CN114945588A - 抗缪勒氏管激素多肽 - Google Patents
抗缪勒氏管激素多肽 Download PDFInfo
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- CN114945588A CN114945588A CN202080090934.2A CN202080090934A CN114945588A CN 114945588 A CN114945588 A CN 114945588A CN 202080090934 A CN202080090934 A CN 202080090934A CN 114945588 A CN114945588 A CN 114945588A
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Abstract
本公开涉及抗缪勒氏管激素(AMH)类似物,更特别是作为AMH II型受体(AMHR2)的激动剂的AMH类似物。更具体地,本公开涉及AMH类似物,其具有存在于SEQ ID NO:1的氨基酸残基533至548中的一个或多个内的修饰。
Description
相关申请的交叉引用
本申请要求于2019年10月30日提交的AU2019904097的优先权,其全部内容以引用方式并入本文。
本文引用或参考的所有文献和本文引用的文献中引用或参考的所有文献以及本文提及或以引用的方式并入本文的任何文献中的任何产品的制造商说明书、描述、产品规格和产品表特此以引用的方式整体并入本文。
序列表的电子提交的全部内容出于所有目的以全文引用的方式并入本文。
技术领域
本公开涉及抗缪勒氏管激素(AMH)类似物,更特别是作为AMH II型受体(AMHR2)的激动剂AMH类似物。
背景技术
癌症是全球第二大死亡原因,并据估计仅在美国在2018年就导致了960万人死亡。在美国,估计到2026年仅有不到200万名年轻的成年癌症存活者(15-39岁)。不幸的是,这些癌症治疗方法中有许多还可能造成不孕症、不育症或提早绝经(Jeruss,JS等人,(2009)NEngl J Med 360,902-911)。由于化学毒性诱导的卵母细胞加速损失,在40%至80%的癌症存活者中报道了不孕症或卵巢早衰(Pereira N等人,(2017)J Oncol Pract 13,643-651)。癌症存活者的生殖健康是患者未来生活品质的主要关注点,并将可能导致心理困扰,因为不孕症是目前和未来关系中压力的预测因素(Rosen A等人,(2009)Semin Oncol Nurs 25,268-277)。女性癌症患者的既定生育力治疗选项限于仅适用于一部分患者的侵入式方法,而研究性方法的实用性有限(Woodruff TK等人,(2010),Nat Rev Clin Oncol7,466-475)。此外,这些侵入式方法伴随着后勤障碍,因为它们在很大程度上依赖于及时的患者转诊和专科之间的护理协调,这可能限制病人获得可用的选项并延长癌症治疗等待时间。此外,由于治疗费用高并且某些保险公司不承保所致的经济障碍进一步限制了侵入式生育力治疗的适用性。理想的肿瘤生育力保存治疗是非干预性药物,其与癌症治疗同时施用,从而保存正在接受癌症治疗的年轻女性的生育力。
人AMH基因位于19号染色体上,并且其表达具有性别二态性。AMH对于正常的男性生殖道发育是绝对需要的,因为它影响双潜能尿生殖嵴的缪勒氏管的退化,如果不受干扰,其将产生女性生殖道结构,诸如子宫、宫颈、输卵管和阴道上部(Cate等人,(1986)Cell 45:685-698)。在男性中,AMH(也称为缪勒氏管抑制物质(MIS))的表达在妊娠9周时在胎儿睾丸中开始,并持续高水平直至青春期,此后表达水平急剧下降。在女性中,从青春期前时期到绝经期,AMH仅在产后在颗粒细胞中产生,其水平类似于成年男性,之后停止表达。在男性胎儿中,AMH造成缪勒氏管的退化,缪勒氏管是输卵管、子宫、宫颈和阴道上部的前体。
AMH在与跨越丝氨酸苏氨酸激酶受体的I型和II型单跨膜异二聚体结合后发挥其生物学作用。AMH与II型受体结合,从而通过II型受体引发来自I型受体的信号传导来导致I型受体的GS盒激酶结构域的交叉磷酸化。随后SMAD 1、5和8被活化并与SMAD 4一起调控基因转录。AMH II型受体(本文中也称为AMHR2)是65kDa的蛋白质,并且已在胚胎和成人缪勒氏管结构中以及乳腺组织、前列腺组织、性腺、运动神经元和脑中检测到。AMHR2的表达也可以在性腺中以及卵巢体腔上皮中检测到。
本领域需要以下化合物,其有利于在治疗慢性疾病或病症(诸如自身免疫疾病)期间,例如通过预防由细胞毒性药物或其他药物治疗(例如,化学疗法)引起的卵巢早衰来保存生育力或者在接受例如不期望怀孕的长期治疗时保存卵巢储备。
发明内容
研究显示,抗缪勒氏管激素(AMH)是卵巢储备(即,原始卵泡的品质和量)的量度(Visser JA等人,(2012)Nat Rev Endocrinol 8,331-341)。AMH测定可用于临床评估不孕症治疗期间以及生殖腺(gonadotoxic)癌症治疗或卵巢手术之后的卵巢储备(Victoria M等人,(2019)J Gynecol Obstet Hum Reprod 48,19-24)。假设化学治疗剂通过(i)诱导生长卵泡的细胞凋亡和(ii)上调Akt依赖性原始卵泡募集来损伤卵巢。总之,这些过程导致卵巢储备快速“耗尽(burnout)”(R.R.Wong RR等人,(2014)Endocr Relat Cancer 21,R227-233)。
发明人使用了定点诱变来鉴定人AMH上的推定的II型受体(AMHR2)结合位点。利用细胞模型,他们鉴定了相对于野生型AMH成熟结构域增加来自AMH受体复合物的信号传导的AMH类似物。认为AMH类似物可用作AMH II型受体的激动剂。这些类似物可应用于肿瘤生育力(即,在癌症治疗期间和之后生育能力的保存)以及治疗妇科癌症并且用作可逆避孕剂。令人惊讶的是,发明人发现,与野生型/天然AMH(SEQ ID NO:1)相比,野生型AMH成熟结构域序列中Gly533的突变导致AMH活性显著增加。鉴于甘氨酸不是通常参与蛋白质-蛋白质相互作用的残基,此发现令人惊讶。预期此类类似物将作为化学疗法期间的生育力保存剂,作为治疗谱系癌症的剂并且作为可能对由促性腺剂引起的卵巢储备的损伤有限的潜在可逆避孕药而用于肿瘤学和生育力相关应用。
在一个方面,本公开提供了一种抗缪勒氏管激素(AMH)类似物,其包含与SEQ IDNO:1所示的天然AMH多肽具有至少80%同一性或与SEQ ID NO:1的氨基酸残基452至560(图1A)具有至少80%同一性的多肽序列。除非另外指示,否则整个说明书中的残基编号关于SEQ ID NO:1(图1A)所示的人AMH前体,其中前体序列中的第一个残基(例如,甲硫氨酸)编号为位置1,并且序列中的最后一个残基编号为位置560。
在一个示例中,AMH类似物包含与SEQ ID NO:1所示的天然AMH多肽具有至少85%、90%、92%、94%、95%、96%、97%、98%或99%同一性或与SEQ ID NO:1的氨基酸残基452至560(图1A)具有至少80%同一性的序列。
在另一方面,本公开提供了一种AMH类似物,其包含多肽序列,所述多肽序列相对于SEQ ID NO:1所示的天然人AMH多肽包含至少一个氨基酸残基修饰,其中修饰存在于SEQID NO:1的氨基酸残基452至560内。
在另一方面,本公开提供了一种分离的抗缪勒氏管激素(AMH)类似物,其包含C末端结构域,所述C末端结构域包含与SEQ ID NO:1的氨基酸残基452至560(图1A)具有至少80%同一性的氨基酸序列。
在另一方面,本公开提供了一种分离的抗缪勒氏管激素(AMH)类似物,其包含C末端结构域序列,其中相对于SEQ ID NO:5所示的天然人成熟加工的AMH多肽,所述C末端结构域包含至少一个氨基酸残基修饰,其中所述修饰存在于SEQ ID NO:1的氨基酸残基533至548中的一个或多个内。在一些示例中,存在于SEQ ID NO:1的氨基酸残基533至548内的修饰是至少一个氨基酸取代。在一些示例中,存在于SEQ ID NO:1的氨基酸残基533至548内的修饰是单一氨基酸取代。
在一个示例中,C末端结构域包含与SEQ ID NO:1的氨基酸残基452至560(图1A)具有至少85%、90%、92%、94%、95%、96%、97%、98%或99%同一性的序列。
在一个示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至447具有至少80%同一性的氨基酸序列。在一个示例中,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至447(图1A)具有至少85%、90%、92%、94%、95%、96%、97%、98%或99%同一性的序列。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至451具有至少90%同一性的序列。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基26至447具有至少90%同一性的序列。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基26至451具有至少90%同一性的序列。
在一个示例中,N末端结构域和C末端结构域不是共价键合的。在一个示例中,N末端结构域和C末端结构域不通过肽键共价键合,即,N末端结构域和C末端结构域是单独的多肽。在一替代示例中,N末端结构域和C末端结构域是共价键合的。在一个示例中,共价键包括肽键。
在一些示例中,N末端结构域包含具有X1X2X3RKKRX8X9X10X11(SEQ ID NO:37)的前蛋白转化酶位点,其中X1不存在或为异亮氨酸,X2不存在或为丝氨酸,X3不存在或为丝氨酸,X8不存在或为丝氨酸,X9不存在或为缬氨酸,X10不存在或为丝氨酸,并且X11不存在或为丝氨酸。在一个示例中,前蛋白转化酶位点包含ISSRKKRSVSS(SEQ ID NO:6)。在一个示例中,前蛋白转化酶位点包含RKKR(SEQ ID NO:40)。
在一些示例中,类似物的活性与天然人AMH的活性相当或比其更高。在一个具体示例中,天然人AMH包含SEQ ID NO:1的残基452至560的多肽序列或SEQ ID NO:5所示的多肽序列。
在一个示例中,AMH类似物的活性等效于天然人AMH,与天然成熟加工的AMH多肽的活性相比为约2倍高、约2.5倍高、约3倍高、约3.5倍高、约4倍高、约4.5倍高、约5倍高或高于5倍。在一些实施方式中,天然成熟加工的AMH多肽包含SEQ ID NO:5所示的序列。在一些实施方式中,天然成熟加工的AMH多肽包含SEQ ID NO:36所示的序列。在一个示例中,类似物的活性通过荧光素酶测定来确定。
在一个示例中,AMH类似物的活性为至少2.5倍高或在2.5倍至5倍高之间。
在一个示例中,序列包含单一氨基酸残基修饰。
在一个示例中,序列包含两个氨基酸残基修饰。
在一个示例中,序列包含三个氨基酸残基修饰。
在另一示例中,序列包含不多于5个氨基酸残基修饰。
在一个示例中,修饰是取代。
在一个示例中,相对于SEQ ID NO:5所示的天然人AMH多肽,C末端结构域包含至少一个氨基酸残基修饰,其中修饰存在于SEQ ID NO:1的氨基酸残基533至548内。
在另一示例中,相对于包含SEQ ID NO:5所示的序列的成熟加工的AMH多肽,C末端结构域包含单一氨基酸残基修饰。在另一示例中,相对于包含SEQ ID NO:5所示的序列的成熟加工的AMH多肽,C末端结构域包含两个氨基残基修饰。在另一示例中,相对于包含SEQ IDNO:5所示的序列的成熟加工的AMH多肽,C末端结构域包含三个氨基残基修饰。
在一些示例中,C末端结构域任选地在N末端包含一个或多个另外的氨基酸残基(例如,相对于SEQ ID NO:5所示的天然人AMH多肽)。
在一些示例中,修饰是氨基酸取代。
在一个示例中,氨基酸残基取代位于SEQ ID NO:1的残基533、535和/或548处。
在一个示例中,氨基酸取代选自由G533、L535和G533+L535组成的组。在另一示例中,取代选自由L535M和G533A+L535M组成的组。
在一个示例中,氨基酸修饰在SEQ ID NO:1的G533处。在另一示例中,修饰选自由SEQ ID NO:1的G533A、G533S、G533K、G533L和G533R组成的组。在另一示例中,修饰选自由SEQ ID NO:1的G533A、G533S和G533K组成的组。
在一个具体示例中,修饰是SEQ ID NO:1的G533K。
在一个示例中,N末端的一个或多个另外的氨基酸残基包含SVSS(SEQ ID NO:41)。
在又一示例中,AMH类似物是AMH II型受体(AMHR2)的激动剂。在一个示例中,AMH类似物与AMHR2特异性结合。
在一些示例中,相对于天然人AMH,AMH类似物对AMHR2的受体结合亲和力增加至少2倍、至少3倍、至少4倍、至少5倍或大于5倍。
在一个示例中,AMH类似物是人多肽。
在一个示例中,AMH衍生自包含SEQ ID NO:3所示的序列的AMH前体。在一个示例中,前体的G533处的氨基酸残基(即SEQ ID NO:3中的残基535)通过取代为丙氨酸、丝氨酸或赖氨酸来修饰。
在一些示例中,AMH类似物或AMH前体序列被进一步修饰以改善蛋白水解加工。在一个示例中,R448至R451处的天然蛋白水解加工位点被ISSRKKRSVSS(SEQ ID NO:6;图1B)所示的序列替换。
在一些示例中,AMH类似物或AMH前体进一步修饰以通过替换天然信号传导肽来增强重组生产。在一个示例中,由MRDLPLTSLALVLSALGALLGTEAL(SEQ ID NO:7)所示的序列组成的天然人AMH信号传导序列被大鼠白蛋白信号肽序列替换。在一个示例,大鼠白蛋白信号序列包含MKWVTFLLLLFISGSAFS(SEQ ID NO:8)所示的序列或由其组成。
在一个示例中,AMH类似物或AMH前体包含对蛋白水解加工位点和信号肽序列的修饰。
在一些示例中,AMH类似物或AMH前体可还包含His标签,例如His6标签以帮助纯化。在一些示例中,N末端结构域可还包含N末端His标签。
在一个具体示例中,AMH前体包含以下所示的序列或由其组成:
在另一示例中,AMH类似物包含缺少如MKWVTFLLLLFISGSAFS(SEQ ID NO:8)所示的信号序列的SEQ ID NO:3或由其组成,其中在G533处的氨基酸残基(以粗体和下划线显示)通过氨基酸取代来修饰。
为避免存疑,对G533的提及是指位于SEQ ID NO:1所示的天然人AMH序列中的残基位置533处的Gly。G533对应于SEQ ID NO:3所示的修饰序列中的G535。
在一个示例中,在SEQ ID NO:3的G533处的氨基酸取代是G533A、G533S或G533K。
在另一方面,本公开提供了一种AMH类似物,其具有包含选自由以下组成的组中的序列的C末端结构域:
在一些示例中,AMH类似物还包含融合搭配物,所述融合搭配物选自Fc蛋白、检测标签、纯化标签或载体分子中的一种或多种。
在另一方面,本发明提供了一种载体,其包含编码本文所述的AMH类似物或AMH前体的多核苷酸,所述多核苷酸可操作地连接至启动子。在一个示例中,多核苷酸包含以下所示的序列或由其组成:
在一个示例中,SEQ ID NO:4中的多核苷酸残基1603至1605选自由gct、gcc、gca、gcg、tct、tcc、tca、tcg、aaa或aag组成的组。
在另一方面,提供了一种AMH前体,其包含具有C末端结构域序列的多肽,其中相对于SEQ ID NO:5所示的天然人成熟加工的AMH多肽,所述C末端结构域包含至少一个氨基酸残基修饰,其中所述修饰存在于SEQ ID NO:1的氨基酸残基533至548中的一个或多个内。
在一些示例中,修饰是G533A、G533K或G533S。
在一些示例中,多肽包含SEQ ID NO:1或SEQ ID NO:3所示的序列,其中对应于SEQID NO:1的G533的氨基酸通过取代为G533A、G533S或G533K被修饰。
在另一方面,提供了一种AMH多核苷酸,其包含SEQ ID NO:4所示的序列,其中SEQID NO:4的核苷酸1603至1605处的多核苷酸序列被修饰成编码丙氨酸(A)、丝氨酸(S)或赖氨酸(K)。
在另一方面,提供了一种AMH多核苷酸,其包含SEQ ID NO:34所示的序列,其中SEQID NO:33的核苷酸1597至1599处的多核苷酸序列被修饰成编码丙氨酸(A)、丝氨酸(S)或赖氨酸(K)。
在另一方面,提供了一种AMH多核苷酸,其包含SEQ ID NO:35所示的序列,其中核苷酸244至246处的多核苷酸序列被修饰成编码丙氨酸(A)、丝氨酸(S)或赖氨酸(K)。
在一个示例中,AMH类似物是重组产生的。在一个示例中,AMH前体是重组产生的。
在一个示例中,编码AMH类似物的多肽在载体,优选地哺乳动物载体中表达。在另一示例中,载体是细菌载体。在另一示例中,载体是病毒载体。在一特定示例中,载体是pcDNA3.1载体。
在一些示例中,载体是腺相关病毒(AAV)载体。在一特定示例中,载体是AAV血清型9(AAV-9)。
在另一方面,本公开提供了一种宿主细胞,其包含本文所述的载体。在一个示例中,宿主细胞是哺乳动物宿主细胞。在另一示例中,宿主细胞选自胚胎肾细胞、CHO细胞或卵巢细胞。在一个示例中,宿主细胞是HEK293T细胞。
在另一方面,本公开提供了一种组合物,其包含本文所述的AMH类似物或编码本文所述的AMH类似物或AMH前体的载体。
在一个示例中,组合物包含具有与SEQ ID NO:1的氨基酸残基452至560具有至少80%同一性的序列的AMH类似物。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至447具有至少90%同一性的序列。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基26至447具有至少90%同一性的序列。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至451具有至少90%同一性的序列。在一些示例中,AMH类似物还包含N末端结构域,N末端结构域包含与SEQ ID NO:1的氨基酸残基26至451具有至少90%同一性的序列。在一些示例中,C末端结构域和N末端结构域不是共价键合的。在一些示例中,AMH类似物包含具有两个C末端结构域和两个N末端结构域的四元复合物。在一些示例中,四元复合物包含C末端同源二聚体和N末端同源二聚体。
在另一示例中,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至447具有至少92%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在另一示例中,N末端结构域包含与SEQ ID NO:1的氨基酸残基30至451具有至少92%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在另一示例中,N末端结构域包含与SEQ ID NO:1的氨基酸残基26至447具有至少92%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在另一示例中,N末端结构域包含与SEQ ID NO:1的氨基酸残基26至451具有至少92%、94%、95%、96%、97%、98%、99%或100%同一性的序列。
在一个示例中,组合物包含AMH类似物,其包含选自由以下组成的组中的C末端结构域:SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ IDNO:14或SEQ ID NO:15。
优选地,根据任何方面的AMH类似物在施用于受试者时是包含两个N末端结构域和两个C末端结构域的四元复合物。在一个示例中,根据任一方面的AMH类似物在施用于受试者时是包含N末端同源二聚体和C末端同源二聚体的四元复合物。优选地,从载体表达后的AMH类似物或AMH前体是同源二聚体。在某些示例中,单体通过二硫键连接。在某些示例中,N末端结构域通过二硫键连接。在某些示例中,C末端结构域通过二硫键连接。在其他示例中,单体通过接头连接。在另一示例中,单体是非共价缔合的。
在一个示例中,AMH类似物以治疗有效量提供。“治疗有效量”可能根据预期用途而有所不同。在一个示例中,治疗有效量是在一定浓度下施用以提供受试者的卵泡生成完全停止的量。在另一示例中,治疗有效量被认为是足以使受试者血液中AMH类似物的浓度与不存在AMH的情况相比高出10-50%或高出50-100%的量。在一个示例中,治疗有效量是足以将受试者血液中AMH类似物的浓度增加1μg/ml至5μg/ml的量。
在另一示例中,组合物包含药学上可接受的载剂。
在一个示例中,将组合物施用于人或非人灵长类动物。在另一示例中,将组合物施用于非人动物。在一个示例中,将组合物施用于选自猫、狗和马的非人动物。在一个示例中,受试者患有癌症。在一个示例中,癌症是妇科癌症。在另一示例中,受试者正接受癌症治疗,诸如免疫疗法、细胞疗法、放射疗法或化学疗法。在另一示例中,受试者精神上无行为能力,使得受试者的绝育和/或卵泡生成的抑制符合受试者幸福的最佳利益。
可以通过本领域技术人员已知的任何方法和途径施用组合物。施用可以是腹膜内或皮下施用或直接注射到卵泡中。施用可以是透皮施用。在一些示例中,施用AMH类似物以用于一贯递送,例如以向量形式作为一次性注射剂,用于需要永久避孕的基因疗法。在其他示例中,AMH类似物以间歇脉冲形式递送,其中单次施用之后是无施用间隔,例如在需要暂时停止卵泡生成的情况下,诸如在临时避孕方法中或在受试者生命的后期阶段需要怀孕的情况下。在一些示例中,脉冲施用包括施用AMH类似物,然后在本文公开的组合物的脉冲施用之间无治疗间隔至少3天、至少7天、约7天至3周。
本公开的组合物可以透皮贴剂、阴道环、生物凝胶的形式或作为可植入的避孕装置诸如子宫内装置(IUD)上的涂层提供。
组合物可以单独施用或与细胞治疗剂、免疫治疗剂、化学治疗剂或放射治疗剂组合施用。
在另一方面,本公开提供了一种预防女性受试者的功能性卵巢储备下降的方法,其包括向受试者施用本公开的AMH类似物或组合物。在一些示例中,预防功能性卵巢储备下降涉及在女性受试者中保存卵巢卵泡储备的方法。在一些示例中,预防功能性卵巢储备下降涉及与不存在AMH类似物的情况相比,将募集的原始卵泡的数目减少至少10%,或与不存在AMH类似物的情况相比,将募集的原始卵泡的数量减少10%至99%或者导致卵泡生成完全停止,或者减慢原始卵泡活化。
在另一方面,本公开提供了一种女性受试者避孕的方法,其包括向受试者施用本公开的AMH类似物或组合物。在一个示例中,受试者是绝经期前女性受试者。在一个示例中,受试者是青春期前女性受试者。本公开的AMH类似物的使用可以是短期或长期的。
在另一方面,本公开提供了一种用于保护受试者的卵巢和/或子宫的方法,其包括向受试者施用本公开的AMH类似物或组合物。
在一个示例中,受试者是35岁以上的人受试者。
在一个示例中,受试者正接受后将接受癌症治疗。在一个示例中,受试者正接受癌症的免疫疗法、细胞疗法、化学疗法或放射疗法治疗。在一个示例中,受试者正接受慢性疾病或病症的治疗。
在一些示例中,与未施用本文所述的AMH类似物的年龄匹配的受试者相比,所述方法将自然年龄相关的功能性卵巢储备下降抑制至少10%、或至少20%、或至少30%、或至少40%、或至少50%或多于50%。
在一些示例中,受试者正接受或即将接受针对癌症的治疗或者正接受或即将接受针对慢性疾病或病症的治疗。
在一些示例中,受试者患有自身免疫疾病并且将用免疫疗法治疗,或目前正用其治疗,或已经用其治疗。
在一些示例中,受试者将用导致子宫或卵巢中的细胞死亡或细胞损伤的细胞毒性药物或细胞毒性剂治疗,或目前正用其治疗,或已经用其治疗。
在另一方面,本公开提供了一种用于治疗受试者的妇科癌症的方法,其包括向受试者施用本公开的AMH类似物或组合物。
在另一方面,本公开提供在制造用于保存卵巢卵泡储备、避孕、子宫保护或治疗妇科癌症的药物中的如本文所述的AMH类似物。
在一些示例中,女性受试者需要保存她们的卵巢储备,或者需要或希望延迟生殖,或者其中受试者患有或易患以下中的任一种:卵巢储备功能减退(diminished ovarianreserve,DOR)、早发性卵巢老化(premature ovarian ageing,POA)、原发性卵巢功能不全(POI)、子宫内膜异位症、BRAC1突变、特纳综合征(Turner syndrome)、自身免疫疾病、甲状腺自身免疫、肾上腺自身免疫或自身免疫性多腺体综合征(autoimmunity polyglandularsyndrome)。
在根据本文所述的任何方法或用途的特定示例中,AMH类似物作为包含N末端同源二聚体和C末端同源二聚体的四元复合物施用。
在另一方面,本公开提供了一种用于根据本文所述的任何方法使用的试剂盒,试剂盒包括:
(i)包含本文所述的AMH类似物的施用装置;和
(ii)用于受试者的说明书。
在一个示例中,施用装置选自泵或输注装置、一个或多个单剂量或多剂量预加载注射器或透皮贴剂。在一个示例中,泵是渗透压泵,例如Alzet泵。在一个示例中,施用装置是例如US 5267963、6277097、6386306或6793646中所述的自动注射器。
附图说明
图1(A)野生型人AMH蛋白序列的注释氨基酸序列(GenBank AAH49194;SEQ ID NO:1)。信号肽以下划线表示并且对应于氨基酸1-25。前蛋白转化酶识别位点(也称为“前蛋白转化酶位点”)包括Arg448至Arg451,并且通过阴影指示,其中裂解发生在Arg451与Ser452之间。前结构域包括从Arg26至Arg451的序列。成熟结构域序列(Ser452至Arg560;SEQ IDNO:5)以粗体指示。Gly533在成熟结构域序列中以粗体和下划线指示。(B)修饰的人AMH的注释氨基酸序列(hAMH+SCUT+RSA;SEQ ID NO:3)。信号肽以下划线表示并且对应于氨基酸1-18。六组氨酸标签通过粗体和下划线指示。超切(SCUT)前蛋白转化酶识别序列(Ile447a至Ser451d)呈灰色阴影,其中裂解发生在Arg451与Ser451a之间。前结构域是从Pro30至Arg451的序列。加工的AMH包含氨基酸Ser451a至Arg560。成熟结构域以粗体指示(Ser452至Arg560)。
图2显示了mAMH变体的表达。通过体外定点诱变对mAMH cDNA进行修饰。为了评估修饰是否影响前体加工,将转染的HEK-293T细胞的条件培养基浓缩12.5倍,并在还原条件下通过蛋白质印迹进行分析。用特异性识别朝向AMH C末端的区域的mAb-5/6A探测印迹。显示了12.5kDa单体成熟结构域和70kDa单体AMH前蛋白。
图3显示了第一队列hAMH突变体的表达。通过体外定点诱变对hAMH+SCUT+RSAcDNA进行修饰。为了评估突变是否阻止蛋白质分泌,将转染的HEK-293T细胞的条件培养基浓缩12.5倍,并在还原条件下通过蛋白质印迹进行分析。用特异性识别朝向AMH C末端的区域的mAb-5/6A探测印迹。显示了12.5kDa单体成熟结构域。
图4显示了第二队列hAMH突变体的表达。通过体外定点诱变对hAMH+SCUT+RSAcDNA进行修饰。为了评估突变是否阻止蛋白质分泌,将转染的HEK-293T细胞的条件培养基浓缩12.5倍,并在还原条件下通过蛋白质印迹进行分析。用特异性识别朝向AMH C末端的区域的mAb-5/6A(下图)和特异性检测加工的hAMH前结构域的mAb-9/6A(上图)探测印迹。显示了12.5kDa单体成熟结构域(下图)和55kDa加工的AMH前结构域(上图)。
图5显示了第三队列hAMH突变体的表达。通过体外定点诱变对hAMH+SCUT+RSAcDNA进行修饰。为了评估突变是否阻止蛋白质分泌,将转染的HEK-293T细胞的条件培养基浓缩12.5倍,并在还原条件下通过蛋白质印迹进行分析。用特异性识别朝向AMH C末端的区域的mAb-5/6A探测印迹。显示了12.5kDa单体成熟结构域。
图6显示了第四队列hAMH突变体的表达。通过体外定点诱变对hAMH+SCUT+RSAcDNA进行修饰。为了评估突变是否阻止蛋白质分泌,将转染的HEK-293T细胞的条件培养基浓缩12.5倍,并在还原条件下通过蛋白质印迹进行分析。用特异性识别朝向AMH C末端的区域的mAb-5/6A(下图)和特异性检测加工的hAMH前结构域的mAb-9/6A(上图)探测印迹。显示了12.5kDa单体成熟结构域(下图)和55kDa加工的AMH前结构域(上图)。
