻糖三乙酸酯(SGD-2084)或者未受处理。在第二天,小鼠还用KLH加强免疫。在最后一次ip给药的次日,对小鼠进行终末采血并获得血清。在第二项研究中,小鼠持续7天在其饮用水中接受100mM的2-氟岩藻糖(SGD-2083)或者接受未经处理的水,用KLH加强免疫,之后继续给予含100mM 2-氟岩藻糖的饮用水或者未经处理的水持续7天,然后进行终末采血。随后获得血清。两项研究中都没有小鼠死亡。两项研究中,血清都通过市售的抗-KLH亲和性柱来获得KLH-特异性的多克隆抗体。通过抗-KLH亲和性柱的流出液通过市售的蛋白质A柱来获得其余抗体。
斑点印迹:将来自未经处理和经处理动物的抗体,以及作为标准的具有已知核心岩藻糖基化量(0至100%岩藻糖)的抗体cAC10,各点样0.5μg到硝酸纤维素膜上。蛋白质水平通过丽春红染色显现。
将印迹用生物素标记的米曲霉L-岩藻糖特异性凝集素(AOL)(能结合岩藻糖基化的抗体)探测并且用链霉亲和素蛋白辣根过氧化物酶(HRP)与ECL成像。凝胶上样(可见)以及岩藻糖信号(生物发光)通过Alpha Innotech相机测定并用机器软件定量。
气相色谱(GC):将已对水透析的来自未经处理和经处理动物的抗体各取40μg,在盐酸甲醇中进行甲醇分解。同样处理带有0至100%岩藻糖的抗体cAC10对照样本。所得甲基糖苷通过使用市售可得的混合物Tri-Sil对单糖醇进行三甲基硅烷化而衍生化。所得三甲基硅烷甲基糖苷在带火焰离子化检测的惠普(Hewlet Packard)气相色谱仪上于安捷伦(Agilent)J&W DB-1柱上以温度梯度进行检测。通过将与抗体样品平行衍生化的糖标准品进行保留时间的比较来鉴定相对峰。峰使用GC软件积分。岩藻糖/甘露糖的峰面积比用于确定抗体的岩藻糖基化状态。
结果:
研究1:图1显示未与KLH结合但从蛋白A柱所收回的抗体的斑点印迹(左侧)。所显示结果为cAC10标准(下方的斑点印迹,最左侧虚线框与上方斑点印迹的对应列),未经处理的对照(下方的斑点印迹,左起第二个虚线框与上方斑点印迹的对应列),以及炔基岩藻糖(SGD-1887;下方的斑点印迹,中间的虚线框与上方斑点印迹的对应列),过乙酸炔基岩藻糖(SGD-1890;下方的斑点印迹,右起第二个虚线框与上方斑点印迹的对应列),以及2-氟岩藻糖(SGD-2083;下方的斑点印迹,最右侧框与上方斑点印迹的对应列)。校正点样量水平,还将岩藻糖基化的百分率显示在右侧坐标图中。平均而言,与未经处理的对照相比,抗体岩藻糖基化的水平降低了约三分之一。
图2显示从处理组中分离出来的抗KLH抗体(图A与B)以及其余血清IgG分子(图C与D)的岩藻糖基化水平。岩藻糖基化水平均显示为基于cAC10抗体标准的岩藻糖基化百分率(图A与C)以及处理组平均值相对未经处理组平均值的百分值(图B与D)。平均而言,抗-KLH抗体的岩藻糖基化水平通过过三种岩藻糖类似物处理后降低约一半。其余所采集抗体也显示出核心岩藻糖基化降低约四分之一。在本研究中,小鼠接触KLH后的总抗体水平(KLH-特异性与非特异性)有上升。因此,多数抗体是处理期间新合成的。这些观察表面在岩藻糖类似物给药后新产生的抗体可显示出降低的核心岩藻糖基化。
研究2:在本研究中,检测岩藻糖类似物口服给药的效果。图3显示通过口服给予岩藻糖类似物治疗小鼠的结果。检测抗体岩藻糖基化水平的是未与KLH结合,但从蛋白A柱所收回的那些抗体。所显示结果为cAC10标准(上方与下方的斑点印迹,最左侧框),未经处理的对照(上方与下方的斑点印迹,左起第二个(上方)及右侧的框),以及2-氟岩藻糖(上方与下方的斑点印迹,左起第二个(下方)以及右起第二个(上方与下方)框)。校正点样量水平后,还将岩藻糖化的百分率显示在右侧坐标图中。来自经处理动物的抗体的核心岩藻糖基化水平几乎已消除:平均而言,经处理动物的岩藻糖基化水平为7%而未经处理动物当为81%。这些观察表明岩藻糖类似物的口服给药是降低抗体岩藻糖基化水平的有效手段。
实施例2:岩藻糖类似物在细胞培养中的体外活性
大致如已公布的美国专利申请2009-0317869中所述,已评估岩藻糖类似物在50μM与1mM浓度下对抗体核心岩藻糖基化的影响。简述方案如下:将产人源化IgG1抗-CD70单克隆抗体的CHO DG44细胞系h1F6(参见国际专利公布WO 06/113909),在2毫升的CHO培养基中以7.5x105个细胞每毫升,于37°、5%CO2并且100RPM振荡培养于六孔细胞培养板中。培养基添加了胰岛素样生长因子(IGF),青霉素,链霉素以及1mM或50μM的岩藻糖类似物。在接种后第5天,将培养物在13000RPM下离心5分钟以使细胞沉淀;随后从上清液纯化抗体。
