CN111712519A - 用于治疗或预防内分泌fgf23-相关疾病的组合物和方法 - Google Patents
用于治疗或预防内分泌fgf23-相关疾病的组合物和方法 Download PDFInfo
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Abstract
本发明提供可用于治疗或预防内分泌FGF相关的疾病或病症的组合物和方法,如但不限于功能异常的磷酸盐体内稳态和慢性肾疾病(CKD)。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求于2017年12月13日提交的美国临时申请号62/598,273的优先权,该申请通过引用以其整体并入本文。
背景技术
由成纤维细胞生长因子(FGFs)引发的细胞信号传导控制成年动物正常胚胎发育和体内稳态过程中的重要生理过程。因此,多种疾病是由FGF-依赖的细胞信号传导通路的基因破坏(genetic disruption)或异常调控引起的。FGF家族的22个成员通过结合成纤维细胞生长因子受体(FGFRs)的四个成员的胞外域刺激它们的细胞反应,成纤维细胞生长因子受体是受体酪氨酸激酶(RTKs)的家族。
经典的(Canonical)FGFs在需要FGF配体与硫酸乙酰肝素蛋白聚糖(硫酸类肝素蛋白多糖,heparan sulfate proteoglycan)(HSPG)一起发挥作用的过程中通过旁分泌或自分泌机制活化FGFR,硫酸乙酰肝素蛋白聚糖(HSPG)作为FGF的关键(critical)共同受体起作用。对HSPGs的该要求将FGFR与大多数其他RTK区别开来,大多数其他RTK典型地通过特异性生长因子与同源受体的胞外域结合而直接活化。与其他RTKs一样,受体二聚化对于FGFR活化是重要的。然而,与其他生长因子(如EGF和PDGF)相比,经典FGFs仅当在与HSPG结合时才能刺激FGFR二聚化。FGFR二聚化导致激酶活化和受体胞质结构域中特定酪氨酸残基的转磷酸作用。这转而通过信号传导分子与活化的FGFR的直接缔合或通过由紧密缔合的停靠蛋白质(如FRS2和Gab1)介导的间接相互作用而触发多个信号传导通路的刺激,停靠蛋白质(如FRS2和Gab1)专门募集信号传导蛋白质的独特补体。
内分泌FGF,FGF19、FGF21是FGF23是FGF家族的成员,FGF家族作为在不同细胞和组织中调控多种关键代谢功能的循环激素起作用。FGF23在控制磷酸盐体内稳态中起重要的作用,FGF19抑制胆汁酸合成,而FGF21调控能量消耗和其他关键代谢过程。FGF23的靶器官是肾和甲状旁腺—FGF23结合分别刺激尿磷酸盐排泄和减少甲状旁腺激素水平。与需要HSPG活化FGFR的经典FGF不同,内分泌FGF不具有此要求,而是对于FGFR活化特别依赖于Klotho共同受体。
存在两种Klotho,由不同基因编码。α-Klotho(KLA)是FGF23-依赖的信号传导需要的,而β-Klotho(KLB)是特定组织和器官中FGF19-或FGF21-依赖的信号传导必要的。尽管在整个身体表达不同FGFR,但是Klotho蛋白的表达限于特定组织—α-Klotho表达限制于肾和甲状旁腺,而β-Klotho表达限于脂肪组织、肝、胰和下丘脑。两种Klotho蛋白是膜受体,由N端胞外区和单次跨膜跨区(spanning region),接着短胞质区组成。每个Klotho胞外区都含有与糖苷水解酶家族的酶共有序列相似性的串联结构域。氨基酸序列对比表明,每个Klotho的糖苷水解酶样结构域(GH域)的两个催化氨基酸残基之一在其进化的某一时刻被取代,表明Klotho的GH结构域缺乏酶活性并可被定义为假酶。然而,一些报道已经表明α-Klotho具有一些可检测的酶活性。
本领域存在鉴定可用于调节(例如抑制或刺激)FGF受体的活性和由内分泌FGF活化的信号传导通路的组合物和方法的需要。在某些实施方式中,这些组合物和方法可用于治疗、改善和/或预防与内分泌FGF相关的疾病(如,但不限于,功能失调的磷酸盐体内稳态)。本发明满足了这些需要。
发明内容
本发明提供防止或最小化FGF受体(FGFR)和/或FGF23与α-Klotho结合的非天然可溶性构建体。在某些实施方式中,该构建体防止FGFR活化。本发明进一步提供包含FGF23多肽的可溶性构建体,其比野生型FGF23更紧密地与α-Klotho结合,并且与野生型FGF23相比引起增强的生物学活性。本发明进一步提供这样的构建体,其同时与FGF23CT-α-Klotho复合体中的FGF23CT上的暴露表位和α-Klotho上的暴露表位结合,稳定FGF23CT-α-Klotho复合体形成(formation),并且与野生型FGF23相比引起增强的生物学活性。本发明进一步提供包含与α-Klotho结合物(binder)融合的FGF23多肽的构建体,其中该构建体具有FGF23刺激活性。本发明进一步提供在需要其的哺乳动物中治疗和/或预防内分泌FGF相关的疾病或病症的方法。
在某些实施方式中,α-Klotho在哺乳动物的细胞的表面上。
在某些实施方式中,构建体是抗体、纳米抗体、重组蛋白质、和/或小分子。在某些实施方式中,构建体是抗体和/或重组肽。在某些实施方式中,抗体选自多克隆抗体、单克隆抗体、人源化抗体、合成抗体、重链抗体、人抗体、抗体的生物活性片段、和其任意组合。
在某些实施方式中,构建体识别并结合到至少一个与α-Klotho结合的FGF23的氨基酸残基,从而防止FGF23结合到α-Klotho。在某些实施方式中,构建体识别和/或结合到至少一个与FGF23结合的α-Klotho的氨基酸残基,从而防止α-Klotho结合到FGF23。在某些实施方式中,构建体识别和/或结合到α-Klotho(SEQ ID NO:1)中的氨基酸残基377-925内的一个或多个氨基酸。
在某些实施方式中,构建体识别和/或结合到选自SEQ ID NO:1的F377、Q378、E390、S391、P392、W417、F418、V419、S420、K429、Y432、Y433、K436、N530、Q639、P640、M641、A642、P643、N688、E689、P690、T692、Q731、D733、V752、D756、S807、Y809、I812、D815、L828、V830、Q831、E832、M833、T834、I836、V845、S872、Y915、S916、A922、P923、和F925中的一个或多个氨基酸。
在某些实施方式中,构建体识别并结合到至少一个与FGFR结合的α-Klotho的氨基酸残基,从而防止α-Klotho结合到FGFR。在某些实施方式中,构建体识别和/或结合到人α-Klotho的胞外区(SEQ ID NO:1的氨基酸残基34-981)内的一个或多个氨基酸。在某些实施方式中,构建体识别和/或结合到人α-Klotho的胞外区片段内的一个或多个氨基酸,该片段包含SEQ ID NO:1的氨基酸残基534-571。
在某些实施方式中,构建体包含能够结合到哺乳动物细胞表面上的α-Klotho并使其隔离(sequestering)的FGF23多肽。
在某些实施方式中,构建体包含SEQ ID NO:3(FGF23CT)的氨基酸残基180-251、或其片段。
在某些实施方式中,构建体包含能够结合到FGF23并使其隔离的α-Klotho多肽。
在某些实施方式中,α-Klotho多肽包含人α-Klotho的胞外区(SEQ ID NO:1的氨基酸34-981)、或其片段。
在某些实施方式中,α-Klotho多肽包含SEQ ID NO:1的氨基酸377-925、或其片段。
在某些实施方式中,构建体包含能够结合到FGFR的α-Klotho多肽。
在某些实施方式中,构建体包含人α-Klotho的胞外区(SEQ ID NO:1的氨基酸残基34-981)、或其片段。
在某些实施方式中,构建体包含SEQ ID NO:1的氨基酸残基534-571、或其片段。
在某些实施方式中,构建体被融合到稳定性增强结构域。在某些实施方式中,稳定性增强结构域包括白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶、和/或抗体的Fc区。在某些实施方式中,多肽和稳定性增强结构域通过包含约1-18个氨基酸的多肽连接。
本发明进一步提供包含FGF23多肽的可溶性构建体,FGF23多肽比野生型FGF23更紧密地与α-Klotho结合并且与野生型FGF23相比引起增强的生物学活性。
在某些实施方式中,FGF23多肽在其C端结构域中具有至少一个突变。
在某些实施方式中,方法包括向哺乳动物给予治疗有效量的构建体,该构建体在哺乳动物的细胞表面上调节FGF23与α-Klotho的相互作用。
在某些实施方式中,构建体防止或最小化FGF23与哺乳动物细胞表面上的α-Klotho的结合。
在某些实施方式中,疾病或病症包括低磷酸盐血症和/或肿瘤诱发的骨软化。
在某些实施方式中,构建体比野生型FGF23更紧密地与哺乳动物细胞表面上的α-Klotho结合。
在某些实施方式中,哺乳动物是人。
在某些实施方式中,构建体通过选自以下的给予途径给予:吸入、口服、直肠、阴道、肠胃外,颅内、局部、经皮、肺、鼻内、颊、眼、鞘内、和静脉内。
在某些实施方式中,构建体被配制以通过选自以下的给予途径给予:吸入、口服、直肠、阴道、肠胃外、颅内、局部、经皮、肺、鼻内、颊、眼、鞘内、和静脉内。
在某些实施方式中,哺乳动物被进一步给予至少一种治疗或预防疾病和/或病症的附加药物。
在某些实施方式中,构建体和至少一种附加药物被共同给予。在某些实施方式中,构建体和至少一种附加药物被共同配制。
附图说明
为了说明本发明的目的,在附图中描绘了本发明的某些实施方式。然而,本发明不限于附图中描绘的实施方式的精确布置和手段。
图1A-1C示例内分泌FGF的C端区的氨基酸序列比对(图1A)和(图1B)和β-Klotho的胞外区(sKLB)与α-Klotho的胞外区(sKLA)的氨基酸序列比对。图1A:所有内分泌FGF中保守的Asp-Pro基序以浅蓝色(深灰色)突出显示,而FGF19和FGF21中的Ser-Pro-Ser基序以黄色(浅灰色)突出显示。FGF21(183-209),SEQ ID NO:6;FGF19(189-216),SEQ ID NO:7,FGF23(180-205),SEQ ID NO:8。图1B-1C:示出sKLB(SEQ ID NO:2的残基34-980)和sKLA(SEQ IDNO:1的残基53-995)的比对。与从晶体结构鉴定的FGF21CT相互作用的sKLB中的氨基酸残基和sKLA中的相应氨基酸残基以在相应序列上的框突出显示。
图2A-2C示例sKLA的非限制性同源性模型。图2A:具有FGF21CT(棒状表示)的复合体中的sKLB(上图(top panel),带状表示)的晶体结构与sKLA(下图(bottom panel),带状表示)的同源性模型之间的比较。在图2B-2C中,结构彼此重叠,并且表明了与FGF21CT结合的(图2B)位点-1或(图2C)位点-2中的关键残基。sKLA的位点-1含有疏水性表面,其可在该区域支持来自FGF21CT、FGF19CT或FGF23CT的残基,而sKLA的位点-2含有具有不同性质的残基,其仅接纳FGF23CT。
图3A-3B示例具有FGF21CT(棒状表示)的复合体中sKLB的晶体结构的非限制性模型(图3A)和sKLA的同源性模型(图3B)。在每个模型的表面表示(surface representation)上表明范围在-6KbT/ec(红色)和+6KbT/ec(蓝色)之间的静电势。可防止FGF21和FGF19结合的sKLA上的带负电荷的表面区域被突出显示(图3B,虚线)。
图4A-4B示例sKLA模型的非限制性表示,突出显示了抑制剂可结合的区域(虚线)。对于氨基酸残基的完整列表参见表1。
具体实施方式
本发明一方面涉及以下发现:α-Klotho是FGF23的主要细胞-表面受体。一方面,本发明提供在治疗或预防内分泌FGF相关的疾病或病症(如例如与调节异常(失调,dysregulated)的磷酸盐体内稳态相关的疾病或病症)方面有用的组合物和方法。
FGF23是扮演肾Pi排泄的重要的生理调节剂的骨源性激素。过表达FGF23的转基因小鼠发生(develop)低磷酸盐血症,而FGF23-敲除小鼠发生高磷酸盐血症,其可通过人FGF23的全身注射来逆转。
重要的是,FGF23的这些体内作用需要α-Klotho的存在。向α-Klotho-敲除小鼠或FGF23/α-Klotho-双敲除小鼠中注射FGF23不影响血清磷酸盐水平。像其他内分泌FGF一样,FGF23展现对FGFR的同工型特异性─其结合并活化FGFR1和FGFR3的IIIc同工型、以及仅展现单一同工型的FGFR4。
FGF23与涉及磷酸盐代谢的调节异常的许多人类疾病相关。X连锁低磷酸盐血症(XLH)是遗传性疾病,其中PHEX(与位于X染色体上的內肽酶具有同源性的磷酸盐调控基因)含有失功能突变,并且该突变的结果是循环FGF23的升高。相似地,在分别携带DMP-1或ENPP-1突变的常染色体隐性低磷酸盐血症佝偻病1(ARHR1)或常染色体隐性低磷酸盐血症佝偻病2(ARHR2)患者中观察到FGF23的水平增加。在常染色体显性低磷酸盐血症佝偻病(ADHR)中,FGF23、R176Q和/或R179Q的获得功能突变防止在这些位点处的天然蛋白酶剪切以产生FGF23的两个无活性片段。不希望受到任何理论限制,这种剪切可表示下调的机制。产生高水平FGF23的包含(harboring)癌症的肿瘤导致肿瘤诱发的骨软化(TIO),其可通过手术去除分泌高FGF23水平的肿瘤来逆转。虽然在患有上述病症的患者中观察到FGF23的活性增加,但在高磷酸盐血症家族性瘤样钙质沉着症(HFTC)的患者中也已发现了FGF23的活性降低。HFTC患者中也发现了KLA中的纯合失功能突变H193R。
两种Klotho蛋白(α-Klotho和β-Klotho)是由大胞外区、跨膜螺旋和小胞内区组成的I型膜蛋白。FGF23与α-Klotho特异性结合,而FGF19和FGF21与β-Klotho特异性结合。与Klotho蛋白的复合体形成由内分泌FGF的C端尾部介导。Klotho蛋白的胞外区含有与具有糖苷水解酶活性的酶具有序列同源性的两个串联结构域。β-Klotho(sKLB)的胞外区的晶体结构显示,两个串联糖苷水解酶样结构域通过非结构化且柔性的接头连接。sKLB中的每个糖苷水解酶样结构域仅保留寡糖底物水解所需的两个谷氨酸残基之一,从而使sKLB成为无活性酶(假糖苷水解酶)。具有C端尾部(FGF21CT)的复合体中的β-Klotho的晶体结构显示,配体结合由位于相隔大约的每个糖苷水解酶样结构域中的两个不同结合位点介导。所占据的配体采用通过在FGF21CT分子内的多个分子内氢键连接的几个转角,从而导致主要与位于β-Klotho的结构域1中的位点-1的疏水性相互作用。相比之下,位于β-Klotho的结构域2上的位点-2通过谷氨酸之间的特异性相互作用与FGF21CT上的“仿糖(sugar-mimicking)”Ser-Pro-Ser基序结合,所述谷氨酸在以活性糖苷水解酶裂解(cleaving)糖中起着重要的催化作用。不希望受到任何理论限制,sKLB中的FGF21CT-结合区和糖苷水解酶中的寡糖-结合区之间的相似性暗示Klotho蛋白家族的胞外区从裂解糖的酶进化而来。