图7显示了hAMH变体的Co-IMAC纯化。将通过瞬时转染的细胞调节的200mL培养基浓缩至约1mL,并用结合缓冲液反向制备至最终体积5mL。将浓缩的条件培养基在含有HisPurTM钴树脂的柱中孵育约2.5小时。收集未结合的蛋白质,然后用PBS洗涤柱两次。为了洗脱结合的蛋白质,将HisPurTM钴树脂在3mL含有500mM咪唑的PBS中孵育约2.5小时。为了回收任何仍结合的蛋白质,将树脂在3mL含有1M咪唑的PBS中孵育约1小时。通过SDS-PAGE分离出10μL每个级分,然后进行蛋白质转移(Western transfer)。通过用mAb-5/6A探测印迹来评估回收率。
图8显示了G533A、G533S和G533K突变体的活性。将用Smad1/5应答性荧光素酶报告基因和AMHR2转染的COV434人颗粒细胞用递增浓度(A,3.1-50ng/mL;B,0.62-50ng/mL)的Co-IMAC纯化的hAMH变体处理过夜。测量的荧光素酶活性表示为相对于对照孔平均值的调整值1.0的倍数变化。
图9显示了G533H、H548K、L535M和G533A+L535M突变体的活性。将用Smad1/5应答性荧光素酶报告基因和AMHR2转染的COV434人颗粒细胞用递增浓度(0.62-50ng/mL)的Co-IMAC纯化的hAMH变体处理过夜。测量的荧光素酶活性表示为相对于对照孔平均值的调整值1.0的倍数变化。
图10显示了形成成熟激素的AMH加工(A)和标记了腕和指结构域的成熟AMH的结构模型(B)。
图11显示了来自人、猫、狗和马的加工的成熟AMH的序列比对。使用ClustalW准备比对(Larkin等人,(2007).Bioinformatics,23,2947-2948;Thompson等人,(1994).Nucleic Acids Res.,22,4673-4680)。使用ESPript准备图(Robert和Gouet(2014)Nucleic Acids Res.,42(W1),W320-W324)。
图12显示了与购自R&D Systems的hAMH的活性相比的由hAMH+SCUT+RSA产生的成熟加工的AMH的活性。使用本文所述的荧光素酶测定确定活性。
序列表的说明
SEQ ID NO:1是天然人AMH前体多肽的氨基酸序列
SEQ ID NO:2是天然小鼠AMH前体多肽的氨基酸序列
SEQ ID NO:3是hAMH+SCUT+RSA(具有修饰的信号序列、六组氨酸纯化标签和修饰的蛋白水解位点的人AMH前体)的氨基酸序列
SEQ ID NO:4是hAMH+SCUT+RSA(具有修饰的信号序列、六组氨酸纯化标签和修饰的蛋白水解位点的人AMH前体)的核苷酸序列
SEQ ID NO:5是人成熟加工的AMH多肽的序列
SEQ ID NO:6是在hAMH+SCUT+RSA中使用的蛋白水解加工位点的序列SEQ ID NO:7是人AMH前导/信号序列的序列
SEQ ID NO:8是hAMH+SCUT+RSA中使用的前导/信号序列的序列
SEQ ID NO:9是AMH类似物的序列
SEQ ID NO:10是AMH类似物的序列
SEQ ID NO:11是AMH类似物的序列
SEQ ID NO:12是AMH类似物的序列
SEQ ID NO:14是AMH类似物的序列
SEQ ID NO:14是AMH类似物的序列
SEQ ID NO:15是AMH类似物的序列
SEQ ID NO:16是信号序列
SEQ ID NO:17是信号序列
SEQ ID NO:18是信号序列
SEQ ID NO:19是信号序列
SEQ ID NO:20是信号序列
SEQ ID NO:21是信号序列
SEQ ID NO:23是信号序列
SEQ ID NO:24是信号序列
SEQ ID NO:25是信号序列
SEQ ID NO:26是信号序列
SEQ ID NO:27是小鼠AMH前体多核苷酸的核苷酸序列
SEQ ID NO:28是马AMH前体多核苷酸的核苷酸序列
SEQ ID NO:29是狗AMH前体多核苷酸的核苷酸序列
SEQ ID NO:30是猫AMH前体多核苷酸的核苷酸序列
SEQ ID NO:31是马AMH前体多肽的氨基酸序列
SEQ ID NO:32是狗AMH前体多肽的氨基酸序列
SEQ ID NO:33是猫AMH前体多肽的氨基酸序列
SEQ ID NO:34是人AMH前体多核苷酸的核苷酸序列
SEQ ID NO:35是编码人成熟加工的AMH的核苷酸序列
SEQ ID NO:36是加工的hAMH+SCUT+RSA的氨基酸序列
SEQ ID NO:37是蛋白水解加工位点的序列
SEQ ID NO:38是蛋白水解加工位点的序列
SEQ ID NO:39是蛋白水解加工位点的序列
SEQ ID NO:40是蛋白水解加工位点的序列
SEQ ID NO:41是C末端结构域的N末端延伸
具体实施方式
通用技术和选定的定义
术语“和/或”(例如“X和/或Y”)应理解为“X和Y”或“X或Y”,并应被视为对两种含义或任何一种含义提供明确支持。
除非上下文另外明确指出,否则如本文所用,术语“一个”、“一种”和“所述”包括单数和复数方面。
对本说明书中包括的文件、法令、材料、装置、物品等的任何讨论不应认为是承认任何或所有这些内容形成现有技术基础的一部分或者是本公开相关领域中的一般常识,因为其在本申请的每个权利要求的优先权日期之前已经存在。
贯穿本说明书,除非另外具体说明或上下文另有要求,否则提及单个步骤、物质成分、步骤组或物质成分组时,应视为涵盖这些步骤、物质成分、步骤组或物质成分组中的一项和多项(即一项或多项)。
除非特别声明,否则本文描述的每个实施例在作必要的修改的情况下适用于本发明各个和每个其他实施例。
本领域的技术人员应了解,本发明容许具体描述的内容以外的变化和修改。应理解,本公开包括所有此类变化和修改。本公开还包括说明书单个地或共同提及或指示的所有步骤、特征、组合物和化合物以及所述步骤或特征的任何和所有组合或任何两种或更多种。
本公开不限于本文所描述的特定实施例的范围,所述特定实施例仅欲出于范例的目的。功能上等效的产品、组合物和方法明确地在本公开的范围内。
除非另有指示,否则在不进行过度实验的情况下使用分子生物学、重组DNA技术、细胞生物学以及免疫学的常规技术来执行本公开。此类程序描述于以下文献中,例如Sambrook,Fritsch&Maniatis,Molecular Cloning:A Laboratory Manual,Cold SpringHarbor Laboratories,New York,第二版(1989),第I卷、第II卷和第III卷全部;DNACloning:A Practical Approach,第I卷和第II卷(D.N.Glover编,1985),IRL Press,Oxford,全文;Oligonucleotide Synthesis:A Practical Approach(M.J.Gait编,1984)IRL Press,Oxford,全文,以及尤其是其中Gait的论文,第l-22页;Atkinson等人,第35-81页;Sproat等人,第83-115页;以及Wu等人,第135-151页;4.Nucleic Acid Hybridization:A Practical Approach(B.D.Hames&S.J.Higgins编,1985)IRL Press,Oxford,全文;Immobilized Cells and Enzymes:A Practical Approach(1986)IRL Press,Oxford,全文;Perbal,B.,APractical Guide to Molecular Cloning(1984);Methods InEnzymology(S.Colowick和N.Kaplan编,Academic Press,Inc.),全系列,Sakakibara,D.,Teichman,J.,Lien,E.Land Fenichel,R.L.(1976).Biochem.Biophys.Res.Commun.73336-342;Merrifield,R.B.(1963).J.Am.Chem.Soc.85,2149-2154;Barany,G.和Merrifield,R.B.(1979),The Peptides(Gross,E.和Meienhofer,J.编),第2卷,第1-284页,Academic Press,New York.12.Wünsch,E.编(1974)Synthese von Peptiden inHouben-Weyls Metoden der Organischen Chemie(Müler,E.编),第15卷,第4版,第1部分和第2部分,Thieme,Stuttgart;Bodanszky,M.(1984)Principles of Peptide Synthesis,Springer-Verlag,Heidelberg;Bodanszky,M.和Bodanszky,A.(1984)ThePractice ofPeptide Synthesis,Springer-Verlag,Heidelberg;Bodanszky,M.(1985)Int.J.PeptideProtein Res.25,449-474;Handbook of Experimental Immunology,第I-IV卷(D.M.Weir和C.C.Blackwell编,1986,Blackwell Scientific Publications);以及Animal CellCulture:Practical Approach,第三版(John R.W.Masters编,2000),ISBN 0199637970,全文。
在整个说明书中,除非上下文另有要求,否则词语“包括”或变化诸如“包含”或“具有”将被理解为意指包括所述步骤或要素或整数或者步骤或要素或整体的组,但是不排除任何其他步骤或要素或整数或者要素或整数的组。
除非确切地另外定义,否则本文使用的所有技术和科学术语应视为具有与本领域(例如,细胞培养、分子遗传学、免疫学、免疫组织化学、蛋白质化学以及生物化学)普通技术人员通常理解的相同的含义。
术语“由……组成”或“由……构成”应理解为意指方法、过程或物质组合物具有所述步骤和/或组分,并且没有额外步骤或组分。
本文所用,当提及可测量的值诸如重量、时间、剂量等的量时,术语“约”意指涵盖指定量的±20%或±10%,更优选地±5%,甚至更优选地±1%,还更优选地±0.1%的变化,因为此类变化适于进行所公开的方法。
如本文所用,术语AMH是指抗缪勒氏管激素。此术语可以与术语缪勒氏管抑制物质(MIS)互换使用。如本文所用,术语“原前蛋白”是指包括前导序列的全长蛋白,例如SEQ IDNO:1所示的序列(野生型AMH蛋白)。如本文所用,术语“前蛋白”或“前结构域”是指缺乏前导序列的AMH蛋白序列,例如从氨基酸残基Arg26至Gly447的序列。如本文所用,术语“成熟”AMH蛋白或多肽是指加工和裂解后的AMH多肽。成熟序列是从Ser452至Arg560的序列。生物活性AMH蛋白是包含两个单体单元的同源二聚体,其中每个单体单元具有从Ser452至Arg560的序列。
应当理解,本文所述的AMH类似物是分离形式。“分离的”意指在自然界中不存在的形式的多肽、多核苷酸、载体或细胞。分离的多肽、多核苷酸、载体或细胞包括已经被纯化到不再以它们在自然界存在的形式的程度的那些。在一些方面,分离的多肽、多核苷酸、载体或细胞是基本上纯的。
如本文所用,当提及AMH类似物时,术语“特异性结合”是指识别并结合AMHR2但基本上不识别和结合样品中的其他分子的AMH类似物。
术语“同一性”或“序列同一性”及其语法变化意指两个或更多个提及的实体是相同的。因此,在两个多肽序列相同的情况下,至少在提及的区域或部分内,它们具有相同的氨基酸序列。在两个核酸序列相同的情况下,至少在提及的区域或部分内,它们具有相同的多核苷酸序列。同一性可以在序列的定义区域(区或结构域)中。%同一性是通过以下方式计算的:在比较窗口内比较两个最佳比对的序列,确定在这两个序列中出现相同的核酸碱基或氨基酸残基的位置数以得到匹配位置数,将匹配位置数除以比较窗口中的位置总数,并且将结果乘以100,得到序列同一性百分比。%同一性可以通过GAP(Needleman和Wunsch,J.Mol Biol.48:444-453.1970)分析(GCG程序)、Smith和Waterman的同源算法(Adv.Appl.Math.2:482(19801))或Pearson和Lipman的方法(PNAS USA 85:2444-48(1988))确定。适于确定百分比序列同一性和序列相似性百分比的另一算法是BLAST算法,其描述于Altschul等人J.Mol.Biol.215:403-410(1990)。
如本文所用,术语“增加”是指相对于参考水平(例如天然AMH多肽)的增加。增加可以是至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%或更多,包括例如至少2倍、至少3倍、至少4倍、至少5倍或更多。增加可以指表达水平、效力或蛋白质活性。
如本文所用,术语“多核苷酸”是指长度大于约100个核碱基的分子。核碱基包括例如DNA(例如,腺苷“A”、鸟嘌呤“G”、胸腺嘧啶“T”或胞嘧啶“C”)或RNA(例如,A、G、尿嘧啶“U”或C)中存在的天然存在的嘌呤或嘧啶碱基。
如本文所用,术语“病毒载体”是指使用病毒或病毒相关载体作为核酸构建体进入细胞的载剂。可以将构建体整合并包装到非复制性的缺陷性病毒基因组中如腺病毒、腺相关病毒(AAV)或单纯疱疹病毒(HSV)或其他病毒,包括逆转录病毒和慢病毒载体,以用于感染细胞或转导到细胞中。载体可以并入或可以不并入细胞基因组中。如果需要,构建体可以包括病毒序列以用于转染。替代地,可以将构建体并入能够进行附加型复制的载体,例如EPV和EBV载体。
如本文所用,术语“药物组合物”意指任何组合物,其含有至少一种治疗或生物活性剂并且适合施用于患者。这些制剂中的任何一种都可以通过本领域熟知并且可接受的方法来制备。参见例如Gennaro,A.R.编,Remington:The Science and Practice ofPharmacy,20th Edition,Mack Publishing Co.,Easton,Pa.(2000)。
本文使用的短语“药学上可接受的”是指在合理的医学判断的范围,适合用于与人和动物的组织接触而不产生过度毒性、刺激、变应性应答和/或其他问题或并发症,同时具有相称的合理受益/风险比的那些化合物、材料、组合物和/或剂型。
如本文所用,术语“治疗”包括缓解与特定病症或病状相关的症状。“治疗”还可以意指与未接受治疗时预期的存活期相比,延长存活期。需要治疗的对象包括已经患有病状或病症的对象,以及易患病状或病症的对象或要预防病状或病症的对象。
如本文所用,术语“预防”包括预防特定病症或病状。术语“预防”是指避免或延迟疾病或病症(例如,POA或DOR)的一种或多种症状或可测量标志物的表现。所述术语不仅包括避免或预防疾病的症状或标志物,而且还包括相对于具有相似的发展疾病或病症的可能性或易感性的对照或未治疗个体中的那些症状或标志物,或相对于基于受疾病或病症影响的群体的历史或统计测量可能出现的症状或标志物,疾病的任何一种症状或标志物的严重性或程度降低。严重性降低意指相对于对照或参考,症状或可测量的疾病标志物的严重性或程度降低至10%,例如至少15%、20%、30%、40%、50%、60%、70%、80%、90%、95%、99%或甚至100%(即无症状或可测量的标志物)。
术语“治疗有效量”应理解为意指如本文所述的AMH类似物或多核苷酸足以减轻疾病或病症的至少一种或多种症状的量,并且是指组合物足以提供所需的效果或提供与病症有关的症状或临床标志物的显著减少的量。治疗的功效可以在生育力的动物模型中评估,并且导致防止怀孕或停止卵泡生成的任何治疗或组合物的施用指示有效治疗。症状的治疗性或预防性显著降低是与对照或未治疗受试者相比的测量参数的例如至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约75%或更多。
除非另外指示,否则如本文所用的术语“野生型”或“天然”是指天然存在的编码人AMH的多肽或多核苷酸序列,因为它通常存在于体内。如本文所公开,人AMH的原前蛋白的野生型氨基酸序列对应于SEQ ID NO:1,其中氨基酸残基1-25对应于前导/信号序列。如本文所公开,AMH的前蛋白形式的野生型氨基酸序列包含SEQ ID NO:1的氨基酸残基26-560(例如缺少前导序列),然后通过蛋白水解裂解对其进行翻译后加工以形成成熟AMH。如本文所公开,成熟AMH的野生型氨基酸序列包含SEQ ID NO:1的氨基酸残基452至560。AMH作为二硫键连接的同源二聚体前体产生,其需要翻译后加工以形成活性AMH。翻译后加工包括从前结构域裂解和解离以释放成熟AMH。对本文所述的变体或突变体肽、多肽或蛋白质的提及包括以下肽、多肽、蛋白质或其片段,其含有至少一个不同于“野生型”或“天然”肽、多肽或蛋白质的氨基酸残基,即包括至少一个不同于SEQ ID NO:1(或其片段,诸如SEQ ID NO:1的氨基酸残基452至560)中提供的人AMH的原前蛋白的氨基酸残基。在一些实施方式中,至少一个不同的氨基酸残基位于SEQ ID NO:1的氨基酸残基452至560(即C末端结构域或成熟加工的AMH)内。如本领域技术人员将理解的,人AMH有至少一种天然存在的序列多晶型物。出于本申请的目的,变体或突变体肽、多肽或蛋白质包括不具有野生型序列的人AMH的任何天然存在的序列多晶型物。
除非另外指示,否则整个说明书中的残基编号关于SEQ ID NO:1(图1A)所示的人AMH前体,其中SEQ ID NO:1中提供的序列中的第一个残基编号为位置1,并且SEQ ID NO:1中提供的序列中的最后一个残基编号为位置560。在多肽中插入额外氨基酸的实施方式中,例如由于包含纯化标签、不同的前导序列、不同的蛋白酶裂解序列等,插入的残基基于紧接在插入之前的野生型残基的残基号和字母表的字母进行标记。参见例如以下表1。
表1:初级裂解位点处氨基酸插入的编号。
在从多肽缺失氨基酸的实施方式中,例如由于包含不同的前导序列、不同的蛋白酶裂解序列等,残基基于SEQ ID NO:1中提供的对应的野生型残基的残基号进行标记。
如本文所用,术语“多肽”是指氨基酸残基的聚合物并且不限于最小长度。所述术语包括多肽的翻译后修饰,例如二硫键形成、糖基化、乙酰化、磷酸化、蛋白水解裂解等。所述术语还包括包含对天然序列的修饰(诸如添加和取代)(在本质上通常是保守的)的多肽,只要多肽维持所需的活性即可。这些修饰可以是通过定点诱变而有意进行的或是由于PCR扩增或其他重组方法所致的错误。在某些情况下,将非天然氨基酸(包括合成的非天然氨基酸取代的氨基酸或一种或多种D-氨基酸)并入多肽中是合乎需要的。与含有L-氨基酸的形式相比,含有D-氨基酸的多肽在体外和体内表现出稳定性增加。
当描述多肽时,术语“保守取代”是指多肽的氨基酸组成的不会显著改变多肽的活性的变化。例如,保守取代是指用氨基酸残基取代具有相似化学性质的不同氨基酸残基。特定氨基酸序列的保守取代是指对多肽活性不重要的那些氨基酸的取代或用具有相似性质的其他氨基酸取代氨基酸,使得即使是关键氨基酸的取代也不会降低多肽的活性。例如,以下六个基团各自含有彼此为保守取代的氨基酸:1)丙氨酸(A)、丝氨酸(S)、苏氨酸(T);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);以及6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。
当提及多肽时,术语“取代”是指不同实体的氨基酸变化,例如另一氨基酸。取代可以是保守或非保守的。
如本文在多核苷酸的语境中所用,术语“重组”意指基因组、cDNA、半合成或合成来源的多核苷酸,所述多核苷酸凭借其来源或操纵不与其在自然界中与之缔合的多核苷酸的全部或一部分缔合。如本文在多肽的语境中所用,术语重组意指通过组多核苷酸的表达重所产生的多肽。
如本文所用,术语“受试者”是指动物或非人动物。受试者可以是用本公开的组合物施用治疗(包括预防性治疗)的人。在一些示例中,非人类动物是伴侣动物,优选地猫、狗或马。在一些示例中,受试者是非人灵长类动物,例如黑猩猩、食蟹猴、蛛猴和猕猴。受试者优选是人类女性。受试者可以是育龄的(例如20至35岁)、青少年(例如13-19岁)或青春期前的(例如6-12岁)。女性受试者可能大于35岁。
如本文关于多肽(例如,AMH)所用,术语“类似物”被广义地定义为意指修饰的多肽,其中肽的一个或多个氨基酸残基已被其他氨基酸残基取代,并且/或者其中一个或多个氨基酸残基已从肽中缺失,并且/或者其中一个或多个氨基酸残基已添加至肽。类似物来源于天然多肽。在一些实施方式中,氨基酸残基的添加或缺失可发生在多肽的N末端、和/或多肽的C末端、和/或多肽的结构域的多肽的N末端、和/或多肽的结构域的多肽的C末端。添加和/或取代的氨基酸残基可以是可编码的氨基酸残基或其他天然存在的残基或纯合成的氨基酸残基。在一些实施方式中,类似物是激动剂。
在自然界中,一些多肽作为复合前体产生,所述复合前体除了靶向诸如信号肽的标记外,还含有其他肽片段,所述肽片段在蛋白质成熟期间的某个点被去除(加工),得到成熟形式的多肽,其不同于初级翻译产物(除了去除信号肽之外)。如本文关于蛋白质所用,术语“成熟”是指翻译后加工的多肽;即,存在于初级翻译产物中的任何原肽或前肽已被裂解或去除的肽。如本文所用,术语“前体蛋白”、或“原前肽”、或“原前蛋白”全部指mRNA的初级翻译产物;即,原肽和前肽仍然存在。此命名法中的“原(pre)”通常是指信号肽。仅去除信号肽但没有进一步加工的翻译产物的形式称为“前肽”或“前蛋白”。待去除的片段或区段本身也可以称为“前肽”。因此,前蛋白或前肽已去除信号肽,但含有前肽(此处指前肽片区段)和将构成成熟蛋白的部分。关于AMH,“成熟”AMH也称为“C末端结构域”,并且前肽区段也称为“N末端结构域”。C末端结构域可以包含选自由SEQ ID NO:9至SEQ ID NO:15组成的组中的序列。如本领域技术人员将理解的,C末端结构域可以任选地在N或C末端包含额外的残基。在一个实施方式中,C末端结构域可以任选地在N末端包含SVSS(例如SEQ ID NO:36)。类似地,N末端结构域可以任选地在N或C末端包含额外的残基。
如本文关于AMH所用,术语“加工的”(即,“加工的AMH”)是指在对初级翻译产物(即,原前蛋白)进行加工以裂解如本文所讨论的原和前结构域之后的成熟AMH(即,SEQ IDNO:1的452至560)。
如本文所用,关于多肽的术语“结构域”被广泛定义并且是指多肽或多肽的区、片段或区段。优选地,多肽或多肽的区、片段或区段形成紧凑的三维结构,例如,其可以是独立稳定和折叠的。然而,本领域技术人员将理解,一些结构域或其部分可以是非结构化的或具有无规卷曲结构。许多蛋白质仅含有单一结构域,而其他蛋白质可能具有多个结构域。
如本文所用,关于AMH类似物,术语“活性”是指类似物通过AMH受体复合物诱导信号传导的能力。例如,在一些实施方式中,通过测量用AMH类似物治疗后的Smad-1/5应答来测量活性。
抗缪勒氏管激素
抗缪勒氏管激素(AMH),也称为缪勒氏管抑制物质(MIS),以二聚前体的形式产生,并经历翻译后加工以实现活化,其需要从N末端(前)结构域裂解和解离以释放生物活性C末端片段(参见图10A)。
随着女性年龄的增长,AMH水平下降,并且促卵泡激素(FSH)水平增加。美国人类生殖中心(US Centre for Human Reproduction)已经确定了年龄特异性AMH和FSH水平,以评估女性的卵巢储备。这些基线水平如以下表2所示:
表2:年龄特异性的AMH和FSH水平
AMH是糖蛋白的大型转化生长因子-β(TGF-β)多基因家族中的140kDa二硫键连接的糖蛋白成员。在还原条件下的蛋白质印迹分析指示,AMH是二硫键连接的二聚体,其每个“单体”可能在生物合成和分泌过程期间被裂解成两种较小的物质。在翻译后加工之后,AMH包含57kDa N末端结构域二聚体和12.5kDa羧基末端(C末端)结构域二聚体,它们一起形成非共价复合物。C末端结构域是生物活性部分,并且裂解是活性需要的。N末端结构域可以帮助蛋白质在体内折叠并促进将C末端肽递送至其受体,例如AMHR2。
AMH激素原可以被枯草杆菌蛋白酶/kexin样前蛋白转化酶(PC)家族的成员(例如弗林蛋白酶)裂解以生成N末端结构域(即前结构域)和C末端结构域(即成熟AMH)。此蛋白水解过程是其生理活性需要的,并且发生在与TGF-β的序列中存在的二元裂解位点相似的位置中的位点。AMH的不可裂解的突变体不具有生物活性。
AMH前体的加工涉及:蛋白水解裂解和去除前导序列(例如,SEQ ID NO:1的氨基酸1-25);裂解AMH蛋白以生成N末端和C末端结构域;以及解离C末端结构域,其二硫键连接至第二C末端结构域以形成生物活性同源二聚体AMH蛋白。成熟AMH二聚体与前结构域二聚体非共价缔合。
裂解主要发生在以RAQR(SEQ ID NO:1的448至451)为特征的kex样位点。第二个精氨酸之后的肽键被裂解。此位点的裂解产生AMH的C末端结构域(例如,SEQ ID NO:1的氨基酸452-560)。如本文所用,术语“前蛋白转化酶位点”是指初级AMH裂解位点并且包含SEQ IDNO:1的残基448至451(RAQR)。
在SEQ ID NO:1的残基254-255处不太频繁地观察到意义未知的二级裂解位点(称为“R/S”)。此位点含有R S,但其他方面不遵循弗林蛋白酶裂解的共有Arg-X-(Arg/Lys)-Arg。
AMH的不可裂解的突变体不具有生物活性,并且截短羧基末端结构域的人基因的突变导致持续性缪勒氏管综合征。氨基末端结构域在体内的作用可能有助于蛋白质折叠并促进将C末端结构域片段递送至其受体。
在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级RAQR裂解位点被枯草杆菌蛋白酶/kexin样前蛋白转化酶(PC)家族的共有序列替换,例如,如Duckert,Brunark&Blom(2004)Protein Eng Des Sel,17:107-112中所述。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级裂解位点被弗林蛋白酶共有序列替换,例如序列基序R-X-[K/R]-R↓,其中X是任何氨基酸残基。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级RAQR裂解位点改变为RARR,如PCT申请PCT/US14/024010中所述。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级裂解位点改变为X1X2X3RKKRX8X9X10X11(SEQ ID NO:37),其中X1不存在或为异亮氨酸,X2不存在或为丝氨酸,X3不存在或为丝氨酸,X8不存在或为丝氨酸,X9不存在或为缬氨酸,X10不存在或为丝氨酸,并且X11不存在或为丝氨酸。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级RAQR裂解位点改变为RKKR(SEQ ID NO:38)。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级裂解位点改变为ISSRKKRSVSS(SEQ ID NO:6;本文中还称为SCUT)。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级裂解位点改变为ISSRKKR(SEQ ID NO:39)。在一些示例中,SEQ ID NO:1的氨基酸位置448-451处的初级裂解位点改变为RKKRSVSS(SEQ ID NO:40)。包含或省略氨基酸X1至X3和X8至X11中的任何一个或多个也在本公开的范围内。应当指出的是,使用全长SCUT(即表1中的选项1)会在成熟AMH上留下N末端SVSS,因为裂解发生在R451与下一个S下游(即S451a)之间。由hAMH+SCUT+RSA产生的成熟加工的AMH的活性与购自R&D Systems的hAMH的活性相当(图12)。如果使用截短的SCUT(参见例如表1中的各种选项),这可能改变额外N末端氨基酸的存在、序列和/或数目。例如,在表1的选项2或3中,SVSS将完全不存在。其他选项和结果对于本领域技术人员将是显而易见的。
如上所讨论,成熟野生型AMH蛋白最初以包含N末端前导序列的前体的形式产生,所述前导序列对应于SEQ ID NO:1的野生型AMH蛋白的氨基酸残基1-25。此前导序列被裂解掉以产生AMH前蛋白。在本公开的所有方面,AMH前体可以具有非内源前导/信号序列,其中SEQ ID NO:1的氨基酸1-25的前导/信号序列已经被不同的前导序列替换,诸如像人血清白蛋白前导序列。在本公开的所有方面,如本文所公开的AMH前体可以是修饰的重组AMH多肽,其中初级RAQR裂解位点被弗林蛋白酶共有序列替换,并且其中内源前导/信号序列已经被异源前导序列替换。在本公开的所有方面,如本文所公开的AMH前体可以是修饰的重组AMH多肽,其中初级RAQR裂解位点被SEQ ID NO:6替换并且其中内源前导/信号序列已经被异源前导序列替换。