抗体纯化通过将条件培养基(conditioned media)施用于经1X磷酸盐缓冲溶液(PBS)预平衡,pH7.4的蛋白质A树脂。在用20倍树脂体积的1X PBS清洗树脂后,用5倍树脂体积的免疫纯IgG洗脱缓冲液(皮尔斯生物技术公司(Pierce Biotechnology),伊利诺伊州罗克福德)洗脱抗体。洗脱组分中加入10%体积pH 8.0的1M Tris缓冲液使之中和。结果如以下表格所示。
表1
“ND”指由于岩藻糖类似物存在下抗体产生差或细胞生长抑制而未检测。
表2
“ND”指由于岩藻糖类似物时存在时抗体产生差或细胞生长抑制而未检测。
测试了某些岩藻糖类似物被纳入抗体的能力。这些岩藻糖类似物在50μM与1mM浓度下使用上述方法来测试。结果见下表所示。
表3
这些试验鉴定了在哺乳动物中抑制核心岩藻糖基化的候选化合物。
实施例3:口服给药后体内非岩藻糖基化抗体的生成
在本研究中,进一步检查口服给予岩藻糖类似物2-氟岩藻糖(SGD-2083)的效果。持续14天在雌性BALC/c小鼠饮用水中给予1,10与100mM 2-氟岩藻糖。小鼠使用TiterMAX经典佐剂免疫,并且持续7天在其饮用水中给予1,10与100mM 2-氟岩藻糖。随后对小鼠终末取血并得到血清。通过将血清通过蛋白质A柱纯化出内源性抗体。
收集的抗体通过如下的斑点印迹来评估岩藻糖基化水平。将来自经处理和未经处理动物的抗体(各0.5μg),以及带有0至100%的岩藻糖的cAC10标准(仅研究1),印迹到硝酸纤维素膜上。蛋白质水平通过丽春红染色呈现。印迹用生物素标记的AOL凝集素探测并且用链霉亲和素HRP与ECL成像(如上所述)。凝胶上样(可见)以及岩藻糖信号(生物发光)通过Alpha Innotech照相机测定并使用机器软件定量。
结果:
岩藻糖基化水平在2-氟岩藻糖(SGD-2083)的三种浓度间有剂量依赖性降低。参见图4,抗体的岩藻糖基化水平在未经处理的对照组与1mM的2-氟岩藻糖组中最高(左图与中图,上方两个框)。2-氟岩藻糖中度浓度组的抗体的岩藻糖基化几乎除净,与高浓度的100mM2-氟岩藻糖组相近。这些结果证实向小鼠给予2-氟岩藻糖可以抑制核心抗体岩藻糖基化。
实施例4:岩藻糖类似物对人细胞的影响
研究了不同岩藻糖类似物抑制人骨髓瘤细胞所产生IgG抗体的岩藻糖基化的能力以及抑制人癌细胞系表面蛋白的岩藻糖基化的能力。在第一项研究中,考察岩藻糖类似物抑制细胞系LP-1所产生IgG的岩藻糖基化的能力得,该细胞系是人多发性骨髓瘤细胞系。未经处理的LP-1细胞所产生并在其培养基中发现的抗体通过用抗-人IgG检测的蛋白质印迹证实为IgG型(数据未显示)。这是通过在T-75培养瓶中将20mL的LP-1细胞(250,000个细胞/毫升)于37℃在含5%CO2的潮湿气氛中,在IgG耗尽的组织培养基(90%RPMI与10%IgG耗尽的热灭活FBS)中培养5天来实现的。通过离心收获细胞(200x g,4℃,5分钟),并且收集培养基。培养基通过0.22μm过滤器过滤,随后与1mL含50%MabSelectTM蛋白质A树脂浆的PBS在4℃旋转孵育过夜来捕获IgG。使树脂浆沉降并且去除大部分培养基。将树脂浆用约0.5mL的培养基转移到两个醋酸纤维素过滤离心管中,并以5000x g离心1分钟。随后将树脂床用0.5mL的PBS清洗3次。用700μL的Pierce IgG洗脱缓冲液洗脱IgG(洗脱后加入52μL pH 9.5的9M Tris缓冲液以调节pH)洗出IgG。所得洗脱液转移至截断值10,000MW的离心浓缩器,将样本浓缩至约20μL。将1μL浓缩样加载到SDS聚丙烯酰胺胶上分离然后印迹到氮纤维素膜上。针对总蛋白的印迹染色使用丽春红,并且使用抗-人IgG抗体来鉴定同种型。总蛋白染色显示出条带与IgG的重链与轻链分子量一致,并且抗-人IgG染色显示出蛋白条带的反应与重链的分子量一致,正如预期。
抗体岩藻糖基化也可以使用生物素标记的米曲霉L-岩藻糖特异性凝集素(AOL)来确定,AOL特异性结合抗体的α-1,6连结岩藻糖。这种岩藻糖检测方法对于已通过SDS-PAGE分离的或者未经分离而上样到硝酸纤维素膜上印迹蛋白都适用。使用AOL-生物素偶联物与链霉亲和素-HRP和ECL检测所产生的荧光信号可以使用Alpha InnotechQ系统来定量。正如预期,分离自LP-1培养物的IgG在对应重链分子量(MW)的条带中显示AOL-依赖信号(数据未显示)。类似物2-氟岩藻糖(SGD-2803)以及2-氟岩藻糖过乙酸酯(SGD-2804)没有显示出抗体的岩藻糖基化,但是炔基岩藻糖过乙酸酯(SGD-1890)有所显示。