一方面,本发明描述了α-Klotho的结合位点、表位和氨基酸序列,其可被抗体、小分子、和其他类型的拮抗物占据,用于治疗由磷酸盐代谢的调节异常引起的病症。
如本文所示,氨基酸序列比对暗示内分泌FGF的保守结合方式。图1A示出FGF21、FGF19、和FGF23的C端区氨基酸序列的比对。序列比对揭示FGF21和FGF19的C端尾部之间的接近的序列相似性,这与FGF21和FGF19及它们的分离的C端区与β-Klotho的相似结合特性一致。FGF21(S205-P206-S207)中的仿糖基序在FGF19(S211-P212-S213)中是保守的。还突出显示了FGF21CT区中的序列D192-P193,其稳定了维持FGF21CT的结合构象中的转角的分子内氢键。该序列在FGF19(D198-P199)中是保守的,暗示在非限制性实施方式中,负责介导FGF19CT中连续转角的相似分子内相互作用也可相似地结合到β-Klotho。此外,由于结合到β-Klotho的FGF21CT内的很多分子内相互作用发生在主链原子之间(如在典型的β-转角结构中观察到的),因此序列中仅几个关键氨基酸(如D198-P199)可足以在FGF19CT中生成相似的多转角(multi-turn)元件,如在与β-Klotho结合的FGF21CT的晶体结构中观察到的。
相比之下,FGF23的C端区(72个氨基酸)比FGF21的C端区(38个氨基酸)或FGF19的C端区(39个氨基酸)长。FGF23的C端区的氨基酸S180-S205对于介导FGF23与α-Klotho之间的相互作用是极重要的(critical)。FGF23的C端区展现了与FGF21和FGF19的C端区序列的弱序列相似性,这与FGF23对α-Klotho而不对β-Klotho的结合特异性一致。然而,如在图1A中突出显示,对于维持多转角元件Asp-Pro极重要的氨基酸在FGF23中是保守的。不希望受到任何理论限制,这表明FGF23在与α-Klotho结合的FGF23CT的区域中还可含有多转角元件。FGF21或FGF19中的仿糖序列Ser-Pro-Ser在FGF23中不存在。不希望受到任何理论限制,这表明结合到α-Klotho的结构域2的FGF23CT的氨基酸残基之间可发生可替代相互作用,那些氨基酸残基来自与sKLB结合的晶体结构FGF21CT中所见的氨基酸残基。
另一方面,β-Klotho(sKLB)和α-Klotho(sKLA)的胞外区的氨基酸序列比对(如图1B-1C中所示)揭示高序列相似性(48.9%同一性)。与FGF21CT相互作用的sKLB的晶体结构中鉴定的氨基酸以绿色突出显示,而sKLA的相应氨基酸以红色突出显示。这些氨基酸的大多数(但不是全部)被α-Klotho中的其他氨基酸取代,增加了取代的氨基酸可在α-Klotho特异性识别FGF23中起作用的可能性。
如本文所示,α-Klotho的同源性模型揭示了FGF23的结合位点和FGF23与α-Klotho之间的独特相互作用。sKLB和sKLA的氨基酸序列中的高序列相似性暗示sKLA结构的同源性模型可基于sKLB的晶体结构以合理的准确度建立(图2A-2C)。如图2A中所见,两个蛋白质的整个折叠是相同的。然而,与FGF21CT相互作用的sKLB中的氨基酸残基与sKLA中的相应氨基酸的比较揭示两个重要的特征:(1)对于与配体疏水性相互作用极重要的结构域1的氨基酸在β-Klotho和α-Klotho中是保守的,如图2B中所示;(2)对于维持与仿糖基序Ser-Pro-Ser的疏水性相互作用极重要的sKLB的结构域2中的苯丙氨酸残基在α-Klotho中被酪氨酸残基取代,如图2C中所描绘。sKLA模型的这两个特征与配体的C端区的氨基酸的序列比对一致:FGF23CT中推定的多转角元件可由由sKLA模型中的F377、W417、和F418创建的疏水性表面支持。sKLA中的酪氨酸残基取代sKLB中的苯丙氨酸残基(在FGF21CT中支持S-P-S)可在位点-2中生成增加的负电荷,这将防止S-P-S基序中的羟基接近sKLA中的极性口袋(如图3A-3B中突出显示)。在某些实施方式中,形成位点-1的氨基酸残基对于配体结合可作为“混杂(promiscuous)”疏水表面的起作用,而位于位点-2中的氨基酸可表示在确定内分泌FGF结合选择性中起极重要作用的口袋。
定义
如本文所用,以下每个术语具有在本节中与其相关的含义。
除非另有定义,否则本文使用的所有技术和科学术语通常具有与本发明所属领域的本领域普通技术人员一般所理解的相同含义。通常,本文所用的命名法和细胞培养、分子遗传学、晶体学、化学、和计算模型中的实验室程序是本领域公知的和常用的的那些。
如本文所用,冠词“一(a)”和“一个(an)”是指一个或多于一个(即,至少一个)冠词的语法对象。举例来说,“一个元件”意指一个元件或多于一个元件。
如本文所用,术语“约”将被本领域普通技术人员理解并将在使用其的上下文中在一定程度上变化。如本文所用,当是指可测量值(如量、时距等)时,术语“约”意在涵盖与规定值的±20%或±10%、±5%、±1%、或±0.1%的变化,因为这种变化适合于执行所公开的方法。
如本文所用,术语“α-Klotho”或“KLA”是指SEQ ID NO:1的氨基序列的蛋白质:
如本文所用,α-Klotho(sKLA)的胞外域对应于SEQ ID NO:1的氨基酸残基34-981。如本文所用,术语“β-Klotho”或“KLB”是指SEQ ID NO:2的氨基序列的蛋白质:
如本文所用,β-Klotho(sKLB)的胞外域对应于SEQ ID NO:2的氨基酸残基53-983。
如本文所用,术语“抗体,”是指与抗原特异性结合的免疫球蛋白分子。抗体可以是源自天然来源或重组来源的完整免疫球蛋白,并且可以是完整免疫球蛋白的免疫反应性部分。抗体典型地是免疫球蛋白分子的四聚体。本发明中的抗体可以多种形式存在,包括,例如,多克隆抗体、单克隆抗体、Fv、Fab和F(ab)2、以及单链抗体和人源化抗体(Harlow etal.,1999,In:Using Antibodies:A Laboratory Manual,Cold Spring HarborLaboratory Press,NY;Harlow et al.,1989,In:Antibodies:A Laboratory Manual,ColdSpring Harbor,New York;Houston et al.,1988,Proc.Natl.Acad.Sci.USA 85:5879-5883;Bird et al.,1988,Science242:423-426)。
术语“抗体片段”是指完整抗体的部分,并且是指完整抗体的抗原决定可变区。抗体片段的实例包括,但不限于,Fab、Fab’、F(ab’)2、和Fv片段、线性抗体、scFv抗体、诸如sdAb(VL或VH)的单域抗体(如骆驼科(camelid)抗体(Riechmann,1999,J.Immunol.Meth.231:25-38),由对靶展现足够亲和性的VL或VH结构域组成的骆驼科VHH结构域)、和由抗体片段(如包含在铰链区通过二硫键连接的两个Fab片段的二价片段,以及抗体的分离的互补性决定区域(CDR)或其他表位结合片段)形成的多特异性抗体。抗原结合片段还可并入到单域抗体、最大抗体(maxibodies)、小分子抗体(minibodies)、纳米抗体、胞内抗体、双抗体、三链抗体、四链抗体、v-NAR和bis-scFv中(参见,例如,Hollinger&Hudson,2005,Nature Biotech.23:1126-1136)。抗原结合片段也可基于诸如纤连蛋白III型(Fn3)的多肽移植到支架中(美国专利号:6,703,199,其描述了纤连蛋白多肽小分子抗体)。抗体片段还包括人抗体或人源化抗体或者人抗体或人源化抗体的部分。
如本文所用的术语“抗原”或“Ag”被定义为激发免疫应答的分子。该免疫应答可涉及抗体产生、或特异性免疫活性细胞的活化、或两者。技术人员将理解任何大分子(实际上包括所有蛋白质或肽)可充当抗原。此外,抗原可衍生自重组或基因组DNA。本领域技术人员将理解,任何DNA包含编码引起免疫应答的蛋白质的核苷酸序列或部分核苷酸序列,因此编码作为本文所用的术语“抗原”。此外,本领域技术人员将理解,抗原不需要仅由基因的全长核苷酸序列编码。显而易见,本发明包括,但不限于,使用多于一个基因的部分核苷酸序列,以及这些核苷酸序列以各种组合排列以引起期望的免疫应答。此外,本领域技术人员将理解,抗原根本不需要由“基因”编码。显而易见,抗原可合成生成或可源自生物样品。这种生物样品可包括,但不限于组织样品、肿瘤样品、细胞或生物流体(biological fluid)。
“反义”特别是指编码多肽的双链DNA分子的非编码链的核酸序列或与非编码链基本上同源的序列。如本文所定义,反义序列与编码多肽的双链DNA分子的序列互补。反义序列不必仅与DNA分子的编码链的编码部分互补。反义序列可与编码多肽的DNA分子的编码链上指定的调节序列互补,该调节序列控制编码序列的表达。
如本文所用的术语,术语“施用器”意指用于给予本发明的化合物和组合物的任何装置包括,但不限于,皮下注射器、移液管等。
如本文所用,“适配体”是指可与另一分子特异性结合的小分子。适配体典型地是多核苷酸-或肽-基分子。多核苷酸的适配体是DNA或RNA分子,经常包含几股核酸,其采用被设计以对在其他有机和无机分子中的具体靶分子(如肽、蛋白质、药物、维生素)具有适当的结合亲和性和特异性的高度特异的三维构象。这种多核苷酸适配体可通过使用配体的系统进化通过指数富集从庞大群体的随机序列中选择。肽适配体典型地是约10至约20个氨基酸的环,该约10至约20个氨基酸附着于与特异性配体结合的蛋白质支架。可使用诸如酵母双杂交系统的方法将肽适配体从组合文库中鉴定和分离。
基因的“编码区”由基因编码链的核苷酸残基和分别与通过基因转录而产生的mRNA分子的编码区同源或互补的基因非编码链的核苷酸组成。mRNA分子的“编码区”还由在mRNA分子的翻译期间与转运RNA分子的反密码子区配对的mRNA分子或编码终止密码子的mRNA分子的核苷酸残基组成。因此,编码区可包括与成熟蛋白质中不存在的由mRNA分子编码的氨基酸残基(例如,蛋白质输出信号序列中的氨基酸残基)对应的核苷酸残基。
“组成性”启动子是这样的核苷酸序列,当其与编码或指定基因产物的多核苷酸可操作地连接时,导致该基因产物在细胞的大多数或全部生理条件下在细胞中产生。
如本文所用,“疾病”是动物的一种健康状态,其中动物不能维持体内稳态,并且其中如果疾病没有改善,那么该动物的健康继续恶化。
如本文所用,动物中的“病症”是一种健康状态,其中动物能够维持体内稳态,但其中动物的健康状态比其不存在病症时更不利。如果不治疗,病症不一定引起动物的健康状态进一步下降。
如本文所用,术语化合物的“有效量”或“治疗有效量”或“药物有效量”可互换使用,是指足以对给予化合物的对象提供有益效果的化合物的量。
如本文所用,“编码”是指多核苷酸(如基因、cDNA、或mRNA)中核苷酸的特定序列充当模板用于在具有确定的核苷酸序列(即,rRNA、tRNA和mRNA)或确定的氨基酸序列的生物过程中合成其他聚合物和大分子的固有性质,以及由此产生的生物性质。因此,如果对应于基因的mRNA的转录和翻译在细胞或其他生物系统中产生蛋白质,则该基因编码蛋白质。编码链(与mRNA序列相同且经常在序列表中提供的核苷酸序列)和非编码链(用作基因或cDNA的转录模板)两者可以被称为编码蛋白质或该基因或cDNA的其他产物。
如本文所用,“内源”是指来自有机体、细胞、组织或系统内部或在其内部产生的任何材料。如本文所用,术语“外源”是指从有机体、细胞、组织或系统的外部引入或从其外部产生的任何材料。
如本文所用的术语“表位”被定义为可引起免疫应答(包括B和/或T细胞应答)的抗原上的小化学分子。抗原可具有一个或多个表位。大多数抗原具有很多表位;即,它们是多价的。一般来说,表位的大小粗略地为5个氨基酸和/或糖。本领域技术人员理解,通常整个三维结构(而不是分子的特定线性序列)是抗原特异性的主要标准,并且因此将一个表位与另一个区分开。
如本文所用的术语“表达”被定义为由其启动子驱动的特定核苷酸序列的转录和/或翻译。
“表达载体”是指包含重组多核苷酸的载体,其包含可操作地连接到待表达的核苷酸序列的表达控制序列。表达载体包含足够的顺式作用元件用于表达;用于表达的其他元件可由宿主细胞或在体外表达系统中提供。表达载体包括本领域中已知的所有载体,如并入重组多核苷酸的黏粒、质粒(例如,裸的或在脂质体中含有的)和病毒(例如,慢病毒、逆转录病毒、腺病毒、和腺伴随病毒)。
如本文所用,术语“FGF19”是指SEQ ID NO:3的多肽:
如本文所用,“FGF19CT”是指对应于SEQ ID NO:3的氨基酸残基170-216的多肽。
如本文所用,术语“FGF21”是指SEQ ID NO:4的多肽:
如本文所用,“FGF21CT”是指对应于SEQ ID NO:4的氨基酸残基169-209的多肽,其在某些实施方式中含有两个突变,P199G和A208E(参见US20120087920,其通过引用以其整体并入本文)。
如本文所用,术语“FGF23”是指SEQ ID NO:5的多肽:
如本文所用,“FGF23CT”是指对应于SEQ ID NO:5的氨基酸残基180-251的多肽。
如本文所用,术语“重链抗体”或“多个重链抗体”包括通过用抗原免疫和随后的血清分离、或通过克隆和表达编码这些抗体的核酸序列而从骆驼科物种获得的免疫球蛋白分子。术语“重链抗体”或“多个重链抗体”进一步涵盖从患有重链疾病的动物分离、或通过克隆和表达来自动物的VH(可变重链免疫球蛋白)基因而制备的免疫球蛋白分子。
如本文所用的“同源”是指两个聚合分子之间——例如,两个核酸分子(如两个DNA分子或两个RNA分子)之间、或两个多肽分子之间——的亚基序列同一性。当两个分子的亚基位置均被被相同单体亚基占据时;例如,如果两个DNA分子中每个的一个位置被腺嘌呤占据,则它们在那个位置同源。两个序列之间的同源性是配对或同源位置的数目的直接函数;例如,如果两个序列中一半(例如,长度为10个亚基的聚合物中的5个位置)的位置是同源的,则两个序列是50%同源的;如果90%的位置(例如,10个中的9个)是配对或同源的,则两个序列是90%同源的。举例来说,DNA序列5'-ATTGCC-3’和5'-TATGGC-3’共有50%同源性。