分泌的蛋白质最初以含有前导序列的前体形式在细胞内表达,确保进入分泌通路中。此类前导序列,也称为信号肽,指导表达的产物穿过内质网(ER)的膜。信号肽通常在易位至ER的期间通过信号肽酶被裂解掉。一旦进入分泌通路中,蛋白质就被运输到高尔基体。从高尔基体,蛋白质可以沿着通往诸如细胞液泡或细胞膜的隔室的不同途径,或者其可以被运出细胞以分泌到外部介质中(Pfeffer和Rothman(1987)Ann.Rev.Biochem.56:829-852)。
在一些示例中,AMH类似物包含修饰的前导/信号序列,其代替对应于SEQ ID NO:1的氨基酸残基1-25的AMH蛋白的野生型前导序列。在一些示例中,SEQ ID NO:1的氨基酸残基1-25的天然前导序列被异源前导序列(例如但不限于白蛋白前导序列)或其功能片段替换。在一些示例中,异源前导序列是人血清白蛋白序列(HSA),例如,对应于SEQ ID NO:26的前导序列。在一些示例中,异源前导序列是大鼠血清白蛋白序列,例如对应于SEQ ID NO:8的前导序列。
HSA前导序列的修饰的形式也涵盖在本公开中,如例如美国专利5,759,802中所公开的,所述专利以引用的方式整体并入本文。在一些示例中,HSA前导序列的功能片段是MKWVTFISLLFLFSSAYS(SEQ ID NO:17)或其变体,其公开于欧洲专利EP2277889中,所述专利整体并入本文。HSA信号序列的原前区(例如,MKWVTFISLLFLFSSAYSRGVFRR,SEQ ID NO:18)的变体包括片段,诸如HSA信号序列的原区(例如,MKWVTFISLLFLFSSAYS,SEQ ID NO:19),或其变体,诸如像MKWVSFISLLFLFSSAYS(SEQ ID NO:20)。
在一些实施方式中,前导序列是与SEQ ID NO:7的氨基酸残基具有至少约60%、或至少约70%、或至少约80%、或至少约90%、或至少约95%、或至少约96%、或至少约97%、或至少约98%、或至少约99%同一性的前导序列。在一些实施方式中,前导序列是与SEQ IDNO:8的氨基酸残基具有至少约60%、或至少约70%、或至少约80%、或至少约90%、或至少约95%、或至少约96%、或至少约97%、或至少约98%、或至少约99%同一性的前导序列。在一些实施方式中,前导序列是与SEQ ID NO:26的氨基酸残基具有至少约60%、或至少约70%、或至少约80%、或至少约90%、或至少约95%、或至少约96%、或至少约97%、或至少约98%、或至少约99%同一性的前导序列。
本公开还考虑了其他前导序列以替换SEQ ID NO:1的氨基酸1至25。此类前导序列是本领域熟知的,并且包括包含融合至组织型纤溶酶原活化物前肽(IgSP-tPA)的免疫球蛋白信号肽的前导序列,如US 2007/0141666中所公开,所述专利以引用方式整体并入本文。许多其他信号肽用于产生分泌蛋白。其中之一是鼠免疫球蛋白信号肽(IgSP,EMBL登录号M13331)。IgSP于1983年由Loh等人(Cell.33:85-93)首先鉴定。已知IgSP在哺乳动物细胞中表达良好。例如。欧洲专利号0382762公开了一种通过在IgSP与辣根过氧化物酶之间构建融合多肽来生产辣根过氧化物酶的方法。其他前导序列包括例如但不限于:MPIF-1信号序列(例如,GenBank登录号AAB51134的氨基酸1-21)MKVSVAALSCLMLVTALGSQA(SEQ ID NO:16);斯钙素信号序列(MLQNSAVLLLLVISASA,SEQID NO:17);蔗糖酶信号序列(例如,MLLQAFLFLLAGFAAKISA,SEQ ID NO:18);酵母交配因子α信号序列(例如,乳酸克鲁维酵母(K.lactis)杀伤毒素前导序列);杂交信号序列(例如,MKWVSFISLLFLFSSAYSRSLEKR,SEQ IDNO:19);HSA/MFa-1杂交信号序列(还称为HSA kex2)(例如,MKWVSFISLLFLFSSAYSRSLDKR,SEQ ID NO:20);乳酸克鲁维酵母杀伤/MFa-1融合前导序列(例如,MNIFYIFLFLLSFVQGSLDKR,SEQ ID NO:21);免疫球蛋白Ig信号序列(例如,MGWSCIILFLVATATGVHS,SEQ ID NO:22);Fibulin B前体信号序列(例如,MERAAPSRRVPLPLLLLGGLALLAAGVDA,SEQ ID NO:23);丛生蛋白前体信号序列(例如,MMKTLLLFVGLLLTWESGQVLG,SEQ ID NO:24);和胰岛素样生长因子结合蛋白4信号序列(例如,MLPLCLVAALLLAAGPGPSLG,SEQ ID NO:25)。
在另外的示例中,AMH前体或编码其的核酸序列还包含标签以帮助纯化。在一些示例中,标签可以是c-myc、多组氨酸或FLAG标签。在一些示例中,标签是多组氨酸标签。在某些示例中,标签的位置使得在翻译后加工(例如,用弗林蛋白酶或类似蛋白酶裂解)之后,C末端结构域片段不加标签。换句话讲,标签的位置使得在翻译后加工(例如,用弗林蛋白酶或类似蛋白酶裂解)之后,N末端结构域加标签。在某些示例中,多组氨酸标签位于前导/信号序列之后,例如在SEQ ID NO:1的氨基酸残基25之后。在某些示例中,多组氨酸标签位于紧接在SEQ ID NO:1的氨基酸残基30之前。多组氨酸标签可以是His6或His8。AMH前体可以包含多于一个标签,其可以是相同或不同的。优选地,标签不干扰或显著影响在结合和活化AMHR2时AMH类似物功能的生物活性。
在另外的示例中,AMH类似物在一个或多个残基上被糖基化。在一些示例中,AMH类似物在N末端结构域中的一个或多个残基上被糖基化。
在一些实施方式中,相对于SEQ ID NO:5所示的天然人AMH多肽,AMH类似物包含至少一个氨基酸残基修饰。在一些实施方式中,至少一个氨基酸修饰在推定的AMH指结构域中(图10B)。在一些实施方式中,至少一个氨基酸修饰在推定的AMH指2中(图10B)。在一些实施方式中,修饰存在于SEQ ID NO:1的氨基酸残基533至548内。在一些实施方式中,修饰存在于SEQ ID NO:1的氨基酸残基533至535内。在一些实施方式中,修饰在SEQ ID NO:1的氨基酸残基533处。在一些实施方式中,修饰在SEQ ID NO:1的氨基酸残基535处。在一些实施方式中,修饰在SEQ ID NO:1的氨基酸残基533和535处。
在一些实施方式中,AMH类似物包含:至少一种C末端结构域多肽,其包含与SEQ IDNO:1的氨基酸残基452至560具有至少80%同一性的氨基酸序列;和至少一个N末端结构域多肽,其包含与SEQ ID NO:1的氨基酸残基30至447具有至少80%同一性的氨基酸序列。在一个示例中,AMH类似物包含:两个C末端结构域多肽,其包含与SEQ ID NO:1的氨基酸残基452至560具有至少80%同一性的氨基酸序列;和两个N末端结构域多肽,其包含与SEQ IDNO:1的氨基酸残基30至447具有至少80%同一性的氨基酸序列。
AMH类似物能够调节AMHR复合物的活性。在一些实施方式中,AMH类似物是AMHR2的激动剂。
以下表3中提供了来自各种非人动物的AMH序列。
表3:AMH序列
图11中提供了来自人和非人动物的成熟AMH序列的比对。
本文所述的AMH类似物还可以例如通过糖基化、酰胺化、羧化或磷酸化,或通过产生酸加成盐、酰胺、酯(特别是C末端酯)和N-酰基衍生物进行进一步修饰。在一些实施方式中,AMH类似物多肽或其对应的前体可以与一种或多种融合搭配物融合。在一个示例中,融合搭配物是Fc蛋白(例如动物或人Fc)。融合蛋白可以还包括第二融合搭配物,诸如纯化或检测标签,例如,可以直接或间接检测的蛋白质,诸如,绿色荧光蛋白、血凝素或碱性磷酸酶;DNA结合结构域(例如,GAL4或LexA);基因活化结构域(GAL4或VP16)、纯化标签或分泌信号肽(例如,原前胰蛋白酶信号序列)。
在一些示例中,AMH类似物多肽与第二融合搭配物诸如载体分子融合以增强其生物利用度。此类载体是本领域已知的并且包括聚(烷基)二醇,诸如聚乙二醇(PEG)。考虑的其他修饰包括与聚合物(例如PEG)的连接。聚乙二醇化的方法是本领域已知的。其他示例包括与转铁蛋白、白蛋白、生长激素或纤维素或其他改善多肽的药代动力学的分子的缀合或基因融合。
在某些示例中,可以修饰AMH类似物以增加类似物的半衰期。在一些示例中,AMH类似物包含或缀合至半衰期延长部分,从而增加AMH类似物的体内半衰期。合适的半衰期延长部分包括但不限于聚乙二醇、脂质和蛋白质(例如,Fc片段、白蛋白结合蛋白、包含作为PAS序列的多肽、XTEN)。与血清白蛋白的融合也可以增加多肽的血清半衰期。如本领域技术人员所理解的,半衰期增加或延长意指特定分子从血液的清除减缓。
半衰期延长部分可以例如包含允许体内与血清白蛋白缔合的肽或蛋白质。特别地,半衰期延长部分可以是白蛋白结合部分。白蛋白结合部分可以例如由天然存在的多肽、或其白蛋白结合片段、或工程化多肽组成。工程化白蛋白结合多肽可以例如是蛋白质支架的变体,其已针对其对白蛋白的特异性结合亲和力而被选择。在具体的实施方式中,蛋白质支架可以选自链球菌蛋白G或其衍生物的结构域。合适的白蛋白结合结构域的其他示例公开于WO2009/016043中。
半衰期延长部分可以例如包含基于多肽的无规卷曲结构域。在一些实施方式中,半衰期延长部分可以是PAS多肽(参见例如Payne等人(2010)Pharm.Dev.Technol.,1-18;Pisal等人(2010)J.Pharm.Sci.99(6),2557-2575;Veronese.(2001)Biomaterials 22(5),405-417;PCT/EP2011/058307和PCT/EP2008/005020)。PAS多肽含有形成稳定无序的多肽的脯氨酸、丙氨酸和任选地丝氨酸(PA/S或PAS)残基的序列。在一些实施方式中,半衰期延长部分可以是XTEN多肽(参见例如Podust等人,(2016)J Control Release 240:52-66)。XTEN完全由形成高亲水性非结构化多肽的丙氨酸、谷氨酸、甘氨酸、脯氨酸、丝氨酸和苏氨酸残基构成。
本领域技术人员将理解,存在许多其他熟知的方法来延长多肽的体内半衰期,并且可以使用任何合适的方法。Zaman等人,(2019)J.Control.Release.301:176-189中也讨论了延长治疗性蛋白半衰期的示例性策略。
突变体AMH多肽的制备
可以使用本领域已知的任何技术制备改变的多肽(AMH类似物)。例如,可以对本发明的多核苷酸进行体外诱变。此类体外诱变技术包括将多核苷酸亚克隆到合适的载体中,将载体转化为“突变子(mutator)”菌株(诸如大肠杆菌XL-1red(Stratagene))以及将转化的细菌繁殖合适的代数。来源于突变/改变的DNA的产物可容易使用本文所述的技术进行筛选,以便确定它们是否具有受体结合活性。在一些实施方式中,可以使用本领域技术人员已知的技术对本发明的多核苷酸进行定点诱变,例如由Stratagene Inc.(现在是Agilenttechnologies)开发的QuikChangeTM方法或其他可商购获得的试剂盒/策略。
在设计氨基酸序列突变体时,突变位点的位置和突变的性质将取决于待修饰的特征。突变的位点可例如通过(1)首先用保守氨基酸选择进行取代,然后用更多基团选择进行取代(这取决于所实现的结果);(2)缺失目标残基;或者(3)与所定位的位点相邻地插入其他残基来单独或连续地修饰。
氨基酸序列缺失的范围通常为约1至15个残基,更优选地约1至10个残基并且通常约1至5个邻接残基。取代突变体在多肽中去除至少一个氨基酸残基并在其位置中插入不同残基。对取代诱变最感兴趣的位点包括鉴定为对受体结合很重要的位点。
在某些示例中,以相对保守的方式取代位点。此类保守取代在“示例性取代”的标题下的表4中示出。
表4:示例性取代
本文所述的氨基酸优选为“L”异构形式。然而,D异构形式的残基可以被任何L-氨基酸残基取代,只要多肽保留所需的结合功能特性即可。修饰还包括结构和功能类似物,例如,具有合成或非天然氨基酸或氨基酸类似物的肽模拟物和衍生形式。
重组产生
载体
本公开的AMH类似物可以使用容易获得的技术和材料(例如自动化肽合成设备)重组生产(参见例如Applied Biosystems,Foster City,Calif.)。
如本文所用的描述核酸分子的术语“重组”意指基因组、cDNA、病毒、半合成或合成来源的多核苷酸,所述多核苷酸凭借其来源或操纵不与其在自然界中与之缔合的多核苷酸的全部或一部分缔合。关于蛋白质或多肽使用的术语重组意指通过重组多核苷酸的表达所产生的多肽。关于宿主细胞使用的术语重组是指已引入了重组多核苷酸的宿主细胞。重组体在本文中还用于指材料(例如,细胞、核酸、蛋白质或载体),所述材料已通过引入异源材料(例如,细胞、核酸、蛋白质或载体)来修饰。
对于重组生产,编码本公开的AMH多肽的核酸优选地被分离并插入至可复制载体中以用于进一步克隆(DNA的扩增)或用于表达。编码多肽的DNA使用常规方法(例如,通过使用能够与编码多肽的DNA特异性结合的寡核苷酸探针)容易地分离或合成。
可使用许多载体。载体组分通常包括但不限于以下中的一种或多种:信号序列、编码本公开的多肽的序列、增强子元件、启动子和转录终止序列。
术语“载体”是指能够转运它所连接的另一核酸的核酸分子;质粒是“载体”所涵盖的属的物种。术语“载体”通常指含有复制起点和在宿主细胞中复制和/或维持所需的其他实体的核酸序列。能够指导它们可操作地连接的基因和/或核酸序列的表达的载体在本文中称为“表达载体”。一般来讲,具有效用的表达载体常常呈“质粒”形式,其是指环状双链DNA环,所述环在其载体形式下不与染色体结合,并且通常包含用于稳定或瞬时表达的实体或所编码的DNA。
(i)信号序列组分。本公开的AMH多肽不仅可以直接重组产生,而且还可以作为与异源多肽的融合多肽产生,所述异源多肽优选地是信号序列或在成熟蛋白或多肽的N末端处具有特定裂解位点的其他多肽。所选择的异源信号序列优选地是由宿主细胞识别并加工(即被信号肽酶裂解)的信号序列。
(ii)启动子组分。表达和克隆载体通常含有被宿主生物体识别并可操作地连接至抗体核酸的启动子。适用于与原核宿主一起使用的启动子包括phoA启动子、β-内酰胺酶和乳糖启动子系统、碱性磷酸酶、色氨酸(trp)启动子系统和杂合启动子(诸如tac启动子)。然而,其他已知的细菌启动子是合适的。用于细菌系统中的启动子还将含有可操作地连接至编码多肽的DNA的Shine-Dalgarno(S.D.)序列。
如本文所用,本文可互换使用的“启动子”、或“启动子区”、或“启动子元件”是指控制与其可操作地连接的核酸序列的转录的一段核酸序列,通常但不限于DNA、或RNA、或其类似物。启动子区包括足以实现RNA聚合酶识别、结合和转录起始的特定序列。这部分启动子区被称为启动子。此外,启动子区包括调节RNA聚合酶的这种识别、结合和转录起始活性的序列。这些序列可以是顺式作用的或者可以对反式作用因子有应答。根据调控的实质,启动子可以是组成型的或调控的。启动子可以指组织特异性启动子(例如,对卵巢或子宫上的表达具有特异性)。
启动子已知用于真核生物。事实上,所有真核基因都具有富AT区,其位于转录起始的位点上游约25至30个碱基处。在许多基因的转录开始的上游70至80个碱基处存在的另一序列是CNCAAT区,其中N可以是任何核苷酸。大多数真核基因的3'末端是AATAAA序列,其可以是向编码序列的3'末端添加poly A尾的信号。将所有这些序列适当地插入真核表达载体中。与酵母宿主一起使用的合适启动序列的例子包括3-磷酸甘油酸酯激酶或其他糖酵解酶的启动子,所述其他糖酵解酶例如烯醇酶、甘油醛-3-磷酸脱氢酶、己糖激酶、丙酮酸脱羧酶、磷酸果糖激酶、葡萄糖-6-磷酸异构酶、3-磷酸甘油酸酯变位酶、丙酮酸激酶、磷酸丙糖异构酶、磷酸葡萄糖异构酶和葡萄糖激酶。其他酵母启动子(其为具有受生长条件控制的转录的额外优势的诱导型启动子)是针对醇脱氢酶2、异细胞色素C、酸性磷酸酶、与氮代谢有关的降解酶、金属硫蛋白、甘油醛-3-磷酸脱氢酶和负责麦芽糖和半乳糖利用的酶的启动子区。EP 73,657中进一步描述了用于酵母表达的合适的载体和启动子。酵母增强子还有利地与酵母启动子一起使用。
(iii)增强子元件组分。高等真核生物对编码本公开的AMH多肽的DNA的转录常常通过将增强子序列插入载体中来增加。目前已知来自哺乳动物基因(球蛋白、弹性蛋白酶、白蛋白、甲胎蛋白和胰岛素)的许多增强子序列。然而,通常使用来自真核细胞病毒的增强子。示例包括复制起点后侧上的SV40增强子(bp 100-270)、巨细胞病毒早期启动子增强子、复制起点后侧的多瘤增强子和腺病毒增强子。关于用于活化真核启动子的增强元件,还参见Yaniv(1982)Nature297:17-18。增强子可在AMH多肽序列的位置5'或3'处剪接到载体中,但优选地位于启动子的位点5'。
(iv)转录终止组分。用于真核宿主细胞(酵母、真菌、昆虫、植物、动物、人或来自其他多细胞生物体的有核细胞)中的表达载体还将含有终止转录和稳定mRNA所必需的序列。此类序列通常可从真核或病毒DNA或cDNA的5'非翻译区和偶尔3'非翻译区获得。这些区包含在编码抗体的mRNA的非翻译部分中转录成聚腺苷酸化片段的核苷酸区段。一种有用的转录终止组分是牛生长激素聚腺苷酸化区。参见WO94/11026及其中公开的表达载体。
(v)宿主细胞的选择和转化。用于在本文的载体中克隆或表达DNA的合适宿主细胞是上文所述的原核生物、酵母或高等真核生物细胞。用于此目的的合适的原核生物包括真细菌,如革兰氏阴性或革兰氏阳性生物体,例如,肠杆菌科(Enterobacteriaceae),如埃希氏菌属(Escherichia)(例如大肠杆菌)、肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯菌属(Klebsiella)、变形杆菌属(Proteus)、沙门菌属(Salmonella)(例如鼠伤寒沙门菌(Salmonella typhimurium))、沙雷菌属(Serratia)(例如粘质沙雷菌(Serratiamarcescans))和志贺菌属(Shigella)以及杆菌属(Bacilli)(例如枯草芽孢杆菌(B.subtilis)和地衣芽孢杆菌(B.licheniformis))、假单胞菌属(Pseudomonas)(如铜绿假单胞菌(P.aeruginosa))以及链霉菌属(Streptomyces)。一种优选的大肠杆菌克隆宿主是大肠杆菌294(ATCC31,446),但其他菌株例如大肠杆菌B、大肠杆菌X1776(ATCC 31,537)和大肠杆菌W3110(ATCC 27,325)是合适的。这些示例是例示性的而非限制性的。
可用于本文的其他表达载体包括但不限于质粒、附加体、细菌人工染色体、酵母人工染色体、噬菌体或病毒载体,并且此类载体可以整合至宿主的基因组中或在特定细胞中自主复制。载体可以是DNA或RNA载体。还可以使用本领域技术人员已知的具有等效功能的其他形式的表达载体,例如自我复制的染色体外载体或整合到宿主基因组中的载体。优选的载体是能够自主复制和/或表达它们所连接的核酸的那些载体。能够指导与其可操作地连接的基因的表达的载体在本文中称为“表达载体”。表达载体可导致DNA的稳定或瞬时表达。用于本公开的示例性表达载体是pcDNA3.1。
在一些示例中,编码AMH类似物的核酸作为病毒载体施用。此类病毒载体适用于例如US5,399,346中所述的基因疗法。可以通过本领域已知的方式促进进入到细胞中,诸如在载体中提供多核苷酸或通过将多核苷酸包封在脂质体中。
可使用与真核细胞相当的表达载体产生重组构建体,以用于表达如本文所述的AMH类似物。真核细胞表达载体在本领域中是已知的并且可从商业来源获得。此类载体通常设置有用于插入DNA的限制位点。这些载体可以是病毒载体,例如腺病毒、腺相关病毒、痘病毒(诸如正痘病毒(例如牛痘病毒)、禽痘病毒)、慢病毒或鼠马洛尼白血病病毒(murineMaloney leukemia virus)。
在一些示例中,可以使用质粒表达载体。质粒表达载体包括pcDNA3.1、pET载体、pGEX载体和pMAL载体,用于在大肠杆菌宿主细胞中的蛋白质表达,例如BL21、AD494(DE3)pLys、Rosetta(DE3)、Origami(DE3)和pCIneo。
在一些示例中,载体是复制缺陷的(replication incompetent)腺病毒载体,例如,pAdeno X、pAd5F35、pLP-Adeno-X-CMVpAd/CMV/V5-DEST、pAd-DEST载体(InvitrogenTMInc.)。
可用于本发明的病毒载体系统包括但不限于:(a)腺病毒载体;(b)逆转录病毒载体;(c)腺相关病毒载体;(d)单纯疱疹病毒载体;(e)SV 40载体;(f)多瘤病毒载体;(g)乳头状瘤病毒载体;(h)小核糖核酸病毒载体;(i)痘病毒载体,诸如正痘病毒,例如牛痘病毒载体或禽痘病毒,例如金丝雀痘病毒或鸡痘病毒;(j)辅助病毒依赖性(helper-dependent)或空壳(gutless)腺病毒。在一个示例中,载体是腺病毒。复制缺陷型病毒也可能是有利的。
如本文所用,术语“腺相关病毒(AAV)载体”是指含有AAV载体基因组的AAV病毒颗粒(其继而包含本文提及的第一和第二表达盒)。合适的AAV载体是本领域技术人员已知的并且包括所有血清型的AAV载体,例如AAV-1至AAV-10,诸如优选地AAV-1(US 6,759,237)、AAV-2、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9及其组合。参见例如国际专利公开号WO02/33269、WO 02/386122(AAV8)和GenBank,以及如何改变此类序列以改正单态错误,例如AAV6.2、AAV6.1、AAV6.1.2、rh64R1和rh8R(参见例如WO 2006/110689,公开于2006年10月19日)。替代地,可以如本文所述修饰其他AAV序列,包括本领域技术人员使用已知技术(参见例如国际专利公开号WO 2005/033321和GenBank)或通过其他方式鉴定的那些。
载体可以并入或可以不并入细胞基因组中。如果需要,构建体可以包括病毒序列以用于转染。替代地,可以将构建体并入能够进行附加型复制的载体,例如EPV和EBV载体。
宿主细胞
用于表达AMH多肽的合适的宿主细胞来源于多细胞生物。无脊椎细胞的示例包括植物细胞和昆虫细胞。已鉴定了许多来自以下宿主的杆状病毒菌株和变体以及对应的容许昆虫宿主细胞:诸如草地夜蛾(Spodoptera frugiperda)(毛虫)、埃及伊蚊(Aedesaegypti)(蚊子)、白纹伊蚊(Aedes albopictus)(蚊子)、黑腹果蝇(Drosophilamelanogaster)(果蝇)以及家蚕(Bombyx mori)。用于转染的多种病毒株是公众可获得的,例如苜蓿银纹夜蛾(Autographa californica)NPV的L-I变体和家蚕NPV的Bm-5株,并且根据本发明,此类病毒可以用作本文的病毒,特别是用于转染草地贪夜蛾细胞。
可用的哺乳动物宿主细胞系的示例是:由SV40转化的猴肾CVl株系(COS-7,ATCCCRL 1651);人胚肾株系(293细胞或被亚克隆来在悬浮培养物中生长的293细胞,Graham等人,J.Gen Virol.36:59(1977));幼小仓鼠肾细胞(BHK,ATCC CCL 10);中国仓鼠卵巢细胞(CHO,Urlaub等人(1980)Proc.Natl.Acad.Sci USA 77:4216);小鼠塞尔托利细胞(sertolicell)(TM4,Mather(1980)Biol.Reprod.23:243-251);猴肾细胞(CVl ATCC CCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL 2);犬肾细胞(MDCK,ATCC CCL 34);水牛大鼠肝细胞(BRL 3A,ATCC CRL 1442);人肺细胞(W138,ATCCCCL 75);人肝细胞(Hep G2,HB 8065);小鼠乳腺肿瘤(MMT 060562,ATCC CCL51);TRI细胞(Mather等人(1982)Annals N.Y.Acad.Sci.383:44-68);MRC5细胞;FS4细胞;和PER.C6TM(Crucell NV)。
在某些示例中,本文所述的AMH类似物可通过本文所述或本领域技术人员已知的一种或多种纯化方法进行分离和/或纯化或基本上纯化。通常,纯度为至少90%,特别是95%,并且通常大于99%。
在某些实施方式中,从更广泛的属的一般描述排除天然存在的化合物。
测量AMH类似物的活性
如本文所用,关于AMH类似物,术语“活性”是指类似物通过AMH受体复合物诱导信号传导的能力。本文所述的AMH类似物可具有与天然人AMH的活性相当或比其高的活性。在一些实施方式中,本文所述的AMH类似物可以能够以与天然人AMH引起的活化水平相当或比其高的水平活化AMHR2。在一些实施方式中,本文所述的AMH类似物可以能够以与天然人AMH引起的活化水平相当或比其高的水平活化AMHR1。在一些实施方式中,本文所述的AMH类似物可以能够以与天然人AMH引起的活化水平相当或比其高的水平活化SMAD1/5(例如,诱导SMAD1/5的磷酸化)。AMH类似物的活性可以使用本领域技术人员已知的技术来确定。例如,在一些实施方式中,通过测量用AMH类似物治疗后的Smad-1/5应答来测量活性。在一些实施方式中,AMH类似物的活性可以使用如本文所述的荧光素酶测定来确定。简而言之,用Smad1/5应答性BRE-荧光素酶报告基因和AMHR2转染COV434细胞。转染后二十四(24)小时,用一系列浓度的AMH类似物处理细胞过夜。在加入底物D-荧光素后立即收获、裂解细胞并测量发光。将荧光素酶活性分析为与基线活性有关的倍数变化。
AMH类似物的治疗用途
本文所述的AMH类似物可用于卵巢和/或子宫保护。如本文所用,“卵巢保护”是指针对由于创伤、损伤或外源剂(例如,治疗剂或治疗)的作用而对一个或两个卵巢造成有害或不利影响的保护。在一些实施方式中,外源剂可以是化学治疗剂或细胞毒性剂。“卵巢保护”还可以指针对卵巢的任何侵害或创伤(例如,移植或损伤)的保护。卵巢保护可以指对一个或两个卵巢的保护。“卵巢保护”是指保护卵巢的功能(例如,产生生殖激素,维持适当促卵泡激素水平或产生卵泡)和卵巢的组织学(例如,大小和组织健康)。施用治疗剂或治疗之后,与所述施用前的卵巢功能相比,卵巢保护维持至少99%、至少95%、至少90%、至少80%、至少70%、至少60%、至少50%、至少40%、至少30%、至少20%、至少10%的卵巢功能。卵巢保护还涵盖由于癌症治疗期间的损伤而对卵巢的保护。
本文所述的AMH类似物还可用于减少卵泡生成,并且因此有助于卵巢保护。卵泡生成是含有未成熟卵母细胞的卵巢卵泡的成熟,并且是作为月经周期的一部分的许多小原始卵泡向大排卵前卵泡的进展。原始卵泡或应答于激素提示的原始卵泡的耗竭标志着绝经期的开始。通过减少卵泡生成,原始卵泡得以保存。与不存在AMH类似物的情况相比,卵巢保护可以减少女性受试者的卵泡生成,或减少募集的原始卵泡的数目至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少99%或更多。
在一些示例中,卵巢保护可以是对卵巢早衰的抑制。如本文所用,“卵巢早衰”是指卵巢功能在40岁之前停止。临床上,卵巢早衰是通过血液中高水平的促卵泡激素和促黄体激素来诊断的。卵巢早衰的原因包括但不限于化学疗法、放射疗法、自身免疫疾病、甲状腺疾病、糖尿病和手术诱导的绝经(例如,子宫切除术或卵巢切除术)。卵巢保护还可以涵盖保护女性生殖系统免受癌症治疗方案诸如化学疗法和放射疗法或其他人为损伤侵害诸如细胞毒性因子、激素剥夺、生长因子剥夺、细胞因子剥夺、细胞受体抗体等的方法。其他侵害包括手术侵害,其中女性的生殖系统部分或全部被手术去除。特别地,由去除一个卵巢导致的激素失衡通过施用本文所述的AMH类似物完全或部分恢复。
本文所述的AMH类似物也可用于子宫保护。如本文所用,“子宫保护”是指针对由治疗剂或治疗(例如,化学治疗剂或细胞毒性剂)引起的对子宫的有害或不利影响的保护。“子宫保护”是指保护子宫的功能(例如,胚胎着床、胎盘发育和怀孕至足月的能力(例如,没有流产或早产))和子宫的组织学(例如,子宫内膜健康)。“子宫保护”还可以指针对卵巢的任何侵害(例如,手术(例如剖腹产)或损伤)的保护。施用治疗剂或治疗之后,与所述施用前的子宫功能相比,子宫保护维持至少99%、至少95%、至少90%、至少80%、至少70%、至少60%、至少50%、至少40%、至少30%、至少20%、至少10%的子宫功能。子宫保护可以是子宫内膜增加。子宫内膜薄可能阻碍胚胎着床至子宫内膜的能力。可使用非侵入式成像(例如盆腔超声或声波图)评估受试者子宫内膜的厚度。在月经期间,子宫内膜为2-4mm;小于2mm指示子宫内膜薄。
