CN103003301B - 血清白蛋白结合分子 - Google Patents
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Abstract
本发明涉及一种基于结合血清白蛋白的纤连蛋白III型第十(10Fn3)结构域的抗体样蛋白质。本发明进一步关于包含结合血清白蛋白的10Fn3连接于异源蛋白质的融合分子,其用于诊断及治疗应用。
Description
相关申请
本申请主张2010年5月3日申请的美国临时申请第61/330,672号的权益,该申请以全文引用的方式并入本文中。
现有技术
许多治疗剂,尤其诸如肽、多肽及多核苷酸的生物制剂的效用因血清半衰期不足而受损。这导致需要以高频率及/或较高剂量投与此类治疗剂,或使用持续释放制剂,以维持为治疗效果所必需的血清水平。频繁地全身投与药物会引起相当大的消极副作用。举例而言,频繁地全身注射给受试者带来相当大的不适,且造成投药相关性感染的高风险,并可能需要住院治疗或频繁地到医院就诊,尤其当欲静脉内投与治疗剂时。另外,在长期治疗中,每天静脉内注射亦会导致相当大的如下副作用:由反复穿刺血管引起的组织疤痕形成及血管病变。已知关于所有频繁的全身性治疗剂投与均存在类似问题,例如向糖尿病患者投与胰岛素,或向罹患多发性硬化症的患者投与干扰素药物。所有此等因素均导致患者顺应性降低并增加卫生系统的成本。
本申请提供可延长各种治疗剂的血清半衰期的化合物、具有延长的血清半衰期的化合物,及延长治疗剂的血清半衰期的方法。用于延长治疗剂的血清半衰期的此类化合物及方法可以成本有效的方式制造或实施,具有理想的生物物理学性质(例如Tm、基本上为单体或良好折叠),且尺寸足够小而允许组织穿透。
发明内容
本发明涉及结合血清白蛋白的纤连蛋白III型第十(10Fn3)结构域及其用途。本文还公开了包含血清白蛋白结合性10Fn3的融合分子及其用途。
在一个方面,本发明提供一种包含纤连蛋白III型第十(10Fn3)结构域的多肽,其中该10Fn3结构域以1μM或更小的KD结合人类血清白蛋白(HSA)的结构域I或II,且其中在白蛋白存在下该多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少5倍。在一个实施方式中,相对于野生型10Fn3结构域,该10Fn3结构域在BC、DE及FG环中的一或多者中包含经修饰的氨基酸序列。
在某些实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内结合HSA。在一个实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内为以200nM或更小的KD结合HSA。在另一个实施方式中,该10Fn3结构域在pH 5.5以200nM或更小的KD结合HSA。
在一些方面中,本文提供一种包含10Fn3结构域的多肽,其中该10Fn3结构域结合HSA且包含与SEQ ID NO:2至少70%同一的氨基酸序列。在一个实施方式中,该10Fn3结构域包括下列中的一或多者:包含SEQ ID NO:5所示的氨基酸序列的BC环、包含SEQ ID NO:6所示的氨基酸序列的DE环、及包含SEQ ID NO:7所示的氨基酸序列的FG环。
在任一上述方面及实施例中,该10Fn3结构域还结合猕猴(rhesus)血清白蛋白(RhSA)、食蟹猴(cynomolgous monkey)血清白蛋白(CySA)或鼠血清白蛋白(MuSA)中的一或多者。在某些实施方式中,该10Fn3结构域不与RhSA、CySA或MuSA中的一或多者交叉反应。
在任一上述方面及实施方式中,该10Fn3结构域以1μM或更小的KD结合HSA。在一些实施方式中,该10Fn3结构域以500nM或更小的KD结合HSA。在其它实施方式中,该10Fn3结构域以至少200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。
在任一上述方面及实施方式中,该10Fn3结构域结合HSA的结构域I或II。在一个实施方式中,该10Fn3结构域结合HSA的结构域I与II。在一些实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内结合HSA。在其它实施方式中,该10Fn3结构域在pH 5.5以200nM或更小的KD结合HSA。在另一个实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内以至少500nM、200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。在一个实施方式中,该10Fn3结构域在pH5.5以至少500nM、200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。
在任一上述方面及实施方式中,在血清白蛋白存在下该多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少2倍。在某些实施方式中,在血清白蛋白存在下该多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少5倍、7倍、10倍、12倍、15倍、20倍、22倍、25倍、27倍或30倍。在一些实施方式中,所述血清白蛋白为HSA、RhSA、CySA或MuSA中的任一者。
在任一上述方面及实施方式中,在血清白蛋白存在下该多肽的血清半衰期为至少20小时。在某些实施方式中,在血清白蛋白存在下该多肽的血清半衰期为至少2小时、2.5小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、12小时、15小时、20小时、25小时、30小时、40小时、50小时、75小时、90小时、100小时、110小时、120小时、130小时、150小时、170小时或200小时。在一些实施方式中,该多肽的半衰期是在灵长类(例如人或猴)或鼠类中观察到的。
在一个方面,本发明提供一种包含10Fn3结构域的多肽,其中该10Fn3结构域结合HSA,且包括:包含SEQ ID NO:5所示的氨基酸序列的BC环、包含SEQ ID NO:6所示的氨基酸序列的DE环、及包含SEQ ID NO:7所示的氨基酸序列的FG环。在另一方面中,该10Fn3结构域包括以下的一或多者:包含SEQID NO:5所示的氨基酸序列的BC环、包含SEQ ID NO:6所示的氨基酸序列的DE环、及包含SEQ ID NO:7所示的氨基酸序列的FG环。
在一个方面,本发明提供一种包含10Fn3结构域的多肽,其中该10Fn3结构域结合HSA,且包括:包含SEQ ID NO:9所示的氨基酸序列的BC环、包含SEQ ID NO:10所示的氨基酸序列的DE环、及包含SEQ ID NO:11所示的氨基酸序列的FG环。在另一方面中,该10Fn3结构域包括以下一或多者:包含SEQID NO:9所示的氨基酸序列的BC环、包含SEQ ID NO:10所示的氨基酸序列的DE环、及包含SEQ ID NO:11所示的氨基酸序列的FG环。
在一个方面,本发明提供一种包含10Fn3结构域的多肽,其中该10Fn3结构域结合HSA,且包括:包含SEQ ID NO:13所示的氨基酸序列的BC环、包含SEQ ID NO:14所示的氨基酸序列的DE环、及包含SEQ ID NO:15所示的氨基酸序列的FG环。在另一方面中,该10Fn3结构域包括以下一或多者:包含SEQ ID NO:13所示的氨基酸序列的BC环、包含SEQ ID NO:14所示的氨基酸序列的DE环及包含SEQ ID NO:15所示的氨基酸序列的FG环。
在一个方面,本发明提供一种包含10Fn3结构域的多肽,其中该10Fn3结构域结合HSA且包括包含SEQ ID NO:17所示的氨基酸序列的BC环、包含SEQ ID NO:18所示的氨基酸序列的DE环及包含SEQ ID NO:19所示的氨基酸序列的FG环。在另一方面中,该10Fn3结构域包括包含SEQ ID NO:17所示的氨基酸序列的BC环、包含SEQ ID NO:18所示的氨基酸序列的DE环及包含SEQ ID NO:19所示的氨基酸序列的FG环中的一或多者。
在任一上述方面及实施方式中,该10Fn3结构域还结合猕猴血清白蛋白(RhSA)、食蟹猴血清白蛋白(CySA)或鼠类血清白蛋白(MuSA)中的一或多者。在一些实施方式中,该10Fn3结构域不与RhSA、CySA或MuSA中的一或多者交叉反应。在某些实施方式中,该10Fn3结构域以1μM或更小的KD结合HSA。在其它实施方式中,该10Fn3结构域以至少1.5μM、1.2μM、1μM、700nM、500nM、300nM、200nM、100nM、75nM、50nM、25nM、10nM或5nM的KD结合HSA。
在任一上述方面及实施方式中,该10Fn3结构域结合HSA的结构域I或II。在某些实施方式中,该10Fn3结构域结合HSA的结构域I与II。在某些实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内结合HSA。在一个实施方式中,该10Fn3结构域在pH 5.5以200nM或更小的KD结合HSA。在另一个实施方式中,该10Fn3结构域在5.5至7.4的pH值范围以至少500nM、200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。在一个实施方式中,该10Fn3结构域在pH5.5以至少500nM、200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。
在任一上述方面及实施方式中,在血清白蛋白存在下该多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少2倍。在某些实施方式中,在血清白蛋白存在下该多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少5倍、7倍、10倍、12倍、15倍、20倍、22倍、25倍、27倍或30倍。在一些实施方式中,所述血清白蛋白为HSA、RhSA、CySA或MuSA中的任一者。
在任一上述方面及实施方式中,在血清白蛋白存在下该多肽的血清半衰期为至少20小时。在某些实施方式中,在血清白蛋白存在下该多肽的血清半衰期为至少2小时、2.5小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、12小时、15小时、20小时、25小时、30小时、40小时、50小时、75小时、90小时、100小时、110小时、120小时、130小时、150小时、170小时或200小时。在一些实施方式中,该多肽的半衰期是在灵长类(例如人类或猴)或鼠类中观察到的。
在一个方面,本发明提供一种包含纤连蛋白III型第十(10Fn3)结构域及异源蛋白质的融合多肽,其中该10Fn3结构域以1μM或更小的KD结合HSA。在某些实施方式中,该10Fn3结构域包含与SEQ ID NO:4至少70%同一的氨基酸序列。在一个实施方式中,该10Fn3结构域包含具有SEQ ID NO:5所示的氨基酸序列的BC环、具有SEQ ID NO:6所示的氨基酸序列的DE环及具有SEQ IDNO:7所示的氨基酸序列的FG环。在另一个实施方式中,该10Fn3结构域包含具有SEQ ID NO:5所示的氨基酸序列的BC环、具有SEQ ID NO:6所示的氨基酸序列的DE环及具有SEQ ID NO:7所示的氨基酸序列的FG环中的一或多者。
在一个实施方式中,该异源蛋白质选自成纤维细胞生长因子21(FGF21)、胰岛素、胰岛素受体肽、GIP(葡萄糖依赖性促胰岛素多肽)、骨形态发生蛋白9(BMP-9)、胰淀素(amylin)、肽YY(PYY3-36)、胰多肽(PP)、白介素21(IL-21)、胰高血糖素样(glucagon-like)肽1(GLP-1)、菌丝霉素(Plectasin)、颗粒蛋白前体(Progranulin)、骨钙蛋白(Osteocalcin,OCN)、Apelin或包含10Fn3结构域的多肽。在其它实施方式中,该异源蛋白质选自GLP-1、Exendin 4、脂连蛋白蛋白(adiponectin)、IL-1RA(白介素1受体拮抗剂)、VIP(血管活性肠肽)、PACAP(垂体腺苷酸环化酶激活多肽)、瘦素、INGAP(胰岛新生相关蛋白)、BMP(骨形态发生蛋白)及骨钙蛋白(OCN)。在一个实施方式中,该异源蛋白质包含SEQ IDNO:118所示的序列。
在某些实施方式中,该异源蛋白质包含结合于除血清白蛋白外的靶蛋白质的第二10Fn3结构域。在其它实施方式中,该融合多肽进一步包含结合靶蛋白质的第三10Fn3结构域。在一个实施方式中,该第三10Fn3结构域结合与第二10Fn3结构域相同的靶。在其它实施方式中,第三10Fn3结构域结合与第二10Fn3结构域不同的靶。
在一个实施方式中,该融合多肽的10Fn3结构域还结合猕猴血清白蛋白(RhSA)、食蟹猴血清白蛋白(CySA)或鼠类血清白蛋白(MuSA)中的一或多者。在其它实施方式中,该10Fn3结构域不与RhSA、CySA或MuSA中的一或多者交叉反应。
在某些实施方式中,该融合多肽的10Fn3结构域以1μM或更小的KD结合HSA。在一些实施方式中,该10Fn3结构域以500nM或更小的KD结合HSA。在其它实施方式中,该10Fn3结构域以至少200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。
在其它实施方式中,该融合多肽的10Fn3结构域结合HSA的结构域I或II。在一个实施方式中,该10Fn3结构域结合HSA的结构域I与II。在一些实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内结合HSA。在其它实施方式中,该10Fn3结构域在pH 5.5以200nM或更小的KD结合HSA。在另一个实施方式中,该10Fn3结构域在5.5至7.4的pH值范围内以至少500nM、200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。在一个实施方式中,该10Fn3结构域在pH5.5下以至少500nM、200nM、100nM、50nM、20nM、10nM或5nM的KD结合HSA。
在一些实施方式中,在血清白蛋白存在下该融合多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少5倍。在某些实施方式中,在血清白蛋白存在下该融合多肽的血清半衰期为在血清白蛋白不存在下该多肽的血清半衰期的至少2倍、5倍、7倍、10倍、12倍、15倍、20倍、22倍、25倍、27倍或30倍。在一些实施方式中,血清白蛋白为HSA、RhSA、CySA或MuSA中的任一者。
在某些实施方式中,在血清白蛋白存在下该融合多肽的血清半衰期为至少20小时。在某些实施方式中,在血清白蛋白存在下该融合多肽的血清半衰期为至少2小时、2.5小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、12小时、15小时、20小时、25小时、30小时、40小时、50小时、75小时、90小时、100小时、110小时、120小时、130小时、150小时、170小时或200小时。在一些实施方式中,该融合多肽的半衰期是在灵长类(例如人类或猴)或鼠类中观察到的。
在任一上述方面及实施方式中,该10Fn3结构域包含选自SEQ ID NO:8、12、16、20及24-44的序列。
在一个方面,本发明提供一种包含纤连蛋白III型第十(10Fn3)结构域的多肽,其中该10Fn3结构域(i)相对于野生型10Fn3结构域,在AB、BC、CD、DE、EF及FG环中的一或多者中包含经修饰的氨基酸序列;(ii)结合野生型10Fn3结构域不结合的靶分子;且(iii)包含具有序列(ED)n的C端尾部,其中n为3至7的整数。在某些实施方式中,该10Fn3结构域包含与SEQ IDNO:1的残基9-94所示的氨基酸序列具有至少60%同一性的氨基酸序列。在一个实施方式中,该C端尾部进一步在N端包含E、I或EI。在一些实施方式中,C端尾部提高该多肽的溶解度及/或减少其聚集。
在某些实施方式中,相对于野生型10Fn3结构域,该10Fn3结构域在BC、DE及FG环的每一者中包含经修饰的氨基酸序列。在某些实施方式中,该多肽以1μM或更小的KD结合靶。
在一些方面中,本发明提供一种包含任一上述方面及实施方式的多肽的药物组合物。在某些实施方式中,该医药组合物包含琥珀酸、甘氨酸及山梨糖醇。在例示性实施方式中,该组合物包含5nM至30mM琥珀酸、5%至15%山梨糖醇及2.5%至10%甘氨酸(pH 6.0)。在某些实施方式中,该组合物包含10mM琥珀酸、8%山梨糖醇及5%甘氨酸(pH 6.0)。在其它实施方式中,该药物组合物进一步包含生理学上可接受的担载体。
附图简述
图1.HAS在小鼠中的体内半衰期。将20mg/kg(图1A)或50mg/kg(图1B)的HSA注入小鼠中。
图2.SABA1-4在小鼠中的半衰期测定结果。图2A:SABA1.1;图2B:SABA2.1;图2C:SABA3.1;及图2D:SABA4.1。
图3.展示当与HSA共注射时SABA1-4在小鼠中的半衰期延长的概要的图。
图4.SABA1.1(图4A)及SABA5.1(图4B)在食蟹猴中的半衰期测定结果。
图5.藉由直接结合ELISA测定法测得的SABA1.2与来自人类、小鼠及大鼠的白蛋白的结合。
图6.SABA1.1及HSA化学计量的测定结果。SABA1.1与HSA以1:1的化学计量结合。
图7.SABA1.2与HSA的重组结构域片段的结合的Biacore分析。
图8.SABA1.2在猴中在投与1mpk及10mpk下的药物动力学概况。
图9.SABA1.2在猴中在静脉内或皮下投予1mpk下的药物动力学概况。
图10.用于生产性表达FGF21及SABA融合物的pET29b载体的质粒图。
图11.在37℃下在PBS缓冲液中SABA-FGF21v1与HSA的融合物的代表性等温滴定热量测定结果。在此测定法中测得的值:N=0.87;KD=3.8×10-9M;ΔH=-15360卡/摩尔。
图12.在37℃下SABA1-FGF21v1与HSA(A)、CySA(B)及MuSA(C)或SABA1-FGF21v3与HSA(D)、CySA(E)及MuSA(F)的结合的SPR传感图数据。
图13.带His标签的FGF21相对于SABA1-FGF21v1在人类血清白蛋白存在下刺激HEKβ-Klotho细胞中的pERK 1/2水平的活性的比较。
图14.在HEK亲本细胞中相对于在HEK β-Klotho细胞中,FGF1、带标签His6的FGF21及SABA1-FGF21v1刺激pERK 1/2水平的活性的比较。HEK亲本细胞(图14A)及HEK β-Klotho表达细胞(图14B)中的pERK 1/2水平的剂量反应刺激的代表图。所绘图中的数据为三份样品的平均值±sem。
图15A及15B.SABA1-FGF21v1在糖尿病ob/ob小鼠中的体内功效的检查结果。餐后血浆葡萄糖水平。
图16.在猴中与带His标签的FGF21相比SABA及FGF21融合物使t1/2增加约27倍。
图17A及17B展示HuSA/SABA1.2复合物的两个视图,其中第二个视图(图17B)绕第一个视图(图17A)垂直轴旋转了70°。HuSA以曲面表现的方式展示,而SABA1.2以示意图(cartoon)展示,即其中β链呈现为箭头而环呈现为带子。SABA1.2上的多样化环以黑色展示,而HuSA上的接触残基以较浅的灰色展示。标出了HuSA的三个结构域(即I、II及III)。
图18.剂量递增及处理群组的示意图(参见实施例A9)。研究周数指示研究的整个持续时间。各群组内的周数(Wk)指示自该群组处理开始起的持续时间。(a)给定群组的处理直至前一群组中的最后一个受试者完成第29天就诊后约4周时才开始,以允许进行PK分析。(b)各群组中的第1、2或3列指示以错开1周的时间间隔(第1群组中的第1与2亚组之间的时间间隔为15天)开始的多个亚组。第1组将包含1个SABA1.2处理的受试者及1个安慰剂受试者;第2组将包含4个SABA1.2处理的受试者及1个安慰剂受试者;第3组将包含5个(对于第1群组)或4个(对于第2及3群组)SABA1.2处理的受试者及1个(对于所有群组)安慰剂受试者。箭头(↑)指示处理(各组的第1及15天);实线(-)指示主动观察期;点线(....)指示安全性追踪。
图19.在ob/ob小鼠中用SABA1-FGF21v1处理14天后的HbA1c水平。
图20.在猴中SABA1-FGF21v1的平均血浆浓度相对于时间的概况(平均值±SD)。
图21.用于固相肽合成的正交保护的氨基酸的实例(上图)。还展示了适用于固相合成的其它构建嵌段(下图)。
发明详述
定义
如本文中所使用的,以下术语及短语应具有下文所述的含义。除非另有定义,否则本文中所使用的所有技术及科学术语均具有与本领域技术人员通常所了解相同的含义。
除非本文另外明确指示,否则单数形式“一”(个/种)及“该”包括复数个指示物。
术语“包含”以包涵性开放意义使用,此意谓可包括其它要素。
术语“包括”用于意谓“包括但不限于”。“包括”及“包括但不限于”可互换使用。
术语“抗体样蛋白质”指具有“免疫球蛋白样折叠”的非免疫球蛋白蛋白质,即包含结构上组织成一组β或β样链,从而形成β片的约80-150个氨基酸残基,其中此类β或β样链藉由插入环部分而连接。这些β片形成抗体样蛋白质的稳定核心,同时产生两个由连接所述β或β样链的环构成的“面”。如本文所述,这些环可经改变而产生定制的配体结合位点,且可在不破坏蛋白质的总体稳定性的情况下产生此类变化。此类抗体样蛋白质的一个实例为“基于纤连蛋白的支架蛋白质”,其意指基于纤连蛋白III型结构域(Fn3)的多肽。在一个方面,抗体样蛋白质基于纤连蛋白III型第十结构域(10Fn3)。
“多肽”意谓具有两个或两个以上氨基酸的任何序列,而与长度、翻译后修饰或功能无关。“多肽”、“肽”及“蛋白质”在本文中可互换使用。
“氨基酸序列同一性百分比(%)”在本文中定义为:在比对序列及必要时引入间隙,以达成最大序列同一性百分比,且不将任何保守性取代视为序列同一性的一部分后,第一序列中与第二序列中的氨基酸残基同一的氨基酸残基的百分比。为测定氨基酸序列同一性百分比的目的,比对可以通过属于本领域技术的范围内的多种方式来实现,例如使用公开可得到的计算机软件,诸如BLAST、BLAST-2、ALIGN、ALIGN-2或Megalign(DNASTAR)软件。本领域技术人员可确定适用于测量比对的参数,包括在所比较的序列全长上达成最大比对所需的任何算法。然而,出于本文的目的,氨基酸序列同一性%值如下文所述藉由使用序列比较计算机程序ALIGN-2来获得。ALIGN-2序列比较计算机程序由Genentech,Inc.创作,其已在美国版权局(U.S.CopyrightOffice)(Washington D.C.,20559)与用户文件一起备案,在美国版权局其以美国版权登记号TXU510087登记,且可公开经由Genentech,Inc.(SouthSanFrancisco,Calif)得到。ALIGN-2程序应经编译以于UNIX操作系统、优选为数字UNIXV4.0D上使用。所有序列比较参数均由ALIGN-2程序设定且并不变化。
为本文的目的,如下计算特定氨基酸序列A与特定氨基酸序列B的氨基酸序列同一性%(其或者可表述为特定氨基酸序列A与特定氨基酸序列B具有或包含某一氨基酸序列同一性%):100×(X/Y),其中X为在A与B的序列比对程序ALIGN-2比对中由该程序评定为同一匹配的氨基酸残基的数目,且其中Y为B的氨基酸残基的总数。应了解,若氨基酸序列A的长度不等于氨基酸序列B的长度,则A与B的氨基酸序列同一性%不会等于B与A的氨基酸序列同一性%。
术语“治疗有效量”指可有效治疗哺乳动物的疾病或病症及/或在一定程度上缓解与该病症相关的一种或多种症状的药物的量。
术语“SABA”指血清白蛋白结合AdnectinsTM(Serum Albumin BindingAdnectinsTM)。AdnectinsTM(Adnexus,一家属于Bristol-Myers Squibb的研发公司)为基于第十纤连蛋白III型结构域,即Fn3的第十模块(10Fn3)的配体结合性支架蛋白质。
氨基酸序列或化合物的半衰期(t1/2)通常可定义为在体内多肽的血清浓度降低50%(例如由于天然机制对该序列或化合物的降解及/或该序列或化合物的清除或螯合)所用的时间。半衰期可以现有技术中已知的任何方式来测定,诸如利用药物动力学分析。参见例如M Gibaldi及D Perron“Pharmacokinetics”,由Marcel Dekker出版,第2修订版(1982)。半衰期可使用诸如t1/2-α、t1/2-β及曲线下面积(AUC)等参数来表示。“半衰期增加”指这些参数中的任一者、这些参数中的任两者或这些参数的所有三个增加。在某些实施方式中,半衰期增加指t1/2-β增加,而t1/2-α或AUC或两者有增加或无增加。