如本文所用,术语“同源性建模”是指基于其序列与一种或多种已知结构(模板)的蛋白质的比对预测靶蛋白的三维结构。同源性建模包括以下步骤:折叠分配(foldassignment)、靶模板对比、模型建立、模型改进、和模型评价。例如,MODELLER基于源自各种来源的空间限制的满意度(包括模板-靶比对和立体化学)生成同源性模型(andBlundell,1993,J Mol.Biol.234:779-815)。
如本文所用,术语“免疫球蛋白”或“Ig”被定义为一类起抗体作用的蛋白质。此类蛋白质中包含的5个成员是IgA、IgG、IgM、IgD、和IgE。IgA是存在于身体分泌物(如唾液、眼泪、母乳、胃肠分泌物和呼吸道和生殖泌尿道(genitor-urinary tracts)的黏液分泌物)中的主要抗体。IgG是最常见的循环抗体。IgM是在大多数哺乳动物中的初次免疫应答中产生的主要免疫球蛋白。其是凝集、补体激活、和其他抗体应答中最有效的免疫球蛋白,并且在防御细菌和病毒中是重要的。IgD是没有已知抗体功能的免疫球蛋白,但可充当抗原受体。IgE是通过在暴露于过敏原时引起介体从肥大细胞和嗜碱性粒细胞释放而介导即发型超敏反应的免疫球蛋白。
“可诱导的”启动子是这样的核苷酸序列,当其与编码或指定基因产物的多核苷酸可操作地连接时,基本上仅当对应于启动子的诱导物存在于细胞中时,才使基因产物在细胞中产生。
如本文所用,术语“抑制”和“拮抗”意指将分子、反应、相互作用、基因、mRNA、和/或蛋白质的表达、稳定性、功能或活性降低可测量的量或完全阻止。抑制物是例如,结合以部分或完全阻断刺激、减少,防止、延迟活化、钝化、脱敏、或下调节蛋白质、基因、和mRNA的稳定性、表达、功能和活性的化合物,例如,拮抗物。
“使用说明材料(指导材料,instructional material)”,如本文所用的术语,包括出版物、记录、图表、或可用于传达试剂盒中的本发明的组合物和/或化合物的有用性的任何其他表达媒介。例如,试剂盒的使用说明材料可以是贴在容纳本发明的化合物和/或组合物的容器或与容纳化合物和/或组合物的容器一起运输。可选地,使用说明材料可与容器分开运输,意图是接收者配合地使用指导材料和化合物。例如,使用说明材料的递送可以是通过出版物或传达试剂盒的有用性的其他表达媒介的实物交付,或者可以可选地通过例如依靠计算机的电子传输(如通过电子邮件、或从网站下载)来实现。
“分离的”意指从天然状态改变或移除。例如,天然存在于活体动物的核酸或肽不是“分离的”,但从其天然状态的共存材料部分或完全分离的相同核酸或肽是“分离的”。分离的核酸或蛋白质可以基本上纯化的形式存在,或可在非天然(non-native)环境(如例如,宿主细胞)中存在。
“分离的核酸”是指已经从以天然存在状态位于其侧翼的序列分离的核酸区段或片段,即,已经从与片段正常相邻的序列(即,与其天然存在的基因组中的片段相邻的序列)移除的DNA片段。该术语也适用于已经基本上从天然伴随核酸的其他组分(即,与其在细胞中天然伴随的RNA或DNA或蛋白质)纯化的核酸。因此,术语包括,例如,并入到载体中、到自主复制质粒或病毒中、或到原核生物或真核生物的基因组DNA中的重组DNA,或者作为独立于其他序列的分离分子(即,作为通过PCR或限制酶消化而产生的cDNA或基因组或cDNA片段)存在的重组DNA。还包括作为编码附加多肽序列的杂合基因的部分的重组DNA。
如本文所用,术语“调节”意味着是指生物状态中的任何变化,即增加、减少等。例如,术语“调节”可解释为是指正调控或负调控靶蛋白的表达、稳定性或活性的能力,包括但不限于靶蛋白mRNA的转录、靶蛋白mRNA的稳定性、靶蛋白mRNA的翻译、靶蛋白稳定性、靶蛋白翻译后修饰、靶蛋白活性,或其任意组合。进一步,术语调节可用于指活性(包括但不限于,靶蛋白活性)的增加、减少、掩蔽、改变、覆盖(overriding)或恢复。
如应用于物体的“天然存在的”是指物体可在自然中找到的事实。例如,存在于有机体(包括病毒)中,可从自然中的来源分离并且未被人有意修饰的多肽或多核苷酸序列是天然存在的序列。
除非另有说明,否则“编码氨基酸序列的核苷酸序列”包括彼此为简并形式并且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质或RNA的短语核苷酸序列在还可包括内含子,某种程度上编码蛋白质的核苷酸序列可以某些形式含有内含子(一个或多个)。
术语“可操作地连接”是指调节序列和异源核酸序列之间的功能性连接,导致后者的表达。例如,当第一核酸序列与第二核酸序列处于功能关系时,第一核酸序列与第二核酸序列可操作地连接。例如,如果启动子影响编码序列的转录或表达,则启动子与编码序列可操作地连接。通常,可操作地连接的DNA序列是邻近的,在必要的情况下将两个蛋白质编码区连接在同一阅读框中。
组合物的“肠胃外”给予包括,例如,皮下(s.c.)、静脉内(i.v.)、肌肉内(i.m.)、或胸骨内注射或输注技术。
如本文所用,术语“药物组合物”是指至少一种本发明内有用的化合物与其他化学组分(如运载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂、和/或赋形剂)的混合物。药物组合物促进化合物向有机体给予。本领域中存在的多种给予化合物的技术包括,但不限于:静脉内、口服、气雾剂、肠胃外、眼、肺、颅内和局部给予。
如本文所用,术语“药学上可接受的”是指不消除组合物的生物活性或性质并且是相对无毒的材料,如运载体或稀释剂,即,可向个体给予而不引起不期望的生物学效果或以有害的方式与其中其含有的组合物的任何组分相互作用的材料。
“药学上可接受的运载体”包括涉及本发明的化合物(一个或多个)在对象内运载或运输或运载或运输至对象的药学上可接受的盐、药学上可接受的材料、组合物或运载体,如液体或固体填料、稀释剂、赋形剂、溶剂或封装材料,使得其可执行其预期功能。典型地,这些化合物被从一个器官或身体的部分运载或运输至另一器官或身体的部分。每种盐或运载体从与制剂的其他成分相容的意义上讲必须是“可接受的”,并且对对象不是有害的。可充当药学上可接受的运载体的材料的一些实例包括:糖,如乳糖,葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;粉状西黄蓍胶;麦芽;明胶;滑石;赋形剂,如可可豆油和栓剂蜡;油,如花生油,棉籽油,红花油,芝麻油,橄榄油,玉米油和大豆油;二醇,如丙二醇;多元醇,如甘油,山梨醇,甘露醇和聚乙二醇;酯,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;褐藻酸;无热原水(pyrogen-free water);等渗盐水;林格溶液;乙醇;磷酸盐缓冲溶液;稀释剂;成粒剂;润滑剂;黏合剂;崩解剂;润湿剂;乳化剂;着色剂;隔离剂;涂层剂;甜味剂;增香剂;加香剂(perfuming agent);防腐剂;抗氧化剂;增塑剂;凝胶;增稠剂;硬化剂;定型剂(settingagent);悬浮剂;表面活性剂;吸湿剂;运载体;稳定剂;和药物制剂中使用的其他无毒的相容物质,或其任意组合。如本文所用,“药学上可接受的运载体”还包括与化合物的活性相容并且是对对象生理上可接受的任何和所有包衣、抗细菌和抗真菌剂、和吸收延迟剂(absorption delaying agents)等。补充活性化合物也可被并入到组合物中。
如本文所用,语言“药学上可接受的盐”是指从药学上可接受的无毒酸制备的给予的化合物的盐,药学上可接受的无毒酸包括无机酸、有机酸、其溶剂化物、水合物、或笼形物。
“多肽”是指氨基酸残基组成的聚合物、相关的天然存在的结构变体、和经由肽键连接的其合成的非天然存在的类似物。合成的多肽可例如使用自动多肽合成仪合成。术语“蛋白质”典型地是指大的多肽。术语“肽”典型地是指短多肽。
本文使用常规符号以描述多肽序列:多肽序列的左端是氨基末端;多肽序列的右端是羧基末端。如本文所用,“拟肽(peptidomimetic)”是含有非肽结构元件的化合物,其能够模仿亲本肽(parent peptide)的生物学作用。拟肽可以或可以不包含肽键。
如本文所用,术语“预防(prevent或prevention)”意指如果没有发生则无病症或疾病发展,或者如果已经有病症或疾病的发展,则无进一步病症或疾病发展。还考虑个体(one)预防与病症或疾病相关的一些或全部症状的能力。疾病和病症在本文可互换使用。
“引物”是指能够与选定的多核苷酸模板特异性杂交并且为互补多核苷酸的合成提供起始点的多核苷酸。当多核苷酸引物被置于其中诱导合成的条件——即,存在核苷酸、互补多核苷酸模板、和用于聚合作用的剂(如DNA聚合酶)——下时,发生这种合成。引物典型地是单链的,但可以是双链的。引物典型地是脱氧核糖核酸,但种类繁多的合成的和天然存在的引物可用于很多应用。引物与被设计与之杂交的模板互补以充当起始合成的位点,但不需要反映模板的确切的序列。在这种情况下,引物与模板的特异性杂交取决于杂交条件的严格度。引物可用例如,显色、放射性、或荧光部分标记,并可用作可检测部分。
“探针”是指能够与另一多核苷酸的选定序列特异性杂交的多核苷酸。探针与靶互补多核苷酸特异性杂交,但不需要反映模板的确切的互补序列。在这种情况下,探针与靶的特异性杂交取决于杂交条件的严格度。探针可用例如,显色、放射性、或荧光部分标记,并且可用作可检测部分。
如本文所用的术语“启动子”被定义为由细胞的合成机制识别的、或引入合成机制的,开始多核苷酸序列的特异性转录所需的DNA序列。
如本文所用,术语“启动子/调节序列”意指与启动子/调节序列可操作地连接的基因产物的表达所需的核酸序列。在一些情况下,该序列可以是核心启动子序列,而在其他情况下,该序列也可包括增强子序列和表达基因产物所需的其他调节元件。启动子/调节序列可以是例如以组织特异性方式表达基因产物的序列。
如本文所用的术语“重组DNA”被定义为通过连接不同来源的DNA片段(pieces)产生的DNA。如本文所用的术语“重组多肽”被定义为通过使用重组DNA方法产生的多肽。
如本文所用的术语“RNA”被定义为核糖核酸。
如本文所用,术语“特异性(specifically bind或specifically binds)”意味着第一分子(例如,抗体)优先地与第二分子(例如,特定抗原表位)结合,但不一定仅与第二分子结合。
如本文所用,“对象”是指人或非人哺乳动物。非人哺乳动物包括,例如,家畜和宠物,如绵羊、牛、猪、犬、猫和鼠哺乳动物。在某些实施方式中,对象是人。
如本文所用,术语“合成抗体”意指使用重组DNA技术生成的抗体,如,例如,通过如本文所用的噬菌体表达的抗体。该术语还应被解释为意指通过合成编码抗体的DNA分子已经生成的抗体,并且其DNA分子表达抗体蛋白质或指定抗体的氨基酸序列,其中DNA或氨基酸序列已经使用在本领域中可获得或熟知的合成DNA或氨基酸序列技术获得。
“组织特异性”启动子是如下核苷酸序列,当与由基因编码或指定的多核苷酸可操作地连接时,基本上只有当细胞是对应于启动子的组织类型的细胞的情况下,才使基因产物在细胞中产生。
如本文所用的术语“转染的”或“转化的”或“转导的”是指外源核酸被转移或引入到宿主细胞中的过程。“转染的”或“转化的”或“转导的”细胞是已经用外源核酸转染的、转化的、或转导的细胞。该细胞包括原代受试细胞(primary subject cell)及其后代。
如本文所用,术语“治疗(treatment或treating)”被定义为向对象应用或给予治疗剂(即,本发明内有用的组合物)(单独或与另一药剂组合),或向从对象分离的组织或细胞系(例如,用于诊断或离体应用)应用或给予治疗剂,该对象具有疾病或病症、疾病或病症的症状或发展疾病或病症的潜能,目的是治愈、愈合、减轻、缓解、改变、治疗(remedy)、改善、改进(improve)或影响疾病或病症、疾病或病症的症状或发展疾病或病症的潜能。这种治疗可以基于药物基因组学领域获得的知识而特异性订制或修改。在任何个别情况下,适当的治疗量可由本领域普通技术人员使用常规(routine)实验法确定。
如本文所用的短语“在转录控制下”或“可操作的连接”意指启动子相对于多核苷酸处于正确位置和方向,以控制RNA聚合酶的转录起始和多核苷酸的表达。
如本文所用的“变体”是这样的核酸序列或肽序列,其序列分别不同于参考核酸序列或肽序列,但保留参考分子的基本性质。核酸变体序列中的变化可能不改变由参考核酸编码的肽的氨基酸序列,或者可导致氨基酸取代、添加、缺失、融合和平截(truncations)。肽变体序列中的变化典型地是有限的或保守的,使得参考肽和变体的序列总体上是非常(closely)相似的,且在很多区是相同的。变体和参考肽的氨基酸序列可通过以任何组合的一个或多个取代、添加、或缺失而不同。核酸或肽的变体可以是天然存在的,如等位变体,或者可以是未知天然存在的变体。核酸和肽的非天然存在的变体可通过诱变技术或通过直接合成来制成。
“载体”是包含分离的核酸且可用于将分离的核酸递送至细胞内部的物质(matter)的组合物。众多载体在本领域中是已知的,包括,但不限于,线性多核苷酸、与离子或两亲性化合物相关的多核苷酸、质粒、和病毒。因此,术语“载体”包括自主复制质粒或病毒。该术语还应解释为包括促进核酸转移到细胞中的非质粒和非病毒化合物,如,例如,聚赖氨酸化合物、脂质体等。病毒载体的实例包括,但不限于,腺病毒载体、腺伴随病毒载体、逆转录转录病毒载体等。
本文所用的缩写包括:FGF,成纤维细胞生长因子;FGFR,成纤维细胞生长因子受体;KLA,α-Klotho;KLB,β-Klotho;GH域,糖苷水解酶样结构域;HSPG,硫酸乙酰肝素蛋白聚糖;RMSD,均方根偏差;RTK,受体酪氨酸激酶;sKLA,α-Klotho的胞外结构域;sKLB,β-Klotho的胞外结构域。
贯穿本公开,本发明的各个方面可以范围格式呈现。应理解,范围格式的描述仅是为了方便和简洁,而不应解释为对本发明的范围的僵化限制。因此,范围的描述应被认为已经具体公开了所可能的子范围以及在该范围内的单个数值。例如,诸如从1至6的范围的描述应被认为已经具体公开了子范围,如从1至3、从1至4、从1至5、从2至4、从2至6、从3至6等,以及该范围内的单个数目,例如,1、2、2.7、3、4、5、5.3、和6。无论范围的广度如何,这都适用。
表1:可用于抑制研究的α-Klotho的氨基酸残基(也参见图1B-1C、和图4A-4B).
F377 | Q378 | E390 | S391 | P392 | W417 | F418 | V419 | S420 |