子宫保护可以抑制或降低女性受试者子宫内膜异位症的可能性。子宫内膜异位症是导致子宫内膜在子宫外,例如,在生殖器官(例如,卵巢、输卵管或子宫周围的组织)上生长的病状。子宫内膜异位症阻碍卵巢、输卵管或子宫的功能,并且可能导致不孕症。子宫保护可以降低怀孕诱导的高血压或先兆子痫的发生率或风险。
本文所述的AMH类似物可用于避孕,意指它暂停了受孕的能力并因此暂停了怀孕的能力或者降低了受孕的可能性并因此降低了怀孕的可能性。向女性受试者施用AMH类似物允许所述女性控制月经周期和生殖激素分泌,并减慢或防止原始卵泡募集和/或活化(例如,施用AMH类似物使月经周期停止)。
可以施用本文所述的AMH类似物以防止女性受试者的功能性卵巢储备(FOR)下降或减少卵泡生成。受试者的年龄可以在15岁与55岁之间,并且将或正在用选自免疫疗法、细胞疗法、化学疗法、放射疗法或化学放射疗法的治疗进行治疗。受试者可能患有癌症或自身免疫疾病。受试者将或正在接受用细胞毒性药物的治疗。减少女性受试者的卵泡生成可以是与不存在AMH类似物的情况相比,募集的原始卵泡的数目减少至少10%,或募集的原始卵泡的数目减少10%至99%,或者与不存在AMH类似物的情况相比,卵泡生成完全停止。
本文所述的AMH类似物可用于治疗癌症,例如表达AMH受体的癌症或AMHR2应答性癌症。在一些实施方式中,癌症表达AMHR2。在一些实施方式中,癌症是AMHR2应答性癌症。在一些实施方式中,本文所述的AMH类似物可用于治疗妇科癌症。如本文所用,“妇科癌症”是指女性生殖系统的癌症,例如宫颈癌、输卵管癌、卵巢癌、胎盘癌、子宫癌、子宫内膜癌、阴道癌和外阴癌。在一些实施方式中,妇科癌症选自由子宫癌、卵巢癌和宫颈癌组成的组。在一些实施方式中,妇科癌症是卵巢癌或包含卵巢癌细胞。在一些实施方式中,妇科癌症是子宫内膜癌或包含子宫内膜癌细胞。在一些实施方式中,受试者将或正在用另外的剂或癌症疗法治疗。在一些示例中,受试者将或正在用选自化学疗法、放射疗法、免疫疗法、细胞疗法或化学放射疗法的治疗进行治疗。在一些示例中,受试者将或正在接受用细胞毒性药物的治疗。在一些实施方式中,AMH受体(例如,AMHR2)的表达在从受试者获得的生物样品中测量,例如癌症或肿瘤组织样品或癌细胞或肿瘤细胞,例如活检组织样品。
AMH类似物的施用
施用治疗有效量或剂量的本文所述的AMH类似物或多核苷酸或组合物以例如停止卵泡生成。例如,有效量是AMH类似物、或编码它的核酸、或编码其前体的核酸与不施用组合物时相比减少募集的原始卵泡的数目至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少99%的量。当向女性受试者施用的包含AMH类似物、或编码它的核酸、或编码其前体的核酸的组合物的量足以将募集的原始卵泡的数目减少至所需数目,或将募集的原始卵泡的概率降低至所需值时,所述量被视为有效。在一些示例中,施用的组合物的量足以实现避孕。
本文所述的组合物可以一次性或分成亚剂量施用。
在一些示例中,施用可以是长期的,例如,在数周或数月的时间段内每天一次或多次剂量和/或治疗。给药和/或治疗排程的示例为在1周、2周、3周、4周、1个月、2个月、3个月、4个月、5个月或6个月或更长时间的一段时间内每天、每天两次、每天三次或每天四次或更多次施用。剂量不应太大而引起不良的副作用。
本公开设想了向受试者的短期或长期施用。短期施用的示例是为保护卵巢免受辐射或化学侵害或如本文所述的癌症治疗的施用。在短期施用中,在即将暴露于侵害之前约三十天的时间段内,施用组合物至少一次。
在更长时间和连续施用中可能需要更低剂量的AMH类似物。
在一些示例中,向受试者的施用可以是体内的。体内施用涵盖口服施用、血管内施用、腹膜内施用、子宫内施用、卵巢内施用、皮下施用、肌肉内施用、直肠施用、外用(粉末、软膏、滴剂、口腔、舌下)施用、阴道内施用、脑池内施用或其组合。在需要卵巢内施用的实施方式中,卵巢内施用可以通过几种方法实现,包括例如通过直接注射到卵巢中。
本文所述的其AMH类似物可通过本领域已知或本文所述的任何途径施用,例如口服施用、肠胃外(例如,静脉内或肌肉内)施用、腹膜内施用、直肠施用、经皮施用、经鼻施用、阴道施用、吸入施用、皮肤(贴剂)施用或眼部施用。AMH类似物可以任何剂量或给药方案施用。
在一些示例中,施用可能足以使卵巢维持在静止状态。
在一个示例中,可以将包含本文所述的AMH类似物的组合物施用于受试者约2周、或约3周、或约4周、或约5周、或超过5周,例如,约2个月、或约3个月、或约4个月、或约5个月、或约6个月或约7个月或更长时间,然后随后在适当的间隔后施用一段额外的时间,例如约2天、或约3天、或约4天、或约五天或超过五天。治疗周期可以紧接着或以在周期之间的不治疗的间隔而发生。通常,在向受试者施用包含如本文所述的AMH类似物的组合物以保存生育力(例如,在停止卵泡生成的方法中)的情况下,可以向受试者施用组合物约3-4个月之间的一段时间、或约4-6个月之间的一段时间、或约6-8个月之间的一段时间、或约8-12个月之间的一段时间、或约12-24个月之间的一段时间、或约24-36个月之间的一段时间或超过约36个月,随后是不递送的间隔。
在一些示例中,当在避孕方法中向受试者施用包含如本文所述的AMH类似物的组合物的情况下,可以向受试者施用组合物约3-4个月之间的一段时间、或约4-6个月之间的一段时间、或约6-8个月之间的一段时间、或约8-12个月之间的一段时间、或约12-24个月之间的一段时间、或约24-36个月之间的一段时间或超过约36个月,或长达受试者不期望怀孕的时间,随后是不递送的间隔。
在某些示例中,包含如本文所述的AMH类似物的组合物可以通过几乎任何方式施用,但在一些实施方式中,以注射剂(例如静脉内、皮下、动脉内)、输注或滴注的形式递送至受试者。在某些实施方式中,包含AMH类似物的组合物通过口服或阴道内施用递送至受试者。
在一些示例中,如本领域普通技术人员已知的,如本文所公开的AMH类似物可以例如使用包括水凝胶、阴道片剂、阴道药栓/栓剂、微粒系统和阴道环来阴道施用。
在一些实施方式中,优选在化疗治疗、免疫疗法、细胞毒性疗法、手术或放射治疗之前将AMH类似物施用于受试者。例如,在施用AMH类似物以实现卵巢和/或子宫保护、减少卵泡生成、抑制卵巢早衰、避孕或防止功能性卵巢储备(FOR)下降的情况下,优选在化疗治疗、免疫疗法、细胞毒性疗法、手术或放射治疗之前将AMH类似物施用于受试者。
在一些示例中,可以向女性受试者施用以下剂量的AMH类似物:13-45岁的女性:1至10ng/mL;45岁以上的女性:小于1ng/mL。剂量值可能根据例如女性的功能性卵巢储备、或卵巢老化的严重性、或待缓解的卵巢储备功能减退而有所不同。
AMH类似物的功效和毒性可通过标准医药程序在细胞培养物或实验动物中确定,例如ED50(其中在50%群体中有效的剂量)和LD50(50%群体致死的剂量)。毒性与治疗效果的剂量比是治疗指数,并且它可表示为比率LD50/ED50。
可以使用的适当的实验模型包括确定可以使用的剂量是缪勒氏管回归生物测定或本领域普通技术人员公知的体内癌症模型。体内癌症模型讨论于Frese等人,“Maximizing mouse cancer models”Nat Rev Cancer.2007年9月;7(9):645-58;以及Santos等人,Genetically modified mouse models in cancer studies.Clin TranslOncol.2008年12月;10(12):794-803;以及“Cancer stem cells in mouse models ofcancer”,6th Annual MDI Stem Cell Symposium,MDI Biological Lab,Salisbury Cove,ME,August 10-11,2007,所述参考文献以引用的方式整体并入本文。例如,可以在小鼠生育力模型中评估治疗有效量的重组人AMH多肽。
如果需要,本公开的组合物可以局部施用至需要治疗的区域(例如卵巢)。这可以例如通过手术期间的局部输注,外用应用,例如通过注射,通过导管,或通过植入物来实现,植入物是多孔、无孔或凝胶状材料,包括膜,诸如硅橡胶膜(sialastic membrane)、纤维或商业皮肤替代品。
还可以使用载体,例如病毒载体,通过本领域技术人员熟知的方法递送剂,例如编码AMH类似物的核酸剂。
在一些示例中,AMH类似物作为单一疗法施用。在一些示例中,AMH类似物与至少一种另外的治疗剂组合施用(例如,在其之前、期间和/或之后)(即共同施用)。例如,AMH类似物可以与化学治疗剂、抗肿瘤剂、放射或手术组合施用。术语“共同施用”指示在一个时间范围内施用至少两种化合物(一种是AMH类似物)中的每一种,其中生物活性或作用的相应周期重叠。因此,所述术语包括依次以及同延(coextensive)施用化合物。与施用化合物类似,多于一种物质的共同施用可以是出于治疗和/或预防目的。当共同施用多于一种物质或化合物时,两种或更多种物质的施用途径不需要相同。本文所述的方法和用途的范围不受可与AMH类似物共同施用的一种或多种物质的身份的限制。
在一些示例中,AMH类似物与检查点抑制剂组合施用。检查点抑制剂可以是与至少一种免疫检查点蛋白特异性结合的小分子、抑制性RNA/RNAi分子(单链和双链)、抗体、抗体试剂或其抗原结合片段。针对治疗剂的常见检查点包括但不限于PD-1、CTLA4、TIM3、LAG3和PD-Ll。
在一些示例中,AMH类似物与免疫疗法(例如,用于治疗自身免疫疾病的药物或剂)组合施用。
组合物
包含如本文所述的AMH类似物的组合物可以任何合适的方式配制,例如作为含有任何相容载剂的无菌注射溶液,载剂诸如各种载媒介物、助剂、添加剂和稀释剂。本公开中利用的化合物可以肠胃外施用于受试者,其形式为缓慢释放的皮下植入物或靶向递送系统诸如单克隆抗体、载体化(vectored)递送、离子电渗系统、聚合物基质、脂质体和微球体。
非水性媒介物诸如棉籽油、芝麻油、橄榄油、大豆油、玉米油、葵花油或花生油和酯诸如肉豆蔻酸异丙酯也可用作组合物的溶剂体系。另外,可以添加增强组合物的稳定性、无菌性和等渗性的各种添加剂,包括抗微生物防腐剂、抗氧化剂、螯合剂和缓冲剂。可以通过各种抗细菌和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚和山梨酸)来确保对微生物作用的预防。在许多情况下,需要包括等渗剂,例如,糖、氯化钠等。可以通过使用延迟吸收的试剂(例如单硬脂酸铝和明胶)实现可注射药物形式的延长吸收。
在一些示例中,组合物可以是基于脂质的制剂。示例包括可提供组合物的持续释放速率的多泡脂质体、多层脂质体和单层脂质体。
在一些示例中,本文所述方法中所用的组合物可以是控制释放形式。多种已知的控制释放或延长释放剂型、制剂和装置可以适于与本公开的组合物一起使用。示例包括美国专利号3,845,770、3,916,899、3,536,809、3,598,123、4,008,719、5674,533、5,059,595、5,591,767、5,120,548、5,073,543、5,639,476、5,354,556、5,733,566和6,365,185中所述的那些。这些剂型可用于使用例如不同比例的羟甲基纤维素、其他聚合物基质、凝胶、可渗透膜、渗透性系统(诸如(Alza Corporation,Mountain View,Calif.USA))或其组合提供所需释放特性以提供一种或多种活性成分的缓慢或控制释放。
在一个示例中,组合物在脂质体中递送(参见Langer(1990)Science 249:1527-1533)。
在一些示例中,包含如本文所述的AMH类似物的组合物可以与任何其他治疗剂结合(例如,组合)施用和/或配制。
本公开的药物组合物包含本公开的化合物和药学上可接受的载剂,其中所述化合物以有效治疗感兴趣的病状的量存在于组合物中。本领域技术人员可以容易地确定适当的浓度和剂量。
药学上可接受的载剂是本领域的技术人员熟悉的。对于配制成液体溶液的组合物,可接受的载剂包括盐水和无菌水,并且可以任选地包括抗氧化剂、缓冲剂、抑菌剂和其他常用添加剂。可用作药学上可接受的载剂的材料的一些示例包括但不限于:糖,诸如乳糖、葡萄糖和蔗糖;淀粉,诸如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉状黄蓍胶;麦芽;明胶;滑石粉;赋形剂,诸如可可脂和栓剂蜡;油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,诸如丙二醇;多元醇,诸如甘油、山梨醇、甘露醇和聚乙二醇;酯,诸如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,诸如氢氧化镁和氢氧化铝;海藻酸;无热原质的水;等渗盐水;林格氏溶液;乙醇;磷酸盐缓冲溶液;和其他用于药物制剂中的无毒相容物质。
组合物还可以配制成丸剂、胶囊、颗粒剂或片剂,除了本发明的化合物之外,其还含有稀释剂、分散剂和表面活性剂、粘合剂和润滑剂。本领域技术人员可以以适当的方式并根据公认的实践进一步配制本公开的化合物,实践诸如Remington's PharmaceuticalSciences,Gennaro编,Mack Publishing Co.,Easton,Pa.1990中公开的那些。
在一些示例中,润湿剂、乳化剂和润滑剂(诸如月桂基硫酸钠和硬脂酸镁)以及着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以存在于组合物中。药学上可接受的抗氧化剂的示例包括:水溶性抗氧化剂,诸如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;油溶性抗氧化剂,诸如抗坏血酸棕榈酸酯、丁基化羟基茴香醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和金属螯合剂,诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
“持续释放”、“控制释放”或类似术语是指以下制剂,其允许活性成分(例如,AMH类似物)随时间释放,并且用于维持活性成分在体内(例如,在血流中)的更一致的水平,并且是本领域中已知的。
本公开的制剂包括适合于静脉内、口服、鼻、外用、透皮、颊、舌下、直肠、阴道和/或肠胃外施用的那些。
适用于口服施用的本发明的制剂包括胶囊、扁囊剂、丸剂、片剂、口含锭(使用经调味的基底,通常是蔗糖和阿拉伯胶或黄蓍胶)、散剂、颗粒剂或作为在水性或非水性液体中的溶液或混悬液、或作为水包油或油包水液体乳剂、或作为酏剂或糖浆、或作为软锭剂(pastille)(使用惰性基底,诸如明胶和甘油,或蔗糖和阿拉伯胶)和/或作为漱口剂等,每种均含有预定量的本公开的化合物作为活性成分。
用于口服施用本公开的化合物的液体剂型包括药学上可接受的乳剂、微乳剂、溶液、混悬液、糖浆和酏剂。除活性成分之外,液体剂型可含有本领域中常用的惰性稀释剂,例如像,水或其他溶剂、增溶剂以及乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别是,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇以及脱水山梨醇的脂肪酸酯及其混合物。除惰性稀释剂之外,口服组合物还可包含助剂,诸如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、芳香剂和防腐剂。
组合物可以被配制用于直肠或阴道施用,例如作为栓剂,其可以通过将一种或多种本公开的化合物(例如,AMH类似物)与一种或多种合适的赋形剂或载剂(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备,并且其在室温下为固体但在体温下为液体,并且因此释放活性化合物。用于这种施用的合适的载剂和制剂是本领域中已知的。
用于如本文所述的重组人AMH多肽的外用或透皮施用(例如用于肌肉施用)的剂型包括散剂、喷雾剂、膏剂、糊剂、乳膏、洗剂、凝胶剂、溶液、贴剂和吸入剂。
透皮贴剂可以通过将化合物溶解或分散在适当的介质中来制备。还可以使用吸收促进剂以增加化合物跨越皮肤的通量。可以通过提供速率控制膜或将活性化合物分散在聚合物基质或凝胶中来控制这种通量的速率。
适合于肠胃外施用的药物组合物包含一种或多种本公开的化合物与一种或多种药学上可接受的无菌等渗水性溶液或非水性溶液、分散液、悬浮液或乳液、或可在临使用前重构成无菌可注射溶液或分散液的无菌粉末的组合,所述组合可以含有抗氧化剂、缓冲剂、抑菌剂、使制剂与预期接受者的血液等渗的溶质、或助悬剂或增稠剂。
这些组合物还可以含有助剂,诸如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等来确保对微生物作用的预防。还可能期望在组合物中包含等渗剂,诸如糖、氯化钠等。此外,可以通过包含延迟吸收的剂(诸如单硬脂酸铝和明胶)来实现可注射药物形式的延长吸收。
在某些示例中,药物组合物可以任选地还包含一种或多种额外的治疗剂。当然,本领域普通技术人员已知的此类治疗剂可以容易地由本领域普通技术人员鉴定。
在某些示例中,组合物可包含与靶向剂缀合或共价连接的AMH类似物,例如以增加组织特异性和对细胞(例如肌肉细胞)的靶向。靶向剂可以包括例如但不限于抗体、细胞因子和受体配体。
需要治疗的受试者
在一个示例中,施用本文所述的AMH类似物的受试者患有癌症并且将用化学疗法或抗癌剂治疗,或正在用其治疗,或已经用其治疗。癌症包括例如结肠癌、胰腺癌、乳腺癌、卵巢癌、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、软骨瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏肿瘤、平滑肌肉瘤、横纹肌肉瘤、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、髓质癌、支气管癌、肾细胞癌、肝瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、威耳姆氏肿瘤、宫颈癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病和急性髓细胞白血病、慢性白血病和真性红细胞增多症、淋巴瘤(霍奇金氏病和非霍奇金氏病)、多发性骨髓瘤、华氏巨球蛋白血症或免疫球蛋白重链疾病。癌症可以是原发性癌症或转移性癌症。
如本文所用,“抗癌剂”可以指具有治疗癌症的预期用途的任何治疗剂(例如,免疫检查点抑制剂、CAR T细胞或靶向疗法),其已显示对子宫和/或卵巢具有不利影响。对卵巢和/或子宫的损伤可以通过例如细胞死亡、组织缺陷或衰退的存在,或卵巢或子宫的异常功能(例如,激素分泌异常、卵泡生成增加或卵泡对激素刺激脱敏)来测量。
在一些示例中,本文所述的方法使女性受试者能够保留产生有活力的后代的能力和/或卵巢储备。在一些示例中,组合物的施用在女性受试者暴露于细胞毒剂或化学治疗剂之前终止,或者替代地与用细胞毒性剂或化学治疗剂的治疗或癌症治疗同时和/或在所述治疗之后。
在另一个示例中,施用本文所述的AMH类似物的受试者患有自身免疫疾病并且将用免疫疗法治疗,或正在用其治疗,或已经用其治疗。如本文所用,“自身免疫疾病或病症”的特征在于患者的免疫系统无法区分外来细胞与健康细胞。自身免疫疾病的非限制性示例包括卵巢炎、炎性关节炎、1型糖尿病、多发性硬化症、牛皮癣、炎性肠病、SLE、和血管炎、过敏性炎症(诸如过敏性哮喘、特应性皮炎和接触性过敏反应)、类风湿性关节炎、多发性硬化症(MS)、系统性红斑狼疮、格雷夫斯病(Graves'disease)(甲状腺功能亢进)、桥本甲状腺炎(Hashimoto's thyroiditis)(甲状腺活动不足)、慢性移植物抗宿主病、具有凝血因子抗体的血友病、乳糜泻、克罗恩病和溃疡性结肠炎、格林-巴利综合征、原发性胆汁性硬化/肝硬化、硬化性胆管炎、自身免疫性肝炎、雷诺现象、硬皮病、干燥综合征、古德帕斯综合征、韦格纳肉芽肿病、风湿性多肌痛、颞动脉炎/巨细胞动脉炎、慢性疲劳综合症(CFS)、牛皮癣、自身免疫性Addison病、强直性脊柱炎、急性播散性脑脊髓炎、抗磷脂抗体综合症、再生障碍性贫血、特发性血小板减少性紫癜、重症肌无力、眼阵挛-肌阵挛综合征、视神经炎、Ord甲状腺炎、天疱疮、恶性贫血、犬多发性关节炎、赖特综合征、多发性大动脉炎、温抗体型自身免疫性溶血性贫血、韦格纳肉芽肿病和纤维肌痛(FM)。
在一个示例中,女性受试者将用导致子宫或卵巢中的细胞死亡或细胞损伤的细胞毒性药物或细胞毒性剂治疗,或目前正用其治疗,或已经用其治疗。
在一个示例中,女性受试者将用长期治疗方案(即针对慢性病状、慢性病状的复发、人免疫缺陷病毒(HIV)、病毒性肝炎、病毒性或细菌性脑膜炎、疟疾或神经退化性疾病的治疗)治疗,或目前正用其治疗,或已经用其治疗。在一个示例中,女性受试者将用不导致对子宫和/或卵巢的损伤的长期治疗方案治疗,或目前正用其治疗,或已经用其治疗。例如,正在接受人免疫缺陷病毒(HIV)治疗的受试者可能希望延迟或减缓原始卵泡募集的募集和/或活化,或保存其生育力。受试者可能希望在长期治疗期间保存她的生育力和/或预防怀孕,其原因包括但不限于因为所施用的治疗剂对胎儿有不利影响,或者由于治疗的副作用(例如,疲劳或恶心),在治疗期间怀孕不是理想的。
在一些示例中,女性受试者可能希望在治疗期间出于除卵巢或子宫保护以外的原因而保存其生育力。由于许多不同的生活方式因素,女性对象可能希望延迟怀孕。在一些示例中,向女性受试者施用本文所述的AMH类似物以保存生育力,并且其不进行额外治疗或接受额外疗法。如本文所用,“生育力保存”是指例如在向患者首次施用AMH类似物时,使受试者的生育力潜能(基于例如卵子的年龄、月经周期的规律、卵巢储备、卵巢功能、卵巢激素分泌的因素的怀孕的可能性)维持在现有状态。“生育力保存”可以指延长生育力超出其自然限度,例如,过生育年龄。“生育力保存”可以指在施用AMH类似物之前维持受试者卵巢中存在的相同数目的原始卵泡。可以将AMH类似物施用于女性受试者以抑制与年龄相关的生育力下降。“与年龄相关的生育力下降”是指由于女性年龄而受孕的可能性降低。女性怀孕的峰值生物学年龄是青少年晚期和二十岁初期;不孕率随着女性年龄的增长而增加。
在一些示例中,如果女性受试者具有或先倾向于卵巢储备功能减退(DOR)、卵巢早衰(POA)、原发性卵巢功能不全(POI)、子宫内膜异位症、一个或多个FMR1前突变或55-200个GCC FMR1重复、BRAC1突变、特纳综合征、自身免疫疾病、卵巢自身免疫疾病(例如,卵巢炎)、甲状腺自身免疫、肾上腺自身免疫或自身免疫多腺综合征,则所述受试者可能希望延迟或减慢原始卵泡募集的募集或保存其生育力。
在一些示例中,AMH类似物在受试者中用作避孕药。因此,本公开还提供了一种避孕方法,其包括向受试者施用本文所述的AMH类似物。在一个示例中,受试者正进行化学疗法。在另一个示例中,避孕药包含在腺病毒载体内编码如本文所述的AMH类似物的多核苷酸。
试剂盒
本公开还提供一种用于本文所述的任何方法的试剂盒,所述试剂盒包括泵或输注装置(其含有本文所述的重组AMH多肽)和用于将泵或输注装置植入女性受试者中以治疗受试者的说明书。
在一个示例中,需要治疗的女性受试者具有卵巢储备功能减退(DOR)、卵巢早衰(POA)、原发性卵巢功能不全(POI)、子宫内膜异位症、一个或多个FMR1前突变或55-200个GCC FMR1重复中的一种或多种,或其中受试者正进行,已进行或将进行癌症治疗。
试剂盒是包含至少一种试剂(例如AMH类似物)的任何制造品(例如,包装或容器),所述制造品作为用于执行本文所述方法的单元被推广、分配或销售。
本文所述的试剂盒可以任选地包含可用于进行本文所述方法的附加组分。举例来说,试剂盒可以包括适合于包含如本文所述的AMH类似物的组合物的流体(例如,缓冲液)、描述如本文所述的方法的进行的说明材料等。试剂盒可以还包括用于递送如本文所述的组合物的装置和/或试剂。另外,试剂盒可以包括说明书和/或可以提供关于所获得的结果的相关性的信息。
本领域技术人员应当理解,在不脱离本公开的广泛总体范围的情况下,可以对上述实施方式进行各种变化和/或修改。因此,本发明的实施方式在所有方面都被认为是说明性的而非限制性的。
实施例
方法
AMH cDNA来源和定点诱变
包含在哺乳动物表达载体pcDNA3.1中的编码全长人抗缪勒氏管激素(hAMH)的修饰形式的cDNA序列由Dr Axel Themmen(Erasmus University,The Netherlands)友情提供,并且之前已由他的实验室描述(Weenen C等人(2004)Molecular Human Reproduction10(2):77-83)。简而言之,对hAMH cDNA的修饰是在Glu29之后插入His-6纯化标签。另外,前结构域的3'末端的蛋白水解加工位点已被取代为‘RARR’以增强蛋白质成熟(本文称为质粒hAMH)。
通过重叠延伸PCR对hAMH进行了另外两种修饰,然后将修饰的cDNA亚克隆到限制位点NotI与HindIII之间的pCDNA3.1(-)(Thermo Fisher Scientific,Waltham,MA)中。第一个修饰是通过将蛋白水解加工位点修饰为理论上理想的‘ISSRKKRSVSS’超切基序来进一步增强蛋白质成熟(Duckert,Brunak和Blom(2004)Protein Engineering Design&Selection 17(1):107-112)。在Gly447与Ser452的序列之间插入超切cDNA序列,并替换‘RARR’残基(本文称为质粒hAMH+SCUT)。先前已报道用人血清白蛋白前导序列替换hAMH前导序列(前25个氨基酸)以增强哺乳动物细胞系的hAMH的重组生产(Peepin D等人(2013)Technology 1(1):63-71)。因此,hAMH+SCUT cDNA被进一步修饰成用大鼠血清白蛋白(RSA)信号肽序列‘MKWVTFLLLLFISGSAFS’(本文称为hAMH+SCUT+RSA)替换His-6标签的氨基酸N末端(残基MRDLPLTSLA LVLSALGALL GTEALRAEE)。随后将hAMH+SCUT+RSA质粒用作进一步修饰的模板,所述修饰是根据制造商的说明书,使用QuikChange Lightning定点诱变试剂盒(Agilent Technologies,Santa Clara,CA)进行的。对于生成的每个构建体,整个cDNA盒由Micromon基因组学设施(Monash University,Clayton,VIC)进行的DNA测序确认。
重组AMH蛋白的表达和纯化
通过使用聚乙烯亚胺(PEI)-MAX(线性;MW 40,000)(Polysciences,Warrington,PA)瞬时转染HEK-293T细胞产生重组AMH蛋白。对于小规模产生以评估所分泌的分子形式,将细胞在补充有10%胎牛血清(FCS)的杜氏改良伊格尔培养基(Dulbecco's modifiedEagle medium,DMEM)中以8×105个细胞/孔铺板在涂有聚D-赖氨酸(Sigma-Aldrich)的6孔板中并在37℃下于5%CO2中孵育。过夜孵育后,将培养基更换为OPTI-MEM(LifeTechnologies,Carlsbad,CA)培养基。然后将质粒DNA(5μg/孔)与PEI-MAX合并10分钟。将DNA-PEI复合物直接添加到细胞中,并在37℃下于5%CO2中在OPTI-MEM培养基中孵育4小时,然后用新鲜的OPTI-MEM培养基替换并在再孵育90小时,然后收集。
分泌后,AMH前结构域和成熟结构域非共价缔合为成熟前复合物(Pepinsky等人(1988)Journal of Biological Chemistry 263(35):18961-18964)。因此,纯化策略针对位于前结构域N末端的聚组氨酸标签。这种方法允许在没有加标签的情况下纯化负责激素生物活性的成熟结构域。在纯化之前,首先使用与上述类似的方法进行更大规模的生产(200mL)。简而言之,将10×106个细胞/板在补充有10%FCS的DMEM中接种到涂有聚-D-赖氨酸的15cm板上并在37℃下于5%CO2中孵育。过夜孵育后,将培养基更换为OPTI-MEM培养基。将质粒DNA(60μgDNA/板)与PEI-MAX合并10分钟。将DNA-PEI复合物直接添加到细胞中,并在37℃下于5%CO2中在OPTI-MEM培养基中孵育4小时,然后用新鲜的含有0.02%牛血清白蛋白(BSA)的OPTI-MEM培养基替换并在孵育90小时,然后收集。