术语“PK”为“药物动力学”的缩写,涵盖化合物的性质,包括例如受试者对其的吸收、分布、代谢及消除。“PK调节蛋白质”或“PK部分”指当与生物活性分子融合或与其一起投与时影响生物活性分子的药物动力学性质的任何蛋白质、肽或部分。
综述
Fn3指纤连蛋白的III型结构域。Fn3结构域为小的、单体的、可溶且稳定。其缺乏二硫键,因此在还原条件下是稳定的。Fn3的总体结构类似于免疫球蛋白折叠。依自N端至C端的次序,Fn3结构域包含β或β样链A;环AB;β或β样链B;环BC;β或β样链C;环CD;β或β样链D;环DE;β或β样链E;环EF;β或β样链F;环FG;及β或β样链G。七个反平行β链排列成两个β片,它们形成稳定的核心,同时产生两个由连接β或β样链的环构成的“面”。环AB、CD及EF位于一个面上且环BC、DE及FG位于相对的面上。任何或所有环AB、BC、CD、DE、EF及FG均可参与配体结合。Fn3存在至少15种不同模块,且虽然此类模块之间的序列同源性较低,但其三级结构均共有高度相似性。
AdnectinsTM(Adnexus,一家Bristol-Myers Squibb的研发公司)为基于第十纤连蛋白III型结构域,即Fn3的第十模块(10Fn3)的配体结合骨架蛋白质。天然存在的人类10Fn3的氨基酸序列如SEQ ID NO:1所示:
VSDVPRDLEVVA ATPTSLLISWDAPAVTVRYYRITYGETGGNSPVQEFTVPGSKSTATISGLKPGVDYTITVYAVTGRGDSPASSKPISINYRT (SEQID NO:1)(对AB、CD及EF环加有下划线,且对BC、FG及DE环以粗体突出)。
在SEQ ID NO:1中,AB环对应于残基15-16,BC环对应于残基21-30,CD环对应于残基39-45,DE环对应于残基51-56,EF环对应于残基60-66,且FG环对应于残基76-87。(Xu等人,Chemistry&Biology 20029:933-942)。BC、DE及FG环沿该分子的一个面排列且AB、CD及EF环沿该分子的相对面排列。在SEQ ID NO:1中,β链A对应于残基9-14,β链B对应于残基17-20,β链C对应于残基31-38,β链D对应于残基46-50,β链E对应于残基57-59,β链F对应于残基67-75,且β链G对应于残基88-94。这些链经由相应环彼此连接,例如链A与B经由环AB以链A、环AB、链B的构造连接。SEQ ID NO:1的开头8个氨基酸(上文中的斜体)可以加以缺失而仍保留分子的结合活性。形成疏水性核心(“核心氨基酸残基”)所涉及的残基包括对应于SEQ IDNO:1的以下氨基酸的氨基酸:L8、V10、A13、L18、I20、W22、Y32、I34、Y36、F48、V50、A57、I59、L62、Y68、I70、V72、A74、I88、I90及Y92,其中核心氨基酸残基以单字母氨基酸符号后随其在SEQ ID NO:1中的位置来表示。参见例如Dickinson等人,J.Mol.Biol.236:1079-1092(1994)。
10Fn3在结构及功能上类似于抗体,尤其是抗体的可变区。虽然10Fn3结构域可描述为“抗体模拟物”或“抗体样蛋白质”,但其提供许多优于常规抗体的优点。具体而言,与抗体相比,其展现更好的折叠及热稳定性性质,且其缺乏已知在某些条件下妨碍或阻碍适当折叠的二硫键。例示性的基于血清白蛋白10Fn3的结合物主要为Tm平均为约65℃的单体。
10Fn3的BC、DE及FG环类似于来自免疫球蛋白的互补决定区(CDR)。在这些环区中氨基酸序列的变化可改变10Fn3的结合特异性。亦可制备在AB、CD及EF环中具有修饰的10Fn3结构域以产生结合所需靶的分子。环外的蛋白质序列类似于来自免疫球蛋白的框架区且在10Fn3的结构构象中起作用。以结构构象不改变到破坏配体结合的程度为限,10Fn3的框架样区中的变化是可允许的。产生10Fn3配体特异性结合物的方法已描述于以下文献中:PCT公开第WO 00/034787号、第WO 01/64942号及第WO 02/032925号,其披露高亲和力TNFα结合物;PCT公开第WO 2008/097497号,其披露高亲和力VEGFR2结合物;及PCT公开第WO 2008/066752号,其披露高亲和力IGFIR结合物。讨论10Fn3结合物及选择结合物的方法的其它参考文献包括PCT公开第WO98/056915号、第WO 02/081497号及第WO 2008/031098号及美国公开第2003186385号。
如上文所述,对应于SEQ ID NO:1的残基21-30、51-56及76-87的氨基酸残基分别定义BC、DE及FG环。然而应了解,并非环区中的每一残基均需要修饰以产生对所需靶(诸如人类血清白蛋白)具有强亲和力的10Fn3结合物。举例而言,在本文所述的许多实例中,仅有对应于BC环的氨基酸23-30及DE环的52-55的残基被修饰而产生高亲和力10Fn3结合物。相应地,在某些实施方式中,BC环可由对应于SEQ ID NO:1的残基23-30的氨基酸定义,且DE环可由对应于SEQ ID NO:1的残基52-55的氨基酸定义。另外,亦可制造环区中的插入及缺失,而仍产生高亲和力的10Fn3结合物。举例而言,SEQ ID NO:4(SABA 1)为HSA结合物的一个实例,其中FG环含有四个氨基酸缺失,即对应于SEQ ID NO:1的21-29的11个残基被替换为7个氨基酸。SEQ ID NO:113为HSA结合物的一个实例,其中FG环含有氨基酸插入,即对应于SEQIDNO:1的氨基酸21-29的11个残基被替换为12个氨基酸。
因此,在一些实施方式中,相对于野生型人类10Fn3中的相应环,选自BC、DE及FG的一或多个环的长度可延伸或缩短。在一些实施方式中,环的长度可延伸2-25个氨基酸。在一些实施方式中,环的长度可减少1-11个氨基酸。具体地,10Fn3的FG环的长度为12个残基,而抗体重链中的相应环在4-28个残基范围内。因此,为最优化抗原结合,10Fn3的FG环的长度及序列均可加以改变以涵盖4-28个残基的CDR3范围以便获得最大可能的抗原结合柔性及亲和力。在一些实施方式中,整联蛋白结合基序“精氨酸-甘氨酸-天冬氨酸”(RGD)可替换为极性氨基酸-中性氨基酸-酸性氨基酸序列(沿N端至C端方向)。
10Fn3通常以对应于SEQ ID NO:1的编号1的氨基酸残基开始。然而,具有氨基酸缺失的结构域亦涵盖于本发明中。在一些实施方式中,对应于SEQID NO:1的开头8个氨基酸的氨基酸残基缺失。亦可添加额外序列至N或C端。举例而言,可将额外的MG序列置于10Fn3的N端。M通常会被切去,在N端留下G。在一些实施方式中,延伸序列可位于10Fn3域的C端,例如EIDKPSQ(SEQ ID NO:54)、EIEKPSQ(SEQ ID NO:60)或EIDKPSQLE(SEQ ID NO:61)。此类C端序列在本文中称为“尾部”或“延伸”,且在本文中有进一步描述。在一些实施方式中,可将His6标签置于N端或C端。
10Fn3的非配体结合序列,即“10Fn3支架”可被改变,条件是10Fn3保留配体结合功能及/或结构稳定性。在一些实施方式中,Asp 7、Glu 9及Asp 23中的一或多者被替换为另一氨基酸,例如非带负电的氨基酸残基(例如Asn、Lys等)。已报导这些突变具有在中性pH值下与野生型形式相比促进突变10Fn3的稳定性提高的作用(参见PCT公开第WO 02/04523号)。已公开了有益或中性的10Fn3支架中的各种其它的有益或中性的变化。参见例如Batori等人,ProteinEng.200215(12):1015-20;Koide等人,Biochemistry 200140(34):10326-33。
10Fn3支架可藉由一或多个保守性取代来修饰。10Fn3支架中的多达5%、10%、20%或甚至30%或更多氨基酸可藉由保守性取代来改变而不实质上改变10Fn3对配体的亲和力。举例而言,支架修饰优选使10Fn3结合物对配体的结合亲和力降低至小于1/100、1/50、1/25、1/10、1/5或1/2。此类变化可能会改变10Fn3的体内免疫原性,而在免疫原性降低的情况下,这样的变化是理想的。如本文中所使用的,“保守性取代”为在物理或功能上类似于相应的参考残基的残基。亦即,保守性取代及其参考残基具有类似的尺寸、形状、电荷、化学性质(包括形成共价键或氢键的能力)或其类似性质。优选的保守性取代为满足Dayhoff等人,Atlasof Protein Sequence and Structure 5:345-352(1978及增刊)中对可接受的点突变所定义的标准的那些保守性取代。保守性取代的实例为以下各组中的取代:(a)缬氨酸、甘氨酸;(b)甘氨酸、丙氨酸;(c)缬氨酸、异亮氨酸、亮氨酸;(d)天冬氨酸、谷氨酸;(e)天冬酰胺、谷氨酰胺;(f)丝氨酸、苏氨酸;(g)赖氨酸、精氨酸、甲硫氨酸;及(h)苯丙氨酸、酪氨酸。
在某些实施方式中,基于10Fn3支架的抗体样蛋白质可由以下序列一般性地定义:
EVVAAT(X)a SLLI(X)x YYRITYGE(X)b QEFTV(X)y ATI(X)c DYTITVYAV(X)z ISINYRT (SEQID NO:2)。
在SEQ ID NO:2中,AB环由Xa表示,CD环由Xb表示,EF环由Xc表示,BC环由Xx表示,DE环由Xy表示,且FG环由Xz表示。X表示任何氨基酸,且X后的下标表示氨基酸数目的整数。具体的,a可为1-15、2-15、1-10、2-10、1-8、2-8、1-5、2-5、1-4、2-4、1-3、2-3或1-2个氨基酸中的任一者;且b、c、x、y及z可各独立地为2-20、2-15、2-10、2-8、5-20、5-15、5-10、5-8、6-20、6-15、6-10、6-8、2-7、5-7或6-7个氨基酸中的任一者。在优选的实施方式中,a为2个氨基酸,b为7个氨基酸,c为7个氨基酸,x为9个氨基酸,y为6个氨基酸,且z为12个氨基酸。相对于SEQID NO:1所示的相应氨基酸,β链的序列可在所有7个支架区中具有0至10、0至8、0至6、0至5、0至4、0至3、0至2或0至1个取代、缺失或添加中的任一者。在一个例示性实施方式中,相对于SEQ ID NO:1所示的相应氨基酸,β链的序列可在所有7个支架区中具有0至10、0至8、0至6、0至5、0至4、0至3、0至2或0至1个保守性取代中的任一者。在某些实施方式中,核心氨基酸残基为固定的,且任何取代、保守性取代、缺失或添加存在于除核心氨基酸残基外的残基处。在例示性实施方式中,由(X)x、(X)y及(X)z表示的BC、DE及FG环分别被替换为包含来自下表2中所示的任意HSA结合物(亦即表2中的SEQ ID NO:4、8、12、16、20及24-44)的BC、DE及FG环序列的多肽。
在某些实施方式中,基于10Fn3支架的抗体样蛋白质可由以下序列一般性定义:
EVVAATPTSLLI(X)x YYRITYGETGGNSPVQEFTV(X)y ATISGLKPGVDYTITVYAV(X)z ISINYRT(SEQ ID NO:3)。
在SEQ ID NO:3中,BC环由Xx表示,DE环由Xy表示,且FG环由Xz表示。X表示任何氨基酸,且X后的下标表示氨基酸数目的整数。具体的,x、y及z可各独立地为2-20、2-15、2-10、2-8、5-20、5-15、5-10、5-8、6-20、6-15、6-10、6-8、2-7、5-7或6-7个氨基酸中的任一者。在优选的实施方式中,x为9个氨基酸,y为6个氨基酸,且z为12个氨基酸。相对于SEQ ID NO:1所示的相应氨基酸,β链的序列可在所有7个支架区中具有0至10、0至8、0至6、0至5、0至4、0至3、0至2或0至1个取代、缺失或添加中的任一者。在一个例示性的实施方式中,相对于SEQ IDNO:1所示的相应氨基酸,β链的序列可在所有7个支架区中具有0至10、0至8、0至6、0至5、0至4、0至3、0至2或0至1个保守性取代中的任一者。在某些实施方式中,核心氨基酸残基是固定的,且任何取代、保守性取代、缺失或添加存在于除核心氨基酸残基外的残基处。在例示性实施方式中,分别由(X)x、(X)y及(X)z表示的BC、DE及FG环被替换为包含来自下表2中所示的任意HSA结合物(亦即表2中的SEQ ID NO:4、8、12、16、20及24-44)的BC、DE及FG环序列的多肽。
具有ED尾部的10Fn3结构域
在一个方面,本发明提供一种包含纤连蛋白III型第十(10Fn3)结构域的多肽,其中该10Fn3结构域(i)相对于野生型10Fn3结构域,在AB、BC、CD、DE、EF及FG环中的一或多者中包含经修饰的氨基酸序列;(ii)结合野生型10Fn3结构域不结合的靶分子;且(iii)包含具有序列(ED)n的C端尾部,其中n为2-10、2-8、2-5、3-10、3-8、3-7、3-5或4-7的整数,或其中n为2、3、4、5、6、7、8、9或10。
在某些实施方式中,10Fn3结构域包含与SEQ ID NO:1的残基9-94所示的氨基酸序列具有至少60%、65%、70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的氨基酸序列。在某些实施方式中,10Fn3结构域包含SEQID NO:1、2或3。在某些实施方式中,10Fn3结构域包含SEQ ID NO:1的氨基酸9-94。
在某些实施方式中,具有ED尾部的10Fn3结构域在C端紧邻着ED重复序列之前包含E、I或EI。在一些实施方式中,ED重复序列提高10Fn3结构域的溶解度及/或减少其聚集。
在某些实施方式中,相对于野生型10Fn3域,具有ED尾部的10Fn3域在BC、DE及FG环的每一者中包含经修饰的氨基酸序列。在其它实施方式中,具有ED尾部的10Fn3结构域以1μM或更小的KD结合所需的靶。
血清白蛋白结合物
10Fn3结构域由于其约10kDa的小尺寸而通过肾过滤及降解自循环快速清除(t1/2=在小鼠体内15-45分钟;在猴体内3小时)。在某些方面中,本申请提供特异性结合血清白蛋白(例如人类血清白蛋白(HSA))以延长10Fn3结构域的t1/2的10Fn3结构域。
HSA的血清浓度为600μM且在人体内t1/2为19天。HSA的t1/2的延伸已部分被归因于其经由新生Fc受体(FcRn)的再循环。在经由内体摄取至内皮细胞中后,HSA以pH值依赖性方式结合FcRn;此相互作用使HSA再循环回到血流中,从而使其避免溶酶体降解。FcRn被广泛地表达,且其再循环路径被认为是组成性的。在大多数细胞类型中,大部分FcRn存在于细胞内分选内体中。HSA容易藉由流体相胞饮作用的非特异性机制内在化,且被FcRn自溶酶体降解中救出。在内体中所见的酸性pH值下,HSA对FcRn的亲和力增加(在pH 6.0下为5μM)。一旦结合于FcRn,则HSA避开溶酶体降解路径,胞转(transcytosed)至细胞表面并在细胞表面释放。
在一个方面,本发明提供包含血清白蛋白结合性10Fn3结构域的抗体样蛋白质。在例示性实施方式中,本文所述的血清白蛋白结合性10Fn3蛋白质以小于3μM、2.5μM、2μM、1.5μM、1μM、500nM、100nM、50nM、10nM、1nM、500pM、100pM、50pM或10pM的KD结合HSA。在某些实施方式中,本文所述的血清白蛋白结合性10Fn3蛋白质在25℃或37℃下在5.5至7.4的pH值范围内以小于3μM、2.5μM、2μM、1.5μM、1μM、500nM、100nM、50nM、10nM、1nM、500pM、100pM、50pM或10pM的KD结合HSA。在一些实施方式中,与在7.4或更大的pH值下对HSA的结合亲和力相比,本文所述的血清白蛋白结合性10Fn3蛋白质在小于7.4的pH值下较紧密地结合于HSA。
在某些实施方式中,本文所述的HSA结合性10Fn3蛋白质亦可结合来自猴、大鼠或小鼠中的一或多者的血清白蛋白。在某些实施方式中,本文所述的血清白蛋白结合性10Fn3蛋白质以小于3μM、2.5μM、2μM、1.5μM、1μM、500nM、100nM、50nM、10nM、1nM、500pM或100pM的KD结合猕猴血清白蛋白(RhSA)或食蟹猴血清白蛋白(CySA)。
在某些实施方式中,本文所述的血清白蛋白结合性10Fn3蛋白质结合HSA的结构域I及/或结构域II。在一个实施方式中,本文所述的血清白蛋白结合性10Fn3蛋白质不结合HSA的结构域III。
在某些实施方式中,血清白蛋白结合性10Fn3(SABA)包含与野生型10Fn3结构域(SEQ ID NO:1)具有至少40%、50%、60%、70%、75%、80%或85%同一性的序列。在一个实施方式中,相对于野生型10Fn3结构域,BC、DE或FG环中的至少一者是经修饰的。在另一个实施方式中,相对于野生型10Fn3结构域,BC、DE或FG环中的至少两者是经修饰的。在另一个实施方式中,相对于野生型10Fn3结构域,BC、DE及FG环中的所有三者均是经修饰的。在其它实施方式中,SABA包含与表2中所示的26个核心SABA序列(即SEQ IDNO:4、8、12、16、20及24-44)中的任一者或表2中所示的延伸SABA序列(亦即SEQ ID NO:89-116,减去6×HIS标签)中的任一者具有至少40%、50%、60%、70%、75%、80%、85%、90%或95%同一性。
在某些实施方式中,如本文所述的SABA可包含如SEQ ID NO:2或3所示的序列,其中分别由(X)x、(X)y及(X)z表示的BC、DE及FG环被替换为来自26个核心SABA序列(亦即表2中的SEQ ID NO:4、8、12、16、20及24-44)中的任一者或与26个核心SABA序列的BC、DE及FG环序列至少75%、80%、85%、90%、95%、97%、98%或99%同一的序列的各别的一组指定的BC、DE及FG环。在例示性实施方式中,如本文所述的SABA由SEQ ID NO:3定义且具有来自26个核心SABA序列(亦即表2中的SEQ ID NO:4、8、12、16、20及24-44)中的任一者的一组BC、DE及FG环序列。相对于SEQ ID NO:1的支架氨基酸残基,此类SABA的支架区可具有0至20、0至15、0至10、0至8、0至6、0至5、0至4、0至3、0至2或0至1个取代、保守性取代、缺失或添加中的任一者。举例而言,SABA1具有SEQ ID NO:4所示的核心序列且包含如SEQ ID NO:5-7分别所示的BC、DE及FG环。因此,基于SABA1核心的SABA可包含SEQ IDNO:2或3,其中(X)x包含SEQ ID NO:5,(X)y包含SEQ ID NO:6,且(X)z包含SEQ ID NO:7。预期使用来自其它SABA核心序列的该组BC、DE及FG环的类似构建体。相对于SEQ ID NO:1的支架氨基酸残基,此类SABA的支架区可包含0至20、0至15、0至10、0至8、0至6、0至5、0至4、0至3、0至2或0至1个取代、保守性取代、缺失或添加中的任一者。可进行此类支架修饰,只要SABA能够以所需KD结合血清白蛋白(例如HSA)即可。
在某些实施方式中,SABA (例如SABA核心序列或如上文所述的基于SABA核心序列的序列)可经修饰以包含N端延伸序列及/或C端延伸序列。例示性延伸序列展示于表2中。举例而言,称为SABA1.1的SEQ ID NO:89包含具有N端序列MGVSDVPRDLE(SEQ ID NO:45,称为AdNT1)及C端序列EIDKPSQ(SEQ ID NO:54,称为AdCT1)的核心SABA 1序列(SEQ ID NO:4)。然而,SABA1.1进一步在C端包含His6标签,应了解His6标签完全是任选的,且可位于N或C端延伸序列中的任何地方。此外,表2中所提供的任一例示性N或C端延伸序列(SEQ ID NO:45-64及215)及其任何变体可用于修饰表2中所提供的任何特定SABA核心序列。在某些实施方式中,表2中所提供的接头序列(SEQ ID NO:65-88、216-221及397)可单独或与SEQ ID NO:54-64或215中的一者组合用作C端尾部序列。
在某些实施方式中,C端延伸序列(亦称为“尾部”)包含E及D残基,且长度可为8至50、10至30、10至20、5至10及2至4个氨基酸。在一些实施方式中,尾部序列包括基于ED的接头,其中序列包含ED的串联重复序列。在例示性实施方式中,尾部序列包含2-10、2-7、2-5、3-10、3-7、3-5、3、4或5个ED重复序列。在某些实施方式中,基于ED的尾部序列亦可包括其它氨基酸残基,例如:EI、EID、ES、EC、EGS及EGC。此类序列部分地基于已知AdnectinTM尾部序列,诸如EIDKPSQ(SEQ ID NO:54),其中残基D及K已被移除。在例示性实施方式中,基于ED的尾部在ED重复序列之前包含E、I或EI残基。
在其它实施方式中,当设计SABA融合分子,例如SEQ ID NO:147(SABA1-FGF21v16)(其中EIEDEDEDEDED与GSGSGSGS连接)时,尾部序列可视需要与其它已知接头序列(例如表2中的SEQ ID NO:65-88、216-221及397)组合。
血清白蛋白结合AdnectinTM(SABA)的融合物
本发明的一个方面提供包含血清白蛋白结合性10Fn3(SABA)及至少一个其它部分的缀合物。该其它部分可适用于任何诊断性、成像或治疗性目的。
在某些实施方式中,相对于不与SABA缀合的部分的血清半衰期,与SABA融合的部分的血清半衰期得到增加。在某些实施方式中,SABA融合物的血清半衰期为该部分不与SABA融合时的血清半衰期的至少20、40、60、80、100、120、150、180、200、400、600、800、1000、1200、1500、1800、1900、2000、2500或3000%。在其它实施方式中,SABA融合物的血清半衰期为该部分不与SABA融合时的血清半衰期的至少1.5倍、2倍、2.5倍、3倍、3.5倍、4倍、4.5倍、5倍、6倍、7倍、8倍、10倍、12倍、13倍、15倍、17倍、20倍、22倍、25倍、27倍、30倍、35倍、40倍或50倍。在一些实施方式中,SABA融合物的血清半衰期为至少2小时、2.5小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、15小时、20小时、25小时、30小时、35小时、40小时、50小时、60小时、70小时、80小时、90小时、100小时、110小时、120小时、130小时、135小时、140小时、150小时、160小时或200小时。
在某些实施方式中,SABA融合蛋白结合HSA的KD为小于3μM、2.5μM、2μM、1.5μM、1μM、500nM、100nM、50nM、10nM、1nM、500pM、100pM、50pM或10pM。在某些实施方式中,SABA融合蛋白在25℃或37℃下在5.5至7.4的pH值范围内以小于3μM、2.5μM、2μM、1.5μM、1μM、500nM、100nM、50nM、10nM、1nM、500pM、100pM、50pM或10pM的KD结合HSA。在一些实施方式中,与在pH7.4下结合相比,SABA融合蛋白在小于7.4的pH值下更紧密地结合HSA。
因此,本文所述的SABA融合分子适用于藉由形成治疗性部分与SABA之间的融合物来增加治疗性部分(例如FGF21)的半衰期。此类融合分子可用于治疗对融合物中所含的治疗性部分的生物活性有反应的病症。本发明涵盖SABA融合分子在由任一以下蛋白质或分子降解所引起的疾病中的用途。
异源部分
在一些实施方式中,SABA与第二部分融合,该第二部分为小有机分子、核酸或蛋白质。在一些实施方式中,SABA与治疗性部分融合,该治疗性部分靶向受体、受体配体、病毒外壳蛋白、免疫系统蛋白质、激素、酶、抗原或细胞信号传导蛋白质。该融合物可藉由将第二部分连接于SABA分子的任意末端(亦SABA-治疗性分子排列或治疗性分子-SABA排列)来形成。