K429 | Y432 | Y433 | K436 | N530 | Q639 | P640 | M641 | A642 |
P643 | N688 | E689 | P690 | T692 | Q731 | D733 | V752 | D756 |
S807 | Y809 | I812 | D815 | L828 | V830 | Q831 | E832 | M833 |
T834 | I836 | V845 | S872 | Y915 | S916 | A922 | P923 | F925 |
化合物和/或组合物
一方面,本发明提供了可用于治疗内分泌FGF相关的疾病或病症的组合物。在某些实施方式中,本发明的组合物防止或最小化FGF23与α-Klotho在哺乳动物细胞表面上结合。
(a)本发明提供防止或最小化α-Klotho与FGF23和/或FGFR在哺乳动物细胞表面上结合的构建体。
一方面,本发明提供防止或最小化FGF23与α-Klotho在哺乳动物细胞表面结合的构建体(如,但不限于,抗体和/或重组肽)。
在某些实施方式中,构建体识别与FGF23结合的α-Klotho的至少一个氨基酸残基,从而防止α-Klotho与FGF23结合。在其他实施方式中,构建体识别和/或结合到α-Klotho中的氨基酸残基34-981(SEQ ID NO:1)内的一个或多个氨基酸。
在某些实施方式中,构建体识别和/或结合到选自以下氨基酸的一个或多个氨基酸:SEQ ID NO:1的F377、Q378、E390、S391、P392、W417、F418、V419、S420、K429、Y432、Y433、K436、N530、Q639、P640、M641、A642、P643、N688、E689、P690、T692、Q731、D733、V752、D756、S807、Y809、I812、D815、L828、V830、Q831、E832、M833、T834、I836、V845、S872、Y915、S916、A922、P923、和F925(参见表1和图4A)。
在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸F377。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸Q378。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸E390。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸S391。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸P392。在某些实施方式中,构建体识别和/或结合到至少SEQID NO:1的氨基酸W417。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸F418。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸V419。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸S420。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸K429。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸Y432。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸Y433。在某些实施方式中,构建体识别和/或结合到至少SEQID NO:1的氨基酸K436。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸N530。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸Q639。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸P640。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸M641。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸A642。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸P643。在某些实施方式中,构建体识别和/或结合到至少SEQID NO:1的氨基酸N688。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸E689。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸P690。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸T692。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸Q731。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸D733。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸V752。在某些实施方式中,构建体识别和/或结合到至少SEQID NO:1的氨基酸D756。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸S807。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸Y809。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸I812。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸D815。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸L828。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸V830。在某些实施方式中,构建体识别和/或结合到至少SEQID NO:1的氨基酸Q831。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸E832。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸M833。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸T834。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸I836。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸V845。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸S872。在某些实施方式中,构建体识别和/或结合到至少SEQID NO:1的氨基酸Y915。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸S916。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸A922。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸P923。在某些实施方式中,构建体识别和/或结合到至少SEQ ID NO:1的氨基酸F925。
在另一方面,本发明提供防止或最小化α-Klotho与FGFR在哺乳动物细胞表面上结合的构建体。
在某些实施方式中,构建体识别结合FGFR的α-Klotho的至少一个氨基酸残基,从而防止α-Klotho结合到FGFR。在其他实施方式中,构建体识别和/或结合到人α-Klotho的胞外区(SEQ ID NO:1的氨基酸残基34-981)内的一个或多个氨基酸、或其片段。在又一实施方式中,构建体识别和/或结合到包含SEQ ID NO:1的氨基酸残基534-571的人α-Klotho的胞外区的片段内的一个或多个氨基酸。
如本领域技术人员将理解的,可识别和特异性结合到FGF23/FGFR/α-Klotho的任何抗体可用于本发明。本发明不应被解释为限于已知或迄今未知的任何一种类型的抗体,条件是抗体可特异性结合到FGF23/FGFR/α-Klotho,并防止或最小化α-Klotho与FGF23和/或FGFR的结合。制作和使用这些抗体的方法在本领域中是公知的。例如,多克隆抗体的生成可通过用抗原接种期望的动物并从中分离特异性结合抗原的抗体来完成。针对蛋白质或肽的全长或肽片段的单克隆抗体可使用任何公知的单克隆抗体制备程序——如,例如,在Harlow et al.(1989,Antibodies,A Laboratory Manual,Cold Spring Harbor,NewYork)中和Tuszynski et al.(1988,Blood 72:109-115)中描述的程序来制备。期望的肽的数量也可使用化学合成技术合成。可选地,编码期望的肽的DNA可在适合于生成大量肽的细胞中从适当的启动子序列克隆和表达。针对肽的单克隆抗体使用如本文所引用的标准程序从用肽免疫的小鼠生成。然而,本发明不应解释为仅限于包括这些抗体的方法和组合物,而应解释为包括其他抗体,如该术语在本文其他地方所定义的。
在一些情况下,期望从各种哺乳动物宿主——如啮齿类动物(例如,小鼠)、灵长类(例如,人)等——制备单克隆抗体。用于制备这些单克隆抗体的技术描述是公知的且描述于,例如,Harlow et al.,ANTIBODIES:A LABORATORY MANUAL,COLD SPRING HARBOR LABORATORY,Cold Spring Harbor,N.Y.(1988);Harlow et al.,USING ANTIBODIES:A LABORATORYMANUAL,(Cold Spring Harbor Press,New York,1998);Breitling et al.,RECOMBINANTANTIBODIES(Wiley-Spektrum,1999);和Kohler et al.,1997Nature 256:495-497;美国专利号5,693,762;5,693,761;5,585,089;和6,180,370中。
使用本文描述的程序获得的编码抗体的核酸可使用本领域中可获得的技术克隆并测序,并被描述于,例如,Wright et al.(Critical Rev.Immunol.1992,12:125-168)和其中引用的参考文献中。进一步,本发明的抗体可使用描述于Wright et al.(supra)中和其中引用的参考文献中,以及Gu et al.(Thrombosis and Hematocyst 1997,77:755-759)中的技术“人源化”。
可选地,抗体可使用噬菌体展示技术来生成。为了生成噬菌体抗体文库,首先从分离自细胞(例如,杂交瘤)的mRNA获得cDNA文库,mRNA在噬菌体表面上表达待表达的期望蛋白质,例如,期望的抗体。使用逆转录酶产生mRNA的cDNA拷贝。指定免疫球蛋白片段的cDNA通过PCR获得,并且将所得DNA克隆到合适的噬菌体载体中以生成包含指定免疫球蛋白基因的DNA的噬菌体DNA文库。用于制备包含异源DNA的噬菌体文库的程序在本领域中是公知的,并且描述于,例如,Sambrook et al.(1989,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor,New York)中。
可将编码期望抗体的噬菌体改造,使得蛋白质以可用于与其对应的结合蛋白质(例如,抗体所针对的抗原)结合的方式展示在其表面上。因此,当表达特异性抗体的噬菌体在表达对应抗原的细胞存在的情况下孵育时,噬菌体将与细胞结合。不表达抗体的噬菌体将不与细胞结合。这种淘选技术在本领域中是公知的,并且描述于,例如,Wright et al.(Critical Rev.Immunol.1992,12:125-168)中。
已经开发了诸如本文描述的那些工艺,用于利用M13噬菌体展示产生人抗体(Burton et al.,1994,Adv.Immunol.57:191-280)。本质上,cDNA文库是由从产生抗体的细胞群中获得的mRNA生成的。mRNA编码重排免疫球蛋白基因,并且因此,cDNA对其进行编码。扩增的cDNA克隆到M13表达载体中,创建在其表面上表达人Fab片段的噬菌体文库。展示感兴趣的抗体的噬菌体通过抗原结合来选择,并且在细菌中繁殖以产生可溶性人Fab免疫球蛋白。因此,与常规单克隆抗体合成相比,该程序使编码人免疫球蛋白的DNA而不是表达人免疫球蛋白的细胞永生化。
刚提出的程序描述编码抗体分子的Fab部分的噬菌体的生成。然而,本发明不应被解释为仅限于编码Fab抗体的噬菌体的生成。而是,编码单链抗体(scFv/噬菌体抗体文库)的噬菌体也包括在本发明中。Fab分子包含整个Ig轻链,也就是说,它们包含轻链的可变和恒定区两者,但仅包含重链的的可变区和第一恒定区结构域(CH1)。单链抗体分子包含蛋白质的单链,该蛋白质包含Ig Fv片段。Ig Fv片段仅包含抗体的重链和轻链的可变区,而不具有其中所含的恒定区。包含scFv DNA的噬菌体文库可根据描述于Marks et al.(1991,JMol Biol 222:581-597)中的以下程序生成。这样生成的用于分离期望抗体的噬菌体的淘选以与描述包含Fab DNA的噬菌体文库相似的方式进行。
本发明还应解释为包括合成的噬菌体展示文库,其中重链和轻链可变区可被合成,使得它们包括几乎所有可能的特异性(Barbas,1995,Nature Medicine 1:837-839;deKruif et al.,1995,J Mol Biol 248:97-105)。
本发明涵盖多克隆、单克隆、合成的抗体等。基于本文提供的公开内容,本领域技术人员将理解,本发明的抗体的重要特征是抗体与FGF23和/或α-Klotho特异性结合。
在又另一方面,本发明提供能够隔离哺乳动物细胞表面上的α-Klotho和/或FGF23的可溶性构建体。