为了进一步评估不同岩藻糖类似物的活性,测试了48种不同岩藻糖类似物及另外四种糖基化抑制剂对LP-1所产生IgG的岩藻糖基化的影响能力。LP-1细胞(250,000个细胞/mL,6孔培养板中每个化合物3mL)与100μM的各岩藻糖类似物一起于37℃在含5%CO2的潮湿气氛中,在IgG耗尽的组织培养基(90%RPMI与10%IgG耗尽的热灭活FBS)中孵育5天。IgG的分离如上所述,每个样品仅使用0.5mL的MabSelectTM蛋白质A树脂浆,和一个离心管,400μLIgG洗脱缓冲液的洗脱液加入25μL pH 9的9M Tris缓冲液。洗脱液浓缩至每个样本10-20μL,经浓缩的洗脱液各取2μL点样至硝酸纤维素膜上并且使用丽春红染色来判断并调节用于AOL染色的样品上样。根据对每个样本中总蛋白的这一判断,各样本取约0.5μg点样到膜上,晾干,并用丽春红染色。该染色膜的图像使用Alpha InnotechQ系统获得。随后此膜在Tris缓冲盐水(TBS)中用5%牛血清白蛋白(BSA)封闭1小时,用TBST(TBS含曲通)洗涤3次后,和5μg/ml生物素化AOL一起孵育1小时。将膜用TBST再洗涤3次,然后用链霉亲和素-HRP孵育30分钟并用TBST最后洗涤3次。生物发光信号使用化学发光试剂(ECL)显现并使用Alpha Innotech Q系统与软件分析。结果见下表所示。对于一些类似物,如表中所示分析了多个样品。
表4
选择3种岩藻糖类似物来进行全面的SDS-PAGE/蛋白质印迹分析来显示此技术能检测到重链上岩藻糖信号的变化。所选择的三种类似物在50μM浓度下使用。这些分析比较了2-氟岩藻糖(SGD-2083),2-氟岩藻糖过乙酸酯(SGD-2804),以及炔基岩藻糖过乙酸酯(SGD-1890)对来自未经处理细胞的抗体的活性。使用炔基岩藻糖过乙酸酯产生的IgG未显示对生物素标记的AOL的反应性,证实该方法能检测AOL信号的变化,而2-氟岩藻糖(SGD-2083)与2-氟岩藻糖过乙酸酯(SGD-2804)的AOL信号未见明显变化。这些结果大体与表4中这些化合物的结果相符。
表4中测试的很多岩藻糖类似物看来降低人骨髓瘤细胞所产生的抗体的岩藻糖基化。用AOL信号减弱作为抑制的指示,所述化合物的斑点印迹显示其中10种是人类细胞中IgG岩藻糖基化的潜在的强抑制剂。这些岩藻糖类似物是:炔基岩藻糖过乙酸酯(SGD-1890),炔基岩藻糖四丙酸酯(SGD-2010),1–甲基岩藻糖三乙酸酯(SGD-2039),5--乙基岩藻糖四乙酸酯(SGD-1989),6-氟岩藻糖四乙酸酯(SGD-1988),6-溴化岩藻糖四乙酸酯(SGD-1969),6'6-二氟岩藻糖四乙酸酯(SGD-2046),6-酮-6-乙基岩藻糖四乙酸酯(SGD-2067),5-环氧岩藻糖四乙酸酯(SGD-2020),和5-甲基酮岩藻糖四乙酸酯(SGD1964)。
为进一步明确AOL斑点印迹的结果,对下列岩藻糖类似物:炔基岩藻糖过乙酸酯;5-乙烯基岩藻糖四乙酸酯;5-甲基酮岩藻糖四乙酸酯;6-溴岩藻糖四乙酸;6-氟岩藻糖四乙酸酯;5-乙基岩藻糖四乙酸酯;5-环氧岩藻糖四乙酸酯;6'6-二氟岩藻糖四乙酸酯;6-酮-6-乙基岩藻糖四乙酸酯(SGD-2067)和2-氟岩藻糖过乙酸酯,分离出被处理的细胞所产生的IgG(斑点印迹的AOL信号显示出中等至强烈减弱)的样品并用还原型PLRP-MS检验来利用重链的分子量(MW)证实岩藻糖基化状态。
如上所述,将40mL的LP-1细胞样品(250,000个细胞/mL)用100μM的岩藻糖类似物处理5天,并且如前所述使用蛋白质A树脂纯化IgG。得率使用UV分光法检测,假定消光系数为1.4AU/(mg/mL)。十个化合物中的七个得到了足够的IgG来进行分析(使用SGD-2067,SGD-1964和SGD-2020产生的IgG<10μg,可能是由于这些类似物对细胞的毒性)。其余IgG用10mMDTT在37℃还原15分钟并用PLRP分离,随后使用QTOF质谱仪进行MS分析。检测获得的重链峰,并且与未经处理的细胞所产生的IgG相比较。
质谱法的结果见表5(下表)所示。通过比较重链相对于重链减去岩藻糖和重链减去岩藻糖加上岩藻糖类似物(若类似物被纳入抗体糖类则可能提高)的峰高度,来评估质谱信号。十个受试化合物中有四个是抗体上1,6-岩藻糖基化的部分或完全抑制剂。炔基岩藻糖过乙酸酯(SGD-1890)提供完全抑制,而2-氟岩藻糖(SGD-2084)抑制70%为次优,其次是6'6-二氟岩藻糖四乙酸酯(SGD-2046)与6-溴岩藻糖四乙酸酯(SGD-1969)抑制约33与20%并伴有所述类似物纳入糖类。
表5.