在例示性实施方式中,该治疗性部分为VEGF、VEGF-Rl、VEGF-R2、VEGF-R3、Her-1、Her-2、Her-3、EGF-I、EGF-2、EGF-3、α3、cMet、ICOS、CD40L、LFA-I、c-Met、ICOS、LFA-I、IL-6、B7.1、Wl.2、OX40、IL-Ib、TACI、IgE、BAFF或BLys、TPO-R、CD19、CD20、CD22、CD33、CD28、IL-I-Rl、TNF-α、TRAIL-Rl、补体受体1、FGFa、骨桥蛋白(Osteopontin)、玻璃连结蛋白(Vitronectin)、埃弗林(Ephrin)A1-A5、埃弗林B1-B3、α-2-巨球蛋白、CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CXCL8、CXCL9、CXCLlO、CXCLI 1、CXCL12、CCL13、CCL14、CCL15、CXCL16、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、PDGF、TGFb、GMCSF、SCF、p40(IL12/IL23)、ILIb、ILIa、ILlra、IL2、IL3、IL4、IL5、IL6、IL8、ILlO、IL12、IL15、IL23、Fas、FasL、Flt3配体、41BB、ACE、ACE-2、KGF、FGF-7、SCF、网蛋白(Netrin)1、网蛋白2、IFNa、IFNb、IFNg、胱天蛋白酶(Caspase)2、胱天蛋白酶3、胱天蛋白酶7、胱天蛋白酶8、胱天蛋白酶10、ADAMS1、ADAM S5、ADAM 8、ADAM 9、ADAM 15、ADAM TS1、ADAM TS5;脂连蛋白(Adiponectin)、ALCAM、ALK-I、APRIL、磷脂结合蛋白(Annexin)V、血管生成素、双调蛋白(Amphiregulin)、血管位蛋白(Angiopoietin)1、血管位蛋白2、血管位蛋白4、B7-1/CD80、B7-2/CD86、B7-H1、B7-H2、B7-H3、Bcl-2、BACE-I、BAK、BCAM、BDNF、bNGF、bECGF、BMP2、BMP3、BMP4、BMP5、BMP6、BMP7、BMP8;CRP、钙黏素6、钙黏素8、钙黏素11;组织蛋白酶A、组织蛋白酶B、组织蛋白酶C、组织蛋白酶D、组织蛋白酶E、组织蛋白酶L、组织蛋白酶S、组织蛋白酶V、组织蛋白酶X;CDlla/LFA-1、LFA-3、GP2b3a、GH受体、RSV F蛋白、IL-23(p40、pl9)、IL-12、CD80、CD86、CD28、CTLA-4、α4-β1、α4-β7、TNF/淋巴毒素、IgE、CD3、CD20、IL-6、IL-6R、BLYS/BAFF、IL-2R、HER2、EGFR、CD33、CD52、地高辛(Digoxin)、Rho(D)、水痘(Varicella)、肝炎、CMV、破伤风、牛痘、抗蛇毒(Antivenom)、肉毒梭菌、Trail-R1、Trail-R2、cMet、TNF-R家族(诸如LA NGF-R)、CD27、CD30、CD40、CD95、淋巴毒素a/b受体、WsI-I、TL1A/TNFSF15、BAFF、BAFF-R/TNFRSF13C、TRAILR2/TNFRSF10B、TRAIL R2/TNFRSF 10B、Fas/TNFRSF6CD27/TNFRSF7、DR3/TNFRSF25、HVEM/TNFRSF 14、TROY/TNFRSF 19、CD40配体/TNFSF5、BCMA/TNFRSF17、CD30/TNFRSF8、LIGHT/TNFSF14、4-1BB/TNFRSF9、CD40/TNFRSF5、GITR/[γ]NFRSF 18、骨保护蛋白(Osteoprotegerin)/TNFRSF 1IB、RANK/TNFRSF 1IA、TRAIL R3/TNFRSF 10C、TRAIL/TNFSFIO、TRANCE/RANK L/TNFSF11、4-1BB配体/TNFSF9、TWEAK/TNFSF12、CD40配体/TNFSFS、Fas配体/TNFSF6、RELT/TNFRSF19L、APRIL/TNFSF13、DcR3/TNFRSF6B、TNF RI/TNFRSFIA、TRAILR1/TNFRSFIOA、TRAILR4/TNFRSF10D、CD30配体/TNFSF8、GITR配体/TNFSF18、TNFSF18、TACI/TNFRSF13B、NGF R/TNFRSF16、OX40配体/TNFSF4、TRAILR2/TNFRSF10B、TRAIL R3/TNFRSF10C、TWEAK R/TNFRSF12、BAFF/BLyS/TNF SF13、DR6/TNFRSF21、TNF-α/TNF SF 1A、Pro-TNF-α/TNFSF1A、淋巴毒素βR/TNFRSF3、淋巴毒素βR(LTbR)/Fc嵌合体、TNF RI/TNFRSFIA、TNF-β/TNFSF 1B、PGRP-S、TNF RI/TNFRSFIA、TNF RII/TNFRSFIB、EDA-A2、TNF-α/TNFSFIA、EDAR、XEDAR、TNFRI/TNFRSFIA。
备受关注的是以纯化形式市售的人类靶蛋白质以及结合于这些靶蛋白质的蛋白质。实例为:4EBP1、14-3-3ζ、53BP1、2B4/SLAMF4、CCL21/6Ckine、4-1BB/TNFRSF9、8D6A、4-1BB配体/TNFSF9、8-氧代-dG、4-氨基-1,8-萘二甲酰亚胺、A2B5、氨肽酶LRAP/ERAP2、A33、氨肽酶N/ANPEP、Aag、氨肽酶P2/XPNPEP2、ABCG2、氨肽酶Pl/XPNPEPl、ACE、氨肽酶PILS/ARTSl、ACE-2、无羊膜(Amnionless)、肌动蛋白、双调蛋白、β-肌动蛋白、AMPK α1/2、活化素(Actin)A、AMPK α1、活化素AB、AMPK α2、活化素B、AMPKβ1、活化素C、AMPK β2、活化素RIA/ALK-2、雄激素R/NR3C4、活化素RIB/ALK-4、血管生成素、活化素RIIA、血管位蛋白-1、活化素RIIB、血管位蛋白-2、ADAM8、血管位蛋白-3、ADAM9、血管位蛋白-4、ADAMlO、血管位蛋白样1、ADAM12、血管位蛋白样2、ADAM15、血管位蛋白样3、TACE/ADAM17、血管位蛋白样4、ADAM19、血管位蛋白样7/CDT6、ADAM33、血管抑制素、ADAMTS4、磷脂结合蛋白Al/磷脂结合蛋白I、ADAMTS5、磷脂结合蛋白A7、ADAMTSl、磷脂结合蛋白AlO、ADAMTSL-1/普克汀(Punctin)、磷脂结合蛋白V、脂连蛋白/Acrp30、ANP、AEBSF、AP位点、聚蛋白聚糖(Aggrecan)、APAF-I、聚集蛋白(Agrin)、APC、AgRP、APE、AGTR-2、APJ、AIF、APLP-I、Akt、APLP-2、Aktl、载脂蛋白(Apolipoprotein)AI、Akt2、载脂蛋白B、Akt3、APP、血清白蛋白、APRIL/TNFSF13、ALCAM、ARC、ALK-I、阿特明(Artemin)、ALK-7、芳基硫酸酯酶AJARSA、碱性磷酸酶、ASAH2/N-酰基神经鞘胺醇酰胺水解酶-2、α2u-球蛋白、ASC、α-1-酸醣蛋白、ASGRl、α-胎蛋白、ASKl、ALS、ATM、釉母细胞(Ameloblastic)ATRIP、AMICA/JAML、奥罗拉(Aurora)A、AMIGO、奥罗拉B、AMIG02、阿星(Axin)-1、AMIG03、AxI、氨基酰化酶/ACYl、天青杀素(Azurocidin)/CAP37/HBP、氨肽酶A/ENPEP、B4GALT1、BIM、B7-1/CD80、6-生物素-17-NAD、B7-2/CD86、BLAME/SLAMF8、B7-H1/PD-L1、CXCL13/BLC/BCA-1、B7-H2、BLIMPl、B7-H3、BIk、B7-H4、BMI-I、BACE-I、BMP-1/PCP、BACE-2、BMP-2、Bad、BMP-3、BAFF/TNFSF 13B、BMP-3b/GDF-10、BAFF R/TNFRSF 13C、BMP-4、Bag-1、BMP-5、BAK、BMP-6、BAMBI/NMA、BMP-7、BARD 1、BMP-8、Bax、BMP-9、BCAM、BMP-10、Bcl-10、BMP-15/GDF-9B、Bcl-2、BMPR-IA/ALK-3、Bcl-2相关蛋白Al、BMPR-IB/ALK-6、Bcl-w、BMPR-II、Bcl-x、BNIP3L、Bcl-xL、BOC、BCMA/TNFRSF17、BOK、BDNF、BPDE、苯甲酰胺、短尾基因(Brachyury)、普通β链、B-Raf、βIG-H3、CXCL14/BRAK、β细胞调节素、BRCAl、β-防御素(Defensin)2、BRCA2、BID、BTLA、双聚糖(Biglycan)、Bub-1、Bik样杀手蛋白(killerprotein)、c-jun、CD90/Thyl、c-Rel、CD94、CCL6/C10、CD97、CIq R1/CD93、CD151、CIqTNFl、CD160、ClqTNF4、CD163、ClqTNF5、CD164、补体组分CIr、CD200、补体组分CIs、CD200Rl、补体组分C2、CD229/SLAMF3、补体组分C3a、CD23/FcεRII、补体组分C3d、CD2F-10/SLAMF9、补体组分C5a、CD5L、钙黏素-4/R-钙黏素、CD69、钙黏素-6、CDC2、钙黏素-8、CDC25A、钙黏素-11、CDC25B、钙黏素-12、CDCPl、钙黏素-13、CDO、钙黏素-17、CDX4、E-钙黏素、CEACAM-l/CD66a、N-钙黏素、CEACAM-6、P-钙黏素、亲环蛋白(Cerberus)1、VE-钙黏素、CFTR、钙结合蛋白(Calbindin)D、cGMP、钙神经蛋白A、Chem R23、钙神经蛋白B、凯莫瑞(Chemerin)、钙网织蛋白(Calreticulin)-2、趋化因子样品包、CaM激酶II、壳聚糖酶(Chitinase)3样1、cAMP、壳三糖苷酶(Chitotriosidase)/CHITl、类大麻酚Rl、Chkl、类大麻酚R2/CB2/CNR2、Chk2、CAR/NR1I3、CHL-l/LlCAM-2、碳酸酐酶I、胆碱乙酰基转移酶/CbAT、碳酸酐酶II、软骨凝集蛋白(Chondrolectin)、碳酸酐酶III、脊索发生素(Chordin)、碳酸酐酶IV、脊索发生素样1、碳酸酐酶VA、脊索发生素(Chordin-like)样2、碳酸酐酶VB、CINC-I、碳酸酐酶VI、CINC-2、碳酸酐酶VII、CINC-3、碳酸酐酶VIII、卡拉斯宾(Claspin)、碳酸酐酶IX、紧密连接蛋白(Claudin)-6、碳酸酐酶X、CLC、碳酸酐酶XII、CLEC-I、碳酸酐酶XIII、CLEC-2、碳酸酐酶XIV、CLECSF13/CLEC4F、羧甲基赖氨酸、CLECSF8、羧肽酶A1/CPA1、CLF-I、羧肽酶A2、CL-P1/COLEC12、羧肽酶A4、簇蛋白(Clusterin)、羧肽酶Bl、簇蛋白样1、羧肽酶E/CPE、CMG-2、羧肽酶Xl、CMV UL146、心肌营养蛋白(Cardiotrophin)-1、CMV UL147、肌肽二肽酶1、CNP、卡隆特(Caronte)、CNTF、CART、CNTF R α、胱天蛋白酶、凝血因子II/凝血酶、胱天蛋白酶-1、凝血因子Ill/组织因子、胱天蛋白酶-2、凝血因子VII、胱天蛋白酶-3、凝血因子X、胱天蛋白酶-4、凝血因子XI、胱天蛋白酶-6、凝血因子XIV/蛋白C、胱天蛋白酶-7、COCO、胱天蛋白酶-8、黏结蛋白(Cohesin)、胱天蛋白酶-9、胶原蛋白I、胱天蛋白酶-10、胶原蛋白II、胱天蛋白酶-12、胶原蛋白IV、胱天蛋白酶-13、常见γ链/IL-2Rγ、胱天蛋白酶肽抑制剂、COMP/凝血栓蛋白(Thrombospondin)-5、过氧化氢酶、补体组分CIrLP、β-连环蛋白(Catenin)、补体组分CIqA、组织蛋白酶1、补体组分CIqC、组织蛋白酶3、补体因子D、组织蛋白酶6、补体因子I、组织蛋白酶A、补体MASP3、组织蛋白酶B、连接蛋白(Connexin)43、组织蛋白酶C/DPPI、接触蛋白(Contactin)-1、组织蛋白酶D、接触蛋白-2/TAGl、组织蛋白酶E、接触蛋白-4、组织蛋白酶F、接触蛋白-5、组织蛋白酶H、库林(Corin)、组织蛋白酶L、库努林(Cornulin)、组织蛋白酶O、CORS26/ClqTNF,3、组织蛋白酶S、大鼠皮层干细胞、组织蛋白酶V、皮质醇、组织蛋白酶XITJ?、COUP-TF I/NR2F1、CBP、COUP-TFII/NR2F2、CCI、COX-I、CCK-A R、COX-2、CCL28、CRACC/SLAMF7、CCRl、C-反应性蛋白、CCR2、肌酸激酶、肌肉/CKMM、CCR3、肌酸酐、CCR4、CREB、CCR5、CREG、CCR6、CRELDl、CCR7、CRELD2、CCR8、CRHBP、CCR9、CRHR-I、CCRlO、CRIMl、CD155/PVR、克里普托(Cripto)、CD2、CRISP-2、CD3、CRISP-3、CD4、横脉缺失(Crossveinless)-2、CD4+/45RA-、CRTAM、CD4+/45RO-、CRTH-2、CD4+/CD62L-/CD44、CRYl、CD4+/CD62L+/CD44、隐秘蛋白(Cryptic)、CD5、CSB/ERCC6、CD6、CCL27/CTACK、CD8、CTGF/CCN2、CD8+/45RA-、CTLA-4、CD8+/45RO-、库比林(Cubilin)、CD9、CX3CR1、CD14、CXADR、CD27/TNFRSF7、CXCL16、CD27配体/TNFSF7、CXCR3、CD28、CXCR4、CD30/TNFRSF8、CXCR5、CD30配体/TNFSF8、CXCR6、CD31/PECAM-1、亲环素蛋白(Cyclophilin)A、CD34、Cyr61/CCN1、CD36/SR-B3、胱抑素(Cystatin)A、CD38、胱抑素B、CD40/TNFRSF5、胱抑素C、CD40配体/TNFSF5、胱抑素D、CD43、胱抑素E/M、CD44、胱抑素F、CD45、胱抑素H、CD46、胱抑素H2、CD47、胱抑素S、CD48/SLAMF2、胱抑素SA、CD55/DAF、胱抑素SN、CD58/LFA-3、细胞色素c、CD59、Apo细胞色素c、CD68、Holo细胞色素c、CD72、细胞角蛋白(Cytokeratin)8、CD74、细胞角蛋白14、CD83、细胞角蛋白19、CD84/SLAMF5、西托宁(Cytonin)、D6、DISPl、DAN、Dkk-1、DANCE、Dkk-2、DARPP-32、Dkk-3、DAX1/NR0B1、Dkk-4、DCC、DLEC、DCIR/CLEC4A、DLLl、DCAR、DLL4、DcR3/TNFRSF6B、d-荧光素、DC-SIGN、DNA连接酶IV、DC-SIGNR/CD299、DNA聚合物β、DcTRAIL R1/TNFRSF23、DNAM-I、DcTRAILR2/TNFRSF22、DNA-PKcs、DDRl、DNER、DDR2、多巴脱羧酶/DDC、DEC-205、DPCR-I、Decapentaplegic、DPP6、核心聚糖(Decorin)、DPP A4、戴克汀(Dectin)-1/CLEC7A、DPPA5/ESG1、Dectin-2/CLEC6A、DPPII/QPP/DPP7、DEP-1/CD 148、DPPIV/CD26、沙漠刺猬因子(Desert Hedgehog)、DR3/TNFRSF25、结蛋白(Desmin)、DR6/TNFRSF21、桥粒芯糖蛋白(Desmoglein)-1、DSCAM、桥粒芯糖蛋白-2、DSCAM-Ll、桥粒芯糖蛋白-3、DSPG3、散乱蛋白(Dishevelled)-1、Dtk、散乱蛋白-3、发动蛋白(Dynamin)、EAR2/NR2F6、EphA5、ECE-I、EphA6、ECE-2、EphA7、ECF-L/CHI3L3、EphA8、ECM-I、EphBl、大肠杆菌抑制剂(Ecotin)、EphB2、EDA、EphB3、EDA-A2、EphB4、EDAR、EphB6、EDG-I、埃弗林、EDG-5、埃弗林-Al、EDG-8、埃弗林-A2、eEF-2、埃弗林-A3、EGF、埃弗林-A4、EGF R、埃弗林-A5、EGRl、埃弗林-B、EG-VEGF/PK1、埃弗林-Bl、eIF2α、埃弗林-B2、eIF4E、埃弗林-B3、EIk-I、埃匹根(Epigen)、EMAP-II、表皮形态发生素(Epimorphin)/突触融合蛋白(Syntaxin)2、EMMPRIN/CD147、表皮调节素(Epiregulin)、CXCL5/ENA、EPR-l/Xa受体、埃杜坎(Endocan)、ErbB2、埃杜格林(Endoglin)/CD 105、ErbB3、四聚糖(Endoglycan)、ErbB4、核酸内切酶III、ERCCl、核酸内切酶IV、ERCC3、核酸内切酶V、ERK1/ERK2、核酸内切酶VIII、ERKl、埃杜里培林(Endorepellin)/基底膜蛋白聚糖(Perlecan)、ERK2、内皮抑制素(Endostatin)、ERK3、内皮素(Endothelin)-1、ERK5/BMK1、英格瑞里德(Engrailed)-2、ERR α/NR3Bl、EN-RAGE、ERR β/NR3B2、肠肽酶/肠激酶、ERR γ/NR3B3、CCLl l/嗜酸粒细胞趋化蛋白(Eotaxin)、红细胞生成素(Erythropoietin)、CCL24/嗜酸粒细胞趋化蛋白-2、红细胞生成素R、CCL26/嗜酸粒细胞趋化蛋白-3(Eotaxin-3)、ESAM、EpCAM/TROP-1、ERα/NR3Al、EPCR、ER β/NR3A2、Eph、核酸外切酶III、EphAl、埃斯托新(Exostosin)样2/EXTL2、EphA2、埃斯托新样3/EXTL3、EphA3、FABPl、FGF-BP、FABP2、FGFRl-4、FABP3、FGF Rl、FABP4、FGF R2、FABP5、FGF R3、FABP7、FGF R4、FABP9、FGF R5、补体因子B、Fgr、FADD、FHR5、FAM3A、纤连蛋白、FAM3B、纤维胶凝蛋白(Ficolin)-2、FAM3C、纤维胶凝蛋白-3、FAM3D、FITC、成纤维细胞活化蛋白α/FAP、FKBP38、Fas/TNFRSF6、Flap、Fas配体/TNFSF6、FLIP、FATPl、FLRG、FATP4、FLRTl、FATP5、FLRT2、FcγRI/CD64、FLRT3、FcγRIIB/CD32b、Flt-3、FcγRIIC/CD32c、Flt-3配体、FcγRIIA/CD32a、卵泡抑素(Follistatin)、FcγRIII/CD 16、卵泡抑素样1、FcRHl/IRTA5、FosB/G0S3、FcRH2/IRTA4、FoxD3、FcRH4/IRTAl、FoxJl、FcRH5/IRTA2、FoxP3、Fc受体样3/CD 16-2、Fpg、FEN-I、FPRl、胎球蛋白(Fetuin)A、FPRLl、胎球蛋白B、FPRL2、酸性FGF、CX3CL1/趋化因子(Fractalkine)、碱性FGF、卷曲蛋白(Frizzled)-1、FGF-3、卷曲蛋白-2、FGF-4、卷曲蛋白-3、FGF-5、卷曲蛋白-4、FGF-6、卷曲蛋白-5、FGF-8、卷曲蛋白-6、FGF-9、卷曲蛋白-7、FGF-IO、卷曲蛋白-8、FGF-11、卷曲蛋白-9、FGF-12、Frk、FGF-13、sFRP-1、FGF-16、sFRP-2、FGF-17、sFRP-3、FGF-19、sFRP-4、FGF-20、弗林蛋白(Furin)、FGF-21、FXR/NR1H4、FGF-22、Fyn、FGF-23、G9a/EHMT2、GFR α-3/GDNF R α-3、GABA-A-R α1、GFRα-4/GDNF R α-4、GABA-A-R α2、GITR/TNFRSF 18、GABA-A-R α4、GITR配体/TNFSF 18、GABA-A-R α5、GLI-I、GABA-A-R α6、GLI-2、GABA-A-Rβ1、GLP/EHMT1、GABA-A-Rβ2、GLP-I R、GABA-A-R β3、胰高血糖素、GABA-A-R γ2、葡糖胺(N-乙酰基)-6-硫酸酯酶/GNS、GABA-B-R2、GIuRl、GAD 1/GAD67、GluR2/3、GAD2/GAD65、GluR2、GADD45α、GluR3、GADD45β、Glutl、GADD45γ、Glut2、半乳糖凝集素(Galectin)-1、Glut3、半乳糖凝集素-2、Glut4、半乳糖凝集素-3、Glut5、半乳糖凝集素-3BP、谷氧还蛋白(Glutaredoxin)1、半乳糖凝集素-4、甘氨酸R、半乳糖凝集素-7、血型糖蛋白(Glycophorin)A、半乳糖凝集素-8、糖苷蛋白(Glypican)2、半乳糖凝集素-9、糖苷蛋白3、GalNAc4S-6ST、糖苷蛋白5、GAP-43、糖苷蛋白6、GAPDH、GM-CSF、Gasl、GM-CSF R α、Gas6、GMF-β、GASP-1/WFIKKNRP、gpl30、GASP-2/WFIKKN、糖原磷酸化酶BB/GPBB、GATA-I、GPR 15、GATA-2、GPR39、GATA-3、GPVI、GATA-4、GR/NR3C 1、GATA-5、Gr-1/Ly-6G、GATA-6、粒溶蛋白(Granulysin)、GBL、颗粒酶(Granzyme)A、GCNF/NR6A1、颗粒酶B、CXCL6/GCP-2、颗粒酶D、G-CSF、颗粒酶G、G-CSF R、颗粒酶H、GDF-I、GRASP、GDF-3GRB2、GDF-5、骨形态形成蛋白拮抗蛋白(Gremlin)、GDF-6、GRO、GDF-7、CXCL1/GRO α、GDF-8、CXCL2/GRO β、GDF-9、CXCL3/GRO γ、GDF-11、生长激素、GDF-15、生长激素R、GDNF、GRP75/HSPA9B、GFAP、GSK-3α/β、GFI-I、GSK-3α、GFR α-1/GDNF R α-1、GSK-3β、GFR α-2/GDNF R α-2、EZFIT、H2AX、组氨酸、H60、HM74A、HAI-I、HMGA2、HAI-2、HMGBl、HAI-2A、TCF-2/HNF-1β、HAI-2B、HNF-3β/FoxA2、HANDl、HNF-4α/NR2Al、HAPLNl、HNF-4γ/NR2A2、气道胰蛋白酶样蛋白酶/HAT、HO-1/HMOX1/HSP32、HB-EGF、HO-2/HMOX2、CCL14a/HCC-l、HPRG、CCL14b/HCC-3、Hrk、CCL16/HCC-4、HRP-I、αHCG、HS6ST2、Hck、HSD-I、HCR/CRAM-A/B、HSD-2、HDGF、HSP 10/EPF、血色素、HSP27、赫帕索辛(Hepassocin)、HSP60、HES-1、HSP70、HES-4、HSP90、HGF、HTRA/蛋白酶Do、HGF活化因子、HTRA1/PRSS11、HGF R、HTRA2/0mi、HIF-I α、HVEM/TNFRSF14、HIF-2α、透明质酸蛋白(Hyaluronan)、HIN-1/分泌球蛋白(Secretoglobulin)3Al、4-羟基壬烯酸、Hip、CCLl/I-309/TCA-3、IL-IO、cIAP(广谱)、IL-IO R α、cIAP-l/HIAP-2、IL-IO Rβ、cIAP-2/HIAP-l、IL-11、IBSP/唾液酸蛋白(Sialoprotein)II、EL-11R α、ICAM-1/CD54、IL-12、ICAM-2/CD102、IL-12/IL-23p40、ICAM-3/CD50、IL-12Rβ1、ICAM-5、IL-12R β2、ICAT、IL-13、ICOS、IL-13R α1、艾杜糖2-硫酸酯酶/EOS、IL-13R α2、EFN、IL-15、IFN-α、IL-15R α、IFN-α1、IL-16、IFN-α2、IL-17、IFN-α4b、IL-17R、IFN-αA、IL-17RC、IFN-αB2、IL-17RD、IFN-αC、IL-17B、IFN-αD、IL-17B R、IFN-αF、IL-17C、IFN-αG、IL-17D、IFN-αH2、IL-17E、IFN-αI、IL-17F、IFN-αJl、IL-18/IL-1F4、IFN-αK、IL-18BPa、IFN-αWA、IL-18BPc、IFN-α/βRl、IL-18BPd、IFN-α/βR2、IL-18R α/IL-1R5、IFN-β、IL-18R β/IL-1R7、IFN-γ、IL-19、IFN-γRl、IL-20、IFN-γR2、IL-20R α、IFN-ω、IL-20R β、IgE、IL-21、IGFBP-I、IL-21R、IGFBP-2、IL-22、IGFBP-3、IL-22R、IGFBP-4、IL-22BP、IGFBP-5、IL-23、IGFBP-6、IL-23R、IGFBP-Ll、IL-24、IGFBP-rpl/IGFBP-7、IL-26/AK155、IGFBP-rPIO、IL-27、IGF-I、EL-28A、IGF-I R、IL-28B、IGF-II、IL-29/EFN-λ1、IGF-II R、IL-31、IgG、EL-31RA、IgM、IL-32α、IGSF2、IL-33、IGSF4A/SynCAM、ILT2/CD85J、IGSF4B、ILT3/CD85k、IGSF8、ILT4/CD85d、IgY、ILT5/CD85a、IkB-β、ILT6/CD85e、IKK α、豪猪蛋白(Indian Hedgehog)、IKKε、INSRR、EKKγ、胰岛素、IL-Iα/IL-IFl、胰岛素R/CD220、IL-I