在某些实施方式中,本发明提供包含FGF23多肽的可溶性构建体,FGF23多肽能够结合到并隔离哺乳动物细胞表面上的α-Klotho。在某些实施方式中,FGF23多肽包含SEQ IDNO:5的氨基酸残基180-251(FGF23CT)。FGF23CT可与另一多肽融合,另一多肽例如如但不限于稳定性增强结构域,如但不限于白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶(GST)、或抗体的Fc区。在某些实施方式中,FGF23CT和稳定性增强结构域通过多肽连接,该多肽包含约1-18个氨基酸、1-17个氨基酸、1-16个氨基酸、1-15个氨基酸、1-14个氨基酸、1-13个氨基酸、1-12个氨基酸、1-11个氨基酸、1-10个氨基酸、1-9个氨基酸、1-8个氨基酸、1-7个氨基酸、1-6个氨基酸、1-5个氨基酸、1-4个氨基酸、1-3个氨基酸、1-2个氨基酸、或单个氨基酸。
在又另一方面,本发明提供包含能够结合到并隔离FGF23的α-Klotho多肽的可溶性构建体。在某些实施方式中,α-Klotho多肽包含人α-Klotho的胞外区(SEQ ID NO:1的氨基酸残基34-981)、或其片段。在其他实施方式中,α-Klotho多肽包含SEQ ID NO:1的氨基酸残基377-925、或其片段。α-Klotho多肽可与另一多肽融合,另一多肽例如但不限于稳定性增强结构域,如但不限于白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶(GST)、或抗体的Fc区。在某些实施方式中,α-Klotho多肽和稳定性增强结构域通过多肽连接,多肽包含1-18个氨基酸、1-17个氨基酸、1-16个氨基酸、1-15个氨基酸、1-14个氨基酸、1-13个氨基酸、1-12个氨基酸、1-11个氨基酸、1-10个氨基酸、1-9个氨基酸、1-8个氨基酸、1-7个氨基酸、1-6个氨基酸、1-5个氨基酸、1-4个氨基酸、1-3个氨基酸、1-2个氨基酸、或单个氨基酸。
在又一实施方式中,本发明提供包含能够与FGFRs结合的α-Klotho多肽的可溶性构建体。在某些实施方式中,α-Klotho多肽包含人α-Klotho的胞外区(SEQ ID NO:1的氨基酸残基34-981)、或其片段。在其他实施方式中,人β-Klotho的胞外区的片段包含SEQ IDNO:1的氨基酸残基534-571。α-Klotho多肽可与另一多肽融合,另一多肽例如但不限于稳定性增强结构域,如但不限于白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶(GST)、或抗体的Fc区。在某些实施方式中,α-Klotho多肽和稳定性增强结构域通过多肽连接,多肽包含1-18个氨基酸、1-16个氨基酸、1-14个氨基酸、1-12个氨基酸、1-10个氨基酸、1-8个氨基酸、1-6个氨基酸、1-5个氨基酸、1-4个氨基酸、1-3个氨基酸、1-2个氨基酸或单个氨基酸。
(b)本发明提供与α-Klotho结合并诱导α-Klotho的二聚化/隔离的组合物。
一方面,本发明提供包含FGF23 C-端多肽的可溶性构建体,FGF23 C-端多肽与α-Klotho结合并α-Klotho的二聚化。在某些实施方式中,FGF23 C-端多肽的序列与对应的野生型FGF23片段相同。在其他实施方式中,FGF23 C-端多肽具有至少一个远离对应野生型FGF23片段的位点定向(site-directed)突变。在某些实施方式中,FGF23 C-端多肽包含FGF23CT(对应于SEQ ID NO:5的氨基酸残基180-251)或其任何位点定向突变体。FGF23多肽可与另一多肽融合,另一多肽例如但不限于稳定性增强结构域,如但不限于白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶、或抗体的Fc区。在某些实施方式中,FGF23多肽和稳定性增强结构域通过多肽连接,多肽包含1-18个氨基酸、1-16个氨基酸、1-14个氨基酸、1-12个氨基酸、1-10个氨基酸、1-8个氨基酸、1-6个氨基酸、1-5个氨基酸、1-4个氨基酸、1-3个氨基酸、1-2个氨基酸或单个氨基酸。
在本发明的组合物中包括的化合物可与酸形成盐,并且这种盐包括在本发明中。在某些实施方式中,盐是药学上可接受的盐。术语“盐”包括(embraces)在本发明的方法中有用的游离酸的加成盐(addition salts)。术语“药学上可接受的盐”是指在药学应用中提供效用(utility)的范围内具有毒性特征(profiles)的盐。尽管如此(nonetheless),药学上不可接受的盐可具有诸如高结晶度的性质,其本发明的实践中具有效用,如例如在本发明的方法中有用的化合物的合成、纯化或配制的过程中的效用。
合适的药学上可接受的酸加成盐可由无机酸或由有机酸制备。无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸、和磷酸。适当的有机酸可选自脂类、环脂类、芳香类、芳代脂肪类(araliphatic class)、杂环类、羧酸类和磺酸类的有机酸,其实例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、苯乙酸、扁桃酸、扑酸(帕莫酸)、甲基磺酸、乙基磺酸、苯磺酸、泛酸、三氟甲磺酸、2-羟基乙磺酸、对甲苯磺酸、磺胺酸、环己基氨基磺酸、硬脂酸、褐藻酸、β-羟基丁酸、水杨酸、半乳糖二酸和半乳糖醛酸。
方法
一方面,本发明包括在有此需要的对象中治疗或预防疾病或病症的方法。
在某些实施方式中,方法包括向对象给予治疗有效量的构建体,该构建体防止或最小化FGF23和/或FGFR与α-Klotho在哺乳动物细胞表面上结合。通过该方法治疗或预防的疾病或病症的非限制性实例包括各种类型的低磷酸盐血症,如,但不限于,X连锁低磷酸盐血症(XLH)、常染色体隐性低磷酸盐血症佝偻病1(ARHR1)、低磷酸盐血症佝偻病2(ARHR2)、和常染色体显性低血磷(hypophatemic)佝偻病(ADHR)。通过该方法治疗或预防的疾病或病症的进一步非限制性实例包括肿瘤诱发的骨软化(TIO)。由于FGF23的水平在患有慢性肾疾病(CKD)的患者中高度增加,α-Klotho或FGF23的抑制剂也可用于CKD患者的治疗。
在某些实施方式中,构建体包含重组肽和/或抗体、和其组合。在其他实施方式中,抗体包含选自以下的至少一种抗体:多克隆抗体、单克隆抗体、人源化抗体、合成抗体、重链抗体、人抗体、抗体的生物活性片段、和其组合。在又一实施方式中,对象是哺乳动物。在又一实施方式中,哺乳动物是人。在又一实施方式中,构建体通过选自以下的给予途径给予:吸入、口服、直肠、阴道、肠胃外、颅内、局部、经皮、肺、鼻内、颊、眼、鞘内、和静脉内。
在某些实施方式中,对象被进一步给予至少一种治疗疾病和/或病症的另外的药物。在其他实施方式中,构建体和至少一种另外的药物被共同给予。在又一实施方式中,构建体和至少一种另外的药物被共同配制。
组合疗法
使用这里描述的方法鉴定的化合物和组合物与可用于治疗本文考虑的疾病或病症的一种或多种另外的化合物组合用于本发明的方法。这些另外的化合物可包括本文鉴定的化合物或已知治疗、预防、或减少本文考虑的疾病或病症的症状的化合物(例如,可商业获得的化合物)。
例如,可使用合适的方法计算协同效果,合适的方法如,例如,Sigmoid-Emax方程(Holford&Scheiner,19981,Clin.Pharmacokinet.6:429-453)、Loewe相加性的方程(Loewe&Muischnek,1926,Arch.Exp.Pathol Pharmacol.114:313-326)和中值效应方程(Chou&Talalay,1984,Adv.Enzyme Regul.22:27-55)。上面提到的每个方程都可应用于实验数据以生成对应图表从而帮助评估药物组合的效果。与上面提到的方程相关的对应图表分别是浓度-效果曲线、等效线图(isobologram)曲线和组合指数曲线。
药物组合物和制剂
本发明还涵盖实践本发明的方法的本发明的药物组合物的用途。
这种药物组合物可以适合于向对象给予的形式提供,并且可包含一种或多种药学上可接受的运载体、一种或多种附加成分(另外的成分,additional ingredient)、或这些的一些组合。如在本领域公知的,本发明的组合物可包含生理学上可接受的盐,如与生理上可接受的阳离子或阴离子组合的本发明中考虑的化合物。
在某些实施方式中,可用于实践本发明的方法的药物组合物可被给予以递送1ng/kg/天和100mg/kg/天之间的剂量。在其他实施方式中,可用于实践本发明的药物组合物可被给予以递送1ng/kg/天和500mg/kg/天之间的剂量。
本发明的药物组合物中活性成分、药学上可接受的运载体、和任何附加成分的相对量将根据所治疗的对象的身份(identity)、大小、和状况而改变,并且进一步根据待给予的组合物的途径而改变。举例来说,组合物可包含0.1%和100%(w/w)之间的活性成分。
可用于本发明的方法的药物组合物可被适当地开发用于吸入、口服、直肠、阴道、肠胃外、局部、颅内、经皮、肺、鼻内、颊、眼、鞘内、静脉内或其他给予途径。其他考虑的制剂包括计划的(设计的,projected)纳米颗粒、脂质体制剂、含有活性成分的重新密封的红细胞、和基于免疫学的(immunologically-based)制剂。给予途径(一个或多个)对本领域技术人员将是显而易见的,并且将取决于任意数目的因素,包括所治疗的疾病的类型和严重度、所治疗的兽医或人患者的类型和年龄等。
本文描述的药物组合物的制剂可通过药理学领域中已知的或以后开发的任何方法制备。一般来说,这种制备方法包括使活性成分与运载体或一种或多种其他辅助成分缔合的步骤,然后,如果必要或期望,将产物成型或包装为期望的单剂量单位或多剂量单位。
如本文所用,“单位剂量”是包含预定量的活性成分的药物组合物的离散量。活性成分的量是通常等于将向对象给予的活性成分的剂量或这种剂量的方便分数(convenientfraction)如,例如,这种剂量的一半或三分之一。单位剂型可以是单次日剂量或多次日剂量之一(例如,每天约1至4次或更多次)。当使用多次日剂量时,单位剂型的每次剂量可以相同或不同。
尽管本文提供的药物组合物的描述主要针对适合于向人的处方(ethical)给予的药物组合物,但本领域技术人员将理解,这种组合物通常适合于向所有种类的动物给予。为了使组合物适合于向各种动物给予,适合于向人给予的药物组合物的修饰(修改,modification)是很好理解的,并且普通技术的兽医药理学家可仅用普通的(若有的话)实验法设计并执行这种修饰。考虑给予本发明的药物组合物的对象包括,但不限于,人和其他灵长类、包括商业相关的哺乳动物的哺乳动物,如牛、猪、马、绵羊、猫、和狗。
在某些实施方式中,本发明的组合物使用一种或多种药学上可接受的赋形剂或运载体配制。在某些实施方式中,本发明的药物组合物包含治疗有效量的本发明的至少一种化合物和药学上可接受的运载体。
制剂可以与常规赋形剂(即,适合于本领域已知的口服、肠胃外、鼻、静脉内、皮下、肠、或任何其他合适的给予方式的药学上可接受的有机或无机运载体物质)掺合(混合,admixture)使用。药学制剂可被灭菌,并且如果期望的话,与助剂,例如,润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压缓冲剂的盐、着色物质、调味物质和/或芳香物质等混合。它们也可在期望的情况下与其他活性剂(例如,其他镇痛剂)组合。
如本文所用,“附加成分”包括,但不限于,以下中的一种或多种:赋形剂;表面活性剂;分散剂;惰性稀释剂;成粒剂和崩解剂;粘合剂;润滑剂;甜味剂;增香剂;着色剂;防腐剂;生理学上可降解的组合物,如明胶;水性媒介物和溶剂;油性媒介物和溶剂;悬浮剂;分散剂或润湿剂;乳化剂,缓和剂;缓冲剂;盐;增稠剂;填料;乳化剂;抗氧化剂;抗生素;抗真菌剂;稳定剂;和药学上可接受的聚合或疏水性材料。本发明的药物组合物中可包括的其他“附加成分”在本领域中是已知的并描述于,例如Genaro,ed.(1985,Remington’sPharmaceutical Sciences,Mack Publishing Co.,Easton,PA)中,其通过引用并入本文。
液体悬浮液可使用常规方法制备以取得活性成分在水性或油性媒介物中的悬浮液。水性媒介物包括,例如,水、和等渗盐水。油性媒介物包括,例如,杏仁油、油性酯、乙醇、植物油(如花生油、橄榄油、芝麻油,或椰子油)、分馏植物油、和矿物油(如液体石蜡)。液体悬浮液可进一步包含一种或多种附加成分,其包括,但不限于,悬浮剂、分散剂或润湿剂、乳化剂、缓和剂、防腐剂、缓冲剂、盐、香料(flavorings),着色剂、和甜味剂。油性悬浮液可进一步包含增稠剂。已知悬浮剂包括,但不限于,山梨醇糖浆、氢化食用脂肪、褐藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶、阿拉伯树胶、和纤维素衍生物,如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素。已知的分散剂或润湿剂包括,但不限于,天然存在的磷脂(如卵磷脂)、烯化氧与脂肪酸、与长链脂族醇、与衍生自脂肪酸和己糖醇的偏酯、或与衍生自脂肪酸和己糖醇酐的偏酯(例如,分别为聚氧乙烯硬脂酸酯、十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxycetanol)、聚氧乙烯山梨醇单油酸酯、和聚氧乙烯山梨糖醇酐单油酸酯)的缩合产物。已知的乳化剂包括,但不限于,卵磷脂、和阿拉伯树胶(acacia)。已知的防腐剂包括,但不限于,对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、或对羟基苯甲酸正丙酯、抗坏血酸、和山梨酸。已知甜味剂包括,例如,甘油、丙二醇、山梨醇、蔗糖、和糖精。油性悬浮液的已知增稠剂包括,例如,蜂蜡、硬石蜡、和鲸蜡醇。
本发明的药学制剂的粉状和颗粒状制剂可使用已知方法制备。这种制剂可向对象直接给予,例如,用于形成片剂、填充胶囊、或通过向其中添加水性或油性媒介物制备水性或油性悬浮液或溶液。这些制剂的每一种可进一步包含分散剂或润湿剂、悬浮剂、和防腐剂的一种或多种。另外的赋形剂,如填料和甜味剂、增香剂、或着色剂,也可包含在这些制剂中。