LP-1所产生IgG的PLRP-MS结果与斑点印迹结果
实施例5:岩藻糖类似物对蛋白质岩藻糖基化的影响
针对人癌细胞测试四种部分或完全抑制剂:炔基岩藻糖过乙酸酯(SGD-1890)、2-氟岩藻糖过乙酸酯(SGD-2084)、6'6-二氟岩藻糖四乙酸酯(SGD-2046)、与6-溴岩藻糖四乙酸酯(SGD-1969)对细胞表面岩藻糖基化的影响,通过五种不同的人源癌细胞系(Caki-1,PC-3,Ramos,LS174t,和HL60cy)的孵育来测试。100μM的各种抑制剂在标准培养环境下使用约1-2周,期间定期更换包括新鲜抑制剂的培养基。在孵育期之后,使用四种不同检测试剂:生物素化扁豆凝集素-A(LCA)、抗-Lewisx抗体(抗-SSEA1)、抗-Lewisy抗体(cBR96)、和重组人P-选择素/CD62P/Fc融合蛋白。过程包括将细胞用FACS缓冲液(PBS+10%小牛血清白蛋白+0.02%叠氮钠)洗涤3次然后用一级检测试剂于4℃孵育1小时,然后用FACS缓冲液清洗3次后与二级检测试剂4℃孵育1小时。最后将细胞用FACS缓冲液清洗3次并重新悬浮在FACS缓冲液中,并使用BD FACScan仪器来检测。LCA试剂识别带有α-连接型甘露糖残基的序列且其亲和性被结合到核心寡糖的N-乙酰壳二糖部分的α-连接型岩藻糖残基显著提高。P-选择素融合蛋白检测位于细胞表面的P-选择素配体,该相互作用涉及P-选择素配体上的唾液酸化Lewisx表位。
被检测的细胞系都显示有LCA试剂染色,该试剂识别含有α-连接型甘露糖残基的序列,它的亲和性被结合到核心寡糖的N-乙酰壳二糖部分的α-连接型岩藻糖残基显著提高。这种糖表位的LCA检测在使用所有抑制剂(100μM)处理细胞后都降低。这提示岩藻糖在细胞表面的总体存在受到用所检测的六种岩藻糖类似物处理的影响。
图7显示上述研究的结果。对于LewisX,所检测的细胞系中只有未经处理的LS1745t与HL60cy在细胞表面明显检测到LewisX(抗-SSEAI染色)(图7A)。该结构的抗-SSEAI检测在使用岩藻糖类似物(100μM)处理细胞后都显著降低。
对于LewisY,所检测的细胞系中只有未经处理的LS1745t与HL60cy在细胞表面明显检测到LewisY(cBR96染色)(图7A)。该结构的cBR96检测在使用所有岩藻糖类似物(100μM)处理细胞后都显著降低。
对于P-选择素,所检测的细胞系中只有未经处理的HL60cy在细胞表面明显检测到P-选择素配体。该配体的检测在使用所有岩藻糖类似物(100μM)处理细胞后都有所降低,用炔基岩藻糖过乙酸酯(SGD-1890)处理的除外(图7C)。未经处理的Ramos细胞显示出极少的P-选择素配体;然而,在使用岩藻糖类似物处理后此配体的信号增强。这是不寻常的并且在以往对这些细胞使用2-氟岩藻糖(SGD-2083)或者炔基岩藻糖(SGD-1887)处理时并未观察到。
结果显示用这些岩藻糖类似物处理总体上可以影响细胞表面的岩藻糖并且也特异性地影响细胞表面LewisX和LewisY修饰的岩藻糖基化以及在P-选择素配体上的唾液酸化LewisX。
实施例6:在2-氟岩藻糖口服给药后的白细胞增多与E-选择素结合降低
在小鼠中,检测岩藻糖类似物对白细胞增多与E-选择素结合的影响。雌性Balb/c小鼠在饮用水中接受口服2-氟岩藻糖(SGD-2083)给药或不做处理。小鼠在给药之前进行采血,之后三周每周采血一次,来评估循环细胞数量以及它们结合E-选择素的能力。在一项研究中,2-氟岩藻糖以1mM、10mM或100mM配制在饮用水中(每组n=3)。在第14天,使用经典佐剂(西格玛公司(Sigma))处理小鼠以激活由B细胞产生的多克隆的、抗原非特异性抗体,并且持续给予含有2-氟岩藻糖的饮用水至第21天。在第二项研究中,小鼠持续3周在引用水中接受配制成10mM与100mM的2-氟岩藻糖而无任何其他处理(n=6)。在第21天,在血液以外,还检测来自于三只动物的淋巴结池(腋部、肱部、浅表腹股沟和肠系膜)。将淋巴结匀浆单细胞悬液,并且通过在血细胞计数器上计数来确定总细胞数,使用台盼蓝来排除死亡的细胞。为了确定每微升血液的总白细胞数量,将来自个体动物的血液样品在血细胞计数器上计数,使用特克溶液(含0.01%龙胆紫的3%醋酸)来排除红细胞(RBC)。为了进行流式细胞分析,通过渗透溶解从剩余血液中除去红细胞。细胞与抗-Gr-1-FITC抗体(BD生物科学公司)一起孵育以鉴定嗜中性粒细胞,并与重组E-选择素-人Fc融合蛋白(R&D系统公司)孵育。细胞经过洗涤后与PE-标记的山羊抗-人IgG-Fc二级抗体(杰克逊免疫研究公司(Jackson Immunoresearch))一起孵育来检测结合的E选择素。样本经FACSCalibur流式细胞仪来收集并且使用CellQuest软件分析。确定Gr-1+细胞的百分率,并用血细胞计数器计数所得总白细胞数来计算嗜中性粒细胞的绝对数量。另外,流式细胞的样品对Gr-1+细胞设门控来通过直方图分析评价E-选择素与嗜中性粒细胞的结合。由直方图确定E-选择素荧光信号的几何平均值。
结果
图5A与5B的结果显示2-氟岩藻糖(SGD-2083)的口服给药导致循环的白血细胞与嗜中性粒细胞以剂量依赖性方式升高。1mM的2-氟岩藻糖给药作用极小,随着2-氟岩藻糖剂量提高到10mM与100mM,观察到作用增强。图5A与5B所示数据来自于第一项研究的第14天。在第一项研究的第7和21天以及第二项研究的第714和21天也观察到类似的结果(数据未显示)。在第二项研究中还评估第21天的淋巴结并且在图5C中显示2-氟岩藻糖口服给药导致淋巴结中细胞性显著降低。与10mM相比,100mM的作用更为剧烈。