通过离心(Centricon Plus-70,5kDa MW截止;Millipore,Billerica,MA)将含有重组蛋白的条件培养基汇集并浓缩(两次,以确保有效的缓冲液交换)至约1mL,然后重新悬浮于结合缓冲液[50mM磷酸盐缓冲液中,300mM NaCl,pH7.4]中至终体积5mL。通过在室温下于含有约0.5mL HisPurTM钴树脂(Thermo Fisher Scientific)的柱中滚动约2.5小时,对浓缩培养基进行钴基固定化金属亲和色谱(Co-IMAC)。洗脱前,将珠子用4mL结合缓冲液洗涤两次。通过在室温下于3mL洗脱缓冲液[50mM磷酸盐缓冲液、300mM NaCl、500mM咪唑]中滚动约2.5小时来洗脱结合的蛋白质。为了洗脱任何仍结合的蛋白质,将HisPurTM钴树脂在室温下于3mL 1M咪唑[50mM磷酸盐缓冲液,300mM NaCl、1M咪唑]中滚动约1小时。根据制造商的指南,使用2mL 3.5K MW截止Slide-A-MINI渗析装置(Thermo FisherScientific),通过渗析从纯化的蛋白质中去除咪唑。用杜氏磷酸盐缓冲盐水(LifeTechnologies)进行缓冲液交换。纯化的蛋白质在-80℃下储存在Protein LoBind管(Eppendorf,Hamburg,Germany)中。
通过蛋白质印迹的AMH蛋白分析
使用蛋白质印迹评估分泌到条件培养基中的AMH的分子形式,并在Co-IMAC和渗析后提供质量估计结果。简而言之,将条件培养基用Nanosep微浓缩器浓缩12.5倍(3kDa MW截止;Pall Life Sciences,Port Washington,NY),同时Co-IMAC级分不需要进一步浓缩。用2XLDS样品缓冲液(Life Technologies)+5%2-巯基乙醇(Bio-Rad,Hercules,CA)制备样品。
将制备的样品在沸水(约95℃)中加热约3分钟。将蛋白质在具有顶部运行缓冲液[3.5mM SDS,100mM tricine、100mM碱(Sigma-Aldrich)]和底部电泳缓冲液[pH8.9,200mM碱]的在垂直电泳槽(Bio-Rad)中运行的10%手灌胶(handcast)十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)凝胶中分离。此单元在80伏下运行,直到染料前沿到达分离凝胶并形成一条均匀的线,然后将电压增加到150伏并运行,直到染料前沿从凝胶底部流出。在通过SDS-PAGE分离之后,将凝胶抵靠0.45μM硝酸纤维素膜(Bio-Rad)放置,并一起组装到充满蛋白质转移缓冲液[10%甲醇,200mM甘氨酸,25mM碱]的Mini槽(Bio-Rad)中。转移单元在100伏下运行至少1小时。转移后,将膜置于封闭溶液[1%BSA (Sigma-Aldrich),在tris缓冲盐水(TBS)[pH 7.5,25mM碱,250mM NaCl]+0.05%20(Sigma-Aldrich)中]至少1小时,然后在摇动的同时用一抗(在封闭溶液中稀释1:5000)探测过夜。在室温下与一抗孵育过夜后,将膜用[pH 7.5,25mM碱,250mM NaCl+0.05%20]洗涤3次,每次洗涤5分钟,然后用TBS洗涤5分钟,洗涤两次。随后在室温下将其与辣根过氧化物酶缀合的抗小鼠IgG(GE Healthcare,Buckinghamshire,UK)二抗(在封闭溶液中1:10,000稀释)孵育1小时。显影前,如上详述将膜再洗涤五次。通过加入1mL Lumi-Light鲁米诺/增强剂溶液(Roche,Basel,Switzerland),然后加入1mL Lumi-Light稳定过氧化物溶液(Roche)来进行膜显影。化学发光显影的图像由ChemiDocTM(Bio-Rad)捕捉并用Image LabTM软件(Bio-Rad)分析。
为了检测成熟AMH蛋白,用mAb-5/6A(Oxford Brookes University,Oxford,UK)探测膜。将mAb-5/6A升至32个氨基酸的肽(VPTAYAGKLLISLSEERISAHH VPNMVATECG,hAMH中的氨基酸527-558),对应于朝向hAMH成熟结构域的C末端的区(Weenen等人(2004)MolecularHuman Reproduction 10(2):77-83)。为了检测人AMH前结构域,用mAb-9/6A(OxfordBrookes University)探测膜。mAb-9/6A通过针对整个hAMH蛋白对小鼠进行免疫而显影。mAb-9/6A先前被报道特异性检测加工的hAMH前结构域,并且最初被其开发人员选择作为AMH ELISA的检测抗体(Al-Qahtani等人(2005)Clinical Endocrinology 63(3):267-273)。
为了评估分子量大小,使用了预染色的蛋白质标准品SeeBlue Plus2(LifeTechnologies)。使用可商购获得的重组hAMH成熟结构域(R&D Systems,Minneapolis,Minnesota)作为标准品来确定浓度估计结果。将一系列五种质量标准品与四种不同体积的纯化材料一起使用,并且将四种体积的平均浓度用作实际浓度的估计结果。在AMH突变体A546M和H548K的情况下,mAb-5/6A识别的表位被破坏。因此,检测和随后的浓度估计结果通过用mAb-9/6A探测膜并评估处理的前结构域相对于先前定量的成熟前AMH制备物的光密度测定来确定。
用COV434细胞的体外转录报告基因测定
颗粒细胞是卵巢内的AMH靶标(Pepin,Sabatini&Donahoe(2018)Current Opinionin Endocrinology Diabetes and Obesity 25(6):399-405),其中AMH活性通过Smad-1/5信号传导在细胞内介导(Sedes L等人(2013)PLoS One 8(11):13)。COV434细胞是永生化人颗粒细胞系(Zhang H等人(2000)Molecular Human Reproduction 6(2):146-153),其先前被报道不内源表达AMH(Weenen C等人(2004)Molecular Human Reproduction 10(2):77-83),允许它们用作人颗粒细胞模型,以用于评估AMH活性,而不受内源AMH的干扰。此实验室(Al-Musawi SL等人(2013)Endocrinology 154(2):888-899;Patino LC等人(2017)Journal of Clinical Endocrinology&metabolism 102(3):1009-1019)和其他实验室(Moore,Otsuka&Shimasaki(2003)Journal of Biological Chemistry 278(1):304-310;Peng J等人(2013)PNAS 110(8):E776-E785)先前报道了COV434细胞在用BMP配体处理之后显示出稳健的Smad-1/5应答。因此,为了评估本研究期间生成的Co-IMAC纯化的AMH蛋白对Smad-1/5通路的活化,在COV434细胞中使用了Smad1/5应答性BRE-荧光素酶测定。这涉及BRE-Luc的瞬时转染,其为含有在启动子下游的荧光素酶基因以及分离自Id1基因启动子的BMP应答元件的两个拷贝的质粒(Korchynskyi和ten Dijke(2002)JBC 277(7):4883-4891)。另外,为了确保细胞对AMH有应答,将细胞与少量用于AMH特异性II型受体AMHR2的质粒共转染(Imbeaud S等人(1995)Nature Genetics 11(4):382-388)。
简而言之,将细胞于DMEM/10%FCS中以7.5×104个细胞/孔铺板到涂有聚-D-赖氨酸的48孔板上并在37℃下于5%CO2中生长过夜。第二天,用250ng/孔由248.44ng pBRE-Luc和1.56ng pAMHR2(GenScript HK Limited,Hong Kong;目录号:OHu22327D;NM_020547)组成的质粒DNA转染细胞。根据制造商的说明书,将质粒DNA与Lipofectamine 3000(LifeTechnologies)合并,然后直接加入到细胞中并在37℃下于5%CO2中孵育24小时。第二天,将转染的COV434细胞用在低血清培养基[具有50mM HEPES和0.2%FCS的DMEM]中稀释的一系列剂量的AMH变体处理。这是通过从细胞中去除转染培养基并替换为每孔200μL处理培养基来实现的。然后将细胞在处理培养基中在37℃中于5%CO2下孵育过夜,每个剂量测试至少一式三份。为了评估荧光素酶蛋白的表达,去除培养基并在在冰上摇动20分钟的同时,在溶解缓冲液[26m双甘氨肽(pH 7.8),16mM MgSO4,4mM EGTA,900μM二硫苏糖醇,1%TritonX-100]中溶解细胞。将溶解产物转移到白色96孔板中。通过在加入含有底物D-虫荧光素的混合物[25mM双甘氨肽(pH 7.8),15mM MgSO4,4mM EGTA,1mM二硫苏糖醇,1.5mM ATP,0.5mMD-虫荧光素(Life Technologies)]后,立即使用CLARIOstar微板读数器(BMG Labtech,Ortenberg,Germany)评估荧光素酶表达。荧光素酶活性以相对于基线活性的倍数变化分析(Chand AL等人(2007)Human Reproduction 22(12):3241-3248)。
实施例1 AMH蛋白序列和修饰
天然人AMH蛋白的序列可从GenBank以标识符AAH49194.1获得。以下提供了此序列。
25个氨基酸的信号序列用下划线指示。蛋白水解加工位点以粗体指示。
野生型小鼠AMH蛋白序列的序列可从GenBank以标识符NP_031471.2获得。以下提供了此序列。
信号序列用下划线指示。
人和小鼠AMH序列共有73%同一性。
hAMH+SCUT+RSA修饰
如方法中所述修饰野生型人AMH序列以掺入His6标签、超切前结构域裂解位点和RSA信号肽。此蛋白质命名为hAMH+SCUT+RSA并且蛋白质序列提供于以下。
信号序列用下划线指示。His6标签用阴影突出显示。蛋白水解加工位点以粗体指示。SEQ ID NO:3中定义的hAMH+SCUT+RSA的加工产生具有SEQ ID NO:36中提供的序列的成熟AMH。
对应的核酸序列提供于以下:
atgaagtgggtaacctttctcctcctcctcttcatctccggttctgccttttcccatcatcatcatcatcatccagctgtgggcaccagtggcctcatcttccgagaagacttggactggcctccaggcagcccacaagagcctctgtgcctggtggcactgggcggggacagcaatggcagcagctcccccctgcgggtggtgggggctctaagcgcctatgagcaggccttcctgggggctgtgcagagggcccgctggggcccccgagacctggccaccttcggggtctgcaacaccggtgacaggcaggctgccttgccctctctacggcggctgggggcctggctgcaggaccctggggggcagcgcctggtggtcctacacctggaggaagtgacctgggagccaacaccctcgctgaggttccaggagcccccgcctggaggagctggccccccagagctggcgctgctggtgctgtaccctgggcctggccctgaggtcactgtgacgagggctgggctgccaggtgcccagagcctctgcccctcccgagacacccgctacctggtgttagcggtggaccgccctgcgggggcctggcgcggctccgggctggccttgaccctgcagccccgcggagaggactcccggctgagtaccgcccggctgcaggcactgctgttcggcgacgaccaccgctgcttcacacggatgaccccggccctgctcctgctgccgcggtccgagcccgcgccgctgcctgcgcacggccagctggacaccgtgcccttcccgccgcccaggccatccgcggaactggaggagtcgccacccagcgcagaccccttcctggagacgctcacgcgcctggtgcgggcgctgcgggtccccccggcccgggcctccgcgccgcgcctggccctggatccggacgcgctggccggcttcccgcagggcctagtcaacctgtcggaccccgcggcgctggagcgcctactcgacggcgaggagccgctgctgctgctgctgaggcccactgcggccaccaccggggatcctgcgcccctgcacgaccccacgtcggcgccgtgggccacggccctggcgcgccgcgtggctgctgaactgcaagcggcggctgccgagctgcgaagcctcccgggtctgcctccggccacagccccgctgctggcgcgcctgctcgcgctctgtccaggaggccccggcggcctcggcgatcccctgcgagcgctgctgctcctgaaggcgctgcagggcctgcgcgtggagtggcgcgggcgggatccgcgcgggccgggtatctcatcgagaaagaaacgctcagtctcatcaagcgcgggggccaccgccgccgacgggccgtgcgcgctgcgcgagctcagcgtagacctccgcgccgagcgctccgtactcatccccgagacctaccaggccaacaattgccagggcgtgtgcggctggcctcagtccgaccgcaacccgcgctacggcaaccacgtggtgctgctgctgaagatgcaggcccgtggggccgccctggcgcgcccaccctgctgcgtgcccaccgcctacgcgggcaagctgctcatcagcctgtcggaggagcgcatcagcgcgcaccacgtgcccaacatggtggccaccgagtgtggctgccggtaa(SEQ ID NO:4)
实施例2重组AMH蛋白表达
通过重叠延伸PCR对hAMH cDNA进行修饰,目的是改善前体加工和蛋白质分泌。为了评估是否达到了预期的结果,用含有修饰的hAMH cDNA的修饰表达载体(分别为hAMH+SCUT和hAMH+SCUT+RSA)瞬时转染HEK-293T细胞。
通过蛋白质印迹,用mAb-5/6A(图2)分析浓缩且还原的条件培养基,检测到12.5kDa单体AMH成熟结构域和70kDa单体AMH前体(图2;泳道4)。含有超切(SCUT)修饰的AMH变体显示出改善的前体加工,如通过在同一样品内相对于12.5kDa成熟形式,微弱地检测出70kDa前体形式所定性判断(图2;泳道5)。将含有SCUT修饰和RSA信号肽的hAMH形式(图2;泳道6)用作随后靶向潜在受体结合表位的突变的模板。
实施例3靶向hAMH的潜在受体结合表位的突变
转化生长因子-β(TGF-β)超家族配体与其受体复合的结构先前已针对许多超家族成员进行了报道(Hinck,Mueller&Springer(2016)Cold Spring harbor Perspectives inBiology 8(12):51)。使用这些报道的结构和蛋白质序列同源性作为指导,发明人试图鉴定出hAMH内介导与其II型受体AMHR2的独特相互作用的氨基酸。为此目的,使用体外定点诱变来产生许多hAMH突变体表达载体队列。
队列一hAMH突变体
最初(图3),生成了G533A和L535A突变体。G533和L535在成熟的天然hAMH序列中以粗体和下划线指示。
L535A突变体分泌不良(数据未显示)。因此,发明人生成了更保守的突变L535M,以尝试并评估此氨基酸的作用(图4)。
队列二hAMH突变体
在第二个队列(图4)中,生成了以下突变体:G533S和双突变体G533A+L535M。
队列三hAMH突变体
在第三个队列(图5)中,生成了以下突变体:G533H、G533K、G533R和G533L。G533L突变体不分泌,而G533R突变体分泌不良,因此未确定这两个突变体的活性。
队列四hAMH突变体
在第四个队列(图6)中,生成了H548K突变体。
实施例4重组AMH蛋白的纯化
为了纯化AMH,使用了HisPurTM钴树脂,其靶向位于AMH前结构域N末端的聚组氨酸标签。这种方法允许在没有加标签的情况下纯化负责激素生物活性的成熟结构域。简而言之,在浓缩200mL条件培养基并与树脂一起孵育约2.5小时后,收集未结合的蛋白质并用PBS洗涤树脂两次以去除任何松散结合的蛋白质。使用两种不同浓度的咪唑释放钴结合的AMH。通过用mAb-5/6A探测的蛋白质印迹评估回收率,大部分结合的AMH在第一次洗脱中回收。一些AMH蛋白也在含有较高浓度咪唑的第二次洗脱中被洗脱,而一些AMH蛋白没有与树脂结合。通过对杜氏磷酸盐缓冲盐水的渗析从制备物中去除咪唑。以与hAMH+SCUT+RSA(本文称为“野生型”)相似的比例回收突变体AMH蛋白,参见图7。
实施例5重组AMH蛋白的活性
为了评估生成的纯化的重组AMH制备物的活性,用Smad1/5应答性BRE-荧光素酶报告基因和AMHR2转染COV434细胞。二十四(24)小时后,将细胞用一系列剂量的AMH处理过夜,然后溶解,并在加入底物D-荧光素后立即测量发光。将荧光素酶活性分析为与基线活性有关的倍数变化。下文基于相对于hAMH+SCUT+RSA(野生型)AMH的刺激BRE-荧光素酶报告基因的能力对不同的AMH突变体进行分组。
(i)活性中等至主要增加的AMH突变蛋白
hAMH+SCUT+RSA(野生型)AMH通常在15-50ng/mL之间COV434 BRE-荧光素酶测定中得到峰值应答,EC50为约6ng/mL。G533A突变体显示出相比“野生型”AMH约2倍高的活性(图8A),而G533S突变体显示出约3倍高的活性(图8A,B)。G533K突变体显示出相比“野生型”AMH约5倍高的活性,同时还在最高剂量下刺激了显著更高的最大应答(图8B)。
(ii)活性无可观察的变化的AMH突变蛋白
突变体G533H、H548K、L535M和双重突变体G533A+L535M在荧光素酶测定中不显示相对于hAMH+SCUT+RSA(野生型)AMH可观察的差异(图9)。
生成的hAMH突变体总结在下表5中。
表5:hAMH突变体
G533残基在AMH指结构域中的位置显示于图10。
效力、活性和应答是相对于“WT”成熟AMH(由hAMH+SCUT+RSA产生;SEQ ID NO:36)。发明人已经表明,由hAMH+SCUT+RSA(SEQ ID NO:36)产生的成熟加工的AMH的活性与购自R&D Systems的hAMH的活性相当。
G=甘氨酸;A=丙氨酸;K=赖氨酸;S=丝氨酸;H=组氨酸;R=精氨酸;L=亮氨酸;M=甲硫氨酸;I=异亮氨酸;N=天冬酰胺。
序列表
<110> 莫纳什大学(Monash University)
<120> 抗缪勒氏管激素多肽
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Leu Ser Leu Glu Pro Glu Ala Leu Pro His Ser Ala Asp Pro Phe Leu
275 280 285
Glu Thr Leu Thr Arg Leu Val Arg Ala Leu Arg Gly Pro Leu Thr Gln
290 295 300
Ala Ser Asn Thr Gln Leu Ala Leu Asp Pro Gly Ala Leu Ala Ser Phe
305 310 315 320
Pro Gln Gly Leu Val Asn Leu Ser Asp Pro Ala Ala Leu Gly Arg Leu
325 330 335
Leu Asp Trp Glu Glu Pro Leu Leu Leu Leu Leu Ser Pro Ala Ala Ala
340 345 350
Thr Glu Arg Glu Pro Met Pro Leu His Gly Pro Ala Ser Ala Pro Trp
355 360 365
Ala Ala Gly Leu Gln Arg Arg Val Ala Val Glu Leu Gln Ala Ala Ala
370 375 380
Ser Glu Leu Arg Asp Leu Pro Gly Leu Pro Pro Thr Ala Pro Pro Leu
385 390 395 400
Leu Ala Arg Leu Leu Ala Leu Cys Pro Asn Asp Ser Arg Ser Ser Gly
405 410 415
Asp Pro Leu Arg Ala Leu Leu Leu Leu Lys Ala Leu Gln Gly Leu Arg
420 425 430
Ala Glu Trp His Gly Arg Glu Gly Arg Gly Arg Thr Gly Arg Ser Ala
435 440 445
Gly Thr Gly Thr Asp Gly Pro Cys Ala Leu Arg Glu Leu Ser Val Asp
450 455 460
Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr Gln Ala Asn
465 470 475 480
Asn Cys Gln Gly Ala Cys Ala Trp Pro Gln Ser Asp Arg Asn Pro Arg
485 490 495
Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala Arg Gly Ala
500 505 510
Ala Leu Gly Arg Leu Pro Cys Cys Val Pro Thr Ala Tyr Ala Gly Lys
515 520 525
Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His His Val Pro
530 535 540
Asn Met Val Ala Thr Glu Cys Gly Cys Arg
545 550
<210> 3
<211> 562
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 修饰的AMH前体
<400> 3
Met Lys Trp Val Thr Phe Leu Leu Leu Leu Phe Ile Ser Gly Ser Ala
1 5 10 15
Phe Ser His His His His His His Pro Ala Val Gly Thr Ser Gly Leu
20 25 30
Ile Phe Arg Glu Asp Leu Asp Trp Pro Pro Gly Ser Pro Gln Glu Pro
35 40 45
Leu Cys Leu Val Ala Leu Gly Gly Asp Ser Asn Gly Ser Ser Ser Pro
50 55 60
Leu Arg Val Val Gly Ala Leu Ser Ala Tyr Glu Gln Ala Phe Leu Gly
65 70 75 80
Ala Val Gln Arg Ala Arg Trp Gly Pro Arg Asp Leu Ala Thr Phe Gly
85 90 95
Val Cys Asn Thr Gly Asp Arg Gln Ala Ala Leu Pro Ser Leu Arg Arg
100 105 110
Leu Gly Ala Trp Leu Gln Asp Pro Gly Gly Gln Arg Leu Val Val Leu
115 120 125
His Leu Glu Glu Val Thr Trp Glu Pro Thr Pro Ser Leu Arg Phe Gln
130 135 140
Glu Pro Pro Pro Gly Gly Ala Gly Pro Pro Glu Leu Ala Leu Leu Val
145 150 155 160
Leu Tyr Pro Gly Pro Gly Pro Glu Val Thr Val Thr Arg Ala Gly Leu
165 170 175
Pro Gly Ala Gln Ser Leu Cys Pro Ser Arg Asp Thr Arg Tyr Leu Val
180 185 190
Leu Ala Val Asp Arg Pro Ala Gly Ala Trp Arg Gly Ser Gly Leu Ala
195 200 205
Leu Thr Leu Gln Pro Arg Gly Glu Asp Ser Arg Leu Ser Thr Ala Arg
210 215 220
Leu Gln Ala Leu Leu Phe Gly Asp Asp His Arg Cys Phe Thr Arg Met
225 230 235 240
Thr Pro Ala Leu Leu Leu Leu Pro Arg Ser Glu Pro Ala Pro Leu Pro
245 250 255
Ala His Gly Gln Leu Asp Thr Val Pro Phe Pro Pro Pro Arg Pro Ser
260 265 270
Ala Glu Leu Glu Glu Ser Pro Pro Ser Ala Asp Pro Phe Leu Glu Thr
275 280 285
Leu Thr Arg Leu Val Arg Ala Leu Arg Val Pro Pro Ala Arg Ala Ser
290 295 300
Ala Pro Arg Leu Ala Leu Asp Pro Asp Ala Leu Ala Gly Phe Pro Gln
305 310 315 320
Gly Leu Val Asn Leu Ser Asp Pro Ala Ala Leu Glu Arg Leu Leu Asp
325 330 335
Gly Glu Glu Pro Leu Leu Leu Leu Leu Arg Pro Thr Ala Ala Thr Thr
340 345 350
Gly Asp Pro Ala Pro Leu His Asp Pro Thr Ser Ala Pro Trp Ala Thr
355 360 365
Ala Leu Ala Arg Arg Val Ala Ala Glu Leu Gln Ala Ala Ala Ala Glu
370 375 380
Leu Arg Ser Leu Pro Gly Leu Pro Pro Ala Thr Ala Pro Leu Leu Ala
385 390 395 400
Arg Leu Leu Ala Leu Cys Pro Gly Gly Pro Gly Gly Leu Gly Asp Pro
405 410 415
Leu Arg Ala Leu Leu Leu Leu Lys Ala Leu Gln Gly Leu Arg Val Glu
420 425 430
Trp Arg Gly Arg Asp Pro Arg Gly Pro Gly Ile Ser Ser Arg Lys Lys
435 440 445
Arg Ser Val Ser Ser Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys
450 455 460
Ala Leu Arg Glu Leu Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu
465 470 475 480
Ile Pro Glu Thr Tyr Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp
485 490 495
Pro Gln Ser Asp Arg Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu
500 505 510