β/IL-lF2、胰岛素原、IL-lra/IL-lF3、胰岛素降解酶(Insulysin)/EDE、IL-1F5/FIL1δ、整联蛋白α2/CD49b、IL-1F6/FIL1ε、整联蛋白α3/CD49c、IL-1F7/FIL1ζ、整联蛋白α3βl/VLA-3、IL-1F8/FIL1η、整联蛋白α4/CD49d、IL-1F9/IL-1Hl、整联蛋白α5/CD49e、IL-1F10/IL-1HY2、整联蛋白α5β1、IL-I RI、整联蛋白α6/CD49f、IL-I RII、整联蛋白α7、IL-I R3/IL-1R AcP、整联蛋白α9、IL-IR4/ST2、整联蛋白αE/CD103、IL-I R6/IL-1R rp2、整联蛋白αL/CD1Ia、IL-IR8、整联蛋白αL β2、IL-I R9、整联蛋白αM/CDl Ib、IL-2、整联蛋白αM β2、IL-2R α、整联蛋白αV/CD51、IL-2Rβ、整联蛋白αV β5、IL-3、整联蛋白αV β3、IL-3R α、整联蛋白αV β6、IL-3R β、整联蛋白αXJCDl Ic、IL-4、整联蛋白β1/CD29、IL-4R、整联蛋白β2/CD18、IL-5、整联蛋白β3/CD61、IL-5R α、整联蛋白β5、IL-6、整联蛋白β6、IL-6R、整联蛋白β7、IL-7、CXCL10/EP-10/CRG-2、IL-7Rα/CD127、IRAKI、CXCRl/IL-8RA、IRAK4、CXCR2/IL-8RB、ERS-I、CXCL8/IL-8、Islet-1、IL-9、CXCLl 1/I-TAC、IL-9R、杰格德(Jagged)1、JAM-4/IGSF5、杰格德2、JNK、JAM-A、JNK1/JNK2、JAM-B/VE-JAM、JNKl、JAM-C、JNK2、激肽原(Kininogen)、激肽释放酶(Kallikrein)3/PSA、高分子激肽原(Kininostatin)、激肽释放酶4、KER/CD158、激肽释放酶5、KER2DL1、激肽释放酶6/甘油磷酸钙(Neurosin)、KIR2DL3、激肽释放酶7、KIR2DL4/CD158d、激肽释放酶8/纽罗普星(Neuropsin)、KIR2DS4、激肽释放酶9、KIR3DL1、血浆激肽释放酶/KLKBl、KER3DL2、激肽释放酶10、Kirrel2、激肽释放酶11、KLF4、激肽释放酶12、KLF5、激肽释放酶13、KLF6、激肽释放酶14、Klotho、激肽释放酶15、Klothoβ、KC、KOR、Keapl、克里曼(Kremen)-1、KeIl、克里曼-2、KGF/FGF-7、LAG-3、LINGO-2、LAIRl、脂质(Lipin)2、LAIR2、脂笼蛋白(Lipocalin)-1、层黏连蛋白(Laminin)α4、脂笼蛋白-2/NGAL、层黏连蛋白γ1、5-脂肪加氧酶(Lipoxygenase)、层黏连蛋白I、LXR α/NRlH3、层黏连蛋白S、LXR β/NRlH2、层黏连蛋白-1、Livin、层黏连蛋白-5、LEX、LAMP、LMIR1/CD300A、兰格林(Langerin)、LMIR2/CD300c、LAR、LMIR3/CD300LF、拉特星(Latexin)、LMIR5/CD300LB、排卵蛋白(Layilin)、LMIR6/CD300LE、LBP、LMO2、LDLR、LOX-1/SR-El、LECT2、LRH-1/NR5A2、LEDGF、LRIGl、莱夫替(Lefty)、LRIG3、莱夫替-1、LRP-I、莱夫替-A、LRP-6、豆荚蛋白(Legumain)、LSECtin/CLEC4G、瘦素、光蛋白聚糖(Lumican)、瘦素R、CXCL15/郎金(Lungkine)、白三烯B4、XCLl/淋巴细胞趋化蛋白(Lymphotactin)、白三烯B4Rl、淋巴毒素、LEF、淋巴毒素β/TNFSF3、LIF R α、淋巴毒素βR/TNFRSF3、LIGHT/TNFSF14、Lyn、立米汀(Limitin)、Lyp、LIMPII/SR-B2、赖氨酰基氧化酶同源物2、LIN-28、LYVE-I、LINGO-I、α2-巨球蛋白、CXCL9/MIG、MAD2L1、骨引导因子(Mimecan)、MAdCAM-1、脊椎蛋白(Mindin)、MafB、盐皮质激素R/NR3C2、MafF、CCL3L1/MIP-1α同功异型物LD78β、MafG、CCL3/MIP-1α、MafK、CCL4L1/LAG-1、MAG/西格乐(Siglec)-4a、CCL4/MIP-1β、MANF、CCL15/MEP-1δ、MAP2、CCL9/10/MIP-1γ、MAPK、MIP-2、马拉普星(Marapsin)/盘克里星(Pancreasin)、CCL19/MIP-3β、MARCKS、CCL20/MIP-3α、MARCO、MIP-I、Mashl、MIP-II、软骨基质蛋白(Matrilin)-2、MIP-III、软骨基质蛋白-3、MIS/AMH、软骨基质蛋白-4、MIS RII、蛋白切割酶(Matriptase)/ST14、MIXLl、MBL、MKK3/MKK6、MBL-2、MKK3、黑素皮质素(Melanocortin)3R/MC3R、MKK4、MCAM/CD 146、MKK6、MCK-2、MKK7、McI-I、MKP-3、MCP-6、MLH-I、CCL2/MCP-1、MLK4α、MCP-11、MMP、CCL8/MCP-2、MMP-1、CCL7/MCP-3/MARC、MMP-2、CCL13/MCP-4、MMP-3、CCL12/MCP-5、MMP-7、M-CSF、MMP-8、M-CSF R、MMP-9、II型MCV、MMP-IO、MD-I、MMP-I l、MD-2、MMP-12、CCL22/MDC、MMP-13、MDL-1/CLEC5A、MMP-14、MDM2、MMP-15、MEA-I、MMP-16/MT3-MMP、MEK1/MEK2、MMP-24/MT5-MMP、MEKl、MMP-25/MT6-MMP、MEK2、MMP-26、整合蛋白β1结合蛋白(Melusin)、MMR、MEPE、MOG、安眠蛋白(Meprin)α、CCL23/MPIF-1、安眠蛋白β、M-Ras/R-Ras3、Mer、Mrel 1、间皮素(Mesothelin)、MRPl镍纹蛋白(Meteorin)、MSK1/MSK2、甲硫胺酸胺肽酶1、MSKl、甲硫胺酸胺肽酶、MSK2、甲硫胺酸胺肽酶2、MSP、MFG-E8、MSP R/Ron、MFRP、Mug、MgcRacGAP、MULT-I、MGL2、木萨施(Musashi)-1、MGMT、木萨施-2、MIA、MuSK、MICA、MutY DNA糖基化酶、MICB、MyD88、MICL/CLEC12A、髓过氧物酶、β2微球蛋白、心肌蛋白(Myocardin)、中期肾蛋白(Midkine)、肌纤蛋白(Myocilin)、MIF、肌红蛋白(Myoglobin)、NAIP NGFI-Bγ/NR4A3、Nanog、NgR2/NgRHl、CXCL7/NAP-2、NgR3/NgRH2、Nbsl、巢蛋白(Nidogen)-1/内动蛋白(Entactin)、NCAM-1/CD56、巢蛋白-2、NCAM-Ll、一氧化氮、黏连蛋白(Nectin)-1、硝基酪氨酸、黏连蛋白-2/CDl 12、NKG2A、黏连蛋白-3、NKG2C、黏连蛋白-4、NKG2D、再生蛋白(Neogenin)、NKp30、脑啡肽酶(Neprilysin)/CDIO、NKp44、脑啡肽酶-2/MMEL1/MMEL2、NKp46/NCRl、巢蛋白(Nestin)、NKp80/KLRFl、NETO2、NKX2.5、网蛋白-1、NMDA R、NRl亚单位、网蛋白-2、NMDA R、NR2A亚单位、网蛋白-4、NMDA R、NR2B亚单位、网蛋白-Gla、NMDA R、NR2C亚单位、网蛋白-G2a、N-Me-6,7-diOH-TIQ、神经调节蛋白(Neuregulin)-1/NRGl、诺德尔(Nodal)、神经调节蛋白-3/NRG3、头蛋白(Noggin)、纽立汀(Neuritin)、勿动蛋白(Nogo)受体、NeuroDl、勿动蛋白-A、神经束蛋白(Neurofascin)、NOMO、神经原质蛋白(Neurogenin)-1、Nope、神经原质蛋白(Neurogenin)-2、诺里蛋白(Norrin)、神经原质蛋白-3、eNOS、溶神经蛋白(Neurolysin)、iNOS、后叶激素运载蛋白(Neurophysin)II、nNOS、神经纤毛蛋白(Neuropilin)-1、诺池(Notch)-1、神经纤毛蛋白-2、诺池-2、纽罗普汀(Neuropoietin)、诺池-3、纽罗曲明(Neurotrimin)、诺池-4、神经秩蛋白(Neurturin)、NOV/CCN3、NFAMl、NRAGE、NF-H、NrCAM、NFkBl、NRL、NFkB2、NT-3、NF-L、NT-4、NF-M、NTB-A/SLAMF6、NG2/MCSP、NTHl、NGFR/TNFRSF16、核干细胞因子(Nucleostemin)、β-NGF、Nurr-1/NR4A2、NGFI-B α/NR4Al、OAS2、食欲蛋白(Orexin)B、OBCAM、OSCAR、OCAM、OSF-2/骨膜蛋白(Periostin)、OCIL/CLEC2d、制癌蛋白(Oncostatin)M/OSM、OCILRP2/CLEC2i、OSM Rβ、Oct-3/4、骨活素(Osteoactivin)/GPNMB、OGGl、骨黏附蛋白聚糖(Osteoadherin)、Olig1、Olig2、Olig3、骨钙蛋白、寡聚物1、成骨细胞分化素(Osteocrin)、Olig2、骨桥蛋白(Osteopontin)、Olig3、骨保护蛋白/TNFRSFlIB、少突胶质细胞(Oligodendrocyte)标记物01、Otx2、少突胶质细胞标记物O4、OV-6、OMgp、OX40/TNFRSF4、眼科新糖蛋白(Opticin)、OX40配体/TNFSF4、食欲蛋白A、OAS2、食欲蛋白B、OBCAM、OSCAR、OCAM、OSF-2/骨膜蛋白、0CIL/CLEC2d、制癌蛋白M/OSM、OCILRP2/CLEC2i、OSM R β、Oct-3/4、骨活素/GPNMB、OGGl、骨黏附蛋白聚糖(Osteoprotegerin)、Olig1、Olig2、Olig3、骨钙蛋白、Olig1、成骨细胞分化素、Olig2、骨桥蛋白、Olig3、骨保护蛋白/TNFRSFl IB、少突胶质细胞标记物01、Otx2、少突胶质细胞标记物04、OV-6、OMgp、OX40/TNFRSF4、眼科新糖蛋白(Opticin)、OX40配体/TNFSF4、食欲蛋白A、RACKl、Ret、Radl、REV-ERBα/NRlDl、Radl7、REV-ERB β/NRlD2、Rad51、Rex-1、Rae-1、RGM-A、Rae-1α、RGM-B、Rae-1β、RGM-C、Rae-1δ、Rheb、Rae-1ε、核糖体蛋白S6、Rae-1γ、RIPl、Raf-1、ROBOl、RAGE、R0B02、RalA/RalB、R0B03、RaIA、ROBO4、RaIB、R0R/NR1F1-3(广谱)、RANK/TNFRSFl lA、ROR α/NRlFl、CCL5/RANTES、ROR γ/NRlF3、RaplA/B、RTK样孤儿受体1/RORl、RARα/NRlBl、RTK样孤儿受体2/ROR2、RAR β/NRlB2、RP 105、RARγNRlB3、RP A2、Ras、RSK(广谱)、RBP4、RSK1/RSK2、RECK、RSKl、Reg 2/PAP、RSK2、Reg I、RSK3、Reg II、RSK4、Reg III、R-脊椎蛋白(Spondin)1、RegIlia、R-脊椎蛋白2、Reg IV、R-脊椎蛋白3、松弛素(Relaxin)-1、RUNX1/CBFA2、松弛素-2、RUNX2/CBFA1、松弛素-3、RUNX3/CBFA3、RELM α、RXRα/NR2Bl、RELM β、RXRβ/NR2B2、RELT/TNFRSF 19L、RXRγ/NR2B3、抵抗素(Resistin)、SlOOAlO、SLITRK5、S100A8、SLPI、S100A9、SMAC/Diablo、SlOOB、Smad1、SlOOP、Smad2、SALLl、Smad3、δ-肌聚糖蛋白(Sarcoglycan)、Smad4、Sca-1/Ly6、Smad5、SCD-I、Smad7、SCF、Smad8、SCF R/c-kit、SMCl、SCGF、α-平滑肌肌动蛋白、SCL/Tall、SMUGl、SCP3/SYCP3、蜗牛蛋白(Snail)、CXCL12/SDF-1、钠钙交换蛋白1、SDNSF/MCFD2、索吉(Soggy)-1、α-分泌酶、音猬蛋白(Sonic Hedgehog)、γ-分泌酶、SorCSl、β-分泌酶、SorCS3、E-选择素、选蛋白(Sortilin)、L-选择素、SOST、P-选择素、SOXl、臂板蛋白(Semaphorin)3A、SOX2、臂板蛋白3C、SOX3、臂板蛋白3E、SOX7、臂板蛋白3F、SOX9、臂板蛋白6A、SOXlO、臂板蛋白6B、SOX 17、臂板蛋白6C、SOX21臂板蛋白6D、SPARC、臂板蛋白7A、SPARC样1、分离酶、SP-D、丝氨酸/苏胺酸磷酸酶受质I、脊骨蛋白(Spinesin)、丝氨酸蛋白酶抑制剂蛋白(Serpin)Al、F-脊椎蛋白、丝氨酸蛋白酶抑制剂蛋白A3、SR-AI/MSR、丝氨酸蛋白酶抑制剂蛋白A4/激肽释放酶结合蛋白(Kallistatin)、Src、丝氨酸蛋白酶抑制剂蛋白A5/蛋白C抑制剂、SREC-I/SR-F1、丝氨酸蛋白酶抑制剂蛋白A8/血管紧张素原、SREC-II、丝氨酸蛋白酶抑制剂蛋白B5、SSEA-I、丝氨酸蛋白酶抑制剂蛋白Cl/抗凝血酶-III、SSEA-3、丝氨酸蛋白酶抑制剂蛋白Dl/肝素辅因子II、SSEA-4、丝氨酸蛋白酶抑制剂蛋白El/PAI-1、ST7/LRP12、丝氨酸蛋白酶抑制剂蛋白E2、斯塔比林(Stabilin)-1、丝氨酸蛋白酶抑制剂蛋白Fl、斯塔比林-2、丝氨酸蛋白酶抑制剂蛋白F2、斯钙素(Stanniocalcin)1、丝氨酸蛋白酶抑制剂蛋白Gl/Cl抑制剂、斯钙素2、丝氨酸蛋白酶抑制剂蛋白12、STATl、血清淀粉样蛋白Al、STAT2、SF-1/NR5A1、STAT3、SGK、STAT4、SHBG、STAT5a/b、SHIP、STAT5a、SHP/NR0B2、STAT5b、SHP-I、STAT6、SHP-2、VE-抑制素(Statin)、SIGIRR、斯蒂拉(Stella)/Dppa3、西格乐-2/CD22、STRO-I、西格乐-3/CD33、物质P、西格乐-5、磺酰胺酶/SGSH、西格乐-6、硫酸酯酶调节因子1/SUMFl、西格乐-7、硫酸酯酶调节因子2/SUMF2、西格乐-9、SUMO1、西格乐-10、SUMO2/3/4、西格乐-11、SUMO3、西格乐-F、过氧化物歧化酶、SIGNR1/CD209、过氧化物歧化酶-1/Cu-Zn SOD、SIGNR4、过氧化物歧化酶-2/Mn-SOD、SIRP β1、过氧化物歧化酶-3/EC-SOD、SKI、凋亡抑制蛋白(Survivin)、SLAM/CD150、突触素(Synapsin)I、睡美人转座酶(Sleeping BeautyTransposase)、多配体蛋白聚糖(Syndecan)-I/CD 138、Slit3、多配体蛋白聚糖-2、SLITRKl、多配体蛋白聚糖-3、S LITRK2、多配体蛋白聚糖-4、SLITRK4、TACI/TNFRSF13B、TMEFF 1/血栓调节蛋白(Tomoregulin)-l、TAO2、TMEFF2、TAPPl、TNF-α/TNFSFIA、CCL17/TARC、TNF-β/TNFSF1B、τ、TNF RI/TNFRSFIA、TC21/R-Ras2、TNF RII/TNFRSF 1B、TCAM-I、TOR、TCCR/WSX-1、TP-I、TC-PTP、TP63/TP73L、TDG、TR、CCL25/TECK、TR α/NRlAl、生腱蛋白(Tenascin)C、TRβ1/NR1A2、生腱蛋白R、TR2/NR2C1、TER-119、TR4/NR2C2、TERT、TRA-1-85、睾丸蛋白聚糖(Testican)1/SPOCKl、TRADD、睾丸蛋白聚糖2/SPOCK2、TRAF-1、睾丸蛋白聚糖3/SPOCK3、TRAF-2、TFPI、TRAF-3、TFPI-2、TRAF-4、TGF-α、TRAF-6、TGF-β、TRAIL/TNFSF 10、TGF-β1、TRAIL Rl/TNFRSFIOA、LAP(TGF-β1)、TRAILR2/TNFRSF 10B、潜伏TGF-β1、TRAIL R3/TNFRSF 10C、TGF-β1.2、TRAILR4/TNFRSF 10D、TGF-β2、TRANCE/TNFSF 11、TGF-β3、TfR(转铁蛋白R)、TGF-β5、Apo-转铁蛋白、潜伏TGF-βbp 1、Holo-转铁蛋白、潜伏TGF-βbp2、Trappin-2/Elafin、潜伏TGF-βbp4、TREM-1、TGF-βRI/ALK-5、TREM-2、TGF-βRII、TREM-3、TGF-βRIIb、TREMLl/TLT-1、TGF-βRIII、TRF-I、嗜热菌蛋白酶、TRF-2、硫氧还蛋白-1、TRH-降解胞外酶/TRHDE、硫氧还蛋白-2、TRIM5、硫氧还蛋白-80、三肽基-肽酶I、硫氧还蛋白样5/TRP14、TrkA、THOPl、TrkB、血栓调节素(Thrombomodulin)/CD141、TrkC、血小板生成素(Thrombopoietin)、TROP-2、血小板生成素R、肌钙蛋白(Troponin)I肽3、凝血栓蛋白-1、肌钙蛋白T、凝血栓蛋白-2、TROY/TNFRSF 19、凝血栓蛋白-4、胰蛋白酶1、胸腺生成素(Thymopoietin)、胰蛋白酶2/PRSS2、胸腺趋化激素-1、胰蛋白酶3/PRSS3、Tie-1、类胰蛋白酶-5/Prss32、Tie-2、类胰蛋白酶α/TPSl、TIM-I/KIM-I/HAVCR、类胰蛋白酶β-1/MCPT-7、TIM-2、类胰蛋白酶β-2/TPSB2、TIM-3、类胰蛋白酶ε/BSSP-4、TIM-4、类胰蛋白酶γ-1/TPSGl、TIM-5、色胺酸羟化酶、TIM-6、TSC22、TIMP-I、TSG、TIMP-2、TSG-6、TIMP-3、TSK、TIMP-4、TSLP、TL1A/TNFSF15、TSLP R、TLRl、TSP50、TLR2、β-III微管蛋白、TLR3、TWEAK/TNFSF12、TLR4、TWEAKR/TNFRSF 12、TLR5、Tyk2、TLR6、磷酸化酪氨酸、TLR9、酪氨酸羟化酶、TLX/NR2E1、酪氨酸磷酸酶受质I、遍在蛋白(Ubiquitin)、UNC5H3、Ugi、UNC5H4、UGRPl、UNG、ULBP-I、uPA、ULBP-2、uPAR、ULBP-3、URB、UNC5H1、UVDE、UNC5H2、辣椒素(Vanilloid)Rl、VEGF R、VASA、VEGFRl/Flt-1、血管抑制蛋白(Vasohibin)、VEGF R2/KDR/Flk-1、伐索林(Vasorin)、VEGF R3/FU-4、血管新生抑制素、多能素(Versican)、Vav-1、VG5Q、VCAM-I、VHR、VDR/NR1I1、波形蛋白(Vimentin)、VEGF、玻璃连结蛋白、VEGF-B、VLDLR、VEGF-C、vWF-A2、VEGF-D、突触核蛋白(Synuclein)-α、Ku70、WASP、Wnt-7b、WIF-I、Wnt-8a WISP-1/CCN4、Wnt-8b、WNKl、Wnt-9a、Wnt-1、Wnt-9b、Wnt-3a、Wnt-10a、Wnt-4、Wnt-10b、Wnt-5a、Wnt-11、Wnt-5b、wnvNS3、Wnt7a、XCRl、XPE/DDB1、XEDAR、XPE/DDB2、Xg、XPF、XIAP、XPG、XPA、XPV、XPD、XRCCl、Yes、YYl、EphA4。
多种人类离子通道为备受关注的靶。非限制性实例包括5-羟色胺3受体亚单位、5-羟色胺3受体前体、5-羟色胺受体3亚单位C、AAD 14蛋白、乙酰胆碱受体蛋白、α亚单位前体、乙酰胆碱受体蛋白、β亚单位前体、乙酰胆碱受体蛋白、δ亚单位前体、乙酰胆碱受体蛋白、ε亚单位前体、乙酰胆碱受体蛋白、γ亚单位前体、酸感应离子通道3剪接变体b、酸感应离子通道3剪接变体c、酸感应离子通道4、ADP-核糖焦磷酸酶、线粒体前体、αA-电压依赖性钙通道、氨氯吡脒(Amiloride)敏感性阳离子通道1、神经元氨氯吡脒敏感性阳离子通道2、神经元氨氯吡脒敏感性阳离子通道4同功异型物2、氨氯吡脒敏感性钠通道、氨氯吡脒敏感性钠通道α-亚单位、氨氯吡脒敏感性钠通道β-亚单位、氨氯吡脒敏感性钠通道δ-亚单位、氨氯吡脒敏感性钠通道γ-亚单位、磷脂结合蛋白A7、顶端样蛋白(Apical-like protein)、ATP敏感性内向性整流钾通道1、ATP敏感性内向性整流钾通道10、ATP敏感性内向性整流钾通道11、ATP敏感性内向性整流钾通道14、ATP敏感性内向性整流钾通道15、ATP敏感性内向性整流钾通道8、钙通道αl2.2亚单位、钙通道αl2.2亚单位、钙通道αlE亚单位、δl9δ40δ46剪接变体、钙活化钾通道α亚单位1、钙活化钾通道β亚单位1、钙活化钾通道β亚单位2、钙活化钾通道β亚单位3、钙依赖性氯通道-1、阳离子通道TRPM4B、CDNA FLJ90453fis、克隆NT2RP3001542(高度类似于含钾通道四聚化域6)、CDNA FLJ90663fis、克隆PLACE 1005031(高度类似于氯化物细胞内通道蛋白5)、CGMP门控阳离子通道β亚单位、氯通道蛋白、氯通道蛋白2、氯通道蛋白3、氯通道蛋白4、氯通道蛋白5、氯通道蛋白6、氯通道蛋白ClC-Ka、氯通道蛋白ClC-Kb、氯通道蛋白、骨骼肌、氯化物细胞内通道6、氯化物细胞内通道蛋白3、氯化物细胞内通道蛋白4、氯化物细胞内通道蛋白5、CHRNA3蛋白、Clcn3e蛋白、CLCNKB蛋白、CNGA4蛋白、滞蛋白(Cullin)-5、环状GMP门控钾通道、环状核苷酸门控阳离子通道4、环状核苷酸门控阳离子通道α3、环状核苷酸门控阳离子通道β3、环状核苷酸门控嗅觉通道、囊性纤维化跨膜传导调节因子、细胞色素B-245重链、敏感性L型二氢吡啶、钙通道α-2/δ亚单位前体、含FXYD结构域的离子转运调节因子3前体、含FXYD结构域的离子转运调节因子5前体、含FXYD结构域的离子转运调节因子6前体、含FXYD结构域的离子转运调节因子7、含FXYD结构域的离子转运调节因子8前体、G蛋白活化内向性整流钾通道1、G蛋白活化内向性整流钾通道2、G蛋白活化内向性整流钾通道3、G蛋白活化内向性整流钾通道4、γ-氨基丁酸受体α-1亚单位前体、γ-氨基丁酸受体α-2亚单位前体、γ-氨基丁酸受体α-3亚单位前体、γ-氨基丁酸受体α-4亚单位前体、γ-氨基丁酸受体α-5亚单位前体、γ-氨基丁酸受体α-6亚单位前体、γ-氨基丁酸受体β-1亚单位前体、γ-氨基丁酸受体β-2亚单位前体、γ-氨基丁酸受体β-3亚单位前体、γ-氨基丁酸受体δ亚单位前体、γ-氨基丁酸受体ε亚单位前体、γ-氨基丁酸受体γ-1亚单位前体、γ-氨基丁酸受体γ-3亚单位前体、γ-氨基丁酸受体pi亚单位前体、γ-氨基丁酸受体ρ-1亚单位前体、γ-氨基丁酸受体ρ-2亚单位前体、γ-氨基丁酸受体θ亚单位前体、GluR6红藻氨酸受体、谷氨酸受体1前体、谷氨酸受体2前体、谷氨酸受体3前体、谷氨酸受体4前体、谷氨酸受体7、谷氨酸受体B、谷氨酸受体δ-1亚单位前体、谷氨酸受体、离子移变红藻氨酸1前体、谷氨酸受体、离子移变红藻氨酸2前体、谷氨酸受体、离子移变红藻氨酸3前体、谷氨酸受体、离子移变红藻氨酸4前体、谷氨酸受体、离子移变红藻氨酸5前体、谷氨酸[NMDA]受体亚单位3A前体、谷氨酸[NMDA]受体亚单位3B前体、谷氨酸[NMDA]受体亚单位ε1前体、谷氨酸[NMDA]受体亚单位ε2前体、谷氨酸[NMDA]受体亚单位ε4前体、谷氨酸[NMDA]受体亚单位ζ1前体、甘氨酸受体α-1链前体、甘氨酸受体α-2链前体、甘氨酸受体α-3链前体、甘氨酸受体β链前体、H/ACA核糖核蛋白复合物亚单位1、高亲和力免疫球蛋白ε受体β-亚单位、假想蛋白DKFZp31310334、假想蛋白DKFZp761M1724、假想蛋白FLJ12242、假想蛋白FLJ14389、假想蛋白FLJ14798、假想蛋白FLJ14995、假想蛋白FLJ16180、假想蛋白FLJ16802、假想蛋白FLJ32069、假想蛋白FLJ37401、假想蛋白FLJ38750、假想蛋白FLJ40162、假想蛋白FLJ41415、假想蛋白FLJ90576、假想蛋白FLJ90590、假想蛋白FLJ90622、假想蛋白KCTD15、假想蛋白MGC15619、1型肌醇1,4,5-三磷酸受体、2型肌醇1,4,5-三磷酸受体、3型肌醇1,4,5-三磷酸受体、中电导钙活化钾通道蛋白4、内向性整流钾通道13、内向性整流钾通道16、内向性整流钾通道4、内向性整流K(+)通道阴性调节因子Kir2.2v、红藻氨酸受体亚单位KA2a、KCNH5蛋白、KCTD 