2-氟岩藻糖口服给药也导致E-选择素与嗜中性粒细胞的结合降低(图6)。岩藻糖类似物的作用也是剂量依赖性的,1mM的作用极小,而10mM与100mM的作用增强(图5B与图5C)。
观察到的循环白血细胞与嗜中性粒细胞的升高(白细胞增多)和嗜中性粒细胞结合E-选择素被抑制相一致。E-选择素介导白细胞外渗到外周血与淋巴结中,并且E-选择素结合的抑制(通过抑制岩藻糖基化)也会降低外渗并导致血液中的白细胞堆积。这些结果提示能抑制蛋白质岩藻糖基化,特别是E-选择素岩藻糖基化的岩藻糖类似物可以抑制自体免疫。
实施例7:通过给予岩藻糖类似物抑制肿瘤生长
研究1
在体外评估人源细胞系对岩藻糖类似物2-氟岩藻糖的敏感性。所用细胞系是:LS174T结肠腺癌,PC-3结肠腺癌,HL-60急性粒细胞性白血病,Ramos伯基特氏淋巴瘤,以及Caki-1肾细胞癌。细胞系在添加100μM的2-氟岩藻糖(SGD-2083)的培养基中,添加100μM炔基岩藻糖(SGD-1887)的培养基中,或者对照培养基(未添加岩藻糖类似物)中培养两周。生长培养基是加有10%FBS的MEM Eagle(LS174T),加有10%FBS的50:50F12和RPMI(PC-3),加有10%FBS的RPMI(HL-60),加有10%FBS的IMDM(Ramos),以及加有10%FBS的McCoy(PC-3)。这些细胞通过FACS评估细胞表面的岩藻糖基化,使用抗体cBR96来检测LewisY,抗体SSEA-1来检测LewisX,P-选择素配体来检测P-选择素,以及AOL凝集素来检测岩藻糖基化的总体水平。
结果:
FACS评估的结果显示不同的细胞系的细胞表面蛋白岩藻糖基化的水平不同(数据未显示)。2-氟岩藻糖(SGD-2083)总体上是比炔基岩藻糖(SGD-1887)更好的蛋白质岩藻糖基化抑制剂。
为了进一步评估这些岩藻糖类似物的活性,使用通过在岩藻糖类似物存在下培养而预处理的肿瘤细胞或使用未经处理的肿瘤细胞在体内进行进一步研究。如下所述将肿瘤细胞植入每组10只小鼠内。对LS174T,PC-3,以及Caki-1细胞系,将25%基质胶(Matrigel)中的5x105个细胞皮下植入到雌性裸鼠体内。对HL-60以及Ramos细胞系,将5x106个细胞皮下植入到雌性SCID小鼠体内。对于植入了未经处理肿瘤细胞的小鼠,提供了常规的饮用水。对植入了经2-氟岩藻糖(SGD-2083)预处理的肿瘤细胞的小鼠,提供添加有20mM 2-氟岩藻糖(SGD-2083)的饮用水。对于植入了经炔基岩藻糖(SGD-1887)预处理的肿瘤细胞的小鼠,提供常规饮用水。小鼠未饮用含有炔基岩藻糖的水。
在饮用含有2-氟岩藻糖的饮用水连续三周之后,小鼠恢复饮用常规饮用水,但带有Caki-1肿瘤的小鼠除外。后者恢复常规饮用水一周。在饮用常规水一周后,将小鼠随机分成两组,每组5只,各饮用加有20mM 2-氟岩藻糖的饮用水或者常规饮用水。当肿瘤达到约1000mm3时,处死小鼠。
参见图8A-E,经2-氟岩藻糖(SGD-2083)处理的LS174T、PC-3和Caki-1细胞观察到体内的肿瘤生长抑制。HL-60和Ramos细胞未观察到肿瘤生长的变化。对Caki-1细胞,在第一处理期未观察到肿瘤生长抑制,但在小鼠恢复2-氟岩藻糖处理后观察到肿瘤生长抑制。对于其他细胞系,肿瘤生长抑制看来在肿瘤体积达到150mm3时开始。生长较慢的Caki-1肿瘤直到2-氟岩藻糖(SGD-2083)的第二处理期才达到这一节点。这些结果表明使用岩藻糖类似物处理可以抑制肿瘤生长。
研究3
在第三项研究中,植入未经岩藻糖类似物预处理的肿瘤细胞。将LS174T结肠腺癌细胞(25%基质胶中的5x105个细胞)皮下植入到雌性裸鼠体内。在植入开始前7天到植入后第21天给予小鼠含有50mM 2-氟岩藻糖(SGD-2083)的饮用水或者常规饮用水。
结果
参见图8F,在饮用水中给予50mM 2-氟岩藻糖(SGD-2083)的小鼠显示出明显的肿瘤生长抑制,达到的肿瘤平均值为110mm3,相比之下给予常规饮用水的小鼠为734mm3。总之,这些结果显示给予岩藻糖类似物能抑制肿瘤生长。
实施例8:肿瘤疫苗模型
在第-21天和第-7天,雌性Balb/c小鼠通过皮下植入方式植入1百万个A20鼠淋巴瘤细胞(经辐射灭活)来免疫。另一组小鼠并未受到任何免疫。在第0天,所有的小鼠都静脉接种1.5百万或者5百万个活的A20细胞,在第-14到+21天,给予小鼠含有50mM 2-氟岩藻糖(SGD-2083)的饮用水或给予常规饮用水。8个处理组如下所示:
1.无免疫,1.5百万个活的A20细胞,常规饮用水
2.无免疫,5百万个活的A20细胞,常规饮用水
3.无免疫,1.5百万个活的A20细胞,含有50mM SGD-2083的饮用水
4.无免疫,5百万个活的A20细胞,含有50mM SGD-2083的饮用水
5.经免疫,1.5百万个活的A20细胞,常规饮用水
6.经免疫,5百万个活的A20细胞,常规饮用水
7.经免疫,1.5百万个活的A20细胞,含有50mM SGD-2083的饮用水
8.经免疫,5百万个活的A20细胞,含有50mM SGD-2083的饮用水
结果
参见图9A,显示了研究方案。参见图9B,从第22-35天,未经免疫处理的小鼠自第22-35天死于活的A20的攻击。接受2-氟岩藻糖(SGD-2083)的小鼠较饮用常规饮用水的小鼠多存活数天。用5百万个灭活的A20细胞免疫并且饮用常规饮用水的两只小鼠死于活的A20的攻击。所有接受免疫并饮用含有2-氟岩藻糖(SGD-2083)的饮用水的小鼠直至数据采集时都仍然存活。
本发明并不限于本文所述的具体实施方式的范围。除本文所述内容以外,本领域技术人员通过前面的描述以及附图会明白本发明的各种变化。所附权利要求书的范围旨在包含这些变化。除非显见于上下文,本发明的任何步骤、元素、实施方式、特征或方面可相互组合使用。本申请中引用的所有专利申请、科学出版物、登录号等均通过引用全文纳入用于所有目的,就如图单独列出各篇文献。