Leu Lys Met Gln Ala Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys
515 520 525
Val Pro Thr Ala Tyr Ala Gly Lys Leu Leu Ile Ser Leu Ser Glu Glu
530 535 540
Arg Ile Ser Ala His His Val Pro Asn Met Val Ala Thr Glu Cys Gly
545 550 555 560
Cys Arg
<210> 4
<211> 1689
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 修饰的AMH前体
<400> 4
atgaagtggg taacctttct cctcctcctc ttcatctccg gttctgcctt ttcccatcat 60
catcatcatc atccagctgt gggcaccagt ggcctcatct tccgagaaga cttggactgg 120
cctccaggca gcccacaaga gcctctgtgc ctggtggcac tgggcgggga cagcaatggc 180
agcagctccc ccctgcgggt ggtgggggct ctaagcgcct atgagcaggc cttcctgggg 240
gctgtgcaga gggcccgctg gggcccccga gacctggcca ccttcggggt ctgcaacacc 300
ggtgacaggc aggctgcctt gccctctcta cggcggctgg gggcctggct gcaggaccct 360
ggggggcagc gcctggtggt cctacacctg gaggaagtga cctgggagcc aacaccctcg 420
ctgaggttcc aggagccccc gcctggagga gctggccccc cagagctggc gctgctggtg 480
ctgtaccctg ggcctggccc tgaggtcact gtgacgaggg ctgggctgcc aggtgcccag 540
agcctctgcc cctcccgaga cacccgctac ctggtgttag cggtggaccg ccctgcgggg 600
gcctggcgcg gctccgggct ggccttgacc ctgcagcccc gcggagagga ctcccggctg 660
agtaccgccc ggctgcaggc actgctgttc ggcgacgacc accgctgctt cacacggatg 720
accccggccc tgctcctgct gccgcggtcc gagcccgcgc cgctgcctgc gcacggccag 780
ctggacaccg tgcccttccc gccgcccagg ccatccgcgg aactggagga gtcgccaccc 840
agcgcagacc ccttcctgga gacgctcacg cgcctggtgc gggcgctgcg ggtccccccg 900
gcccgggcct ccgcgccgcg cctggccctg gatccggacg cgctggccgg cttcccgcag 960
ggcctagtca acctgtcgga ccccgcggcg ctggagcgcc tactcgacgg cgaggagccg 1020
ctgctgctgc tgctgaggcc cactgcggcc accaccgggg atcctgcgcc cctgcacgac 1080
cccacgtcgg cgccgtgggc cacggccctg gcgcgccgcg tggctgctga actgcaagcg 1140
gcggctgccg agctgcgaag cctcccgggt ctgcctccgg ccacagcccc gctgctggcg 1200
cgcctgctcg cgctctgtcc aggaggcccc ggcggcctcg gcgatcccct gcgagcgctg 1260
ctgctcctga aggcgctgca gggcctgcgc gtggagtggc gcgggcggga tccgcgcggg 1320
ccgggtatct catcgagaaa gaaacgctca gtctcatcaa gcgcgggggc caccgccgcc 1380
gacgggccgt gcgcgctgcg cgagctcagc gtagacctcc gcgccgagcg ctccgtactc 1440
atccccgaga cctaccaggc caacaattgc cagggcgtgt gcggctggcc tcagtccgac 1500
cgcaacccgc gctacggcaa ccacgtggtg ctgctgctga agatgcaggc ccgtggggcc 1560
gccctggcgc gcccaccctg ctgcgtgccc accgcctacg cgggcaagct gctcatcagc 1620
ctgtcggagg agcgcatcag cgcgcaccac gtgcccaaca tggtggccac cgagtgtggc 1680
tgccggtaa 1689
<210> 5
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 修饰的成熟AMH序列
<400> 5
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Gly Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 6
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 加工位点
<400> 6
Ile Ser Ser Arg Lys Lys Arg Ser Val Ser Ser
1 5 10
<210> 7
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 7
Met Arg Asp Leu Pro Leu Thr Ser Leu Ala Leu Val Leu Ser Ala Leu
1 5 10 15
Gly Ala Leu Leu Gly Thr Glu Ala Leu
20 25
<210> 8
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 8
Met Lys Trp Val Thr Phe Leu Leu Leu Leu Phe Ile Ser Gly Ser Ala
1 5 10 15
Phe Ser
<210> 9
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 9
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Lys Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 10
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 10
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Ser Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 11
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 11
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Ala Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 12
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 12
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala His Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 13
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 13
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Gly Lys Met Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 14
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 14
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Ala Lys Met Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 15
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AMH类似物
<400> 15
Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
1 5 10 15
Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
20 25 30
Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro Gln Ser Asp Arg
35 40 45
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
50 55 60
Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr
65 70 75 80
Ala Ala Lys Met Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
85 90 95
Lys Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
100 105
<210> 16
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 16
Met Lys Val Ser Val Ala Ala Leu Ser Cys Leu Met Leu Val Thr Ala
1 5 10 15
Leu Gly Ser Gln Ala
20
<210> 17
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 17
Met Leu Gln Asn Ser Ala Val Leu Leu Leu Leu Val Ile Ser Ala Ser
1 5 10 15
Ala
<210> 18
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 18
Met Leu Leu Gln Ala Phe Leu Phe Leu Leu Ala Gly Phe Ala Ala Lys
1 5 10 15
Ile Ser Ala
<210> 19
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 19
Met Lys Trp Val Ser Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Ser Leu Glu Lys Arg
20
<210> 20
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 20
Met Lys Trp Val Ser Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Ser Leu Asp Lys Arg
20
<210> 21
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 21
Met Asn Ile Phe Tyr Ile Phe Leu Phe Leu Leu Ser Phe Val Gln Gly
1 5 10 15
Ser Leu Asp Lys Arg
20
<210> 22
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 22
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 23
<211> 29
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 23
Met Glu Arg Ala Ala Pro Ser Arg Arg Val Pro Leu Pro Leu Leu Leu
1 5 10 15
Leu Gly Gly Leu Ala Leu Leu Ala Ala Gly Val Asp Ala
20 25
<210> 24
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 24
Met Met Lys Thr Leu Leu Leu Phe Val Gly Leu Leu Leu Thr Trp Glu
1 5 10 15
Ser Gly Gln Val Leu Gly
20
<210> 25
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 25
Met Leu Pro Leu Cys Leu Val Ala Ala Leu Leu Leu Ala Ala Gly Pro
1 5 10 15
Gly Pro Ser Leu Gly
20
<210> 26
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 信号序列
<400> 26
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser
<210> 27
<211> 1665
<212> DNA
<213> 小家鼠(Mus musculus)
<400> 27
atgcaggggc cacacctctc tccactggta ctgctgctag cgactatggg ggctgtgtta 60
cagcctgagg cggttgaaaa cctggccacc aataccaggg gcctcatctt ccttgaagat 120
gagctctggc cccccagcag cccccctgaa cctttgtgcc tggtgacagt gagaggagag 180
gggaacacaa gcagagcttc cctgagggtg gtggggggtc tgaacagcta tgagtatgcc 240
ttcctggagg ctgtccagga gtctcgctgg ggaccccaag acctggccac cttcggagtc 300
tgcagcactg actcccaggc taccctgcct gccctgcagc gccttggggc ctggctaggg 360
gagactggag aacagcagtt gctagtccta catctggctg aagtgatatg ggagcccgag 420
ctcttgctga agttccaaga gcctccacct gggggagcca gccgctggga gcaggccctg 480
ttagtgctat accctggacc aggcccccag gtcacagtca cagggactgg actgcggggc 540
acacagaacc tctgccctac tcgggacacc cgctatttgg tgctaaccgt ggacttccca 600
gcgggggcct ggagcggctc gggcctcatc ttaacccttc aaccaagcag agaaggtgcc 660
accctgagca tcgatcagct gcaagccttt ctatttggct ctgattcccg ctgtttcacg 720
cggatgactc ccaccctggt ggtgctgcca cccgccgagc cgtcaccgca gccagcacac 780
ggccagctgg acaccatgcc tttcccgcag cctggactgt ccctggagcc tgaggccctg 840
ccacacagcg ccgacccctt cctagagacc ctcactcgct tggttcgtgc tctgcgggga 900
cctctgaccc aggcttcgaa cacgcaactg gccctggacc ctggtgcgct ggccagcttc 960
ccacagggcc tggtcaacct gtcagacccc gcagcactgg gacgcctgct cgactgggag 1020
gaacccctat tactgctgct gtcacccgct gcggccacgg agagggaacc tatgccgctg 1080
cacggccccg cttctgctcc ctgggcagcg ggcctgcaac gcagggtggc agtggagctg 1140
caggcggcag cctcagagct gcgggacctc ccgggtctgc cacccacagc tcccccgctg 1200
ctggcgcgcc tgctagcgct gtgtcccaac gactcccgca gctccgggga cccgctgcgc 1260
gcgctgctgc tgctaaaggc gctgcagggc ttacgtgccg agtggcatgg gcgggaaggg 1320
cgtgggagaa cggggcgcag cgcggggaca gggacagacg ggccttgcgc gctgcgcgag 1380
ctgagtgtag atctgcgcgc ggagcgttca gtgctcatcc cggagaccta ccaagccaac 1440
aactgccaag gcgcctgcgc gtggccgcag tctgaccgta atccgcgcta cgggaaccac 1500
gtggtgctgc tgctaaaaat gcaggctcgc ggggctgccc tgggccgcct gccctgctgc 1560
gtgcccactg cctacgcggg caagctgctc atcagcctgt ccgaggagcg catcagcgcg 1620
caccacgtgc ccaacatggt agccaccgag tgcggctgcc ggtga 1665
<210> 28
<211> 1722
<212> DNA
<213> 马(Equus caballus)
<400> 28
atgcgggctc cgtctctctc gtggctggcg cttgtgctgt cagctgtggg ggctctgctg 60
agggccggga cccccggaga agaggtctcc agcaccccag ctttgcctgg ggagccagcc 120
acaggcaccg ggggcctcat cttccaccag gactgggact ggccgccagg cagcccccaa 180
gaacccctgg ggtgcttggt gacgctggac gagggtggca accagagcag cgccccgctg 240
cgggtggcgg gggccctgag cggctacgag caggccttcc tggaggccgt gcagcgcacc 300
cactggagcc cccgcgacct gcccaccttc ggggtctgct cccctgccga ccggcaggcg 360
gccgtaccat ctctgcagcg cctgcaggcc tggctggggg caccctgggg gcagcggctg 420
gtggtcctgc acctggagga agtgatgtgg gagccgacgc cctcgctgag gttccaggag 480
cccccatctg gaggagccaa ccccctggag ccagcgctgc tggtgctgta cgccgggccc 540
ggccctgagg tcactgtcac gggggccggg ctgccagggg cccagagcct ctgcccgtcc 600
ccggacaccc gctacctggc gctggccgtc gaccacccag cacgggcctg gcgccaccct 660
gggctcatcc tgaccctgca gcctcgcgga gacggtgccc ccctgagcac ggcccagctg 720
cagacgctgc tgttcggcgc cgacccccgc tgcttcacgc ggatgacccc cgccctgttc 780
ctgctgcagc ggccggggcc cgcgcccatg cccgcgcacg gccgactcga cacggtgccc 840
ttcccgccag ccaggccgtc cccggagccc gaggagccgc ggcccagcgc cgaccccttc 900
ctggagacgc tcacgcgcct ggtgcgcgcg ctgcgggggc ccccgactcc ggcctcgccg 960
ccacgcctgg ccctggaccc gggcgcgctg gccagcttcc cgcagggcct ggtcaacctg 1020
tcggaccccg cggcgctgga gcgcctgctc gacggcgagg agccgctgct gctgctgctg 1080
ccgcccaccg cggccgctgc cggggacccc gcgccattgc cggaccccgc gtcggcgccc 1140
tgggccgcgg gcctggcgcg ccgcgtggcc gccgagctgc aggcggcggc ggccgagctg 1200
cgcagcctcc cggggctgcc ccccgccgca gagccgctgc tggcgcgcct gctcgcactg 1260
tgcccggggg acgccgagga ccagggcggc ccgggcggcc cgctgcgcgc gctgctgctg 1320
ctgaaggcgc tgcaaggcct gcgcgccgag tggcgcgggc gcgagcggag cgggcccggg 1380
cgggcgcagc gcaacgcggg ggccggggcc gccgacgggc cgtgcgcgct gcgcgagctg 1440
cgcgtggact tgcgcgccga gcgctccgtg ctcatccccg agacgtacca ggccaacaac 1500
tgccagggcg cgtgcggctg gccgcagtcg gaccgcaacc cgcgctacgg caaccacgtg 1560
gtgctgctgc taaagatgca ggcccgcggc gccgccctgg cgcgcgcgcc ctgctgcgtg 1620
cccactgcct acgcgggcaa gctgctcatc agcctgtccg aggagcgcat cagcgcgcac 1680
cacgtgccca acatggtggc caccgagtgc ggctgccggt ga 1722
<210> 29
<211> 1719
<212> DNA
<213> 家犬(Canis lupus familiaris)
<400> 29
atgggggctc tggcgctctg gccgctggcc ctggcgctgt cggggatggg gcccctgctg 60
ggagccgagg cccccggagg tgaggtctcg ggcaccccag cctcgcccgg agagccggcc 120
acaggcactg ggggtctcct cttccagcca gactgggact ggccgcctag cgccccacaa 180
gaccccctgt gcctggtgac cctggacaag ggaggcaacg ggagcagccc cccgcttcgg 240
gtggcggggg ccctccgagg ctacgagcac accttcctcg aggccgtgcg gcgagcccgc 300
tggggtcccc acgacctggc caccttcggg gcctgcgccg ccagcgacgg ccggaccacc 360
cagctctccc tgcggcagct gcaagcctgg ctgggggcgc ccggggggcg gcggctggtg 420
gtgctgcacc tggaggaagt gacatgggag ccagcgctgt cgctgaagtt ccaggagccc 480
ccacctggag gagccagtcc cctagagctg gcgctgctgg tgctctaccc tgggccaggc 540
cctgaggtcg ctgtcaccgg ggctggactg ccaggcaccc agaacctttg ccggtcccgg 600
aacacgcgct acctggtgct ggccctggac cacccggtgg gggcctggca cagccctagg 660
gtcaccctga ccgtgcacgc ccgaggagac ggtgccccgc tgagcacccc ccagctgcag 720
gagctgctgt tcgggcccga tgcccgctgc ttcacgcgga tgacgcccgc gctgctcgtg 780
ctgcggctgc ccgggcccac ggcggtgccg gcgcgcggcc tgctggacct cgtgcccttc 840
ccgccgccca ggccctcccg ggagcccgcg gagccccctc ccagcgcaga ccccttcctg 900
gagacgctca cgcgcctggt gcgcgccctg cgcgggccgc cgacccccgc ctcgccgccg 960
cgcctggccc tggaccccgg cgcgctggcg ggcttcccgc agggcctgct caacctgtcg 1020
gaccccgcga cacaggagcg cctgctgggc ggcgaggagc ccctgctgct gctgctgcca 1080
ccccccacgg ccgcggccgg gccccccgcg ccgccgcccc gccccgcgtc cgcgccctgg 1140
gccgcgggcc tcgccctgcg cgtggccgcc gagctgcggg ccgcggccgc cgagctccgc 1200
gggctcccgg ggctgccccc cgccgccgcg ccgctgctgg agcgcctgct cgccctctgc 1260
cccgggggct cggggggctc ggggggctcg ggggacccgc tgcgcgcgct gctgctgctc 1320
aaggcgttgc agggcctgcg cgccgagtgg cgcgggcggg agcggggcgg gcccccccgg 1380
gcgcagcgca gcgcgggggc gggggcggcc gacgggccct gcgcgctgcg cgagctgagc 1440
gtggacctgc gcgccgagcg ctccgtgctc atccccgaga cctaccaggc caacaactgc 1500
cagggcgcgt gcgggtggcc gcagtccgac cgcaacccgc gctacggcaa ccacgtggtg 1560
ctgctgctca agatgcaggc ccgcggcgcc gcgctggctc gcccgccctg ctgcgtgccc 1620
acggcctacg gcggcaagct gctcatcagc ctgtcggagg agcgcatcag cgcgcaccac 1680