17蛋白、KCTD2蛋白、角蛋白形成细胞相关跨膜蛋白1、Kv通道相互作用蛋白4、梅拉斯达汀(Melastatin)1、膜蛋白MLCl、MGC 15619蛋白、黏脂蛋白(Mucolipin)-1、黏脂蛋白-2、黏脂蛋白-3、多重抗药性相关蛋白4、N-甲基-D-天冬胺酸受体2C亚单位前体、NADPH氧化酶同源物1、Navl.5、神经元乙酰胆碱受体蛋白、α-10亚单位前体、神经元乙酰胆碱受体蛋白、α-2亚单位前体、神经元乙酰胆碱受体蛋白、α-3亚单位前体、神经元乙酰胆碱受体蛋白、α-4亚单位前体、神经元乙酰胆碱受体蛋白、α-5亚单位前体、神经元乙酰胆碱受体蛋白、α-6亚单位前体、神经元乙酰胆碱受体蛋白、α-7亚单位前体、神经元乙酰胆碱受体蛋白、α-9亚单位前体、神经元乙酰胆碱受体蛋白、β-2亚单位前体、神经元乙酰胆碱受体蛋白、β-3亚单位前体、神经元乙酰胆碱受体蛋白、β-4亚单位前体、神经元电压依赖性钙通道α2D亚单位、P2X嘌呤受体1、P2X嘌呤受体2、P2X嘌呤受体3、P2X嘌呤受体4、P2X嘌呤受体5、P2X嘌呤受体6、P2X嘌呤受体7、胰钾通道TALK-Ib、胰钾通道TALK-Ic、胰钾通道TALK-Id、磷酸神经膜前体、浆脂蛋白(Plasmolipin)、多囊性肾病2相关蛋白、多囊性肾病2样1蛋白、多囊性肾病2样2蛋白、多囊性肾病及卵胶相关蛋白前体的受体、多囊肾蛋白(Polycystin)-2、钾通道调节因子、钾通道亚家族K成员1、钾通道亚家族K成员10、钾通道亚家族K成员12、钾通道亚家族K成员13、钾通道亚家族K成员15、钾通道亚家族K成员16、钾通道亚家族K成员17、钾通道亚家族K成员2、钾通道亚家族K成员3、钾通道亚家族K成员4、钾通道亚家族K成员5、钾通道亚家族K成员6、钾通道亚家族K成员7、钾通道亚家族K成员9、含钾通道四聚化域3、含钾通道四聚化域蛋白12、含钾通道四聚化域蛋白14、含钾通道四聚化域蛋白2、含钾通道四聚化域蛋白4、含钾通道四聚化域蛋白5、含钾通道四聚化域10、含钾通道四聚化域蛋白13、含钾通道四聚化域1、钾电压门控通道亚家族A成员1、钾电压门控通道亚家族A成员2、钾电压门控通道亚家族A成员4、钾电压门控通道亚家族A成员5、钾电压门控通道亚家族A成员6、钾电压门控通道亚家族B成员1、钾电压门控通道亚家族B成员2、钾电压门控通道亚家族C成员1、钾电压门控通道亚家族C成员3、钾电压门控通道亚家族C成员4、钾电压门控通道亚家族D成员1、钾电压门控通道亚家族D成员2、钾电压门控通道亚家族D成员3、钾电压门控通道亚家族E成员1、钾电压门控通道亚家族E成员2、钾电压门控通道亚家族E成员3、钾电压门控通道亚家族E成员4、钾电压门控通道亚家族F成员1、钾电压门控通道亚家族G成员1、钾电压门控通道亚家族G成员2、钾电压门控通道亚家族G成员3、钾电压门控通道亚家族G成员4、钾电压门控通道亚家族H成员1、钾电压门控通道亚家族H成员2、钾电压门控通道亚家族H成员3、钾电压门控通道亚家族H成员4、钾电压门控通道亚家族H成员5、钾电压门控通道亚家族H成员6、钾电压门控通道亚家族H成员7、钾电压门控通道亚家族H成员8、钾电压门控通道亚家族KQT成员1、钾电压门控通道亚家族KQT成员2、钾电压门控通道亚家族KQT成员3、钾电压门控通道亚家族KQT成员4、钾电压门控通道亚家族KQT成员5、钾电压门控通道亚家族S成员1、钾电压门控通道亚家族S成员2、钾电压门控通道亚家族S成员3、钾电压门控通道亚家族V成员2、钾电压门控通道亚家族H成员7同功异型物2、钾/钠超极化活化环状核苷酸门控通道1、钾/钠超极化活化环状核苷酸门控通道2、钾/钠超极化活化环状核苷酸门控通道3、钾/钠超极化活化环状核苷酸门控通道4、可能的线粒体输入受体亚单位TOM40同源物、嘌呤型受体P2X5同功异型物A、假定的4重复电压门控离子通道、假定的氯通道蛋白7、假定的GluR6红藻氨酸受体、假定的离子通道蛋白CATSPER2变体1、假定的离子通道蛋白CATSPER2变体2、假定的离子通道蛋白CATSPER2变体3、钾通道蛋白变体1的假定调节因子、假定的酪氨酸-蛋白磷酸酶TPTE、雷诺定(Ryanodine)受体1、雷诺定受体2、雷诺定受体3、SH3KBP1结合蛋白1、短的暂时受体潜在通道1、短的暂时受体潜在通道4、短的暂时受体潜在通道5、短的暂时受体潜在通道6、短的暂时受体潜在通道7、小电导钙活化钾通道蛋白1、小电导钙活化钾通道蛋白2同功异型物b、小电导钙活化钾通道蛋白3同功异型物b、小电导钙活化钾通道SK2、小电导钙活化钾通道SK3、钠通道、钠通道β-1亚单位前体、II型钠通道蛋白α亚单位、III型钠通道蛋白α亚单位、IV型钠通道蛋白α亚单位、IX型钠通道蛋白α亚单位、V型钠通道蛋白α亚单位、VII型钠通道蛋白α亚单位、VIII型钠通道蛋白α亚单位、X型钠通道蛋白α亚单位、XI型钠通道蛋白α亚单位、钠及氯化物活化ATP敏感性钾通道、转运钠/钾的ATP酶γ链、精子相关阳离子通道1、精子相关阳离子通道2同功异型物4、突触融合蛋白-lBl、暂时受体潜在阳离子通道亚家族A成员1、暂时受体潜在阳离子通道亚家族M成员2、暂时受体潜在阳离子通道亚家族M成员3、暂时受体潜在阳离子通道亚家族M成员6、暂时受体潜在阳离子通道亚家族M成员7、暂时受体潜在阳离子通道亚家族V成员1、暂时受体潜在阳离子通道亚家族V成员2、暂时受体潜在阳离子通道亚家族V成员3、暂时受体潜在阳离子通道亚家族V成员4、暂时受体潜在阳离子通道亚家族V成员5、暂时受体潜在阳离子通道亚家族V成员6、暂时受体潜在通道4ε剪接变体、暂时受体潜在通道4ζ剪接变体、暂时受体潜在通道7γ剪接变体、肿瘤坏死因子、α诱导性蛋白1、内皮细胞双孔钙通道蛋白2、VDAC4蛋白、钾电压门控通道Kv3.2b、电压门控钠通道βlB亚单位、电压依赖性阴离子通道、电压依赖性阴离子通道2、电压依赖性阴离子敏感性通道蛋白1、电压依赖性阴离子敏感性通道蛋白2、电压依赖性阴离子敏感性通道蛋白3、电压依赖性钙通道γ-1亚单位、电压依赖性钙通道γ-2亚单位、电压依赖性钙通道γ-3亚单位、电压依赖性钙通道γ-4亚单位、电压依赖性钙通道γ-5亚单位、电压依赖性钙通道γ-6亚单位、电压依赖性钙通道γ-7亚单位、电压依赖性钙通道γ-8亚单位、电压依赖性L型钙通道α-1C亚单位、电压依赖性L型钙通道α-1D亚单位、电压依赖性L型钙通道α-IS亚单位、电压依赖性L型钙通道β-1亚单位、电压依赖性L型钙通道β-2亚单位、电压依赖性L型钙通道β-3亚单位、电压依赖性L型钙通道β-4亚单位、电压依赖性N型钙通道α-1B亚单位、电压依赖性P/Q型钙通道α-1A亚单位、电压依赖性R型钙通道α-1E亚单位、电压依赖性T型钙通道α-1G亚单位、电压依赖性T型钙通道α-1H亚单位、电压依赖性T型钙通道α-1I亚单位、电压门控L型钙通道α-1亚单位、钾电压门控通道β-1亚单位、钾电压门控通道β-2亚单位、钾电压门控通道β-3亚单位、钾电压门控通道KCNA7。人电压门控钠通道的Navl.x家族亦为特别有前途的靶。此家族包括例如通道Navl.6及Navl.8。
在其它实施方式中,治疗性蛋白质可为G蛋白偶合受体(GPCR)。例示性GPCR包括但不限于A类视紫质样受体,诸如脊椎动物1型毒蕈碱乙酰胆碱、脊椎动物2型毒蕈碱乙酰胆碱、脊椎动物3型毒蕈碱乙酰胆碱、脊椎动物4型毒蕈碱乙酰胆碱;肾上腺素受体(1型α肾上腺素受体、2型α肾上腺素受体、1型β肾上腺素受体、2型β肾上腺素受体、3型β肾上腺素受体、脊椎动物1型多巴胺(Dopamine)、脊椎动物2型多巴胺、脊椎动物3型多巴胺、脊椎动物4型多巴胺、1型组胺、2型组胺、3型组胺、4型组胺、1型血清素、2型血清素、3型血清素、4型血清素、5型血清素、6型血清素、7型血清素、8型血清素、其它血清素类型、痕量胺、1型血管紧张素、2型血管紧张素、铃蟾素(Bombesin)、缓激肽(Bradykinin)、C5a过敏毒素(anaphylatoxin)、Fmet-leu-phe、APJ样、A型白介素-8、B型白介素-8、其它类型白介素-8、C-C趋化激素1型至1型1及其它类型、C-X-C趋化激素(2至6型及其它类型)、C-X3-C趋化激素、胆囊收缩素CCK、A型CCK、B型CCK、其它CCK、内皮素、黑皮素(黑皮素细胞刺激激素、促肾上腺皮质激素、黑皮素激素)、达菲抗原(Duffy antigen)、泌乳素释放肽(GPRlO)、神经肽Y(1至7型)、神经肽Y、其它神经肽Y、神经调压素(Neurotensin)、类鸦片(D、K、M、X型)、生长抑素(1至5型)、速激肽(受质P(NKl)、受质K(NK2)、神经调节肽K(NK3)、速激肽样1、速激肽样2、血管加压素/加压催产素(1至2型)、加压催产素、催产素/中催产素、海螺紧张素(Conopressin)、神经节肽(Galanin)样、蛋白酶活化样、食欲蛋白(Orexin)及神经肽FF.QRFP、趋化激素受体样、神经调节肽U样(神经调节肽U、PRXamide)、激素受体(卵泡刺激激素、促黄体激素-绒膜促性腺素激素、促甲状腺素、I型促性腺激素、II型促性腺激素)、(视紫质)视蛋白、脊椎动物视紫质(1-5型)、脊椎动物5型视紫质、节肢动物视紫质、节肢动物1型视紫质、节肢动物2型视紫质、节肢动物3型视紫质、软件动物视紫质、视紫质、嗅觉(嗅觉II家族1至13)、前列腺素(前列腺素E2亚型EPl、前列腺素E2/D2亚型EP2、前列腺素E2亚型EP3、前列腺素E2亚型EP4、前列腺素F2-α、前列环素)、血栓素、1至3型腺苷、嘌呤受体、嘌呤受体P2RYl-4,6,l l GPR91、嘌呤受体P2RY5,8,9,10GPR35,92,174、嘌呤受体P2RY12-14GPR87(UDP-葡萄糖)、类大麻酚、血小板活化因子、促性腺激素释放激素、I型促性腺激素释放激素、II型促性腺激素释放激素、脂动激素样、库拉左宁(Corazonin)、促甲状腺素释放激素及促泌素、促甲状腺素释放激素、生长激素促泌素、生长激素促泌素样、蜕皮引发激素(ETHR)、褪黑素(Melatonin)、溶性鞘脂及LPA(EDG)、神经鞘胺醇1-磷酸酯Edg-1、溶血磷脂酸Edg-2、神经鞘胺醇1-磷酸酯Edg-3、溶血磷脂酸Edg-4、神经鞘胺醇1-磷酸酯Edg-5、神经鞘胺醇1-磷酸酯Edg-6、溶血磷脂酸Edg-7、神经鞘胺醇1-磷酸酯Edg-8、其它Edg白三烯B4受体、白三烯B4受体BLTl、白三烯B4受体BLT2、A类孤儿/其它、假定的神经传递素、SREB、Mas原癌基因及Mas相关(MRGs)、GPR45样、半胱胺酰基白三烯、G蛋白偶连胆汁酸受体、游离脂肪酸受体(GP40、GP41、GP43)、B类分泌素样、降钙素、促皮质素释放因子、胃抑制、胰高血糖素、生长激素释放激素、甲状旁腺激素、PACAP、分泌素、血管活性肠多肽、蜘蛛毒素亲和蛋白(Latrophilin)、1型蜘蛛毒素亲和蛋白、2型蜘蛛毒素亲和蛋白、3型蜘蛛毒素亲和蛋白、ETL受体、脑特异性血管生成抑制剂(BAI)、玛士撒拉样蛋白(Methuselah-like protein,MTH)、钙黏素EGF LAG(CEL SR)、极大G蛋白偶合受体、C类促代谢型谷氨酸/信息素、I至III组促代谢型谷氨酸、钙感应样、细胞外钙感应、信息素、其它钙感应样、假定的信息素受体、GABA-B、GABA-B亚型1、GABA-B亚型2、GABA-B样、孤儿GPRC5、孤儿GPCR6、无七的新娘蛋白(Bride of sevenless protein,BOSS)、味觉受体(TlR)、D类真菌信息素、真菌信息素A-因子样(STE2.STE3)、真菌信息素B样(BAR、BBR、RCB、PRA)、E类cAMP受体、眼白化病蛋白、卷曲蛋白/斯木森德(Smoothened)家族、A组卷曲蛋白(Fz 1及2及4及5及7-9)、B组卷曲蛋白(Fz 3及6)、C组卷曲蛋白(其它)、犁鼻受体、线虫化学受体、昆虫气味受体及Z类古菌/细菌/真菌视蛋白。
在其它实施方式中,本文所述的SABA融合物可包含任一以下活性多肽:BOTOX、Myobloc、Neurobloc、Dysport(或其它血清型的肉毒杆菌神经毒素)、阿葡糖苷酶α、达托霉素(daptomycin)、YH-16、绒膜促性腺激素α、非格司亭(filgrastim)、西曲瑞克(cetrorelix)、白介素-2、阿地白介素(aldesleukin)、替西白介素(teceleukin)、地尼白介素(denileukin diftitox)、干扰素α-n3(注射剂)、干扰素α-nl、DL-8234、干扰素、桑托里(Suntory)(γ-Ia)、干扰素γ、胸腺素α1、他索纳明(tasonermin)、DigiFab、ViperaTAb、EchiTAb、CroFab、奈西立肽(nesiritide)、阿巴西普(abatacept)、阿法赛特(alefacept)、利比(Rebif)、艾托特明α(eptotermin alfa)、特立帕肽(teriparatide)(骨质疏松症)、可注射降钙素(骨病)、降钙素(鼻部、骨质疏松症)、依那西普(etanercept)、血色素格鲁他姆(glutamer)250(牛)、德罗崔库金(drotrecogin)α、胶原蛋白酶、卡培立肽(carperitide)、重组人类表皮生长因子(外用凝胶,伤口愈合)、DWP-401、达贝泊汀α(darbepoetin alfa)、依泊汀ω(epoetin omega)、依泊汀β、依泊汀α、地西卢定(desirudin)、来匹卢定(lepirudin)、比伐卢定(bivalirudin)、诺那凝血素α(nonacog alpha)、凝血因子Ⅸ粉针剂(Mononine)、依他凝血素α(eptacogalfa)(活化)、重组因子VIII+VWF、浓缩的重组抗血友病因子(Recombinate)、重组因子VIII、因子VIII(重组)、血源性凝血因子(Alphanate)、辛凝血素α(octocog alfa)、因子VIII、帕里弗明(palifermin)、印地激酶(Indikinase)、替奈普酶(tenecteplase)、阿替普酶(alteplase)、帕米普酶(pamiteplase)、瑞替普酶瑞替普酶(reteplase)、那替普酶(nateplase)、孟替普酶(monteplase)、促卵泡素α(follitropinalfa)、rFSH、hpFSH、米卡芬净(micafungin)、非格司亭(peglgrastim)、来诺拉提(lenograstim)、那托司亭(nartograstim)、舍莫瑞林(sermorelin)、胰高血糖素、艾塞那肽(exenatide)、普兰林肽(pramlintide)、伊米苷酶(imiglucerase)、加硫酶(galsulfase)、留可曲平(Leucotropin)、莫拉司亭(molgramostim)、乙酸曲普瑞林(triptorelinacetate)、组胺瑞林(histrelin)(皮下植入,Hydron)、地洛瑞林(deslorelin)、组胺瑞林、那法瑞林(nafarelin)、亮丙瑞林(leuprolide)持续释放储存物(ATRIGEL)、亮丙瑞林植入物(DUROS)、戈舍瑞林(goserelin)、索玛曲平(somatropin)、优曲平(Eutropin)、KP-102程序、索玛曲平、索玛曲平、美卡舍明(mecasermin)(生长失败)、恩夫韦地(enfuvirtide)、Org-33408、精胰岛素(insulin glargine)、赖谷胰岛素(insulinglulisine)、胰岛素(吸入型);赖脯胰岛素(insulin lispro)、地特胰岛素(insulindetemir)、胰岛素(经颊)、RapidMist)、美卡舍明林菲培(mecasermin rinfabate)、阿那白滞素(anakinra)、西莫白介素(celmoleukin)、99mTc-阿西肽(99mTc-apcitide)注射剂、麦罗匹德(myelopid)、贝特丝绒(Betaseron)、乙酸格拉默(glatiramer acetate)、格旁(Gepon)、沙格司亭(sargramostim)、奥普瑞白介素(oprelvekin)、人类白细胞衍生α干扰素、Bilive、胰岛素(重组)、重组人类胰岛素、门冬胰岛素(insulin aspart)、美卡舍明、罗扰素-A(Roferon-A)、干扰素-α2、阿尔法弗隆(Alfaferone)、干扰素alfacon-1、干扰素α、阿温耐克斯(Avonex)重组人类促黄体生成激素、阿法错道酶α(dornase alfa)、曲弗明(trafermin)、齐考诺肽(ziconotide)、他替瑞林(taltirelin)、地博特明α(diboterminalfa)、阿托西班(atosiban)、贝卡普勒明(becaplermin)、依替巴肽(eptifibatide)、扎马拉(Zemaira)、CTC-111、夏伐克(Shanvac)-B、HPV疫苗(四价)、NOV-002、奥曲肽(octreotide)、兰瑞肽(lanreotide)、安瑟斯替(ancestim)、无半乳糖甘酶(agalsidase)β、无半乳糖甘酶α、艾杜糖醛酸水解酶(laronidase)、醋肽铜(prezatide copper acetate)(外用凝胶)、拉布立酶(rasburicase)、兰尼单抗(ranibizumab)、阿克替姆(Actimmune)、佩乐能(PEG-Intron)、曲可明(Tricomin)、重组马尘螨过敏去敏注射剂、重组人类甲状旁腺激素(PTH)1-84(sc,骨质疏松症)、依泊汀δ、转基因基因抗凝血酶III、格兰蒂曲平(Granditropin)、透明质酸酶(Vitrase)、重组胰岛素、干扰素-α(口服口含锭)、GEM-2IS、伐普肽(vapreotide)、艾杜硫酶(idursulfase)、奥马曲拉(omapatrilat)、重组血清白蛋白、赛妥珠单抗(certolizumabpegol)、谷卡匹酶(glucarpidase)、人类重组Cl酯酶抑制剂(血管性水肿)、拉诺替普酶(lanoteplase)、重组人类生长激素、恩夫韦地(enfuvirtide)(无针注射,Biojector2000)、VGV-I、干扰素(α)、芦西纳坦(lucinactant)、阿肽地尔(aviptadil)(吸入型,肺病)、艾替班特(icatibant)、埃可兰肽(ecallantide)、奥米加南(omiganan)、奥罗格雷(Aurograb)、乙酸培西加南(pexiganan acetate)、ADI-PEG-20、LDI-200、地加瑞克(degarelix)、贝辛白介素(cintredekin besudotox)、FavId、MDX-1379、ISAtx-247、利拉鲁肽(liraglutide)、特立帕肽(骨质疏松症)、替法可近(tifacogin)、AA-4500、T4N5脂质体洗液、卡托马单抗(catumaxomab)、DWP-413、ART-123、克里萨林(Chrysalin)、去氨普酶(desmoteplase)、安地普酶(amediplase)、绒促卵泡素α(corifollitropin alpha)、TH-9507、替度鲁肽(teduglutide)、戴麦德(Diamyd)、(DWP-412)、生长激素(持续释放注射)、重组G-CSF、胰岛素(吸入型,AIR)、胰岛素(吸入型,Technosphere)、胰岛素(吸入型,AERx)、RGN-303、DiaPep277、干扰素β(C型肝炎病毒感染(HCV))、干扰素α-n3(口服)、贝拉他西普(belatacept)、经皮胰岛素贴片、AMG-531、MBP-8298、西雷西普(Xerecept)、奥培巴坎(opebacan)、AIDSVAX、GV-1001、LymphoScan、豹蛙酶(ranpirnase)、利普散(Lipoxysan)、卢舒普肽(lusupultide)、MP52(β-磷酸三钙载体,骨再生)、黑色素瘤疫苗、西普乐克(sipuleucel)-T、CTP-37、印瑟吉(Insegia)、维特斯朋(vitespen)、人类凝血酶(冷冻,手术抽血)、凝血酶、TransMID、蛇毒纤溶酶(alfimeprase)、聚乙二醇化重组猪尿酸酶(Puricase)、特利加压素(terlipressin)(静脉内,肝肾综合征)、EUR-1008M、重组FGF-I(可注射,血管疾病)、BDM-E、罗替格普肽(rotigaptide)、ETC-216、P-113、MBI-594AN、耐久霉素(duramycin)(吸入型,囊性纤维化)、SCV-07、OPI-45、内皮抑制素、血管抑制素、ABT-510、保曼布克(Bowman Birk)抑制剂浓缩物、XMP-629、99mTc-Hynic-磷脂结合蛋白V、卡哈拉德(kahalalide)F、CTCE-9908、替维瑞克(teverelix)(延伸释放)、奥扎里克(ozarelix)、罗米德普(romidepsin)、BAY-50-4798、白介素-4、PRX-321、佩斯坎(Pepscan)、埃布他德金(iboctadekin)、rh乳铁传递蛋白(rh lactoferrin)、TRU-015、IL-21、ATN-161、西仑吉肽(cilengitide)、阿尔布芬(Albuferon)、比费西克斯(Biphasix)、IRX-2、ω干扰素、PCK-3145、CAP-232、帕斯雷肽(pasireotide)、huN901-DM1、卵巢癌免疫治疗疫苗、SB-249553、Oncovax-CL、OncoVax-P、BLP-25、CerVax-16、多表位肽黑色素瘤疫苗(MART-I,gp100,酪氨酸酶)、奈米非肽(nemifitide)、rAAT(吸入型)、rAAT(皮肤病)、CGRP(吸入型,哮喘)、(pegsunercept)、胸腺素β-4、普利德普(plitidepsin)、GTP-200、雷莫拉宁(ramoplanin)、GRASPA、OBI-I、AC-100、鲑鱼降钙素(口服,eligen)、降钙素(口服,骨质疏松症)、艾沙瑞林(examorelin)、卡普瑞林(capromorelin)、卡德法(Cardeva)、维拉弗明(velafermin)、131I-TM-601、KK-220、TP-10、乌拉立肽(ularitide)、地来司他(depelestat)、赫马肽(hematide)、克里萨林(表面)、rNAPc2、重组因子VIII(聚乙二醇化脂质体)、bFGF、聚乙二醇化重组葡激酶变体、V-10153、SonoLysis Prolyse、NeuroVax、CZEN-002、胰岛细胞新生疗法、rGLP-1、BIM-51077、LY-548806、埃克斯肽(exenatide)(控制释放,Medisorb)、AVE-0010、GA-GCB、阿伏瑞林(avorelin)、AOD-9604、乙酸利那洛肽(linaclotide acetate)、CETi-I、赫莫斯盘(Hemospan)、VAL(可注射)、快速作用胰岛素(可注射,Viadel)、鼻内胰岛素、胰岛素(吸入型)、胰岛素(口服,eligen)、重组甲硫胺酰基人类瘦素、皮崔金拉(pitrakinra)(皮下注射,eczema)、皮崔金拉(吸入型干粉,哮喘)、木替金(Multikine)、RG-1068、MM-093、NBI-6024、AT-001、PI-0824、Org-39141、CpnlO(自体免疫疾病/炎症)、ta乳铁传递蛋白(talactoferrin)(表面)、rEV-131(眼用)、rEV-131(呼吸道疾病)、口服重组人类胰岛素(糖尿病)、RPI-78M、奥普瑞白介素(口服)、CYT-99007CTLA4-Ig、DTY-001、(valategrast)、干扰素α-n3(表面)、IRX-3、RDP-58、涛弗隆(Tauferon)、胆汁盐刺激性脂肪酶、梅里斯普酶(Merispase)、碱性磷酸酶、EP-2104R、美拉诺坦(Melanotan)-II、布雷默浪丹(bremelanotide)、ATL-104、重组人微纤维蛋白溶酶(recombinant humanmicroplasmin)、AX-200、SEMAX、ACV-I、Xen-2174、CJC-1008、强啡肽(dynorphin)A、SI-6603、LAB GHRH、AER-002、BGC-728、疟疾疫苗(病毒颗粒,PeviPRO)、ALTU-135、细小病毒B19疫苗、流感疫苗(重组神经胺糖酸苷酶)、疟疾/HBV疫苗、炭疽病疫苗、Vacc-5q、Vacc-4x、HIV疫苗(口服)、HPV疫苗、Tat类毒素、YSPSL、CHS-13340、PTH(1-34)脂质粒乳膏(Novasome)、奥斯布尔(Ostabolin)-C、PTH类似物(表面,牛皮癣)、MBRI-93.02、MTB72F疫苗(肺结核)、MVA-Ag85A疫苗(肺结核)、FAR-404、BA-210、重组噬菌体FlV疫苗、AG-702、OxSODrol、rBetVl、Der-pl/Der-p2/Der-p7过敏靶向性疫苗(尘螨过敏)、PRl肽抗原(白血病)、突变ras疫苗、HPV-16E7脂肽疫苗、迷路疫苗(腺癌)、CML疫苗、WTl-肽疫苗(癌症)、IDD-5、CDX-110、朋曲斯(Pentrys)、诺雷林(Norelin)、CytoFab、P-9808、VT-111、艾罗卡肽(icrocaptide)、替柏明(telbermin)(皮肤病,糖尿病足部溃疡)、芦平曲韦(rupintrivir)、雷替库罗(reticulose)、rGRF、PlA、α-半乳糖苷酶A、ACE-011、ALTU-140、CGX-1160、血管紧张素治疗疫苗、D-4F、ETC-642、APP-018、rhMBL、SCV-07(口服,肺结核)、DRF-7295、ABT-828、ErbB2特异性免疫毒素(抗癌剂)、DT388IL-3、TST-10088、PRO-1762、库姆波托(Comboto x)、缩胆囊肽-B/胃泌素-受体结合肽、l l lln-hEGF、AE-37、曲妥珠单抗(trastuzumab)-DMl、拮抗剂G、IL-12(重组)、PM-02734、IMP-321、rhIGF-BP3、BLX-883、CUV-1647(表面)、基于L-19的放射免疫治疗剂(癌症)、Re-188-P-2045、AMG-386、DC/I540/KLH疫苗(癌症)、VX-001、AVE-9633、AC-9301、NY-ESO-I疫苗(肽)、NA17.A2肽、黑色素瘤疫苗(脉冲抗原治疗剂)、前列腺癌疫苗、CBP-501、重组人类乳铁传递蛋白(干眼病)、FX-06、AP-214、WAP-8294A2(可注射)、ACP-HIP、SUN-11031、肽YY[3-36](肥胖,鼻内)、FGLL、阿塞西普(atacicept)、BR3-Fc、BN-003、BA-058、人类甲状旁腺激素1-34(鼻内,骨质疏松症)、F-18-CCRl、AT-1001(乳糜泻/糖尿病)、JPD-003、PTH(7-34)脂质粒乳膏(Novasome)、耐久霉素(眼用,干眼病)、CAB-2、CTCE-0214、糖聚乙二醇化红细胞生成素、EPO-Fc、CNTO-528、AMG-114、JR-013、因子XIII、氨基康定(aminocandin)、PN-951、716155、SUN-E7001、TH-0318、BAY-73-7977、替维瑞克(立即释放)、EP-51216、hGH(控制释放,Biosphere)、OGP-I、(sifuvirtide)、TV-4710、ALG-889、Org-41259、rhCCIO、F-991、胸腺五肽(thymopentin)(肺病)、r(m)CRP、肝选择性胰岛素、苏巴林(subalin)、L 19-IL-2融合肽、内生多肽(elafin)、NMK-150、ALTU-139、EN-122004、rhTPO、血小板生成素受体促效剂(血小板减少症)、AL-108、AL-208、神经生长因子拮抗剂(疼痛)、SLV-317、CGX-1007、INNO-105、口服特立帕肽(eligen)、GEM-OSl、AC-162352、PRX-302、LFn-p24融合物疫苗(Therapore)、EP-1043、肺炎链球菌(S pneumoniae)儿科疫苗、疟疾疫苗、脑膜炎奈瑟菌(Neisseriameningitidis)B类疫苗、新生儿B类链球菌疫苗)、炭疽热疫苗、HCV疫苗(gpE1+gpE2+MF-59)、中耳炎疗法、HCV疫苗(核心抗原+ISCOMATRIX)、hPTH(1-34)(经皮,ViaDerm)、768974、SYN-101、PGN-0052、阿维库明(aviscumine)、BIM-23190、肺结核疫苗、多表位酪氨酸酶肽、癌症疫苗、恩卡斯替母(enkastim)、APC-8024、GI-5005、ACC-OOl、TTS-CD3、血管靶向性TNF(实体肿瘤)、去氨加压素(desmopressin)(经颊控制释放)、奥那西普(onercept)、TP-9201。