Claims (55)
1.岩藻糖类似物在药物制备中的用途,所述药物用于抑制哺乳动物中的蛋白质岩藻糖基化,所述岩藻糖类似物选自以下分子式(V)或(VI)其中之一或其生物学可接受的盐或溶剂化物:
其中化学式(V)或(VI)各自可以是α或β异头物或对应的醛糖形式;
R1、R2、R2a、R3、R3a和R4各自独立地选自以下基团:-OH、-OC(O)H、-OC(O)C1-C10烷基、-OC(O)C2-C10烯基、-OC(O)C2-C10炔基、-OC(O)芳基,-OC(O)杂环、-OC(O)C1-C10亚烷基(芳基)、-OC(O)C2-C10亚烯基(芳基)、-OC(O)C2-C10亚炔基(芳基)、-OC(O)C1-C10亚烷基(杂环)、-OC(O)C2-C10亚烯基(杂环)、-OC(O)C2-C10亚炔基(杂环)、-OCH2OC(O)烷基、-OCH2OC(O)O烷基、-OCH2OC(O)芳基、-OCH2OC(O)O芳基、-OC(O)CH2O(CH2CH2O)nCH3、-OC(O)CH2CH2O(CH2CH2O)nCH3、-O-三-C1-C3烷基甲硅烷基、–OC1-C10烷基和小的吸电子基团,其中各n是独立选自0-5的整数;
R5是选自下组的成员:–CH3、-CHX2、-CH2X、由卤素取代的或未取代的-CH(X')-C1-C4烷基、由卤素取代的或未取代的-CH(X')-C2-C4烯基、由卤素取代的或未取代的-CH(X')-C2-C4炔基、-CH=C(R10)(R11)、-C(CH3)=C(R12)(R13)、-C(R14)=C=C(R15)(R16)、由甲基或卤素取代的或未取代的-C3碳环、由卤素或甲基取代的或未取代的-CH(X')-C3碳环、由卤素或甲基取代的或未取代的C3杂环、由卤素或甲基取代的或未取代的-CH(X')-C3杂环、-CH2N3、-CH2CH2N3和苄氧甲基,或R5是小的吸电子基团;其中
R10是氢或被卤素取代或未取代的C1-C3烷基;
R11是被卤素取代的或未取代的C1-C3烷基;
R12是氢,卤素或被卤素取代的或未取代的C1-C3烷基;以及
R13是氢,或被卤素取代的或未取代的C1-C3烷基;
R14是氢或甲基;
R15和R16独立地选自氢,甲基与卤素;
X是卤素;以及
X'是卤素或氢;以及
另外,R1、R2、R2a、R3和R3a各自可选为氢;可选在邻近碳原子上的R1,R2,R2a,R3和R3a中的两个在上述邻近碳原子之间联合形成双键;以及
前提是R1、R2、R2a、R3、R3a、R4、R5中至少一个为小的吸电子基团,或R5包含卤素,不饱和位点,碳环,杂环或叠氮化物,除非(i)R2与R2a均为氢,(ii)R3与R3a均为氢,(iii)R1为氢,(iv)在所述邻近碳原子之间存在双键,或(v)R5为苄氧甲基。
2.如权利要求1所述的用途,其特征在于,所述岩藻糖类似物选自以下分子式(I)或(II)或其生物学上可接受的盐或溶剂化物:
其中:
化学式(I)或(II)各自可以是α或β异头物或对应的醛糖形式;
R1至R4各自独立地选自以下基团:-OH、-OC(O)H、-OC(O)C1-C10烷基、-OC(O)C2-C10烯基、-OC(O)C2-C10炔基、-OC(O)芳基,-OC(O)杂环、-OC(O)C1-C10亚烷基(芳基)、-OC(O)C2-C10亚烯基(芳基)、-OC(O)C2-C10亚炔基(芳基)、-OC(O)C1-C10亚烷基(杂环)、-OC(O)C2-C10亚烯基(杂环)、-OC(O)C2-C10亚炔基(杂环)、-OCH2OC(O)烷基、-OCH2OC(O)O烷基、-OCH2OC(O)芳基、-OCH2OC(O)O芳基、-OC(O)CH2O(CH2CH2O)nCH3、-OC(O)CH2CH2O(CH2CH2O)nCH3、-O-三-C1-C3烷基甲硅烷基、-OC1-C10烷基,其中各n是独立选自于0-5的整数;并且
R5选自下组:-C≡CH、-C≡CCH3、-CH2C≡CH、-C(O)OCH3、-CH(OAc)CH3、-CN、-CH2CN、-CHX2(其中各X是F、Br或Cl),-CH2X(其中X是F、Br、Cl或I)和甲基环氧乙烷。
3.如权利要求1或2所述的用途,其特征在于,所述药物用于治疗或预防癌症。
4.如权利要求1或2所述的用途,其特征在于,所述药物用于治疗自体免疫疾病。
5.如权利要求1或2所述的用途,其特征在于,所述药物与治疗或预防癌症的化疗剂联用。
6.如权利要求1或2所述的用途,其特征在于,R1至R4各自独立地选自下组:-OH、-OC(O)H、-OC(O)C1-C10烷基、-OC(O)C2-C10烯基、-OC(O)C2-C10炔基、-OC(O)芳基、-OC(O)杂环、-OC(O)C1-C10亚烷基(芳基)、-OC(O)C2-C10亚烯基(芳基)、-OC(O)C2-C10亚炔基(芳基)、-OC(O)C1-C10亚烷基(杂环)、-OC(O)C2-C10亚烯基(杂环)、-OC(O)C2-C10亚炔基(杂环)、-OC(O)CH2O(CH2CH2O)nCH3和-OC(O)CH2CH2O(CH2CH2O)nCH3;并且R5选自下组:-C≡CH、-C≡CCH3、-CH2C≡CH、-C(O)OCH3、-CH(OAc)CH3、-CN、-CH2CN、-CH2X(其中X是F、Br、Cl或I)和甲基环氧乙烷。
7.如权利要求1或2所述的用途,其特征在于,R1至R4各自独立地选自下组:-OH-OC(O)H和-OC(O)C1-C10烷基。
8.如权利要求7所述的用途,其特征在于,R1至R4各自独立地选自-OH和–OAc。