gtgcccaaca tggtggccac cgagtgcggc tgccggtga 1719
<210> 30
<211> 1767
<212> DNA
<213> 家猫( Felis catus)
<400> 30
atgcctggtc tgctctctcc gccggccctg gtgctgtcgg tgatgggggc tctgctgatg 60
gccggggacc ctggggaaga ggtctccagc accccggccc tgcctggagg gccagccaca 120
ggcaccgggg gtctcatctt ccacccggat tgggactggc agcccccggg cagtccccaa 180
gaccccctgt gcctggtgac gctggacagg ggtggtaacg ggagcggctc cccgcttcgg 240
gtggtggggg cgctgagagg ctacgagcac gccttcctcg aggctgtgcg gcgggcccgc 300
tggggtcccc acggcctggc caccttcgga gtttgcaccc ccagggacag gcaggccgcc 360
ccgttctctc tgcggcagct gcaggcgtgg ctgggggagc ccggggggcg gcggctggtg 420
gtgctgcacc tggaggaagt gacatgggag ccgacaccct cactgaagtt ccaggagccc 480
ccgcctggag gggccggtcc cctagagctg gcgatgctgg tgctgtaccc tggccctggc 540
cccgaggtca cggtcacagg ggctgggctg ccaggcaccc agagcctctg tcagtcccgg 600
gacacccgct acctggtgct ggcggtggac cacccagaag gggcctggcg cagccccggg 660
ctcaccctga ccctgcaacc ccgcagagac ggtgcgcccc tgagcaccgc ccagctgcag 720
gagctgctgt tcggccccga cccccgctgc ttcacacgca tgaccccggc gctgctcctg 780
ctgccggggc ccgcgcctgc accgctgccc gcgcgtggcc tgctggacca agtgcctctc 840
ccgccgccca ggccctccca ggagcaggcg cccgaggagc cacggtccag cgccgacccc 900
ttcctggaga cgctcacgcg cctggtgcgc gcgctgcggg ggcccccggc ccaggcctcg 960
ccggcgcgcc tggccctgga ccccggcgcg ctggccggct tcccgcaggg cctggtcaac 1020
ctgtcggacc ccgcggcgca ggagcgcctg ctcaacggcg gcgacgagcc gctgctgctg 1080
cttctgctgc cacccgccac gcccaccgcc gccgccgccg ccgccgggga ccccgcgccg 1140
ccgcgcggcc cggcgtccgc gccctgggcc gccggcctag cgcgtcgcgt ggccgccgag 1200
ctgcaggccg cggccgccga gctgcgaggg ctcccggggc tgccgccggc cgccacgccg 1260
ctgctggcgc gcctgctcgc gctgtgcccc ggggattcgg gggactcggg ggacccgggg 1320
gccccccccg gcggcccggg cggcccgctg cgcgcgctgc tgctgctcaa ggcgctgcag 1380
ggtctgcgcg cggagtggcg cgggcgcgag caggccggac cggcgcgggc acagcgcagc 1440
gcgggggccg gggcggccga cgggccgtgc gcgctgcgcg agctgagcgt ggacctgcgc 1500
gccgagcgct ccgtgctcat cccggagacg taccaggcca acaactgcca gggcgcgtgc 1560
ggctggccgc agtccgaccg caacccgcgc tacggcaacc acgtggtgct gctgctcaag 1620
atgcaggccc gcggcgccgc cctggcgcgc ccgccctgct gcgtgcccac ggcctacgcg 1680
ggcaagctcc tcatcagcct gtcggaggag cgcatcagcg cgcaccacgt gcccaacatg 1740
gtggccaccg agtgcggctg ccggtga 1767
<210> 31
<211> 573
<212> PRT
<213> 马(Equus caballus)
<400> 31
Met Arg Ala Pro Ser Leu Ser Trp Leu Ala Leu Val Leu Ser Ala Val
1 5 10 15
Gly Ala Leu Leu Arg Ala Gly Thr Pro Gly Glu Glu Val Ser Ser Thr
20 25 30
Pro Ala Leu Pro Gly Glu Pro Ala Thr Gly Thr Gly Gly Leu Ile Phe
35 40 45
His Gln Asp Trp Asp Trp Pro Pro Gly Ser Pro Gln Glu Pro Leu Gly
50 55 60
Cys Leu Val Thr Leu Asp Glu Gly Gly Asn Gln Ser Ser Ala Pro Leu
65 70 75 80
Arg Val Ala Gly Ala Leu Ser Gly Tyr Glu Gln Ala Phe Leu Glu Ala
85 90 95
Val Gln Arg Thr His Trp Ser Pro Arg Asp Leu Pro Thr Phe Gly Val
100 105 110
Cys Ser Pro Ala Asp Arg Gln Ala Ala Val Pro Ser Leu Gln Arg Leu
115 120 125
Gln Ala Trp Leu Gly Ala Pro Trp Gly Gln Arg Leu Val Val Leu His
130 135 140
Leu Glu Glu Val Met Trp Glu Pro Thr Pro Ser Leu Arg Phe Gln Glu
145 150 155 160
Pro Pro Ser Gly Gly Ala Asn Pro Leu Glu Pro Ala Leu Leu Val Leu
165 170 175
Tyr Ala Gly Pro Gly Pro Glu Val Thr Val Thr Gly Ala Gly Leu Pro
180 185 190
Gly Ala Gln Ser Leu Cys Pro Ser Pro Asp Thr Arg Tyr Leu Ala Leu
195 200 205
Ala Val Asp His Pro Ala Arg Ala Trp Arg His Pro Gly Leu Ile Leu
210 215 220
Thr Leu Gln Pro Arg Gly Asp Gly Ala Pro Leu Ser Thr Ala Gln Leu
225 230 235 240
Gln Thr Leu Leu Phe Gly Ala Asp Pro Arg Cys Phe Thr Arg Met Thr
245 250 255
Pro Ala Leu Phe Leu Leu Gln Arg Pro Gly Pro Ala Pro Met Pro Ala
260 265 270
His Gly Arg Leu Asp Thr Val Pro Phe Pro Pro Ala Arg Pro Ser Pro
275 280 285
Glu Pro Glu Glu Pro Arg Pro Ser Ala Asp Pro Phe Leu Glu Thr Leu
290 295 300
Thr Arg Leu Val Arg Ala Leu Arg Gly Pro Pro Thr Pro Ala Ser Pro
305 310 315 320
Pro Arg Leu Ala Leu Asp Pro Gly Ala Leu Ala Ser Phe Pro Gln Gly
325 330 335
Leu Val Asn Leu Ser Asp Pro Ala Ala Leu Glu Arg Leu Leu Asp Gly
340 345 350
Glu Glu Pro Leu Leu Leu Leu Leu Pro Pro Thr Ala Ala Ala Ala Gly
355 360 365
Asp Pro Ala Pro Leu Pro Asp Pro Ala Ser Ala Pro Trp Ala Ala Gly
370 375 380
Leu Ala Arg Arg Val Ala Ala Glu Leu Gln Ala Ala Ala Ala Glu Leu
385 390 395 400
Arg Ser Leu Pro Gly Leu Pro Pro Ala Ala Glu Pro Leu Leu Ala Arg
405 410 415
Leu Leu Ala Leu Cys Pro Gly Asp Ala Glu Asp Gln Gly Gly Pro Gly
420 425 430
Gly Pro Leu Arg Ala Leu Leu Leu Leu Lys Ala Leu Gln Gly Leu Arg
435 440 445
Ala Glu Trp Arg Gly Arg Glu Arg Ser Gly Pro Gly Arg Ala Gln Arg
450 455 460
Asn Ala Gly Ala Gly Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu
465 470 475 480
Arg Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr
485 490 495
Gln Ala Asn Asn Cys Gln Gly Ala Cys Gly Trp Pro Gln Ser Asp Arg
500 505 510
Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala
515 520 525
Arg Gly Ala Ala Leu Ala Arg Ala Pro Cys Cys Val Pro Thr Ala Tyr
530 535 540
Ala Gly Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His
545 550 555 560
His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
565 570
<210> 32
<211> 572
<212> PRT
<213> 家犬(Canis lupus familiaris)
<400> 32
Met Gly Ala Leu Ala Leu Trp Pro Leu Ala Leu Ala Leu Ser Gly Met
1 5 10 15
Gly Pro Leu Leu Gly Ala Glu Ala Pro Gly Gly Glu Val Ser Gly Thr
20 25 30
Pro Ala Ser Pro Gly Glu Pro Ala Thr Gly Thr Gly Gly Leu Leu Phe
35 40 45
Gln Pro Asp Trp Asp Trp Pro Pro Ser Ala Pro Gln Asp Pro Leu Cys
50 55 60
Leu Val Thr Leu Asp Lys Gly Gly Asn Gly Ser Ser Pro Pro Leu Arg
65 70 75 80
Val Ala Gly Ala Leu Arg Gly Tyr Glu His Thr Phe Leu Glu Ala Val
85 90 95
Arg Arg Ala Arg Trp Gly Pro His Asp Leu Ala Thr Phe Gly Ala Cys
100 105 110
Ala Ala Ser Asp Gly Arg Thr Thr Gln Leu Ser Leu Arg Gln Leu Gln
115 120 125
Ala Trp Leu Gly Ala Pro Gly Gly Arg Arg Leu Val Val Leu His Leu
130 135 140
Glu Glu Val Thr Trp Glu Pro Ala Leu Ser Leu Lys Phe Gln Glu Pro
145 150 155 160
Pro Pro Gly Gly Ala Ser Pro Leu Glu Leu Ala Leu Leu Val Leu Tyr
165 170 175
Pro Gly Pro Gly Pro Glu Val Ala Val Thr Gly Ala Gly Leu Pro Gly
180 185 190
Thr Gln Asn Leu Cys Arg Ser Arg Asn Thr Arg Tyr Leu Val Leu Ala
195 200 205
Leu Asp His Pro Val Gly Ala Trp His Ser Pro Arg Val Thr Leu Thr
210 215 220
Val His Ala Arg Gly Asp Gly Ala Pro Leu Ser Thr Pro Gln Leu Gln
225 230 235 240
Glu Leu Leu Phe Gly Pro Asp Ala Arg Cys Phe Thr Arg Met Thr Pro
245 250 255
Ala Leu Leu Val Leu Arg Leu Pro Gly Pro Thr Ala Val Pro Ala Arg
260 265 270
Gly Leu Leu Asp Leu Val Pro Phe Pro Pro Pro Arg Pro Ser Arg Glu
275 280 285
Pro Ala Glu Pro Pro Pro Ser Ala Asp Pro Phe Leu Glu Thr Leu Thr
290 295 300
Arg Leu Val Arg Ala Leu Arg Gly Pro Pro Thr Pro Ala Ser Pro Pro
305 310 315 320
Arg Leu Ala Leu Asp Pro Gly Ala Leu Ala Gly Phe Pro Gln Gly Leu
325 330 335
Leu Asn Leu Ser Asp Pro Ala Thr Gln Glu Arg Leu Leu Gly Gly Glu
340 345 350
Glu Pro Leu Leu Leu Leu Leu Pro Pro Pro Thr Ala Ala Ala Gly Pro
355 360 365
Pro Ala Pro Pro Pro Arg Pro Ala Ser Ala Pro Trp Ala Ala Gly Leu
370 375 380
Ala Leu Arg Val Ala Ala Glu Leu Arg Ala Ala Ala Ala Glu Leu Arg
385 390 395 400
Gly Leu Pro Gly Leu Pro Pro Ala Ala Ala Pro Leu Leu Glu Arg Leu
405 410 415
Leu Ala Leu Cys Pro Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Asp
420 425 430
Pro Leu Arg Ala Leu Leu Leu Leu Lys Ala Leu Gln Gly Leu Arg Ala
435 440 445
Glu Trp Arg Gly Arg Glu Arg Gly Gly Pro Pro Arg Ala Gln Arg Ser
450 455 460
Ala Gly Ala Gly Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu Ser
465 470 475 480
Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr Gln
485 490 495
Ala Asn Asn Cys Gln Gly Ala Cys Gly Trp Pro Gln Ser Asp Arg Asn
500 505 510
Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala Arg
515 520 525
Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr Gly
530 535 540
Gly Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His His
545 550 555 560
Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
565 570
<210> 33
<211> 588
<212> PRT
<213> 家猫(Felis catus)
<400> 33
Met Pro Gly Leu Leu Ser Pro Pro Ala Leu Val Leu Ser Val Met Gly
1 5 10 15
Ala Leu Leu Met Ala Gly Asp Pro Gly Glu Glu Val Ser Ser Thr Pro
20 25 30
Ala Leu Pro Gly Gly Pro Ala Thr Gly Thr Gly Gly Leu Ile Phe His
35 40 45
Pro Asp Trp Asp Trp Gln Pro Pro Gly Ser Pro Gln Asp Pro Leu Cys
50 55 60
Leu Val Thr Leu Asp Arg Gly Gly Asn Gly Ser Gly Ser Pro Leu Arg
65 70 75 80
Val Val Gly Ala Leu Arg Gly Tyr Glu His Ala Phe Leu Glu Ala Val
85 90 95
Arg Arg Ala Arg Trp Gly Pro His Gly Leu Ala Thr Phe Gly Val Cys
100 105 110
Thr Pro Arg Asp Arg Gln Ala Ala Pro Phe Ser Leu Arg Gln Leu Gln
115 120 125
Ala Trp Leu Gly Glu Pro Gly Gly Arg Arg Leu Val Val Leu His Leu
130 135 140
Glu Glu Val Thr Trp Glu Pro Thr Pro Ser Leu Lys Phe Gln Glu Pro
145 150 155 160
Pro Pro Gly Gly Ala Gly Pro Leu Glu Leu Ala Met Leu Val Leu Tyr
165 170 175
Pro Gly Pro Gly Pro Glu Val Thr Val Thr Gly Ala Gly Leu Pro Gly
180 185 190
Thr Gln Ser Leu Cys Gln Ser Arg Asp Thr Arg Tyr Leu Val Leu Ala
195 200 205
Val Asp His Pro Glu Gly Ala Trp Arg Ser Pro Gly Leu Thr Leu Thr
210 215 220
Leu Gln Pro Arg Arg Asp Gly Ala Pro Leu Ser Thr Ala Gln Leu Gln
225 230 235 240
Glu Leu Leu Phe Gly Pro Asp Pro Arg Cys Phe Thr Arg Met Thr Pro
245 250 255
Ala Leu Leu Leu Leu Pro Gly Pro Ala Pro Ala Pro Leu Pro Ala Arg
260 265 270
Gly Leu Leu Asp Gln Val Pro Leu Pro Pro Pro Arg Pro Ser Gln Glu
275 280 285
Gln Ala Pro Glu Glu Pro Arg Ser Ser Ala Asp Pro Phe Leu Glu Thr
290 295 300
Leu Thr Arg Leu Val Arg Ala Leu Arg Gly Pro Pro Ala Gln Ala Ser
305 310 315 320
Pro Ala Arg Leu Ala Leu Asp Pro Gly Ala Leu Ala Gly Phe Pro Gln
325 330 335
Gly Leu Val Asn Leu Ser Asp Pro Ala Ala Gln Glu Arg Leu Leu Asn
340 345 350
Gly Gly Asp Glu Pro Leu Leu Leu Leu Leu Leu Pro Pro Ala Thr Pro
355 360 365
Thr Ala Ala Ala Ala Ala Ala Gly Asp Pro Ala Pro Pro Arg Gly Pro
370 375 380
Ala Ser Ala Pro Trp Ala Ala Gly Leu Ala Arg Arg Val Ala Ala Glu
385 390 395 400
Leu Gln Ala Ala Ala Ala Glu Leu Arg Gly Leu Pro Gly Leu Pro Pro
405 410 415
Ala Ala Thr Pro Leu Leu Ala Arg Leu Leu Ala Leu Cys Pro Gly Asp
420 425 430
Ser Gly Asp Ser Gly Asp Pro Gly Ala Pro Pro Gly Gly Pro Gly Gly
435 440 445
Pro Leu Arg Ala Leu Leu Leu Leu Lys Ala Leu Gln Gly Leu Arg Ala
450 455 460
Glu Trp Arg Gly Arg Glu Gln Ala Gly Pro Ala Arg Ala Gln Arg Ser
465 470 475 480
Ala Gly Ala Gly Ala Ala Asp Gly Pro Cys Ala Leu Arg Glu Leu Ser
485 490 495
Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile Pro Glu Thr Tyr Gln
500 505 510
Ala Asn Asn Cys Gln Gly Ala Cys Gly Trp Pro Gln Ser Asp Arg Asn
515 520 525
Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu Lys Met Gln Ala Arg
530 535 540
Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val Pro Thr Ala Tyr Ala
545 550 555 560
Gly Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg Ile Ser Ala His His
565 570 575
Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys Arg
580 585
<210> 34
<211> 1683
<212> PRT
<213> 智人(Homo sapiens)
<400> 34
Ala Thr Gly Cys Gly Gly Gly Ala Cys Cys Thr Gly Cys Cys Thr Cys
1 5 10 15
Thr Cys Ala Cys Cys Ala Gly Cys Cys Thr Gly Gly Cys Cys Cys Thr
20 25 30
Ala Gly Thr Gly Cys Thr Gly Thr Cys Thr Gly Cys Cys Cys Thr Gly
35 40 45
Gly Gly Gly Gly Cys Thr Cys Thr Gly Cys Thr Gly Gly Gly Gly Ala
50 55 60
Cys Thr Gly Ala Gly Gly Cys Cys Cys Thr Cys Ala Gly Ala Gly Cys
65 70 75 80
Ala Gly Ala Gly Gly Ala Gly Cys Cys Ala Gly Cys Thr Gly Thr Gly
85 90 95
Gly Gly Cys Ala Cys Cys Ala Gly Thr Gly Gly Cys Cys Thr Cys Ala
100 105 110
Thr Cys Thr Thr Cys Cys Gly Ala Gly Ala Ala Gly Ala Cys Thr Thr
115 120 125
Gly Gly Ala Cys Thr Gly Gly Cys Cys Thr Cys Cys Ala Gly Gly Cys
130 135 140
Ala Gly Cys Cys Cys Ala Cys Ala Ala Gly Ala Gly Cys Cys Thr Cys
145 150 155 160
Thr Gly Thr Gly Cys Cys Thr Gly Gly Thr Gly Gly Cys Ala Cys Thr
165 170 175
Gly Gly Gly Cys Gly Gly Gly Gly Ala Cys Ala Gly Cys Ala Ala Thr
180 185 190
Gly Gly Cys Ala Gly Cys Ala Gly Cys Thr Cys Cys Cys Cys Cys Cys
195 200 205
Thr Gly Cys Gly Gly Gly Thr Gly Gly Thr Gly Gly Gly Gly Gly Cys
210 215 220
Thr Cys Thr Ala Ala Gly Cys Gly Cys Cys Thr Ala Thr Gly Ala Gly
225 230 235 240
Cys Ala Gly Gly Cys Cys Thr Thr Cys Cys Thr Gly Gly Gly Gly Gly
245 250 255
Cys Cys Gly Thr Gly Cys Ala Gly Ala Gly Gly Gly Cys Cys Cys Gly
260 265 270
Cys Thr Gly Gly Gly Gly Cys Cys Cys Cys Cys Gly Ala Gly Ala Cys
275 280 285
Cys Thr Gly Gly Cys Cys Ala Cys Cys Thr Thr Cys Gly Gly Gly Gly
290 295 300
Thr Cys Thr Gly Cys Ala Ala Cys Ala Cys Cys Gly Gly Thr Gly Ala
305 310 315 320
Cys Ala Gly Gly Cys Ala Gly Gly Cys Thr Gly Cys Cys Thr Thr Gly