在其它例示性实施方式中,SABA与选自(但不限于)以下的部分融合:FGF21(成纤维细胞生长因子21)、GLP-1(胰高血糖素样肽1)、Exendin4、胰岛素、胰岛素受体肽、GIP(葡萄糖依赖性促胰岛素多肽)、脂连蛋白、IL-1Ra(白介素1受体拮抗剂)、VIP(血管活性肠肽)、PACAP(垂体腺苷酸环化酶激活多肽)、瘦素、INGAP(胰岛新生相关蛋白)、BMP-9(骨形态发生蛋白-9)、胰淀素、PYY3-36(肽YY3-36)、PP(胰多肽)、IL-21(白介素21)、菌丝霉素、PRGN(颗粒蛋白前体)、Atstrrin、IFN(干扰素)、Apelin及骨钙蛋白(OCN)。
在其它例示性实施方式中,SABA与一或多个其它10Fn3结构域融合。举例而言,SABA可与一个、两个、三个、四个或四个以上其它10Fn3结构域融合。此类其它10Fn3结构域可结合除血清白蛋白外的相同或不同靶。
在某些实施方式中,本申请提供一种可由下式表示的SABA-Y融合物:SABA-X1-Y或Y-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),且Y为如本文所述的治疗性部分。
在某些实施方式中,本申请案提供一种可由下式表示的SABA-Y融合物:SABA-X1-Cys-X2-Y或Y-X1-Cys-X2-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸,X1为4任选的多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),Cys为半胱氨酸残基,X2为化学衍生的间隔物(适合间隔物的实例展示于表1中),且Y为如本文所述的治疗性部分。在例示性实施方式中,该化学衍生的间隔物含有马来酰亚胺部分,其可用于藉由如本文进一步所述的迈克尔加成(Michael addition)使治疗性部分缀合于SABA多肽的C端Cys,或使SABA多肽缀合于治疗性部分的C端Cys。
在其它方面中,SABA可结合于两个或两个以上治疗性部分。举例而言,两个部分可以以多种排列结合SABA,例如下述自融合物序列的N端至C端:X-Y-SABA、X-SABA-Y或SABA-X-Y,其中X及Y表示两个不同治疗性部分。该两个不同治疗性部分可选自本文公开的任一部分。
1.FGF21
成纤维细胞生长因子21(FGF21)为信号传导蛋白质的FGF家族的成员。这些蛋白质藉由结合并活化FGF受体(细胞表面酪氨酸激酶家族的成员)来起作用。FGF21为该家族的非典型成员,因为其不结合肝素,而需要β-klotho(其为单向跨膜蛋白)作为活性的共受体。这些受体具有广泛组织的分布,但β-klotho表达局限于某些组织(肝脏、脂肪及胰脏),并且恰恰是β-klotho的组织选择性表达赋予FGF21靶特异性的。体外研究表明FGFR1c(FGFR1的一种同型物)及FGFR4分别为白脂肪组织及肝脏中的优选受体。
FGF21充当代谢调节因子,且FGF21的失调可导致各种代谢病症。FGF21藉由诱导ERK磷酸化及GLUT1表达而增加3T3-L1脂肪细胞及原代人类脂肪细胞培养物的葡萄糖摄取。在INS-1E细胞及分离的胰岛中,FGF21诱导ERK及AKT磷酸化。在肝细胞系中,FGF21刺激典型FGF信号传导(ERK磷酸化)且减少葡萄糖产生。如下文进一步所述,本文所述的SABA-FGF21融合物可用于治疗或预防各种代谢疾病及病症。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的FGF21及此类融合物(本文通常称为FGF21-SABA融合物)的用途。FGF21-SABA融合物指具有各种排列的融合物,包括例如SABA-FGF21、FGF21-SABA、FGF21-SABA-FGF21等。某些例示性构建体展示于表2中。然而,应了解如本文所揭示的FGF21包括保留FGF21功能活性的FGF21变体、截短形式及任何经修饰形式。亦即,如本文所述的FGF-21亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留FGF-21的生物活性即可。
举例而言,野生型全长FGF21如SEQ ID NO:117所示。表2中所呈现的所有FGF21变体均含有SEQ ID NO:118所示的核心FGF21序列。各种N端序列(诸如SEQ ID NO:119-124中的任一者所示的那些序列)可添加至核心FGF21序列(SEQ ID NO:118)的N端并保留功能活性。另外,His6标签可添加至N端(例如SEQ ID NO:128-131)。核心FGF21序列缺乏C端丝氨酸,其可或可不添加至核心序列的C端而不影响其活性。此外,FGF21与SABA融合分子可以按照FGF21-SABA或SABA-FGF21的次序(包括如本文所述且现有技术中已知的任何任选的末端延伸及接头序列)连接而不影响FGF21功能活性(参见例如实例B6)。
在例示性实施方式中,本申请提供一种SABA-FGF21融合物,其中该FGF21部分包含SEQ ID NO:117-118或125-131的序列,或与SEQ ID NO:117-118或125-131中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-FGF21融合物包含SEQ ID NO:132-174中的任一者的序列,或与SEQ ID NO:132-174中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-FGF21融合物:SABA-X1-FGF21或FGF21-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQID NO:65-88、216-221或397中的任一者),且FGF21为如本文所述的FGF21肽。
2.胰岛素
在另一方面中,本发明描述SABA与胰岛素融合分子。胰岛素为调节体内能量及葡萄糖代谢的激素。这种多肽由胰β-胰岛细胞分泌于血液中,在血液中该多肽刺激肝脏、肌肉及脂肪细胞自血液摄取葡萄糖并促进糖原生成及脂质生成。胰岛素分泌及/或活动中的任何步骤失灵可导致许多病症,包括氧利用、脂肪生成、糖原生成、脂质生成、葡萄糖摄取、蛋白质合成、热生成及维持基础代谢率的失调。此失灵导致包括但不限于下述的疾病及/或病症:高胰岛素血症、胰岛素抗性、胰岛素缺乏、高血糖症、高脂质血症、高酮血症、糖尿病及糖尿病性肾病。因此,本文所述的SABA-胰岛素融合多肽可适用于治疗患有此类疾病及/或病症的受试者。
在例示性实施方式中,可应用于本发明的胰岛素部分包括天然存在的胰岛素、生物合成胰岛素、胰岛素衍生物及类似物。胰岛素类似物为天然存在的胰岛素蛋白质(诸如人类胰岛素或动物形式的胰岛素)的类似物,其中已经取代、添加及/或移除了至少一个氨基酸残基。此类氨基酸可为合成或经修饰氨基酸。胰岛素衍生物为天然存在的胰岛素或胰岛素类似物的衍生物,其已经过了化学修饰,例如藉由向一个或多个氨基酸添加一个或多个特定化学基团来化学修饰。例示性胰岛素类似物描述于美国专利第7,476,652号中,该案以全文引用的方式并入本文中。
3.胰岛素受体肽
在一个方面,本发明描述SABA与胰岛素受体肽的融合分子。在某些实施方式中,该胰岛素受体肽包含胰岛素受体的氨基酸687至710(KTDSQILKELEESSFRKTFEDYLH;SEQ IDNO:175)。胰岛素受体是一种由激素胰岛素活化的跨膜受体酪氨酸激酶。胰岛素受体活化引发信号级联反应,最终使得葡萄糖转运体转运至细胞表面,以使得细胞可自血液摄取葡萄糖。葡萄糖摄取主要在脂肪细胞及肌细胞中进行。胰岛素受体的功能障碍与胰岛素不敏感性或抗性相关,其通常导致2型糖尿病及当细胞无法吸收葡萄糖时所引起的其它并发症。与胰岛素受体基因突变相关的其它病症包括多诺霍综合征(Donohue Syndrome)及罗布森-曼登赫尔综合征(Rabson-MendenhallSyndrome)。因此,本文所述的SABA-胰岛素受体肽融合物的例示性用途可包括治疗患有如2型糖尿病或与细胞葡萄糖摄取不足相关的其它病症、多诺霍综合征及罗布森-曼登赫尔综合征的病症的受试者。
4.BMP-9
在某些方面中,本发明描述SABA与BMP-9融合分子。各种BMP-9组合物描述于美国专利第5,661,007号及第6,287,816号中,此类专利以全文引用的方式并入本文中。骨形态发生蛋白(BMP)属于生长因子及细胞激素的TGF-β家族。BMP诱导骨及软骨形成并介导许多其它组织中的形态生成变化。BMP信号传导为胚胎发育以及出生后组织的生长及维持所必需的。信号传导路径亦与从脊椎病症至癌症乃至反流诱发性食管炎等疾病相关。
已发现超过二十种BMP。在这些分子中,BMP-9主要在非实质性肝细胞中表达,且与肝细胞的增殖及功能(尤其肝葡萄糖产生)有关。BMP-9还似乎在癌细胞凋亡、内皮细胞中的信号传导、骨生成、软骨生成、认知等中起其它作用。因此,本文所述的SABA-BMP-9融合多肽可适用于治疗各种疾病及病症,例如治疗各种类型的伤口及展现肝脏退化的疾病,以及治疗包括骨及/或软骨缺损、牙周病及各种癌症的其它疾病及/或病症。
5.胰淀素(amylin)
在一些方面中,本发明描述SABA与胰淀素的融合分子。胰淀素(或胰岛淀粉样蛋白多肽,IAPP)为由胰β细胞分泌的具有37个氨基酸的小肽激素。胰淀素与胰岛素同时分泌,且被认为在控制胰岛素分泌、葡萄糖稳态、胃排空及向脑部传达饱腹感信号中起作用。胰淀素形成原纤维,后者与胰β细胞的凋亡性细胞死亡有关。与此发现一致的是,胰淀素通常见于罹患2型糖尿病或具有胰岛素瘤(一种神经内分泌肿瘤)的患者的胰岛中。
胰淀素可用作糖尿病患者的治疗剂。胰淀素肽的制备描述于美国专利第5,367,052号中,该申请全文以引用的方式并入本文中。类似地,美国专利第6,610,824号及第7,271,238号(全文以引用的方式并入本文中)描述藉由Asn、Ser及/或Thr残基的糖基化所形成的胰淀素的激动剂类似物,其可用于治疗或预防低血糖状况。因此,本文所述的SABA-胰淀素融合多肽可例如适用于治疗患有低血糖症、肥胖、糖尿病、饮食障碍、胰岛素抗性综合征及心血管疾病的受试者。SABA-胰淀素融合物的制备描述于实施例中。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的胰淀素及此类融合物(本文中统称为SABA-胰淀素融合物)的用途。SABA-胰淀素融合物指具有各种排列的融合物,包括例如SABA-胰淀素及胰淀素-SABA。在例示性实施方式中,SABA-胰淀素融合物是如此排列的,以使得胰淀素肽的C端游离,这允许羧基端进行酰胺化。某些例示性SABA-胰淀素融合构建体展示于表2中。然而,应了解如本文所公开的胰淀素包括保留胰淀素功能活性的胰淀素变体、截短形式及任何经修饰形式。亦即,如本文所述的胰淀素亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留胰淀素的生物活性即可。例示性胰淀素序列以SEQ ID NO:296-303呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-胰淀素融合物,其中该胰淀素部分包含SEQ ID NO:296-303中的任一者的序列,或与SEQ ID NO:296-303中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-胰淀素融合物包含SEQ IDNO:304-328中的任一者的序列,或与SEQ ID NO:304-328中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-胰淀素融合物:SABA-X1-胰淀素,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),且胰淀素为如本文所述的胰淀素肽。胰淀素肽优选在C端经酰胺化。胰淀素肽可另外包含Cys1,7或Cys2,7二硫键。
在某些实施方式中,本申请提供一种可由下式表示的SABA-胰淀素融合物:SABA-X1-Cys-X2-胰淀素,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为任选的多肽接头(适合的接头包括例如SEQ IDNO:65-88、215-221或397中的任一者),Cys为半胱氨酸残基,X2为化学衍生的间隔物(适合间隔物的实例展示于表1中),且胰淀素为如本文所述的胰淀素肽。胰淀素肽优选在C端经酰胺化。胰淀素肽可另外包含Cys1,7或Cys2,7二硫键。在例示性实施方式中,化学衍生的间隔物含有马来酰亚胺部分,其可用于藉由如本文进一步所述的迈克尔加成使胰淀素肽结合于SABA多肽的C端Cys。
6.PYY3-36
在其它方面中,本发明描述SABA与PYY融合分子。肽YY(亦称为PYY、肽酪氨酸酪氨酸,或胰肽YY)为由回肠及结肠中的细胞响应进食而释放的具有36个氨基酸的蛋白质。PYY分泌于胰脏中且通过抑制胰脏分泌(例如胰岛素)来帮助控制能量稳态,由此使得血糖水平提高并传导需要减少进食的信号。存在PYY的两种主要形式,即全长形式(1-36)及截短形式(3-36)。循环PYY免疫反应性的最常见形式为PYY3-36。PYY3-36对Y2受体的亲和力高于PYY1-36。另外,PYY13-36对Y2受体具有类似高效力,从而表明残基4-12对于此受体并不重要(K.McCrea等人,2-36[K4,RYYSA(19-23)]PP a novelY5-receptor preferring ligand with strongstimulatory effect on food intake,Regul.Pept 87 1-3(2000),第47-58页)。此外,已描述基于PYY(22-36)及(25-36)的结构的更短的PYY片段类似物,其显示相对于其它NPY受体(Y1、Y4及Y5)的Y2选择性。参见例如美国专利第5,604,203号及第6,046,167号,这些专利以引用的方式并入本文中。PYY肽及偶连于反应性基团的功能衍生物描述于美国专利第7,601,691号中,该专利以引用的方式并入本文中。
已发现PYY与许多生理活性有关,包括营养摄取、细胞增殖、脂肪分解及血管收缩。具体的,已显示PYY3-36降低人类的食欲及食物摄取(参见例如Batterham等人,Nature 418:656-654,2002)。因此,本文所述的SABA-PYY融合多肽的例示性用途可包括治疗肥胖、糖尿病、饮食障碍、胰岛素抗性综合征及心血管疾病。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的PYY及此类融合物(本文通常称为SABA-PYY融合物)的用途。SABA-PYY融合物指具有各种排列的融合物,包括例如SABA-PYY及PYY-SABA。在例示性实施方式中,SABA-PYY融合物具有如此的排列,使得PYY肽的C端游离,这允许羧基端进行酰胺化。某些例示性SABA-PYY融合构建体展示于表2中。然而,应了解如本文所公开的PYY包括保留PYY功能活性的PYY变体、截短形式及任何经修饰形式。亦即,如本文所述的PYY亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留PYY的生物活性即可。例示性PYY序列以SEQID NO:329-337及408-418呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-PYY融合物,其中该PYY部分包含SEQID NO:329-337或408-418中的任一者的序列;与SEQ ID NO:329-337或408-418中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列;具有SEQ ID NO:329-333或335-337中的任一者的残基3-36、13-36、21-36、22-36、24-36或25-36的序列;与具有SEQ IDNO:329-333或335-337中的任一者的残基3-36、13-36、21-36、22-36、24-36或25-36的序列具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列;或具有V31L取代的任一上述序列。在某些实施方式中,SABA-PYY融合物包含SEQ ID NO:338-344中的任一者的序列,或与SEQ IDNO:338-344中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-PYY融合物:SABA-X1-PYY,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),且PYY为如本文所述的PYY肽。PYY肽优选在C端经酰胺化。
在某些实施方式中,本申请提供一种可由下式表示的SABA-PYY融合物:SABA-X1-Cys-X2-PYY,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为任选的多肽接头(适合的接头包括例如SEQ IDNO:65-88、215-221或397中的任一者),Cys为半胱氨酸残基,X2为化学衍生的间隔物(适合间隔物的实例展示于表1中),且PYY为如本文所述的PYY肽。PYY肽优选在C端经酰胺化。在例示性实施方式中,化学衍生的间隔物含有马来酰亚胺部分,其可用于藉由如本文进一步所述的迈克尔加成使PYY肽结合于SABA多肽的C端Cys。
7.胰多肽
在一些方面中,本发明描述SABA与胰多肽融合分子。胰多肽(PP)为胰多肽激素家族的成员,该家族亦包括神经肽Y(NPY)及肽YY(PYY)。PP为由胰多肽细胞响应进食、运动及禁食而释放的具有36个氨基酸的蛋白质。PP见于胰脏、胃肠道及CNS中,在其中其影响胆囊收缩、胰脏分泌、肠运动以及诸如糖原分解及降低脂肪酸水平等代谢功能。PP亦与食物摄取、能量代谢及下视丘肽及胃内激素的表达有关。另外,PP在与食物摄取增加相关的状况中减少。PP亦可与肿瘤发生有关,诸如胰肽细胞的罕见恶性肿瘤。PP可投与患者,例如用来减少肝葡萄糖产生(美国专利第5,830,434号)。本文所公开的SABA-PYY融合多肽的例示性用途可包括治疗肥胖、糖尿病、饮食障碍、胰岛素抗性综合征及心血管疾病。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的PYY及此类融合物(本文统称为SABA-PP融合物)的用途。SABA-PP融合物指具有各种排列的融合物,包括例如SABA-PP及PP-SABA。在例示性实施方式中,SABA-PP融合物具有这样的排列,使得PP肽的C端游离,这允许羧基端进行酰胺化。某些例示性SABA-PP融合构建体展示于表2中。然而,应了解如本文所公开的PP包括保留PP功能活性的PP变体、截短形式及任何经修饰形式。亦即,如本文所述的PP亦包括经修饰的形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留PP的生物活性即可。例示性PP序列以SEQ ID NO:345-357呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-PP融合物,其中该PP部分包含SEQ IDNO:345-357中的任一者的序列,或与SEQ ID NO:345-357中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-PP融合物包含SEQ ID NO:358-364中的任一者的序列,或与SEQ ID NO:358-364中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-PP融合物:SABA-X1-PP,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),且PP为如本文所述的PP肽。PP肽优选在C端经酰胺化。
在某些实施方式中,本申请提供一种可由下式表示的SABA-PP融合物:SABA-X1-Cys-X2-PP,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为任选的多肽接头(适合的接头包括例如SEQ ID NO:65-88、215-221或397中的任一者),Cys为半胱氨酸残基,X2为化学衍生的间隔物(适合间隔物的实例展示于表1中),且PP为如本文所述的PP肽。PP肽优选在C端经酰胺化。在例示性实施方式中,化学衍生的间隔物含有马来酰亚胺部分,其可用于藉由如本文进一步所述的迈克尔加成使PP肽结合于SABA多肽的C端Cys。
8.白介素21(IL-21)
在另一方面中,本发明描述SABA与IL-21融合分子。IL-21为I型细胞因子,其与IL-2、IL-4、IL-7、IL-9及IL-15享有共同的受体γ链。IL-21在活化的人类CD4+T细胞中表达,在T辅助细胞的Th2及Th17亚群、T滤泡细胞及NK T细胞中上调。这种细胞因子在调节所有这些细胞类型的功能中均具有作用。B细胞亦由IL-21调节。视与协同刺激信号的相互作用及B细胞的发育阶段而定,IL-21可在小鼠与人类中诱导增殖、向产生Ig的浆细胞的分化,或细胞凋亡。单独的IL-21及IL-21与Th细胞衍生的细胞因子的组合可调节向IgG、IgA或IgE同型的类别转换重组,表明其在塑造B细胞的效应物功能中的重要作用。因此,经由其对免疫细胞的多种作用,IL-21在正常免疫反应的许多方面中起作用。