9.如权利要求1或2所述的用途,其特征在于,R5选自-C≡CH和-C≡CCH3。
10.如权利要求9所述的用途,其特征在于,R5为-C≡CH。
11.如权利要求1或2所述的用途,其特征在于,R5为-CH2X,其中X是F、Br、Cl或I。
12.如权利要求11所述的用途,其特征在于,R5为-CH2X,其中X是F。
13.如权利要求11所述的用途,其特征在于,R5为-CH2X,其中X是Br。
14.如权利要求1或2所述的用途,其特征在于,R5为-CHX2,其中X是F。
15.如权利要求1或2所述的用途,其特征在于,R5为-CHX2,其中X是F。
16.如权利要求1或2所述的用途,其特征在于,R5为-CHF2并且R1至R4为OAc。
17.如权利要求1或2所述的用途,其特征在于,R5为–CH2Br并且R1-R4为-OAc。
18.如权利要求1或2所述的用途,其特征在于,R5为-C≡CH并且R1-R4为-OAc。
19.如权利要求1所述的用途,其特征在于,所述岩藻糖类似物选自分子式(III)或(IV)其中之一或其生物学上可接受的盐或溶剂化物:
其中化学式(III)或(IV)各自可以是α或β异头物或对应的醛糖形式;
R1至R4各自独立地选自:氟、氯、OH、-OC(O)H、-OC(O)C1-C10烷基、-OC(O)C2-C10烯基、-OC(O)C2-C10炔基、-OC(O)芳基、-OC(O)杂环、-OC(O)C1-C10亚烷基(芳基)、-OC(O)C2-C10亚烯基(芳基)、-OC(O)C2-C10亚炔基(芳基)、-OC(O)C1-C10亚烷基(杂环)、-OC(O)C2-C10亚烯基(杂环)、-OC(O)C2-C10亚炔基(杂环)、-OCH2OC(O)烷基、-OCH2OC(O)O烷基、-OCH2OC(O)芳基、-OCH2OC(O)O芳基、-OC(O)CH2O(CH2CH2O)nCH3、-OC(O)CH2CH2O(CH2CH2O)nCH3、-O-三-C1-C3烷基甲硅烷基与-OC1-C10烷基、其中各n独立选自0-5的整数;并且
R2a至R3a各自独立地选自H、F与Cl;
R5选自下组:-CH3,-CHF2,-CH=C=CH2,-C≡CH,-C≡CCH3,-CH2C≡CH,-C(O)OCH3,-CH(OAc)CH3,-CN,-CH2CN,-CH2X(其中X是F、Br、Cl或I)和甲基环氧乙烷。
20.如权利要求19所述的用途,其特征在于,R1为F。
21.如权利要求19所述的用途,其特征在于,R2为F。
22.如权利要求19所述的用途,其特征在于,R3为F。
23.如权利要求19所述的用途,其特征在于,R2与R2a分别为F。
24.如权利要求19所述的用途,其特征在于,R1与R2分别为F。
25.如权利要求19所述的用途,其特征在于,R2a与R3a分别为氢。
26.如权利要求1所述的用途,其特征在于,R5选自下组:-CH3、-CH2CH3、-C≡CH、-CH2C≡CH、-CH=CHCH3、-环丙基、-环氧乙烷、甲基取代的-环氧乙烷、-CH2F、-CH2Cl、-CH2Br、-CH2I,-CHF2、-CH=C=CH2、-CH2N3和-CH2CH2N3。
27.如权利要求1所述的用途,其特征在于,所述小的吸电子基团选自下组:氟、氯、溴、-CHF2、-CH=C=CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-CO2H、-C(O)OC1-C4烷基、-CH(OAc)CH3、-CN、-CH2CN、-CH2X(其中X为F、Br、Cl或I)和甲基环氧乙烷。
28.如权利要求19所述的用途,其特征在于,R5为-C≡CH。
29.如权利要求19所述的用途,其特征在于,R5为-CH2X,其中X为F、Br、Cl或I。
30.如权利要求29所述的用途,其特征在于,R5为-CH2X,其中X为F。
31.如权利要求29所述的用途,其特征在于,R5为-CH2X,其中X为Br。
32.如权利要求19所述的用途,其特征在于,R5为-CHX2,其中X为F。
33.如权利要求25所述的用途,其特征在于,R5为-CHX2,其中X为F。
34.如权利要求19所述的用途,其特征在于,R5为-CHF2,并且R1-R4为-OAc。
35.如权利要求19所述的用途,其特征在于,R5为-CH2Br,并且R1-R4为-OAc。
36.如权利要求19所述的用途,其特征在于,R5为-C≡CH,并且R1-R4为-OAc。
37.如权利要求1所述的用途,其特征在于,R1,R2,R2a,R3,R3a与R4其中至少两个为小的吸电子基团。
38.如权利要求19所述的用途,其特征在于,所述岩藻糖类似物选自表1、2、3的化合物。
39.如权利要求1所述的用途,其特征在于,R1、R3与R4各自独立地选自–OH和–OC(O)C1-C10烷基;R2是F;以及R5是-CH3。
40.如权利要求1所述的用途,其特征在于,R1、R3与R4各自独立地选自–OH和–OAc;R2是F;以及R5是-CH3。
41.如权利要求1所述的用途,其特征在于,R1、R3与R4各自独立地选自–OH和–OC(O)C1-C10烷基;R2是F;R2a和R3a分别为H;以及R5是-CH3。
42.组合物在配制用于给予哺乳动物的药物中的用途,所述组合物包含有效量的岩藻糖类似物,其选自以下分子式(V)或(VI)其中之一或是其生物学可接受的盐或溶剂化物:
其中化学式(V)或(VI)各自可以是α或β异头物或对应的醛糖形式;
R1,R2,R2a,R3,R3a,R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OCH2OC(O)烷基,-OCH2OC(O)O烷基,-OCH2OC(O)芳基,-OCH2OC(O)O芳基,-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3烷基甲硅烷基,-OC1-C10烷基,和小的吸电子基团,其中各n是独立选自于0-5的整数;