本发明的药物组合物也可以水包油乳剂或油包水乳剂的形式制备、包装、或销售。油相可以是植物油(如橄榄油或花生油)、矿物油(如液体石蜡)、或这些的组合。这种组合物可进一步包含一种或多种乳化剂,如天然存在的树胶(如阿拉伯树胶或黄蓍树胶)、天然存在的磷脂(如大豆或卵磷脂磷脂)、衍生自脂肪酸和己糖醇酐的组合的酯或偏酯(如山梨糖醇酐单油酸酯)、和这种偏酯与氧化乙烯的缩合产物(如聚氧乙烯山梨糖醇酐单油酸酯)。这些乳剂还可含有附加成分(包括,例如,甜味剂或增香剂)。
用于用化学组合物浸渍或包衣材料的方法在本领域中是已知的,并且包括,但不限于在经或不经随后干燥的情况下,化学组合物沉积或结合到表面上的方法、在材料的合成(即,如用生理上可降解的材料)期间将化学组合物参入到材料的结构中的方法、和将水性或油性溶液或悬浮液吸收到吸收性材料中的方法。
给予/给药
给予方案可影响有效量的构成。治疗性制剂可在表现与疾病或状况相关的症状之前或之后向患者给予。进一步,几个均分剂量以及交错剂量可被每日或顺序地给予,或者剂量可被连续输注,或可被弹丸注射。进一步,如通过治疗性或预防性情况的紧急情况表明,治疗性制剂的剂量可以成比例地增加或减少。
本发明的组合物向患者(如哺乳动物(如人))的给予可使用已知程序,以对在患者中治疗疾病或状况有效的剂量和时间段实施。对取得治疗性效果必要的治疗性化合物的有效量可根据如下因素而改变:如所使用的特定化合物的活性;给予的时间;化合物的排泄率;治疗的持续时间;与化合物组合使用的其他药物、化合物或材料;所治疗患者的疾病或病症的状态、年龄、性别、重量、状况、总体健康和既往病史、和医学领域中公知的类似因素。可调整剂量方案以提供最佳治疗性反应。例如,几个均分剂量可被每天给予,或者如通过治疗性情况的紧急情况表明的,剂量可被成比例地减少。本发明的治疗性化合物的有效剂量范围的非限制性实例是约0.01至(and)50mg/kg的体重/每天。本领域普通技术人员将能够研究相关因素,并且关于治疗性化合物的有效量无需过度实验即可做出确定。
化合物可被每天几次频繁地向动物给予,或者其可被较不频繁地给予,如一天一次、一周一次、每两周一次、一月一次、或甚至更不频繁地,如每几个月一次,或甚至一年一次或更少。应理解,在非限制性实例中,每天给药的化合物的量可以每天、每隔一天、每2天、每3天、每4天、或每5天给予。例如,在每隔一天给予的情况下,可在星期一开始5mg/日剂量,在星期三给予第一个随后的5mg/日剂量,在星期五给予第二个随后的5mg/日剂量,以此类推。剂量的频率对本领域技术人员而言将是显而易见的,并且将取决于任意数目的因素,如,但不限于,所治疗的疾病的类型和严重度、动物的类型和年龄等。
本发明的药物组合物中活性成分的实际剂量水平可以改变,以获得对于特定患者、组合物、和给予方式取得期望的治疗性反应有效而对患者无毒的活性成分的量。
具有本领域普通技术的医学博士(例如,医师或兽医)可容易地确定和开处方需要的药物组合物的有效量。例如,为了取得期望的治疗性效果,医师或兽医可以以低于需要的水平开始在药物组合物中使用的本发明的化合物的剂量,并且逐渐增加剂量,直到取得期望的效果。
在具体实施方式中,为了便于给予和剂量的均匀性,以剂量单位形式配制化合物是特别有利的。如本文所用的剂量单位形式是指适合作为待治疗患者的单位(unitary)剂量的物理上离散的单位;每个单位含有预定量的经计算与需要的药学媒介物缔合产生期望治疗性效果的治疗性化合物。本发明的剂量单位形式受制于(dictated by)且直接取决于:(a)治疗性化合物的独特特性和待取得的特定治疗性效果,以及(b)本领域中配合/配制用于治疗患者中癌症的这种治疗性化合物的固有局限性。
在某些实施方式中,本发明的组合物以每天1至5次或更多次的范围的剂量向患者给予。在其他实施方式中,本发明的组合物以包括,但不限于,每天一次、每两天一次、每三天一次至一周一次、和每两周一次的剂量范围向患者给予。对本领域技术人员而言将显而易见的是,本发明各种组合的组合物的给予频率将因对象而异(vary from subject tosubject),这取决于很多因素,包括,但不限于,年龄、待治疗的疾病或病症、性别、整体健康、和其他因素。因此,本发明不应被解释为限于任何具体的剂量方案,并且待向任何患者给予的精确剂量和组合物将由主治医师(attending physical)考虑关于患者的所有其他因素来确定。
用于给予的本发明的化合物的范围可以是约1μg至约7,500mg、约20μg至约7,000mg、约40μg至约6,500mg、约80μg至约6,000mg、约100μg至约5,500mg、约200μg至约5,000mg、约400μg至约4,000mg、约800μg至约3,000mg、约1mg至约2,500mg、约2mg至约2,000mg、约5mg至约1,000mg、约10mg至约750mg、约20mg至约600mg、约30mg至约500mg、约40mg至约400mg、约50mg至约300mg、约60mg至约250mg、约70mg至约200mg、约80mg至约150mg、以及其间的任何和所有全部或部分增量。
在一些实施方式中,本发明的化合物的剂量为约0.5μg至约5,000mg。在一些实施方式中,用于本文所描述的组合物中使用的本发明的化合物的剂量为少于约5,000mg、或少于约4,000mg、或少于约3,000mg、或少于约2,000mg、或少于约1,000mg、或少于约800mg、或少于约600mg、或少于约500mg、或少于约200mg、或少于约50mg。相似地,在一些实施方式中,本文描述的第二化合物的剂量为少于约1,000mg、或少于约800mg、或少于约600mg、或少于约500mg、或少于约400mg、或少于约300mg、或少于约200mg、或少于约100mg、或少于约50mg、或少于约40mg、或少于约30mg、或少于约25mg、或少于约20mg、或少于约15mg、或少于约10mg、或少于约5mg、或少于约2mg、或少于约1mg、或少于约0.5mg,以及其任何和所有全部或部分增量。
在某些实施方式中,本发明是针对包装的药物组合物,该药物组合物包括单独或与第二药剂组合的容纳(holding)治疗有效量的本发明的化合物的容器;以及用于使用化合物以在患者中治疗、预防、或减少疾病或病症的一种或多种症状的使用说明。
术语“容器(container)”包括容纳药物组合物的任何容器(receptacle)。例如,在某些实施方式中,容器是含有药物组合物的包装。在其他实施方式中,容器不是含有药物组合物的包装,即,容器是含有包装的药物组合物或未包装的药物组合物以及使用药物组合物的使用说明的容器,如盒子或小瓶。此外,包装技术在本领域中是公知的。应理解,使用药物组合物的使用说明可包含在含有药物组合物的包装上,并由此,使用说明与包装产品形成增强的功能关系。然而,应理解,使用说明可含有与执行其预期功能(例如,治疗、预防、或减少患者中的疾病或病症)的化合物的能力有关的信息。
给予的途径
本发明的任何组合物的给予途径包括吸入、口服、鼻、直肠、肠胃外、舌下、经皮、经粘膜(例如,舌下、舌、(经)颊、(经)尿道、阴道(例如,经-和阴道周),鼻(内)、和(经)直肠)、膀胱内、肺内、十二指肠内、胃内、鞘内、皮下、肌肉内、皮内、动脉内、静脉内、支气管内、吸入、颅内、和局部给予。
合适的组合物和剂型包括,例如,片剂(tablet)、胶囊剂、囊片、丸剂、囊性片(gelcaps)、片剂(troches)、分散液、悬浮液、溶液、糖浆、颗粒剂、珠、透皮贴片(transdermalpatches)、凝胶、散剂、小丸剂、乳浆剂、锭剂、乳膏、糊剂、硬膏剂、洗剂、盘、栓剂、用于鼻或口服给予的液体喷雾剂、用于吸入的干粉或雾化制剂、用于膀胱内给予的组合物和制剂等。应理解,将可用于本发明的制剂和组合物不限于本文描述的具体制剂和组合物。
口服给予
对于口服应用,特别合适的是片剂、糖衣丸、液体、滴剂、栓剂、或胶囊剂、囊片和囊性片。适合于口服给予的其他制剂包括,但不限于,粉状或颗粒状制剂、水性或油性悬浮液、水性或油性溶液、糊剂、凝胶、牙膏、漱口剂、上光剂(coating)、口腔冲洗剂(oral rinse)、或乳剂。预期用于口服使用的组合物可根据本领域已知的任何方法制备,并且这种组合物可含有一种或多种选自适合于制造片剂的惰性、无毒的药学上赋形剂的剂。这种赋形剂包括,例如惰性稀释剂,如乳糖;成粒剂和崩解剂,如玉米淀粉;粘合剂,如淀粉;和润滑剂,如硬脂酸镁。
片剂可以是非包衣的,或者它们可以使用已知方法包衣以在对象的胃肠道内取得延迟崩解,从而提供活性成分的持续释放和吸收。举例来说,可将材料(如单硬脂酸甘油酯或二硬脂酸甘油酯)用于包衣片剂。进一步举例来说,片剂可使用描述于美国专利号4,256,108;4,160,452;和4,265,874中的方法包衣以形成渗透地控制释放片剂。为了提供药学上优雅的(elegant)且可口的制剂,片剂可进一步包含甜味剂、增香剂、着色剂、防腐剂、或这些的一些组合。
肠胃外给予
如本文所用,药物组合物的“肠胃外给予”包括特征在于物理破坏(physicalbreaching)对象的组织并且通过组织中的缺口(breach)给予药物组合物的任何给予途径。肠胃外给予因此包括,但不限于,通过组合物的注射、通过组合物通过手术切口的应用、通过组合物通过穿透组织的非手术伤口的应用等给予药物组合物。特别地,考虑肠胃外给予包括,但不限于,皮下、静脉内、腹膜内、肌肉内、胸骨内注射、和肾透析输注技术。
适合于肠胃外给予的药物组合物的制剂包含与药学上可接受的运载体(如无菌水或无菌等渗盐水)组合的活性成分。这种制剂可以适合于弹丸给予或连续给予的形式制备、包装、或销售。可注射制剂可以单位剂型(如以安瓿或以含有防腐剂的多剂量容器)制备、包装、或销售。肠胃外给予的制剂包括,但不限于,悬浮液、溶液、油性或水性媒介物中的乳剂、糊剂、和可植入的持续-释放或生物可降解的制剂。这种制剂可进一步包含一种或多种附加成分,其包括,但不限于,悬浮剂、稳定剂、或分散剂。在用于肠胃外给予的制剂的一种实施方式中,活性成分以干燥形式(即,粉状或颗粒状)提供,以在肠胃外给予重构的组合物之前用合适的媒介物(例如,无菌无热原水)重构。
药物组合物可以无菌可注射水性或油性悬浮液或溶液的形式制备、包装、或销售。该悬浮液或溶液可根据已知技术(art)配制,并且除了活性成分之外,可包含附加成分,如本文描述的分散剂、润湿剂、或悬浮剂。例如,这种无菌可注射制剂可使用无毒的肠胃外-可接受的稀释剂或溶剂(如水或1,3-丁二醇)制备。其他可接受的稀释剂和溶剂包括,但不限于,林格溶液、等渗氯化钠溶液、和固定油(不挥发性油,fixed oil)(如合成的甘油单酯或甘油二酯)。其他有用的可肠胃外给予的(parentally-administrable)制剂包括包含微晶形式的活性成分、脂质体制剂中的活性成分、或作为生物可降解的聚合物系统的组分的活性成分的制剂。用于持续释放或植入的组合物可包含药学上可接受的聚合或疏水性材料,如乳剂、离子交换树脂、微溶聚合物、或微溶盐。
另外的给予形式
本发明的另外的剂型包括如描述于美国专利号6,340,475、6,488,962、6,451,808、5,972,389、5,582,837、和5,007,790中的剂型。本发明的另外的剂型还包括如描述于美国专利申请号20030147952、20030104062、20030104053、20030044466、20030039688、和20020051820中的剂型。本发明的另外的剂型还包括如描述于PCT申请号WO 03/35041、WO03/35040、WO 03/35029、WO 03/35177、WO 03/35039、WO 02/96404、WO 02/32416、WO 01/97783、WO 01/56544、WO 01/32217、WO 98/55107、WO 98/11879、WO 97/47285、WO 93/18755、和WO 90/11757中的剂型。
控制释放制剂和药物递送系统
本发明的药物组合物的控制-或持续-释放制剂可使用常规技术制成。在一些情况下,可使用,例如,羟丙基甲基(hydropropylmethyl)纤维素、其他聚合物基质、凝胶、透性膜、渗透系统、多层包衣、微粒、脂质体、或微球体或其组合以其中一种或多种活性成分的缓慢或控制-释放形式提供待使用的剂型,以提供不同比例的期望释放特征。可容易地选择本领域普通技术人员已知的合适的控制-释放制剂(包括本文描述的那些),以与本发明的药物组合物一起使用。因此,本发明涵盖适合于口服给予的适于控制-释放的单次单位剂型,如片剂、胶囊剂、囊性片、和囊片。
大多数控制-释放药物产品具有共同目标是相比它们的非控制相对物(counterparts)改善药物治疗。理想地,在医学治疗中使用最佳设计的控制-释放制剂的特征在于,在最短时间内使用最少的药品以治愈或控制状况。控制-释放制剂的优点包括延长药物的活性、减少剂量频率、和增加患者顺从性(compliance)。另外,控制-释放制剂可用于影响作用发作的时间或其他特性,如药物的血液水平,并因此可影响副作用的发生。
大多数控制-释放制剂被设计以最初释放迅速产生期望的治疗性效果的一定量的药物,并且逐渐且连续释放其它量的药物以在延长的时间段内维持该水平的治疗性效果。为了维持身体中药物的该恒定水平,药物必须以一定速率从剂型释放,这样将代替从身体代谢和排泄的药物的量。
活性成分的控制-释放可被各种诱导物(例如pH、温度、酶、水、或其它生理条件或化合物)刺激。本发明的上下文中的术语“控制-释放组分”在本文定义为化合物或多种化合物,包括,但不限于,促进控制-释放活性成分的聚合物、聚合物基质、凝胶、透性膜、脂质体、或微球体或其组合。
在某些实施方式中,本发明的制剂可以是,但不限于,短期、快速弥补(rapid-offset)、以及控制,例如,持续释放、延迟释放和脉冲式释放的制剂。
术语持续释放在其常规意义上是用于指一种药物制剂,该药物制剂在延长的时间段内提供药物的逐渐释放,并且尽管不一定,但可在延长的时间段内导致大体上恒定的药物的血液水平。该时间段可长达一个月或更长时间,并且应该是长于弹丸形式给予的相同量的释放时间段。
对于持续释放,化合物可用合适的聚合物或疏水性材料配制,聚合物或疏水性材料为化合物提供持续释放性质。由此,例如,用于本发明的方法的化合物可以微粒的形式通过注射给予,或以薄片(wafers)或盘的形式通过植入给予。
在本发明的某些实施方式中,使用持续释放制剂,本发明的化合物单独或与另一药剂组合向患者给予。
术语延迟释放以其常规意义在本文使用,是指这样的药物制剂,其在药物给予后延迟一些后提供药物的初始释放,并且尽管不一定,但可(mat)包括从约10分钟长至约12小时的延迟。
术语脉冲式释放以其常规意义在本文使用,是指这样的药物制剂,其在药物给予后以产生药物的脉冲血浆特征(profile)的方式提供药物的释放。
术语立即释放以其常规意义使用,是指在药物给予后立即提供药物释放的药物制剂。