作为免疫系统的调节剂,已研究了IL-21作为用于癌症疗法的免疫刺激剂(单独地或与其它疗法组合)的用途、作为免疫疗法的辅助疗法的用途,及作为病毒疗法的用途,以及其他期望上调免疫系统的用途。临床与临床前治疗的具体癌症已有转移性黑色素瘤、肾细胞癌、结肠癌、胰腺癌、乳癌、胸腺瘤、头颈部鳞状细胞癌及神经胶质瘤(综述参见Sondergaard及Skak,TissueAntigens,74(6):467-479,2009)。另外,IL-21上调与各种人类T细胞介导T细胞相关的炎性病理有关,包括克罗恩氏病(Crohn's disease,CD)、溃疡性结肠炎、炎性肠病(IBD)的主要形式、幽门螺旋杆菌相关胃炎(Helicobacterpylori-relatedgastritis)、乳糜泻、特应性皮炎(AD)、全身性红斑狼疮、类风湿性关节炎及银屑病(综述参见Monteleone等人,Trends Pharmacol Sci,30(8),441-7,2009)。例示性IL-21蛋白描述于美国专利第6,307,024号及第7,473,765号中,这些专利以引用的方式并入本文中。
本文所述的SABA-IL21融合多肽的例示性用途包括治疗某些类型的癌症、病毒相关疾病以及各种T细胞介导或T细胞相关的炎性病症,诸如克罗恩氏病(CD)、溃疡性结肠炎、炎性肠病(IBD)的主要形式、幽门螺旋杆菌相关胃炎、乳糜泻、特应性皮炎(AD)、全身性红斑狼疮、类风湿性关节炎及银屑病。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的IL-21及此类融合物(本文通常称为SABA-IL21融合物)的用途。SABA-IL21融合物指具有各种排列的融合物,包括例如SABA-IL21及IL21-SABA。某些例示性SABA-IL21融合构建体展示于表2中。然而,应了解如本文所公开的IL-21包括保留IL-21功能活性的IL-21变体、截短形式及任何经修饰形式。亦即,如本文所述的IL-21亦包括经修饰的形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留IL-21的生物活性即可。例示性IL-21序列以SEQ ID NO:286-287呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-IL21融合物,其中该IL21部分包含SEQ ID NO:286-287中的任一者的序列,或与SEQ ID NO:286-287中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-IL21融合物包含SEQ ID NO:290-295中的任一者的序列,或与SEQ ID NO:290-295中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-IL21融合物:SABA-X1-IL21或IL21-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ IDNO:65-88、216-221或397中的任一者),且IL21为如本文所述的IL-21肽。
9.胰高血糖素样肽1(GLP-1)/Exendin-4
在另一方面中,本发明描述SABA与GLP-1融合分子。胰高血糖素样肽1(GLP-1)为由肠内分泌L细胞响应营养摄取而释放的具有30或31个氨基酸的肽(SEQ ID NO:226及227)。此激素可藉由多种机制起作用以调节葡萄糖稳态及发挥抗糖尿病作用。GLP-1信号传导在动物模型中可增强葡萄糖依赖性胰岛素分泌,以葡萄糖依赖性方式抑制胰高血糖素分泌,延缓胃排空,使得食物摄取及体重降低,并引起β细胞质量增加。
天然GLP-1的治疗性效用是有限的,因为其活体内半衰期小于2分钟,原因是其被普遍存在的蛋白酶二肽基肽酶IV(DPP-IV)快速降解。因为DPP-IV优先切割在第二位置具有丙氨酸或脯氨酸的氨基端二肽,所以一种增加半衰期的策略是改变活性GLP-1中的第二氨基酸(第8位)以使得该肽不再为DPP-IV底物。第8位的丙氨酸可经各种天然(或非天然)氨基酸置换,包括甘氨酸、丝氨酸、苏氨酸或缬氨酸,以产生具有DPP-IV抗性的GLP-1类似物。然而,具有DPP-IV抗性的GLP-1类似物仍具有相对短的药物动力学半衰期,因为它们经由肾脏清除而被消除。举例而言,有效且具有DPP-IV抗性的GLP-1受体激动剂——合成Exendin-4(SEQ ID NO:228;Byetta中的有效药物成分)仍必须对人类糖尿病患者每日投与两次,因为其被肾脏快速清除。
另一种产生长效GLP-1受体激动剂的方法是在与长寿命蛋白质(诸如白蛋白或转铁蛋白)相同的开放阅读框中表达具有DPP-IV抗性的GLP-1类似物。一种这样的融合蛋白,阿必鲁泰(albiglutide),是与人类血清白蛋白融合的DPP-IV抗性GLP-1类似物,目前正在III期临床试验中接受评估。在所有报导的情况下,活性融合蛋白中DPP-IV抗性GLP-1受体激动剂均位于融合蛋白的氨基端;C端融合物的功效显著较低。
在例示性实施方式中,SABA-GLP-1融合蛋白自N端至C端包含:DPP-IV抗性GLP-1受体激动剂(可能包括基于GLP-1或Exendin-4的序列)、接头、及SABA。
SABA-GLP-1及SABA-Exendin融合多肽的例示性用途包括治疗糖尿病、肥胖、肠易激综合征及将其他可得益于降低血浆葡萄糖、抑制胃及/或肠运动及抑制胃及/或肠排空或抑制食物摄取的病状。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的GLP-1或Exendin及此类融合物(本文统称为SABA-GLP-1或SABA-Exendin融合物)的用途。SABA-GLP-1或SABA-Exendin融合物指具有各种排列的融合物,包括例如SABA-GLP-1、GLP-1-SABA、SABA-Exendin及Exendin-SABA。某些例示性SABA-GLP-1及SABA-Exendin融合构建体展示于表2中。然而,应了解如本文所公开的GLP-1及Exendin包括保留GLP-1或Exendin功能活性的GLP-1及Exendin变体、截短形式及任何经修饰形式。亦即,如本文所述的GLP-1及Exendin亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留GLP-1或Exendin的生物活性即可。例示性GLP-1序列以SEQ ID NO:226-227呈现于表2中,且例示性Exendin序列以SEQ ID NO:228呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-GLP-1融合物,其中该GLP-1部分包含SEQ ID NO:226-227中的任一者的序列,或与SEQ ID NO:226-227中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-GLP-1融合物包含SEQ IDNO:229-232中的任一者的序列,或与SEQ ID NO:229-232中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-GLP-1融合物:SABA-X1-GLP-1或GLP-1-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQID NO:65-88、216-221或397中的任一者),且GLP-1为如本文所述的GLP-1肽。
在例示性实施方式中,本申请提供一种SABA-Exendin融合物,其中该Exendin部分包含SEQ ID NO:228,或与SEQ ID NO:228具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-Exendin融合物包含SEQ ID NO:233-236中的任一者的序列,或与SEQ ID NO:233-236中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-Exendin融合物:SABA-X1-Exendin或Exendin-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),且Exendin为如本文所述的Exendin肽。
10.菌丝霉素
在另一方面中,本发明描述SABA与菌丝霉素融合分子。菌丝霉素(Plectasin)为自真菌腐生子囊菌假黑盘菌(Pseudoplectania nigrella)分离的新杀菌性抗微生物肽。在活体外,菌丝霉素可以以与万古霉素(vancomycin)与青霉素(penicillin)相当的速率快速杀死金黄色葡萄球菌(Staphylococcus aureus)及肺炎链球菌(Streptococcus pneumonia),包括对常规抗生素具有抗性的多种菌株,但对哺乳动物细胞无细胞毒性作用。在活体内,菌丝霉素亦显示在小鼠中的极低毒性且可与万古霉素及青霉素同样有效地治愈由肺炎链球菌引起的腹膜炎及肺炎。参见例如Mygind PH等人,Plectasin is a peptideantibioticwith therapeutic potential from a saprophytic fungus,Nature 437:975-980(2005);Brinch KS等人,Plectasin shows intracellular activityagainstStaphylococcus aureus in human THP-1monocytes and in the mouseperitonitismodel,Antimicrob Agents Chemother 53:4801-4808(2009);3.Hara S等人,Plectasin has antibacterial activity and no effect on cell viability or IL-8production,Biochem Biophys Res Commun 374:709-713(2008);及OstergaardC等人,High cerebrospinal fluid(C SF)penetration and potent bactericidalactivity inC SF of NZ2114,a novel plectasin variant,during experimentalpneumococcalmeningitis,Antimicrob Agents Chemother 53:1581-1585(2009)。考虑到这些特征,菌丝霉素是有希望的抗生素产品的具有吸引力的候选者。参见例如Xiao-Lan J等人,High-Level Expression ofthe Antimicrobial PeptidePlectasin in Escherichia coli,Curr Microbiol 61:197-202(2010)。因此,本文所述的SABA-菌丝霉素融合多肽可用作抗细菌剂。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的菌丝霉素及此类融合物(本文统称为SABA-菌丝霉素融合物)的用途。SABA-菌丝霉素融合物指具有各种排列的融合物,包括例如SABA-菌丝霉素及菌丝霉素-SABA。某些例示性SABA-菌丝霉素融合构建体展示于表2中。然而,应了解如本文所公开的菌丝霉素包括保留菌丝霉素功能活性的菌丝霉素变体、截短形式及任何经修饰形式。亦即,如本文所述的菌丝霉素亦包括经修饰的形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留菌丝霉素的生物活性即可。例示性菌丝霉素序列以SEQ ID NO:237呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-菌丝霉素融合物,其中该菌丝霉素部分包含SEQ ID NO:237,或与SEQ ID NO:237具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-菌丝霉素融合物包含SEQ ID NO:238-239中的任一者的序列,或与SEQ ID NO:238-239中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-菌丝霉素融合物:SABA-X1-菌丝霉素或菌丝霉素-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),且菌丝霉素为如本文所述的菌丝霉素肽。
11.颗粒蛋白前体(PRGN)及Atstrrin
在另一方面中,本发明描述SABA与颗粒蛋白前体或SABA与Atstrrin融合分子。颗粒蛋白前体及Atstrrin (一种经工程改造的包含来自颗粒蛋白前体的3个片段的蛋白质)为肿瘤坏死因子(TNF)受体结合物,其拮抗TNF信号传导。颗粒蛋白前体及Atstrrin在小鼠关节炎模型中预防炎症。参见例如Tang,W等人,The Growth Factor Progranulin Bindsto TNF Receptors and IsTherapeutic Against Inflammatory Arthritis in Mice,Science,ScienceExpress,2011年3月10日,补充数据。任一蛋白质的SABA融合物可为TNFα介导性疾病的潜在治疗剂。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的颗粒蛋白前体或Atstrrin及此类融合物(本文统称为SABA-PRGN或SABA-Atstrrin融合物)的用途。SABA-PRGN或SABA-Atstrrin融合物指具有各种排列的融合物,包括例如SABA-PRGN、PRGN-SABA、SABA-Atstrrin及Atstrrin-SABA。某些例示性SABA-PRGN及SABA-Atstrrin融合构建体展示于表2中。然而,应了解如本文所公开的颗粒蛋白前体及Atstrrin包括保留颗粒蛋白前体或Atstrrin功能活性的颗粒蛋白前体及Atstrrin变体、截短形式及任何经修饰形式。亦即,如本文所述的颗粒蛋白前体及Atstrrin亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留颗粒蛋白前体或Atstrrin的生物活性即可。例示性颗粒蛋白前体序列以SEQ ID NO:240-241呈现于表2中,且例示性Atstrrin序列以SEQID NO:242呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-PRGN融合物,其中该PRGN部分包含SEQ ID NO:240-241中的任一者的序列,或与SEQ ID NO:240-241中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-PRGN融合物包含SEQ IDNO:243-246中的任一者的序列,或与SEQ ID NO:243-246中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-PRGN融合物:SABA-X1-PRGN或PRGN-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQID NO:65-88、216-221或397中的任一者),且PRGN为如本文所述的颗粒蛋白前体肽。
在例示性实施方式中,本申请提供一种SABA-Atstrrin融合物,其中该Atstrrin部分包含SEQ ID NO:242,或与SEQ ID NO:242具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-Atstrrin融合物包含SEQ ID NO:247-250中的任一者的序列,或与SEQ ID NO:247-250中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-Atstrrin融合物:SABA-X1-Atstrrin或Atstrrin-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQID NO:65-88、216-221或397中的任一者),且Atstrrin为如本文所述的Atstrrin肽。
12.骨钙蛋白(OCN)
在某些方面中,本发明描述SABA与骨钙蛋白的融合分子。骨钙蛋白(OCN,亦称为骨Gla蛋白或BGP)是一种具有49个氨基酸的蛋白质,由成骨细胞产生并分泌于血流及骨基质中。血浆OCN水平经受生物学变化,包括昼夜循环、季节、性别、年龄及月经周期。OCN以羧化、未羧化及羧化不全形式存在,未羧化及羧化不全形式通过刺激胰岛素分泌、胰β细胞增殖及增强胰岛素敏感性(部分经由脂连蛋白介导)而参与能量代谢调节。胰岛素促进骨重塑,且其在成骨细胞中的信号传导可增加未羧化及/或羧化不全OCN释放至循环中,进而改善葡萄糖处理。因此,本文所述的SABA-OCN融合多肽可用于治疗胰岛素相关病症,包括氧利用、脂肪生成、糖原生成、脂质生成、葡萄糖摄取、蛋白质合成、热生成及基础代谢率维持的失调。上述机能障碍导致包括(但不限于)高胰岛素血症、胰岛素抗性、胰岛素缺乏、高血糖症、高脂质血症、高酮血症、糖尿病及糖尿病性肾病的疾病及/或病症。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的OCN及此类融合物(本文统称为SABA-OCN融合物)的用途。SABA-OCN融合物指具有各种排列的融合物,包括例如SABA-OCN及OCN-SABA。某些例示性SABA-OCN融合构建体展示于表2中。然而,应了解如本文所公开的OCN包括保留OCN功能活性的OCN变体、截短形式及任何经修饰形式。亦即,如本文所述的OCN亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留OCN的生物活性即可。例示性OCN序列以SEQ ID NO:365-378呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-OCN融合物,其中该OCN部分包含SEQID NO:365-378中的任一者的序列,或与SEQ ID NO:365-378中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-OCN融合物包含SEQ ID NO:379-396中的任一者的序列,或与SEQ ID NO:379-396中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-OCN融合物:SABA-X1-OCN或OCN-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ IDNO:65-88、216-221或397中的任一者),且OCN为如本文所述的OCN肽。
在某些实施方式中,本申请提供一种可由下式表示的SABA-OCN融合物:SABA-X1-Cys-X2-OCN或OCN-X1-Cys-X2-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为任选的多肽接头(适合的接头包括例如SEQ ID NO:65-88、216-221或397中的任一者),Cys为半胱氨酸残基,X2为化学衍生的间隔物(适合间隔物的实例展示于表1中),且OCN为如本文所述的OCN肽。在例示性实施方式中,该化学衍生的间隔物含有马来酰亚胺部分,其可用于藉由如本文进一步所述的迈克尔加成使OCN肽缀合于SABA多肽的C端Cys,或使SABA多肽缀合于OCN肽的C端Cys。
13.干扰素λ(IFNλ)
在另一方面中,本发明描述SABA与干扰素-λ(IFN-λ)融合分子。人类干扰素(IFN)分成三个主要类型:I型、II型及III类型。I型IFN被表达作为针对病毒感染的第一道防御。I型IFN的主要作用为在病毒感染的最先数日内限制病毒扩散,从而给予足够时间产生针对感染的强适应性免疫反应。II型及III型IFN显示I型IFN的一些抗病毒性质。
IFN-λ是一种III型IFN。人类编码三种IFN-λ分子:IFN-λ1(IL-29)、IFN-λ2(IL-28A)及IFN-λ3(IL-28B)。如US 7,135,170中所述,已显示IL-28及IL-29适用于治疗肝炎病毒感染。重要的是,显示IL-28及IL-29具有这些抗病毒活性,而没有与使用其它先前已知IFN疗法相关的一些毒性。与I型IFN疗法相关的毒性之一是骨髓抑制。这是由于骨髓祖细胞的I型IFN抑制。因为IL-29并不如I型IFN治疗所见的显著抑制骨髓细胞扩增或B细胞增殖,所以IL-29将具有较小的与治疗相关的毒性。预期IL-28A及IL-28B具有类似结果。
因此,本文所述的SABA-IFN-λ融合多肽的例示性用途包括治疗病毒感染的受试者,包括例如诸如甲型肝炎、乙型肝炎、丙型肝炎及丁型肝炎的病毒感染。本文所述的SABA-IFN-λ融合多肽亦可用作治疗与以下相关的病毒感染的抗病毒剂:呼吸道合胞病毒、疱疹病毒、埃-巴二氏病毒(Epstein-Barrvirus)、流感病毒、腺病毒、副流感病毒、鼻病毒、柯萨奇病毒(coxsackie virus)、痘苗病毒、西尼罗河病毒(west nile virus)、登革热病毒、委内瑞拉马脑炎病毒(Venezuelan equine encephalitis virus)、伯钦特病毒(pichindevirus)及脊髓灰质炎病毒。本文所述的SABA-IFN-λ融合多肽可用于治疗具有慢性或急性病毒感染的受试者。
在某些实施方式中,本文所述的SABA-IFNλ融合物可提供优于与其它药物动力学部分(例如PEG)融合的IFNλ多肽的益处。具体的,本文所提供的SABA-IFNλ融合物可使得与PEG-IFNλ缀合物相比IFNλ分子的血清半衰期得到显著改善。此类半衰期的增加可允许降低频率的给药方案,例如与使用其它IFNλ治疗剂(如PEG-IFNλ缀合物)的更频繁的给药(诸如每周给药一次)相比,SABA-IFNλ融合物可允许每月给药一次。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的IFNλ及此类融合物(本文统称为SABA-IFNλ融合物)的用途。SABA-IFNλ融合物指具有各种排列的融合物,包括例如SABA-IFNλ及IFNλ-SABA。某些例示性SABA-IFNλ融合构建体展示于表2中。然而,应了解如本文所公开的IFNλ包括保留IFNλ功能活性的IFNλ变体、截短形式及任何经修饰形式。亦即,如本文所述的IFNλ亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留IFNλ的生物活性即可。例示性IFNλ序列以SEQ IDNO:251-257呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-IFNλ融合物,其中该IFNλ部分包含SEQ ID NO:251-257中的任一者的序列,或与SEQ ID NO:251-257中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-IFNλ融合物包含SEQ ID NO:258-285中的任一者的序列,或与SEQ ID NO:258-285中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-IFNλ融合物:SABA-X1-IFNλ或IFNλ-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQ IDNO:65-88、216-221或397中的任一者),且IFNλ为如本文所述的IFNλ肽。
14.Apelin