325 330 335
Cys Cys Cys Thr Cys Thr Cys Thr Ala Cys Gly Gly Cys Gly Gly Cys
340 345 350
Thr Gly Gly Gly Gly Gly Cys Cys Thr Gly Gly Cys Thr Gly Cys Gly
355 360 365
Gly Gly Ala Cys Cys Cys Thr Gly Gly Gly Gly Gly Gly Cys Ala Gly
370 375 380
Cys Gly Cys Cys Thr Gly Gly Thr Gly Gly Thr Cys Cys Thr Ala Cys
385 390 395 400
Ala Cys Cys Thr Gly Gly Ala Gly Gly Ala Ala Gly Thr Gly Ala Cys
405 410 415
Cys Thr Gly Gly Gly Ala Gly Cys Cys Ala Ala Cys Ala Cys Cys Cys
420 425 430
Thr Cys Gly Cys Thr Gly Ala Gly Gly Thr Thr Cys Cys Ala Gly Gly
435 440 445
Ala Gly Cys Cys Cys Cys Cys Gly Cys Cys Thr Gly Gly Ala Gly Gly
450 455 460
Ala Gly Cys Thr Gly Gly Cys Cys Cys Cys Cys Cys Ala Gly Ala Gly
465 470 475 480
Cys Thr Gly Gly Cys Gly Cys Thr Gly Cys Thr Gly Gly Thr Gly Cys
485 490 495
Thr Gly Thr Ala Cys Cys Cys Thr Gly Gly Gly Cys Cys Thr Gly Gly
500 505 510
Cys Cys Cys Thr Gly Ala Gly Gly Thr Cys Ala Cys Thr Gly Thr Gly
515 520 525
Ala Cys Gly Ala Gly Gly Gly Cys Thr Gly Gly Gly Cys Thr Gly Cys
530 535 540
Cys Gly Gly Gly Thr Gly Cys Cys Cys Ala Gly Ala Gly Cys Cys Thr
545 550 555 560
Cys Thr Gly Cys Cys Cys Cys Thr Cys Cys Cys Gly Ala Gly Ala Cys
565 570 575
Ala Cys Cys Cys Gly Cys Thr Ala Cys Cys Thr Gly Gly Thr Gly Thr
580 585 590
Thr Ala Gly Cys Gly Gly Thr Gly Gly Ala Cys Cys Gly Cys Cys Cys
595 600 605
Thr Gly Cys Gly Gly Gly Gly Gly Cys Cys Thr Gly Gly Cys Gly Cys
610 615 620
Gly Gly Cys Thr Cys Cys Gly Gly Gly Cys Thr Gly Gly Cys Cys Thr
625 630 635 640
Thr Gly Ala Cys Cys Cys Thr Gly Cys Ala Gly Cys Cys Cys Cys Gly
645 650 655
Cys Gly Gly Ala Gly Ala Gly Gly Ala Cys Thr Cys Cys Cys Gly Gly
660 665 670
Cys Thr Gly Ala Gly Thr Ala Cys Cys Gly Cys Cys Cys Gly Gly Cys
675 680 685
Thr Gly Cys Ala Gly Gly Cys Ala Cys Thr Gly Cys Thr Gly Thr Thr
690 695 700
Cys Gly Gly Cys Gly Ala Cys Gly Ala Cys Cys Ala Cys Cys Gly Cys
705 710 715 720
Thr Gly Cys Thr Thr Cys Ala Cys Ala Cys Gly Gly Ala Thr Gly Ala
725 730 735
Cys Cys Cys Cys Gly Gly Cys Cys Cys Thr Gly Cys Thr Cys Cys Thr
740 745 750
Gly Cys Thr Gly Cys Cys Gly Cys Gly Gly Thr Cys Cys Gly Ala Gly
755 760 765
Cys Cys Cys Gly Cys Gly Cys Cys Gly Cys Thr Gly Cys Cys Thr Gly
770 775 780
Cys Gly Cys Ala Cys Gly Gly Cys Cys Ala Gly Cys Thr Gly Gly Ala
785 790 795 800
Cys Ala Cys Cys Gly Thr Gly Cys Cys Cys Thr Thr Cys Cys Cys Gly
805 810 815
Cys Cys Gly Cys Cys Cys Ala Gly Gly Cys Cys Ala Thr Cys Cys Gly
820 825 830
Cys Gly Gly Ala Ala Cys Thr Cys Gly Ala Gly Gly Ala Gly Thr Cys
835 840 845
Gly Cys Cys Ala Cys Cys Cys Ala Gly Cys Gly Cys Ala Gly Ala Cys
850 855 860
Cys Cys Cys Thr Thr Cys Cys Thr Gly Gly Ala Gly Ala Cys Gly Cys
865 870 875 880
Thr Cys Ala Cys Gly Cys Gly Cys Cys Thr Gly Gly Thr Gly Cys Gly
885 890 895
Gly Gly Cys Gly Cys Thr Gly Cys Gly Gly Gly Thr Cys Cys Cys Cys
900 905 910
Cys Cys Gly Gly Cys Cys Cys Gly Gly Gly Cys Cys Thr Cys Cys Gly
915 920 925
Cys Gly Cys Cys Gly Cys Gly Cys Cys Thr Gly Gly Cys Cys Cys Thr
930 935 940
Gly Gly Ala Thr Cys Cys Gly Gly Ala Cys Gly Cys Gly Cys Thr Gly
945 950 955 960
Gly Cys Cys Gly Gly Cys Thr Thr Cys Cys Cys Gly Cys Ala Gly Gly
965 970 975
Gly Cys Cys Thr Ala Gly Thr Cys Ala Ala Cys Cys Thr Gly Thr Cys
980 985 990
Gly Gly Ala Cys Cys Cys Cys Gly Cys Gly Gly Cys Gly Cys Thr Gly
995 1000 1005
Gly Ala Gly Cys Gly Cys Cys Thr Ala Cys Thr Cys Gly Ala Cys
1010 1015 1020
Gly Gly Cys Gly Ala Gly Gly Ala Gly Cys Cys Gly Cys Thr Gly
1025 1030 1035
Cys Thr Gly Cys Thr Gly Cys Thr Gly Cys Thr Gly Ala Gly Gly
1040 1045 1050
Cys Cys Cys Ala Cys Thr Gly Cys Gly Gly Cys Cys Ala Cys Cys
1055 1060 1065
Ala Cys Cys Gly Gly Gly Gly Ala Thr Cys Cys Thr Gly Cys Gly
1070 1075 1080
Cys Cys Cys Cys Thr Gly Cys Ala Cys Gly Ala Cys Cys Cys Cys
1085 1090 1095
Ala Cys Gly Thr Cys Gly Gly Cys Gly Cys Cys Gly Thr Gly Gly
1100 1105 1110
Gly Cys Cys Ala Cys Gly Gly Cys Cys Cys Thr Gly Gly Cys Gly
1115 1120 1125
Cys Gly Cys Cys Gly Cys Gly Thr Gly Gly Cys Thr Gly Cys Thr
1130 1135 1140
Gly Ala Ala Cys Thr Gly Cys Ala Ala Gly Cys Gly Gly Cys Gly
1145 1150 1155
Gly Cys Thr Gly Cys Cys Gly Ala Gly Cys Thr Gly Cys Gly Ala
1160 1165 1170
Ala Gly Cys Cys Thr Cys Cys Cys Gly Gly Gly Thr Cys Thr Gly
1175 1180 1185
Cys Cys Thr Cys Cys Gly Gly Cys Cys Ala Cys Ala Gly Cys Cys
1190 1195 1200
Cys Cys Gly Cys Thr Gly Cys Thr Gly Gly Cys Gly Cys Gly Cys
1205 1210 1215
Cys Thr Gly Cys Thr Cys Gly Cys Gly Cys Thr Cys Thr Gly Cys
1220 1225 1230
Cys Cys Ala Gly Gly Thr Gly Gly Cys Cys Cys Cys Gly Gly Cys
1235 1240 1245
Gly Gly Cys Cys Thr Cys Gly Gly Cys Gly Ala Thr Cys Cys Cys
1250 1255 1260
Cys Thr Gly Cys Gly Ala Gly Cys Gly Cys Thr Gly Cys Thr Gly
1265 1270 1275
Cys Thr Cys Cys Thr Gly Ala Ala Gly Gly Cys Gly Cys Thr Gly
1280 1285 1290
Cys Ala Gly Gly Gly Cys Cys Thr Gly Cys Gly Cys Gly Thr Gly
1295 1300 1305
Gly Ala Gly Thr Gly Gly Cys Gly Cys Gly Gly Gly Cys Gly Gly
1310 1315 1320
Gly Ala Thr Cys Cys Gly Cys Gly Cys Gly Gly Gly Cys Cys Gly
1325 1330 1335
Gly Gly Thr Cys Gly Gly Gly Cys Ala Cys Ala Gly Cys Gly Cys
1340 1345 1350
Ala Gly Cys Gly Cys Gly Gly Gly Gly Gly Cys Cys Ala Cys Cys
1355 1360 1365
Gly Cys Cys Gly Cys Cys Gly Ala Cys Gly Gly Gly Cys Cys Gly
1370 1375 1380
Thr Gly Cys Gly Cys Gly Cys Thr Gly Cys Gly Cys Gly Ala Gly
1385 1390 1395
Cys Thr Cys Ala Gly Cys Gly Thr Ala Gly Ala Cys Cys Thr Cys
1400 1405 1410
Cys Gly Cys Gly Cys Cys Gly Ala Gly Cys Gly Cys Thr Cys Cys
1415 1420 1425
Gly Thr Ala Cys Thr Cys Ala Thr Cys Cys Cys Cys Gly Ala Gly
1430 1435 1440
Ala Cys Cys Thr Ala Cys Cys Ala Gly Gly Cys Cys Ala Ala Cys
1445 1450 1455
Ala Ala Thr Thr Gly Cys Cys Ala Gly Gly Gly Cys Gly Thr Gly
1460 1465 1470
Thr Gly Cys Gly Gly Cys Thr Gly Gly Cys Cys Thr Cys Ala Gly
1475 1480 1485
Thr Cys Cys Gly Ala Cys Cys Gly Cys Ala Ala Cys Cys Cys Gly
1490 1495 1500
Cys Gly Cys Thr Ala Cys Gly Gly Cys Ala Ala Cys Cys Ala Cys
1505 1510 1515
Gly Thr Gly Gly Thr Gly Cys Thr Gly Cys Thr Gly Cys Thr Gly
1520 1525 1530
Ala Ala Gly Ala Thr Gly Cys Ala Gly Gly Thr Cys Cys Gly Thr
1535 1540 1545
Gly Gly Gly Gly Cys Cys Gly Cys Cys Cys Thr Gly Gly Cys Gly
1550 1555 1560
Cys Gly Cys Cys Cys Ala Cys Cys Cys Thr Gly Cys Thr Gly Cys
1565 1570 1575
Gly Thr Gly Cys Cys Cys Ala Cys Cys Gly Cys Cys Thr Ala Cys
1580 1585 1590
Gly Cys Gly Gly Gly Cys Ala Ala Gly Cys Thr Gly Cys Thr Cys
1595 1600 1605
Ala Thr Cys Ala Gly Cys Cys Thr Gly Thr Cys Gly Gly Ala Gly
1610 1615 1620
Gly Ala Gly Cys Gly Cys Ala Thr Cys Ala Gly Cys Gly Cys Gly
1625 1630 1635
Cys Ala Cys Cys Ala Cys Gly Thr Gly Cys Cys Cys Ala Ala Cys
1640 1645 1650
Ala Thr Gly Gly Thr Gly Gly Cys Cys Ala Cys Cys Gly Ala Gly
1655 1660 1665
Thr Gly Thr Gly Gly Cys Thr Gly Cys Cys Gly Gly Thr Gly Ala
1670 1675 1680
<210> 35
<211> 330
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 成熟加工的AMH
<400> 35
agcgcggggg ccaccgccgc cgacgggccg tgcgcgctgc gcgagctcag cgtagacctc 60
cgcgccgagc gctccgtact catccccgag acctaccagg ccaacaattg ccagggcgtg 120
tgcggctggc ctcagtccga ccgcaacccg cgctacggca accacgtggt gctgctgctg 180
aagatgcagg tccgtggggc cgccctggcg cgcccaccct gctgcgtgcc caccgcctac 240
gcgggcaagc tgctcatcag cctgtcggag gagcgcatca gcgcgcacca cgtgcccaac 300
atggtggcca ccgagtgtgg ctgccggtga 330
<210> 36
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 成熟加工的AMH
<400> 36
Ser Val Ser Ser Ser Ala Gly Ala Thr Ala Ala Asp Gly Pro Cys Ala
1 5 10 15
Leu Arg Glu Leu Ser Val Asp Leu Arg Ala Glu Arg Ser Val Leu Ile
20 25 30
Pro Glu Thr Tyr Gln Ala Asn Asn Cys Gln Gly Val Cys Gly Trp Pro
35 40 45
Gln Ser Asp Arg Asn Pro Arg Tyr Gly Asn His Val Val Leu Leu Leu
50 55 60
Lys Met Gln Ala Arg Gly Ala Ala Leu Ala Arg Pro Pro Cys Cys Val
65 70 75 80
Pro Thr Ala Tyr Ala Gly Lys Leu Leu Ile Ser Leu Ser Glu Glu Arg
85 90 95
Ile Ser Ala His His Val Pro Asn Met Val Ala Thr Glu Cys Gly Cys
100 105 110
Arg
<210> 37
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 蛋白酶裂解位点
<220>
<221> X
<222> (1)..(1)
<223> X不存在或为异亮氨酸
<220>
<221> X
<222> (2)..(2)
<223> X 不存在或为丝氨酸
<220>
<221> X
<222> (3)..(3)
<223> X 不存在或为丝氨酸
<220>
<221> X
<222> (8)..(8)
<223> X 不存在或为丝氨酸
<220>
<221> X
<222> (9)..(9)
<223> X不存在或为异亮氨酸
<220>
<221> X
<222> (10)..(10)
<223> X 不存在或为丝氨酸
<220>
<221> X
<222> (11)..(11)
<223> X 不存在或为丝氨酸
<400> 37
Xaa Xaa Xaa Arg Lys Lys Arg Xaa Xaa Xaa Xaa
1 5 10
<210> 38
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 蛋白酶裂解位点
<400> 38
Arg Lys Lys Arg
1
<210> 39
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 蛋白酶裂解位点
<400> 39
Ile Ser Ser Arg Lys Lys Arg
1 5
<210> 40
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 蛋白酶裂解位点
<400> 40
Arg Lys Lys Arg Ser Val Ser Ser
1 5
<210> 41
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> N末端延伸
<400> 41
Ser Val Ser Ser
1
Claims (41)
1.一种分离的抗缪勒氏管激素(AMH)类似物,其包含C末端结构域序列,其中相对于SEQID NO:5所示的天然人成熟加工的AMH多肽,所述C末端结构域包含至少一个氨基酸残基修饰,其中所述修饰存在于SEQ ID NO:1的氨基酸残基533至548中的一个或多个内。
2.根据权利要求1所述的AMH类似物,其中所述AMH类似物的活性相比所述天然成熟加工的AMH多肽的活性为至少2.5倍高。
3.根据权利要求1或权利要求2所述的AMH类似物,其还包含N末端结构域,所述N末端结构域包含与SEQ ID NO:1的氨基酸残基30至447具有至少90%同一性的氨基酸序列。
4.根据权利要求3所述的AMH类似物,其中所述N末端结构域包含具有X1X2X3RKKRX8X9X10X11(SEQ ID NO:37)的前蛋白转化酶位点,其中X1不存在或为异亮氨酸,X2不存在或为丝氨酸,X3不存在或为丝氨酸,X8不存在或为丝氨酸,X9不存在或为缬氨酸,X10不存在或为丝氨酸,并且X11不存在或为丝氨酸。
5.根据权利要求4所述的AMH类似物,其中所述前蛋白转化酶位点包含ISSRKKRSVSS(SEQ ID NO:6)。
6.根据权利要求4所述的AMH类似物,其中所述前蛋白转化酶位点包含RKKR(SEQ IDNO:40)。
7.根据权利要求3至6中任一项所述的AMH类似物,其中所述N末端结构域和C末端结构域是单独的多肽。
8.根据权利要求1至7中任一项所述的AMH类似物,其中存在于SEQ ID NO:1的氨基酸残基533至548中的所述修饰为至少一个氨基酸取代。
9.根据权利要求8所述的AMH类似物,其中存在于SEQ ID NO:1的氨基酸残基533至548中的所述修饰为单氨基酸取代。
10.根据权利要求8或9所述的AMH类似物,其中所述氨基酸取代位于SEQ ID NO:1的氨基酸残基533、535或548处。
11.根据权利要求5至7中任一项所述的AMH类似物,其中所述氨基酸取代选自由(i)G533、(ii)L535和(iii)G533+L535组成的组。
12.根据权利要求8至11中任一项所述的AMH类似物,其中所述取代选自由(i)L535M和(ii)G533A+L535M组成的组。
13.根据权利要求1至12中任一项所述的AMH类似物,其中所述修饰选自由(i)G533A、(ii)G533S、(iii)G533K、(iv)G533L和(v)G533R组成的组。
14.根据权利要求1至13中任一项所述的AMH类似物,其中所述修饰为G533K。
15.根据权利要求1至14中任一项所述的AMH类似物,其中所述C末端结构域包含选自由以下组成的组中的序列:
(i)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYAKKLLISLSEERISAHHVPNMVATECGCR(SEQ ID NO:9);
(ii)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYASKLLISLSEERISAHHVPNMVATECGCR(SEQ ID NO:10);
(iii)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYAAKLLISLSEERISAHHVPNMVATECGCR(SEQ ID NO:11);
(iv)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYAHKLLISLSEERISAHHVPNMVATECGCR(SEQ ID NO:12);
(v)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYAGKMLISLSEERISAHHVPNMVATECGCR(SEQ ID:13);
(vi)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYAAKMLISLSEERISAHHVPNMVATECGCR(SEQ ID NO:14);以及
(vii)SAGATAADGPCALRELSVDLRAERSVLIPETYQANNCQGVCGWPQSDRNPRYGNHVVLLLKMQARGAALARPPCCVPTAYAAKMLISLSEERISAHKVPNMVATECGCR(SEQ ID NO:15)。
16.根据权利要求1至15中任一项所述的AMH类似物,其中所述C末端结构域任选地包含在N末端处的一个或多个另外的氨基酸残基。
17.根据权利要求16所述的AMH类似物,其中所述在N末端处的一个或多个另外的氨基酸残基包含SVSS(SEQ ID NO:41)。
18.根据权利要求1至17中任一项所述的AMH类似物,其还包含融合搭配物,所述融合搭配物选自Fc蛋白、检测标签、纯化标签或载体分子中的一种或多种。
19.一种AMH前体,其包含具有C末端结构域序列的多肽,其中相对于SEQ ID NO:5所示的天然人成熟加工的AMH多肽,所述C末端结构域包含至少一个氨基酸残基修饰,其中所述修饰存在于SEQ ID NO:1的氨基酸残基533至548中的一个或多个内。
20.根据权利要求19所述的AMH前体,其中所述修饰为G533A、G533K或G533S。
21.根据权利要求19或权利要求20所述的AMH前体,其中所述多肽包含SEQ ID NO:1或SEQ ID NO:3所示的序列,其中对应于SEQ ID NO:1的G533的氨基酸通过取代为G533A、G533S或G533K被修饰。
22.一种AMH多核苷酸,其包含SEQ ID NO:4所示的序列,其中SEQ ID NO:4的核苷酸1603至1605处的多核苷酸序列被修饰成编码丙氨酸(A)、丝氨酸(S)或赖氨酸(K)。
23.一种AMH多核苷酸,其包含SEQ ID NO:34所示的序列,其中SEQ ID NO:33的核苷酸1597至1599处的多核苷酸序列被修饰成编码丙氨酸(A)、丝氨酸(S)或赖氨酸(K)。
24.一种AMH多核苷酸,其包含SEQ ID NO:35所示的序列,其中核苷酸244至246处的多核苷酸序列被修饰成编码丙氨酸(A)、丝氨酸(S)或赖氨酸(K)。
25.一种多核苷酸,其编码根据权利要求1至18中任一项所述的AMH类似物或根据权利要求19至21中任一项所述的AMH前体。
26.一种载体,其包含根据权利要求22至25中任一项所述的多核苷酸。
27.根据权利要求26所述的载体,其为AAV载体。
28.一种宿主细胞,其包含根据权利要求26或27所述的载体。
29.一种组合物,其包含根据权利要求1至18中任一项所述的AMH类似物、根据权利要求22至25中任一项所述的多核苷酸或根据权利要求26或27所述的载体。
30.根据权利要求29所述的组合物,其中所述组合物与细胞治疗剂、免疫治疗剂、化学治疗剂或放射治疗剂组合施用。
31.一种预防女性受试者的功能性卵巢储备下降的方法,其包括向所述受试者施用根据权利要求1至18中任一项所述的AMH类似物或根据权利要求29或30所述的组合物。
32.一种女性受试者避孕的方法,其包括向所述受试者施用根据权利要求1至18中任一项所述的AMH类似物或根据权利要求29或30所述的组合物。
33.一种用于受试者的卵巢和/或子宫保护的方法,其包括向所述受试者施用根据权利要求1至18中任一项所述的AMH类似物或根据权利要求29或30所述的组合物。
34.一种用于治疗受试者的妇科癌症的方法,其包括向所述受试者施用根据权利要求1至18中任一项所述的AMH类似物或根据权利要求29或30所述的组合物。
35.根据权利要求31至34中任一项所述的方法,其中所述受试者正接受或即将接受针对癌症的治疗,或者正接受或即将接受针对慢性疾病或病症的治疗。
36.根据权利要求35所述的方法,其中所述受试者患有自身免疫疾病并且将要用、或目前正用、或已经用免疫疗法治疗,或者所述受试者将要用、或目前正用、或已经用造成子宫或卵巢中的细胞的细胞死亡或细胞损伤的细胞毒性药物或细胞毒性剂治疗。
37.根据权利要求31至36中任一项所述的方法,其中所述受试者为人。
38.根据权利要求31至36中任一项所述的方法,其中所述受试者为选自猫、狗和马的非人动物。
39.根据权利要求1至18中任一项所述的AMH类似物在制造用于保存卵巢卵泡储备、避孕、子宫保护或治疗妇科癌症的药物中的用途。
40.根据权利要求31至38中任一项所述的方法或根据权利要求39所述的用途,其中所述AMH类似物作为包含N末端同源二聚体和C末端同源二聚体的四元复合物施用。
41.一种根据权利要求31至38中任一项所述的方法使用的试剂盒,其包括:
(i)施用装置,其包含根据权利要求1至18中任一项所述的AMH类似物;和
(ii)在受试者上使用的说明书。
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