如本文所用,短期是指长达和包括以下的任何时间段:在药物给予后约8小时、约7小时、约6小时、约5小时、约4小时、约3小时、约2小时、约1小时、约40分钟、约20分钟、基片约10分钟,以及药物给予后其任何和所有全部或部分增量。
如本文所用,快速弥补(rapid-offset)是指长达和包括以下的任何时间段:约8小时、约7小时、约6小时、约5小时、约4小时、约3小时、约2小时、约1小时、约40分钟、约20分钟、或约10分钟,以及在药物给予后其任何和所有全部或部分增量。
本领域技术人员将认识到,或能够仅使用常规实验确定本文描述的具体程序、实施方式、权利要求、和实施例的众多等同物。这样的等同物被认为在本发明的范围内,并且由所附的权利要求覆盖。例如,应理解,用本领域认可的(art-recognized)替代方案且仅是用常规实验对反应和测定条件进行修改在本申请的范围内。
应理解,无论本文提供的值和范围如何,这些值和范围涵盖的所有值和范围意味着被包括在本发明的范围内。此外,本申请还考虑落入这些范围的所有值,以及该值范围的上限或下限。
以下实施例进一步说明本发明的方面。然而,它们绝对不是对如本文所述的本发明的教导或公开的限制。
实施例
现在参考以下实施例描述本发明。提供这些实施例仅出于说明目的,并且本发明不限于这些实施例,而是涵盖由于本文提供的教导而明显的所有变化。
材料&方法:
除非另外指出,所有原材料获自商业供应商,且在没有纯化的情况下使用。
在美国临时申请号62/529,215中列举了用β-Klotho进行的某些建模实验,其通过引用以其整体并入本文。
用程序MODELLER v9.15,使用FGF21CT-结合的β-Klotho(sKLB)的晶体结构作为建模模板,生成处于apo状态和FGF19-与FGF23-结合的状态的α-Klotho(sKLA)的胞外区的同源性模型(and Blundell,1993,J Mol.Biol.234:779-815)。
使用Clustal Omega(Sievers et al.,2011,Mol.Syst.Biol.7:539)用默认设置将sKLA(残基34-955)的序列与sKLB中的对应残基(FGF21-结合的sKLB晶体结构中的残基53-969)进行比对。使用PROMALS3D(Pei&Grishin,2014,Methods Mol.Biol.1079:263-271)将FGF19CT(残基192-216)和FGF23CT(残基182-205)的序列与模板FGF21CT结构进行比对。
对于apo sKLA模型和sKLA-FGFCT复合体模型中的每个,首先生成20个初始模型,并且随后用两个周期的优化进行精炼,包括使用可变-目标函数的300次共轭梯度迭代和用模拟退火的分子动力学。使用开源分子可视化程序PyMOL视觉上对模型进行检查。
为了在(om)sKLA模型上可视化蛋白质表面的静电势,首先使用PDB2PQR对蛋白质残基进行参数化(Dolinsky et al.,2004,Nucleic Acids Res.32:W665-W667),然后使用APBS(Baker et al.,2001,Proc.Natl.Acad.Sci.USA 98:10037-10041)通过PyMOL插件Apbsplugin(pymolwiki dot org/index.php/Apbsplugin,retrieved on 10/12/2017),使用默认设置计算静电势。
本文引用的每个专利、专利申请、和出版物的公开在此通过引用以其整体并入本文。
虽然已经参考具体实施方式公开了本发明,但是显然,本领域其他技术人员可以设计本发明的其他实施方式和变型而不脱离本发明的真实精神和范围。所附权利要求旨在解释包括所有这些实施方式和等同物变型。
序列表
<110> 耶鲁大学
伊坎西奈山医学院
J·施莱辛格
S·李
A·施莱辛格
M-U·昂格
<120> 用于治疗或预防内分泌FGF23-相关疾病的组合物和方法
<130> 047162-7158WO1(00837)
<150> US 62/598,273
<151> 2017-12-13
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Phe Ser Asp Pro His Leu Tyr Val Trp Asn Ala Thr Gly Asn Arg Leu
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Leu His Arg Val Glu Gly Val Arg Leu Lys Thr Arg Pro Ala Gln Cys
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Thr Asp Phe Val Asn Ile Lys Lys Gln Leu Glu Met Leu Ala Arg Met
580 585 590
Lys Val Thr His Tyr Arg Phe Ala Leu Asp Trp Ala Ser Val Leu Pro
595 600 605
Thr Gly Asn Leu Ser Ala Val Asn Arg Gln Ala Leu Arg Tyr Tyr Arg
610 615 620
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625 630 635 640
Leu Tyr Tyr Pro Thr His Ala His Leu Gly Leu Pro Glu Pro Leu Leu
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His Ala Asp Gly Trp Leu Asn Pro Ser Thr Ala Glu Ala Phe Gln Ala
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Tyr Ala Gly Leu Cys Phe Gln Glu Leu Gly Asp Leu Val Lys Leu Trp
675 680 685
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690 695 700
Gly Asn Asp Thr Tyr Gly Ala Ala His Asn Leu Leu Val Ala His Ala
705 710 715 720
Leu Ala Trp Arg Leu Tyr Asp Arg Gln Phe Arg Pro Ser Gln Arg Gly
725 730 735
Ala Val Ser Leu Ser Leu His Ala Asp Trp Ala Glu Pro Ala Asn Pro
740 745 750
Tyr Ala Asp Ser His Trp Arg Ala Ala Glu Arg Phe Leu Gln Phe Glu
755 760 765
Ile Ala Trp Phe Ala Glu Pro Leu Phe Lys Thr Gly Asp Tyr Pro Ala
770 775 780
Ala Met Arg Glu Tyr Ile Ala Ser Lys His Arg Arg Gly Leu Ser Ser
785 790 795 800
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805 810 815
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820 825 830
His Glu Gln Leu Ala Gly Ser Arg Tyr Asp Ser Asp Arg Asp Ile Gln
835 840 845
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865 870 875 880
Gly Asp Met Asp Ile Tyr Ile Thr Ala Ser Gly Ile Asp Asp Gln Ala
885 890 895
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Glu Val Leu Lys Ala Tyr Leu Ile Asp Lys Val Arg Ile Lys Gly Tyr
915 920 925
Tyr Ala Phe Lys Leu Ala Glu Glu Lys Ser Lys Pro Arg Phe Gly Phe
930 935 940
Phe Thr Ser Asp Phe Lys Ala Lys Ser Ser Ile Gln Phe Tyr Asn Lys
945 950 955 960
Val Ile Ser Ser Arg Gly Phe Pro Phe Glu Asn Ser Ser Ser Arg Cys
965 970 975
Ser Gln Thr Gln Glu Asn Thr Glu Cys Thr Val Cys Leu Phe Leu Val
980 985 990
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995 1000 1005
Val Leu Leu Leu Ser Ile Ala Ile Phe Gln Arg Gln Lys Arg Arg
1010 1015 1020
Lys Phe Trp Lys Ala Lys Asn Leu Gln His Ile Pro Leu Lys Lys
1025 1030 1035
Gly Lys Arg Val Val Ser
1040
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Met Arg Ser Gly Cys Val Val Val His Val Trp Ile Leu Ala Gly Leu
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35 40 45
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85 90 95
Ser Val Arg Tyr Leu Cys Met Gly Ala Asp Gly Lys Met Gln Gly Leu
100 105 110
Leu Gln Tyr Ser Glu Glu Asp Cys Ala Phe Glu Glu Glu Ile Arg Pro
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130 135 140
Leu Ser Ser Ala Lys Gln Arg Gln Leu Tyr Lys Asn Arg Gly Phe Leu
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Pro Leu Ser His Phe Leu Pro Met Leu Pro Met Val Pro Glu Glu Pro
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Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
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Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
65 70 75 80
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
85 90 95
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
100 105 110
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
115 120 125
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
130 135 140
His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
145 150 155 160
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu
165 170 175
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
180 185 190
Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
195 200 205
Ser
<210> 5
<211> 251
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Gly Ser Ser Trp Gly Gly Leu Ile His Leu Tyr Thr Ala Thr Ala Arg
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Asn Ser Tyr His Leu Gln Ile His Lys Asn Gly His Val Asp Gly Ala
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Pro His Gln Thr Ile Tyr Ser Ala Leu Met Ile Arg Ser Glu Asp Ala
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Gly Phe Val Val Ile Thr Gly Val Met Ser Arg Arg Tyr Leu Cys Met
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Asp Phe Arg Gly Asn Ile Phe Gly Ser His Tyr Phe Asp Pro Glu Asn
100 105 110
Cys Arg Phe Gln His Gln Thr Leu Glu Asn Gly Tyr Asp Val Tyr His
115 120 125