R5选自下组:-CH3,-CHX2,-CH2X,被卤素取代的或未取代的-CH(X’)-C1-C4烷基,被卤素取代的或未取代的-CH(X’)-C2-C4烯基,被卤素取代的或未取代的-CH(X’)-C2-C4炔基,-CH=C(R10)(R11),-C(CH3)=C(R12)(R13),-C(R14)=C=C(R15)(R16),被甲基或卤素取代的或未取代的-C3碳环,被甲基或卤素取代的或未取代的-CH(X’)-C3碳环,被甲基或卤素取代的或未取代的C3杂环,被甲基或卤素取代的或未取代的-CH(X’)-C3杂环,-CH2N3,-CH2CH2N3,和苄氧甲基,或R5是小的吸电子基团;其中
R10是氢或被卤素取代或未取代的C1-C3烷基;
R11是被卤素取代或未取代的C1-C3烷基;
R12是氢,卤素或被卤素取代或未取代的C1-C3烷基;
R13是氢,或被卤素取代或未取代的C1-C3烷基;
R14是氢或甲基;
R15与R16独立地选自氢、甲基或卤素;
X为卤素;以及
X’为卤素或氢;以及
另外,R1,R2,R2a,R3与R3a各自可选为氢;可选位于邻近碳原子上的R1,R2,R2a,R3与R3a其中两个相结合而在所述邻近碳原子之间形成双键;以及
前提是,R1,R2,R2a,R3,R3a,R4与R5中至少一个为小的吸电子基团,或R5包含卤素,不饱和位点,碳环,杂环或叠氮化物,除非(ⅰ)R2与R2a均为氢,(ⅱ)R3与R3a均为氢,(ⅲ)R1为氢,(ⅳ)所述邻近碳原子之间存在双键,或(ⅴ)R5为苄氧甲基。
43.如权利要求42所述的用途,其特征在于,
R1至R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OCH2OC(O)烷基,-OCH2OC(O)O烷基,-OCH2OC(O)芳基,-OCH2OC(O)O芳基,-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3烷基甲硅烷基,-OC1-C10烷基,其中各n是独立地选自0-5的整数;以及
R5选自下组:-C≡CH、-C≡CCH3、-CH2C≡CH、-C(O)OCH3、-CH(OAc)CH3、-CN、-CH2CN、-CH2X(其中各X是F、Br、Cl或I),-CH2X(其中X是F、Br、Cl或I)和甲基环氧乙烷。
44.如权利要求42所述的用途,其特征在于,
R1、R3和R4各自独立地选自下组:-OH,-OC(O)H,-OC(O)C1-C10烷基,-OC(O)C2-C10烯基,-OC(O)C2-C10炔基,-OC(O)芳基,-OC(O)杂环,-OC(O)C1-C10亚烷基(芳基),-OC(O)C2-C10亚烯基(芳基),-OC(O)C2-C10亚炔基(芳基),-OC(O)C1-C10亚烷基(杂环),-OC(O)C2-C10亚烯基(杂环),-OC(O)C2-C10亚炔基(杂环),-OCH2OC(O)烷基,-OCH2OC(O)O烷基,-OCH2OC(O)芳基,-OCH2OC(O)O芳基,-OC(O)CH2O(CH2CH2O)nCH3,-OC(O)CH2CH2O(CH2CH2O)nCH3,-O-三-C1-C3烷基甲硅烷基,-OC1-C10烷基,其中各n是独立地选自0-5的症状;并且R2为F,R2a与R3a分别为H,R5为-CH3。
45.如权利要求42所述的用途,其特征在于,R1为F。
46.如权利要求42所述的用途,其特征在于,R2为F。
47.如权利要求42所述的用途,其特征在于,R3为F。
48.如权利要求42所述的用途,其特征在于,R2与R2a分别为F。
49.如权利要求42所述的用途,其特征在于,R1与R2分别为F。
50.如权利要求42所述的用途,其特征在于,R2a与R3a分别为氢。
51.如权利要求42所述的用途,其特征在于,R5选自下组:-CH3、-CH2CH3、-C≡CH、-CH2C≡CH、-CH=CHCH3、-环丙烷、-环氧乙烷、甲基取代的-环氧乙烷、-CH2F、-CH2Cl、-CH2Br、-CH2I,-CHF2、-CH=C=CH2、-CH2N3和-CH2CH2N3。
52.如权利要求42所述的用途,其特征在于,所述小的吸电子基团选自下组:氟、氯、溴、-CHF2、-CH=C=CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-CO2H、-C(O)OC1-C4烷基、-CH(OAc)CH3、-CN、-CH2CN、-CH2X(其中X为F、Br、Cl或I)和甲基环氧乙烷。
53.如权利要求42所述的用途,其特征在于,R5为-C≡CH。
54.如权利要求42所述的用途,其特征在于,R5为-CH2X,其中X为F、Br、Cl或I。
55.如权利要求42所述的用途,其特征在于,R5为-CH2X,其中X为F。
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US20090317869A1 (en) * | 2008-05-02 | 2009-12-24 | Seattle Genetics, Inc. | Methods and compositions for making antibodies and antibody derivatives with reduced core fucosylation |
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