Ser Pro Gln Tyr His Phe Leu Val Ser Leu Gly Arg Ala Lys Arg Ala
130 135 140
Phe Leu Pro Gly Met Asn Pro Pro Pro Tyr Ser Gln Phe Leu Ser Arg
145 150 155 160
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165 170 175
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Claims (42)
1.非天然可溶性构建体,其防止或最小化FGF受体(FGFR)和/或FGF23与α-Klotho的结合,从而防止FGFR活化。
2.权利要求1所述的构建体,其中所述α-Klotho在哺乳动物细胞表面上。
3.权利要求1所述的构建体,其是抗体、纳米抗体、重组蛋白、和/或小分子。
4.权利要求1所述的构建体,其是抗体和/或重组肽。
5.权利要求4所述的构建体,其中所述抗体选自多克隆抗体、单克隆抗体、人源化抗体、合成抗体、重链抗体、人抗体、抗体的生物活性片段、和其任意组合。
6.权利要求1所述的构建体,其识别并结合到与α-Klotho结合的FGF23的至少一个氨基酸残基,从而防止FGF23与α-Klotho结合。
7.权利要求1所述的构建体,其识别和/或结合到与FGF23结合的α-Klotho的至少一个氨基酸残基,从而防止α-Klotho与FGF23结合。
8.权利要求7所述的构建体,其识别和/或结合到α-Klotho中氨基酸残基377-925(SEQID NO:1)内的一个或多个氨基酸。
9.权利要求7所述的构建体,其识别和/或结合到选自以下的一个或多个氨基酸:SEQID NO:1的F377、Q378、E390、S391、P392、W417、F418、V419、S420、K429、Y432、Y433、K436、N530、Q639、P640、M641、A642、P643、N688、E689、P690、T692、Q731、D733、V752、D756、S807、Y809、I812、D815、L828、V830、Q831、E832、M833、T834、I836、V845、S872、Y915、S916、A922、P923、和F925。
10.权利要求1所述的构建体,其识别并结合到与FGFR结合的α-Klotho的至少一个氨基酸残基,从而防止α-Klotho与FGFR结合。
11.权利要求10所述的构建体,其识别和/或结合到人α-Klotho的胞外区(SEQ ID NO:1的氨基酸残基34-981)内的一个或多个氨基酸。
12.权利要求10所述的构建体,其识别和/或结合到包含SEQ ID NO:1的氨基酸残基534-571的人α-Klotho的胞外区的片段内的一个或多个氨基酸。
13.权利要求1所述的构建体,包含FGF23多肽,所述FGF23多肽能够在哺乳动物细胞表面上结合到并隔离α-Klotho。
14.权利要求13所述的构建体,其包含SEQ ID NO:3(FGF23CT)的氨基酸残基180-251、或其片段。
15.权利要求1所述的构建体,包含α-Klotho多肽,所述α-Klotho多肽能够结合到并隔离FGF23。
16.权利要求15所述的构建体,其中所述α-Klotho多肽包含人α-Klotho(SEQ ID NO:1的氨基酸34-981)的胞外区、或其片段。
17.权利要求16所述的构建体,其中所述α-Klotho多肽包含SEQ ID NO:1的氨基酸377-925、或其片段。
18.权利要求1所述的构建体,包含α-Klotho多肽,所述α-Klotho多肽能够与FGFR结合。
19.权利要求18所述的构建体,其包含人α-Klotho(SEQ ID NO:1的氨基酸残基34-981)的胞外区、或其片段。
20.权利要求19所述的构建体,其包含SEQ ID NO:1的氨基酸残基534-571、或其片段。
21.权利要求1-20中任一项所述的构建体,其与稳定性增强结构域融合。
22.权利要求21所述的构建体,其中所述稳定性增强结构域包括白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶、和/或抗体的Fc区。
23.权利要求21所述的构建体,其中所述多肽和所述稳定性增强结构域通过包含约1-18个氨基酸的多肽连接。
24.包含FGF23多肽的可溶性构建体,所述FGF23多肽比野生型FGF23更紧密地与α-Klotho结合并且相比于野生型FGF23引起增强的生物活性。
25.权利要求24所述的构建体,其中所述FGF23多肽在其C端结构域中具有至少一个突变。
26.权利要求24所述的构建体,其与稳定性增强结构域融合。
27.权利要求26所述的构建体,其中所述稳定性增强结构域包括白蛋白、硫氧还蛋白、谷胱甘肽S-转移酶、和/或抗体的Fc区。
28.权利要求26所述的构建体,其中所述多肽和所述稳定性增强结构域通过包含约1-18个氨基酸的多肽连接。
29.构建体,所述构建体同时与FGF23CT-α-Klotho复合体中FGF23CT上的暴露表位和α-Klotho上的暴露表位结合,稳定所述FGF23CT-α-Klotho复合体形成并且相比于野生型FGF23引起增强的生物活性。
30.权利要求29所述的构建体,其是抗体、纳米抗体、重组蛋白、和/或小分子。
31.权利要求29所述的构建体,其是抗体和/或重组肽。
32.权利要求30所述的构建体,其中所述抗体选自多克隆抗体、单克隆抗体、人源化抗体、合成抗体、重链抗体、人抗体、抗体的生物活性片段、和其任意组合。
33.包含与α-Klotho结合物融合FGF23多肽的构建体,其中所述构建体具有FGF23刺激活性。
34.在需要其的哺乳动物中治疗和/或预防内分泌FGF相关的疾病或病症的方法,所述方法包括向所述哺乳动物给予治疗有效量的构建体,所述构建体调节FGF23与α-Klotho在所述哺乳动物细胞表面上的相互作用。
35.权利要求34所述的方法,其中所述构建体防止或最小化FGF23与α-Klotho在所述哺乳动物细胞表面上的结合。
36.权利要求35所述的方法,其中所述疾病或病症包括低磷酸盐血症和/或肿瘤诱发的骨软化。
37.权利要求34所述的方法,其中所述构建体在所述哺乳动物细胞表面上比野生型FGF23更紧密地与α-Klotho结合。
38.权利要求34所述的方法,其中所述哺乳动物是人。
39.权利要求34所述的方法,其中所述构建体通过选自以下的给予途径给予:吸入、口服、直肠、阴道、肠胃外、颅内、局部、经皮、肺、鼻内、颊、眼、鞘内、和静脉内。
40.权利要求34所述的方法,其中所述哺乳动物进一步给予至少一种治疗或预防所述疾病和/或病症的附加药物。
41.权利要求40所述的方法,其中所述构建体和所述至少一个附加药物被共同给予。
42.权利要求41所述的方法,其中所述构建体和所述至少一个附加药物被共同配制。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201762598273P | 2017-12-13 | 2017-12-13 | |
US62/598,273 | 2017-12-13 | ||
PCT/US2018/065236 WO2019118620A1 (en) | 2017-12-13 | 2018-12-12 | Compositions and methods for treating or preventing endocrine fgf23-linked diseases |
Publications (1)
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CN111712519A true CN111712519A (zh) | 2020-09-25 |
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CN201880089162.3A Pending CN111712519A (zh) | 2017-12-13 | 2018-12-12 | 用于治疗或预防内分泌fgf23-相关疾病的组合物和方法 |
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US (1) | US20200331978A1 (zh) |
EP (1) | EP3724230A4 (zh) |
JP (1) | JP2021506792A (zh) |
CN (1) | CN111712519A (zh) |
AU (1) | AU2018384735A1 (zh) |
CA (1) | CA3085322A1 (zh) |
WO (1) | WO2019118620A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090192087A1 (en) * | 2008-01-28 | 2009-07-30 | Novartis Ag | Methods and Compositions Using Klotho-FGF Fusion Polypeptides |
US20110190207A1 (en) * | 2009-10-30 | 2011-08-04 | New York University | Inhibiting binding of fgf23 to the binary fgfr-klotho complex for the treatment of hypophosphatemia |
WO2011158655A1 (ja) * | 2010-06-15 | 2011-12-22 | 国立大学法人広島大学 | 石灰化組織における可溶化Klotho、FGF23およびFGFR複合体形成機構を利用した用途 |
WO2016088059A1 (en) * | 2014-12-04 | 2016-06-09 | Novartis Ag | Methods and compositions using klotho variant polypeptides |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200539890A (en) * | 2004-03-12 | 2005-12-16 | Brigham & Womens Hospital | Methods of modulating immune responses by modulating tim-1, tim-2 and tim-4 function |
US10464979B2 (en) * | 2014-03-28 | 2019-11-05 | New York University | FGF23 c-tail fusion proteins |
-
2018
- 2018-12-12 CN CN201880089162.3A patent/CN111712519A/zh active Pending
- 2018-12-12 WO PCT/US2018/065236 patent/WO2019118620A1/en unknown
- 2018-12-12 JP JP2020532608A patent/JP2021506792A/ja active Pending
- 2018-12-12 AU AU2018384735A patent/AU2018384735A1/en active Pending
- 2018-12-12 CA CA3085322A patent/CA3085322A1/en active Pending
- 2018-12-12 US US16/772,100 patent/US20200331978A1/en not_active Abandoned
- 2018-12-12 EP EP18887470.5A patent/EP3724230A4/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090192087A1 (en) * | 2008-01-28 | 2009-07-30 | Novartis Ag | Methods and Compositions Using Klotho-FGF Fusion Polypeptides |
US20110190207A1 (en) * | 2009-10-30 | 2011-08-04 | New York University | Inhibiting binding of fgf23 to the binary fgfr-klotho complex for the treatment of hypophosphatemia |
WO2011158655A1 (ja) * | 2010-06-15 | 2011-12-22 | 国立大学法人広島大学 | 石灰化組織における可溶化Klotho、FGF23およびFGFR複合体形成機構を利用した用途 |
WO2016088059A1 (en) * | 2014-12-04 | 2016-06-09 | Novartis Ag | Methods and compositions using klotho variant polypeptides |
Non-Patent Citations (1)
Title |
---|
SHALHOUB等: "Fibroblast growth factor 23(FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization", 《CALCIF TISSUE INT.》 * |
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AU2018384735A1 (en) | 2020-06-25 |
EP3724230A4 (en) | 2022-01-19 |
CA3085322A1 (en) | 2019-06-20 |
EP3724230A1 (en) | 2020-10-21 |
JP2021506792A (ja) | 2021-02-22 |
WO2019118620A1 (en) | 2019-06-20 |
US20200331978A1 (en) | 2020-10-22 |
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Application publication date: 20200925 |