在另一方面中,本申请提供SABA与Apelin的融合分子。Apelin为G蛋白偶联受体APJ的内源性配体。Apelin基因编码具有77个氨基酸的前原蛋白,其被切割为较短的活性片段。全长成熟肽为Apelin-36,但Apelin-17及Apelin-13亦具有活性(M Kleinz等人,Pharmacol.Ther.107:198-211(2005))。Apelin在中枢神经系统及外周组织中广泛表达,且细胞表达包括内皮细胞及脂肪细胞(见上)。已显示Apelin在临床前模型中使得血管扩张且改善心脏衰竭患者的血液动力学及心脏概况,以及预防动脉粥样硬化(AG Japp等人,Circ.121:1818-1827(2010);及HY Chun等人,J.Clin.Invest.118:3343-3354(2008))。另外,Apelin投药与在糖尿病临床前模型中胰岛素敏感性的改善相关(C Dray等人,CellMetabolism 8:437-445(2008))。因此,本文所述的SABA-Apelin融合多肽的例示性用途可包括治疗糖尿病、肥胖、饮食障碍、胰岛素抗性综合征及心血管疾病(例如心脏衰竭、动脉粥样硬化及高血压)。
在一个方面,本申请提供与血清白蛋白结合性10Fn3(亦即SABA)融合的Apelin及此类融合物(本文统称为SABA-APLN融合物)的用途。SABA-APLN融合物指具有各种排列的融合物,包括例如SABA-APLN及APLN-SABA。某些例示性SABA-APLN融合构建体展示于表2中。然而,应了解如本文所公开的Apelin包括保留Apelin功能活性的IFNλ变体、截短形式及任何经修饰形式。亦即,如本文所述的Apelin亦包括经修饰形式,包括某些氨基酸已缺失或经取代的片段以及变体,及一或多个氨基酸已变为经修饰的氨基酸或非天然存在的氨基酸的修饰,及诸如糖基化的修饰,只要经修饰形式保留Apelin的生物活性即可。例示性Apelin序列以SEQ ID NO:419-423呈现于表2中。
在例示性实施方式中,本申请提供一种SABA-APLN融合物,其中该Apelin部分包含SEQ ID NO:419-423中的任一者的序列,或与SEQ ID NO:419-423中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。在某些实施方式中,SABA-APLN融合物包含SEQ IDNO:424-430中的任一者的序列,或与SEQ ID NO:424-430中的任一者具有至少70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列。
在某些实施方式中,本申请提供一种可由下式表示的SABA-APLN融合物:SABA-X1-APLN或APLN-X1-SABA,其中SABA为如本文所述的SABA多肽(包括任何N端及/或C端延伸),X1为多肽接头(适合的接头包括例如SEQID NO:65-88、216-221或397中的任一者),且APLN为如本文所述的APLN肽。
15.其它AdnectinTM
在某些方面中,本申请提供与结合除血清白蛋白(例如HSA)外的标靶分子的10Fn3结构域融合的SABA,产生SABA-10Fn3或10Fn3-SABA构型的AdnectinTM二聚体融合分子。在其它方面中,本申请提供与两个或两个以上10Fn3结构域融合的SABA,由此形成多聚体。举例而言,在一个实施方式中,本申请提供与两个10Fn3结构域(10Fn3a及10Fn3b)融合的SABA,其中10Fn3a及10Fn3b各自结合不同的靶分子,且皆不结合血清白蛋白(例如HSA)。所得AdnectinTM三聚体的构型可为:SABA-10Fn3a-10Fn3b、10Fn3a-SABA-10Fn3b或10Fn3a-10Fn3b-SABA。
在例示性实施方式中,SABA与包含SEQ ID NO:1-3中的任一者或与SEQ ID NO:1-3中的任一者具有至少50%、60%、65%、70%、75%、80%、85%、90%、95%、97%、98%或99%同一性的序列的10Fn3结构域融合,其中BC、DE及FG环分别相对于野生型BC、DE及FG环的序列经修饰,且其中该10Fn3结构域结合靶(除整联蛋白外)的KD为小于500μM。10Fn3结构域可进一步包含如本文所述的N端及/或C端延伸。在某些实施方式中,10Fn3结构域结合如本文所述的治疗性部分的靶。在例示性实施方式中,在包含一个额外10Fn3结构域的融合物中,该10Fn3结构域结合VEGFR2、TNF α、IGF1R或EGFR。在例示性实施方式中,在包含两个额外10Fn3结构域的融合物中,所述10Fn3结构域结合VEGFR2及IGF1R,或EGFR及IGF1R。
缀合/接头
SABA融合物可以是共价或非共价连接的。在一些实施方式中,血清白蛋白结合性10Fn3可直接或经由多肽接头间接连接于异源分子。适合于使SABA连接于所关注的蛋白质的接头是这样的接头,它们使得各个结构域彼此独立地折叠,形成不会破坏融合蛋白的任一成员的功能性的三维结构。例示性接头以SEQ ID NO:65-88、216-221及397提供于表2中。
本公开提供许多适合的接头,包括基于甘氨酸-丝氨酸的接头、基于甘氨酸-脯氨酸的接头以及具有氨基酸序列PSTSTST(SEQ ID NO:85)的接头。在一些实施方式中,接头为基于甘氨酸-丝氨酸的接头。这些接头包含氨酸甘氨酸及丝氨酸残基,且长度可为8至50、10至30及10至20个氨基酸。实例包括具有氨基酸序列(GS)7(SEQ ID NO:72)、G(GS)6(SEQ IDNO:67)及G(GS)7G(SEQ ID NO:69)的接头。其它接头含有谷氨酸,包括例如(GSE)5(SEQ IDNO:74)及GGSE GGSE(SEQ ID NO:78)。其它例示性甘氨酸-丝氨酸接头包括(GS)4(SEQ IDNO:71)、(GGGGS)7(SEQ ID NO:80)、(GGGGS)5(SEQ ID NO:81)及(GGGGS)3G(SEQ ID NO:82)。在一些实施方式中,接头为基于甘氨酸-脯氨酸的接头。这些接头包含甘氨酸及脯氨酸残基且长度可为3至30、10至30及3至20个氨基酸。实例包括具有氨基酸序列(GP)3G(SEQID NO:83)、(GP)5G(SEQ ID NO:84)及GPG的接头。在其它实施方式中,接头可为长度为3至30、10至30及3至20个氨基酸的基于脯氨酸-丙氨酸的接头。基于脯氨酸丙氨酸的接头的实例包括例如(PA)3(SEQ ID NO:86)、(PA)6(SEQ ID NO:87)及(PA)9(SEQ ID NO:88)。预期最佳接头长度及氨基酸组成可藉由现有技术中熟知的方法使用常规实验来确定。
在一些实施方式中,本文所述的融合物经由具有可由血液或靶组织中的蛋白酶切割的蛋白酶位点的多肽接头连接于SABA。此类实施方式可用于释放治疗性蛋白质以实现更好的投递或治疗性质或更有效的产生。
可在Fn3结构域的C端、Fn3结构域与多肽接头之间引入其它接头或间隔物。可在Fn3结构域的N端、Fn3结构域与多肽接头之间引入其它接头或间隔物。
在一些实施方式中,治疗性部分可直接或经由聚合物接头间接连接于SABA。聚合物接头可用于最优地改变融合物各组分之间的距离以形成具有一或多种以下特征的蛋白质融合物:1)当结合所关注的蛋白质时,一或多个蛋白质结构域的结合位阻降低或增加;2)蛋白质稳定性或溶解度增加;3)蛋白质聚集减少;及4)蛋白质的总亲合力(avidity)或亲和力增加。
在一些实施方式中,治疗性部分经由生物相容性聚合物(诸如聚合糖)连接于SABA。该聚合糖可包括酶切割位点,其可被血液或靶组织中的酶切割。此类实施方式可用于释放治疗性蛋白质以实现更好的投递或治疗性质或更有效的产生。
SABA-神经肽融合物
在某些实施方式中,本申请提供SABA-神经肽融合物。例示性神经肽包括例如胰淀素、PYY及PP。SABA-神经肽融合物可以构建为多肽融合物,或构建为经化学衍生的间隔物连接的缀合物。在一个实施方式中,SABA-神经肽融合物为包含SABA、氨基酸接头及神经肽的多肽融合物。因为许多神经肽在C端经酰胺化,所以融合蛋白的一个例示性排列自N端至C端为:SABA、氨基酸接头及神经肽。在另一个实施方式中,SABA-神经肽融合物含有将SABA连接于神经肽的化学衍生的间隔物。SABA-神经肽缀合物的例示性排列如下:(1)SABA-Cys-化学衍生的间隔物-神经肽;或(2)SABA-氨基酸接头-Cys-化学衍生的间隔物-神经肽。SABA-神经肽融合物可在宿主细胞中产生,诸如如本文进一步所述的微生物或哺乳动物细胞。由化学衍生的间隔物连接的SABA-神经肽融合物的肽组分可由宿主细胞或由化学合成或其组合产生。在一个例示性实施方式中,由化学衍生的间隔物连接的SABA-神经肽融合物是由宿主细胞(诸如大肠杆菌)中产生的SABA及由化学合成产生的神经肽组装而成的。下文及实施例中描述了产生SABA-神经肽融合物的进一步详情。
许多神经肽含有C端α-酰胺基,对于其生物活性很重要。举例而言,胰淀素、PYY及PP肽均具有C端酰胺化。在哺乳动物细胞中,α-酰胺化可由肽基-甘氨酸α-酰胺化单加氧酶(PAM)(一种催化肽基-甘氨酸底物转化为α-酰胺化产物的双功能酶)处理。
存在多种制备C端酰胺化肽的技术。举例而言,可在体外用纯化的PAM酶处理肽前体(具有C端甘氨酸或甘氨酸-赖氨酸-精氨酸或其它延伸)。PAM及使用PAM制备C端酰胺化肽的方法为本领域技术人员所已知。参见例如US4,708,934、US 5,789,234及US 6,319,685。C端酰胺化亦可在表达内源性PAM的哺乳动物表达系统中完成。融合蛋白可表达为具有甘氨酸或甘氨酸-赖氨酸-精氨酸序列延伸的前体分子。当在真核细胞(例如CHO、NIH 3T3及BHK)中表达为分泌性蛋白质时,该蛋白质可被内源性PAM酶切割且产生C端羧酰胺。参见例如Endocrinology(1991)V129:553-555(1991);and Molecular andCellular Endocrinology91:135-141(1993)。C端酰胺化亦可在共表达人类PAM的哺乳动物表达系统中完成。参见例如Chinese Journal of Biotechnology(2002)v18:20-24(2002)。
除从COOH到CONH2的活体外PAM酶促转化外,可使用马瑞费德合成(Merrifieldsynthesis)形成所关注的蛋白质上的羧酰胺末端。马瑞费德合成容许在马瑞费德合成过程期间马来酰亚胺部分连接于肽的N端。马来酰亚胺部分允许使用位于两个多肽结构域之间且可用作间隔物的各种非氨基酸部分在两个氨基酸序列(包括例如SABA及羧基酰胺化神经肽)之间形成缀合物。可用作间隔物的适宜的非氨基酸部分的实例展示于下表1中。马来酰亚胺缀合反应的益处在于其可容易地对蛋白质实施,其在有利于蛋白质分子的温和条件下得到高产率,且其具有高度特异性,几乎没有副产物。
表1.用于使SABA分子缀合于在N端具有马来酰亚胺部分的肽的例示性接头/间隔物。
在一些实施方式中,本文所述的C端酰胺化合成肽可藉由下述方式在溶液状态下与含有C端Cys残基的SABA缀合:使SABA的C端Cys的氢硫基迈克尔加成至所述肽的马来酰亚胺衍生物上(所述马来酰亚胺基团通常位于所述肽的N端),而得到稳定的硫醚键。相同的缀合可藉由用肽的卤烷基衍生物(诸如用溴乙酸或碘乙酸酰化而引入至肽上的溴甲基或碘甲基)使SABA的Cys氢硫基烷基化来达成。本领域技术人员应认识到,此类型的肽-蛋白质缀合可使用若干种不同方法来达成,例如类似G.T.Hermanson,“BioconjugateTechniques”,Academic Press,San Diego,CA,1996所述的那些生物缀合程序。
在另一个实施方式中,将中性接头或间隔物置于肽上的巯基-反应性基团与天然或经修饰的肽序列之间。接头或间隔物可使得位阻降低且有助于肽结合于其关联受体或蛋白质配偶体。适合的接头包括(但不限于)表1中所述的那些接头。接头8-11显示具有巯基-反应性马来酰亚胺或碘乙酰基,且其可使用现有技术中描述的相应N-琥珀酰亚胺基活性酯偶连于肽。
本文所述的肽及肽类似物可藉由化学合成,使用诸如以下中所述的那些技术的各种固相技术来制备:G.Barany及R.B.Merrifield,“The Peptides:Analysis,Synthesis,Biology”;第2卷“Special Methods in Peptide Synthesis,Part A”,第3-284页,E.Gross及J.Meienhofer编,Academic Press,New York,1980;或W.C.Chan及P.D.White,“FmocSolid Phase Peptide Synthesis-APractical Approach”,Oxford University Press.,Oxford,UK,2000。用于肽合成的例示性策略基于用于暂时保护α-氨基的Fmoc(9-芴基甲基甲氧羰基)基团与用于暂时保护氨基酸侧链的叔丁基组合(参见例如E.Atherton及R.C.Sheppard,“The Fluorenylmethoxycarbonyl Amino Protecting Group”,“ThePeptides:Analysis,Synthesis,Biology”;第9卷“Special Methods inPeptideSynthesis,Part C”,第1-38页,S.Undenfrend及J.Meienhofer编,AcademicPress,San Diego,1987)。
可以逐步方式在不溶性聚合物载体(亦称为“树脂”)上自肽的羧基端开始来合成肽。合成通过形成酰胺或酯键而使肽的C端氨基酸附接于树脂来开始。这样使得所得的肽能够分别以C端酰胺或甲酸形式的最终释放。
对于C端氨基酸及用于合成的所有其它氨基酸而言,优选它们的α-氨基与侧链官能基(若存在)以不同的方式保护,使得α-氨基保护基可在合成期间选择性移除。氨基酸的偶连通过活化其羧基为活性酯形式,并使其与附于树脂的N端氨基酸的未封端α-氨基反应来进行。重复α-氨基脱保护与偶连的循环直至整个肽序列被组装。接着从树脂释放肽,伴随侧链官能基的脱保护,此过程通常在适当清除剂存在下进行以限制副反应。所得肽可藉由反相制备型HPLC来纯化。
用作最终肽的前体的肽基-树脂的合成可利用市售交联聚苯乙烯聚合物树脂(Novabiochem,San Diego,CA)或ChemMatrix PEG聚合物树脂(PCASBioMatrix,QuebecCity,Canada)。优选的固体载体包括例如:4-(2',4'-二甲氧基苯基-Fmoc-氨基甲基)-苯氧基乙酰基-对甲基二苯甲基胺树脂(Rink酰胺MBHA树脂);9-Fmoc-氨基-呫吨-3-基氧基-马瑞费德树脂(Sieber酰胺树脂);用于C端羧酰胺的4-(9-Fmoc)氨基甲基-3,5-二甲氧基苯氧基)戊酰基-氨基甲基-马瑞费德树脂(PAL树脂),及相应基于ChemMatrix PEG的树脂。第一个与随后的氨基酸的偶连可使用分别由DIC/HOBt、HBTU/HOBt或DIC/6-Cl-HOBt或HCTU/6-Cl-HOBt制备的HOBt或6-Cl-HOBt活性酯完成。
本文所述的肽及肽类似物的合成可使用自动肽合成器,诸如Liberty微波肽合成器(CEM Corp.,Matthews,North Carolina)来进行。逐步固相肽合成可使用实施例中所述的Fmoc/叔丁基保护策略来进行。在一些实施方式中,可使用图21中所示的Fmoc氨基酸衍生物。
在胰淀素衍生物的情况下,受Acm保护的Cys残基(例如Cys2,7或Cys1,7)之间的二硫键可经由树脂上的碘介导氧化来形成(Chan及White,2000)。用于其各别肽的肽基-树脂前体可使用任何标准程序切割及脱保护(参见例如D.S.King等人,Int.J.Peptide ProteinRes.36:255-266(1990))。在一些实施方式中,在水、TIS及苯酚存在下使用TFA作为清除剂。通常,在室温下在TFA/水/TIS(94:3:3,v:v:v;每100mg肽基树脂1mL)或TFA/水/苯酚(90:5:5;v :v :w)中搅拌肽基-树脂2-3小时。接着滤除废树脂且在减压下浓缩或干燥TFA溶液。所得粗肽可沉淀且用Et2O洗涤或直接再溶解于DMSO、DMF或50%AcCN水溶液中以藉由制备型HPLC进行纯化。
具有所需纯度的肽可藉由使用制备型HPLC纯化(例如在ShimadzuLC-8A型号液相层析仪上)来获得。举例而言,可将粗肽溶液注射至Phenomenex Luna C18(5μm,21.2×250mm)柱上且用MeCN于水(两者皆经0.1%TFA缓冲)中的线性梯度,使用14-20mL/min的流速洗脱,其中藉由220nm下的UV吸光度来监测洗脱物。经纯化肽的结构可藉由电喷雾LCMS分析来证实。举例而言,可藉由LC/MS,在连接于Waters Acquity超效液相层析仪(UPLC)的Waters ZQ 2000单四极质谱仪(Milford,MA)上分析肽样品。可使用2.1×50mm、1.7μm、Acquity BEH300C 18柱(Waters,Milford,MA),用在0.8mL/min下梯度溶离来达成层析分离。柱温度可为50℃。流动相A可为含0.05%TFA的98:2水:乙腈且流动相B可为含0.04%TFA的乙腈。线性梯度可在1、2或5分钟内由2%至80%流动相B形成。可使用2μL注射液且ESI MS数据可自m/z 500至m/z 1500或自m/z 1000至m/z 2000得到。仪器可以单位分辨率来操作。
结合多肽的去免疫化
可改变血清白蛋白结合物及其融合物的氨基酸序列以消除一或多个B细胞或T细胞抗原表位。包括本文所述的SABA融合物的蛋白质可经去免疫化以使其对特定物种而言不具有免疫原性或免疫原性较小。去免疫化可通过对蛋白质的结构改变来达成。可使用本领域技术人员已知的任何去免疫化技术,参见例如WO 00/34317,其公开内容全部以引用方式并入本文中。
在一个实施方式中,可分析血清白蛋白结合物及其融合物的序列中MHC II型结合基序的存在。举例而言,可与MHC结合基序的数据库进行比较,例如藉由在万维网上在sitewehil.wehi.edu.au上检索“基序”数据库。或者,MHC II型结合肽可使用计算穿线(computational threading)方法来鉴定,诸如由Altuvia等人(J.Mol.Biol.249244-250(1995))设计的那些方法,藉此测试多肽的连续重叠肽与MHC II类蛋白的结合能。计算结合预测算法包括iTopeTM、Tepitope、SYFPEITHI、EpiMatrix(EpiVax)及MHCpred。为帮助鉴别MHC II类结合肽,可寻找与被成功呈递的肽(诸如两亲性及Rothbard基序)及组织蛋白酶B及其它处理酶的切割位点有关的相关序列特征。
鉴别出潜在(例如人类)T细胞抗原表位后,再通过改变一或多个氨基酸(按照消除T细胞表位所需要的)来消除这些抗原表位。这通常将涉及改变T细胞抗原表位自身中的一或多个氨基酸。这可涉及改变在蛋白质的一级结构上邻近于抗原表位的氨基酸,或在一级结构上不邻近但在分子的二级结构上邻近的氨基酸。考虑到的常见改变将为氨基酸取代,但有可能在某些情况下,氨基酸添加或缺失将为适当的。所有改变均可藉由重组DNA技术来完成,以使得最终分子可藉由自重组宿主表达来制备,例如藉由充分确立的方法,但亦可使用蛋白质化学或任何其它分子改变方法。
一旦移除所鉴别的T细胞抗原表位,可再次分析去免疫化序列以确保尚未形成新T细胞抗原表位,且若其已形成,则可删去该抗原表位。
并非所处通过计算鉴别的T细胞抗原表位都需要移除。本领域技术人员应了解特定抗原表位的“强度”,更确切地说潜在免疫原性的重要性。各种计算方法产生潜在抗原表位的得分。本领域技术人员应认识到,仅高得分的抗原表位方可能需要移除。本领域技术人员亦应认识到,移除潜在抗原表位与维持蛋白质的结合亲和力或其它生物活性之间存在平衡。因此,一种策略是将取代顺序地引入SABA或SABA融合蛋白中,然后测试靶结合或其它生物活性及免疫原性。
在一个方面,与人类受试者中的初始蛋白相比,去免疫化SABA或SABA融合蛋白的免疫原性较小(更确切而言,引起更低的HAMA反应)。测定免疫原性的测定法在本领域技术人员的知识范围内。可进行测定免疫反应的公认方法以监测特定受试者或在临床试验期间的HAMA反应。可在开始施用治疗时及整个治疗过程中对投与去免疫化蛋白质的受试者进行免疫原性评估。HAMA反应的测量例如通过使用本领域技术人员已知的方法(包括表面等离子共振技术(BIAcore)及/或固相ELISA分析)检测来自受试者的血清样品中去免疫化蛋白质的抗体来实现。或者,设计为测量T细胞活化事件的体外测定法亦可指示免疫原性。
其它修饰
在某些实施方式中,血清白蛋白结合物及其融合物可进一步包含翻译后修饰。例示性翻译后蛋白质修饰包括磷酸化、乙酰化、甲基化、ADP核糖基化、遍在蛋白化、糖基化、羰基化、SUMO(遍在蛋白样小修饰物)化(sumoylation)、生物素化或添加多肽侧链或疏水基团。因此,经修饰的血清白蛋白结合物及其融合物可含有非氨基酸组分,诸如脂质、多糖或单糖及磷酸酯。糖基化的优选的形式为唾液酸化(sialylation),其使一或多个唾液酸部分缀合于多肽。唾液酸部分改善溶解度及血清半衰期,同时亦降低蛋白质的可能免疫原性。参见例如Raju等人Biochemistry.2001 Jul 31;40(30):8868-76。可测试此类非氨基酸组分对血清白蛋白结合物或其融合物的功能性的影响,以确定它们结合特定的血清白蛋白(例如HSA或RhSA)的能力及/或在融合物的环境下由特异性非10Fn3部分赋予的功能作用(例如FGF21对葡萄糖摄取的作用)。
载体及多核苷酸实施方式
本发明亦包括编码本文所述的任一蛋白质的核酸序列。如本领域技术人员所了解的,由于第三碱基简并性,几乎每一种氨基酸均可由编码核苷酸序列中的一种以上三联密码子表示。另外,次要的碱基对变化可导致所编码的氨基酸序列中的保守性取代,但预期不会实质上改变基因产物的生物活性。因此,对于编码本文所述的蛋白质的核酸序列,其序列可略微修改而仍可编码其各自的基因产物。编码本文所述的血清白蛋白结合物及其融合物的某些例示性核酸包括具有表3中所示的序列的核酸。
编码本文所公开的各种蛋白质或多肽中的任一者的核酸可经化学合成。可选择密码子用法以改善在细胞中的表达。该密码子用法将视所选细胞类型而定。已开发了用于大肠杆菌及其它细菌,以及哺乳动物细胞、植物细胞、酵母细胞及昆虫细胞的专用密码子用法模式。参见例如:Mayfield等人,ProcNatl Acad Sci U S A.2003100(2):438-42;Sinclair等人Protein Expr Purif.2002(1):96-105;Connell ND.Curr Opin Biotechnol.2001(5):446-9;Makrides等人Microbiol Rev.199660(3):512-38;及Sharp等人Yeast.19917(7):657-78。
用于核酸操作的通用技术在本领域技术人员的能力范围内,且亦例如描述于Sambrook等人,Molecular Cloning:A Laboratory Manual,第1-3卷,ColdSpring HarborLaboratory Press,第2版,1989,或F.Ausubel等人,CurrentProtocols in MolecularBiology (Green Publishing and Wiley-Interscience:NewYork,1987)及定期更新中,此类文献以引用的方式并入本文中。编码蛋白质的DNA可操作地连接于来源于哺乳动物、病毒或昆虫基因的合适的转录或翻译调节组件。此类调节组件包括转录启动子、任选的控制转录的操纵序列、编码合适的mRNA核糖体结合位点的序列及控制转录及翻译终止的序列。进一步组入在宿主中复制的能力(通常由复制起点赋予)及有助于识别转化体的选择基因。适合的调节组件是本领域熟知的。
本文所述的蛋白质及融合蛋白可以作为与异源多肽的融合蛋白产生,后者优选为信号序列或其它在成熟蛋白质或多肽的N端具有特异性切割位点的多肽。所选的异源信号序列优选为可由宿主细胞识别并加工(即由信号肽酶切割)的信号序列。对于不识别及加工天然信号序列的原核宿主细胞而言,将信号序列替换成原核信号序列,例如选自碱性磷酸酶、青霉素酶、lpp或热稳定肠毒素II前导序列的原核信号序列。为了酵母分泌,可将天然信号序列替换为例如酵母转化酶前导序列、a因子前导序列(包括酵母属(Saccharomyces)及克鲁维酵母属(Kluyveromyces)α-因子前导序列)或酸性磷酸酶前导序列、白色念珠菌(C.albicans)葡糖淀粉酶前导序列、或PCT公开WO 90/13646中所述的信号。在哺乳动物细胞表达中,可使用哺乳动物信号序列以及病毒分泌性前导序列,例如单纯疱疹gD信号。此类前体区域的DNA可按照符合阅读框的方式连接于编码蛋白质的DNA。
用于真核宿主细胞(例如酵母、真菌、昆虫、植物、动物、人类或来自其它多细胞生物体的有核细胞)的表达载体亦将含有终止转录及稳定化mRNA所必需的序列。此类序列通常可得自真核生物或病毒DNA或cDNA的5'及有时3'未翻译区。这些区域含有转录为编码多价抗体的mRNA的非翻译部分中的聚腺苷酸化片段的核苷酸区段。一种适用的转录终止组分为牛生长激素聚腺苷酸化区域。参见PCT公开第WO 94/11026号及其中所公开的表达载体。
重组DNA亦可包括任何类型的蛋白质标签序列,其可适用于纯化蛋白质。蛋白质标签的实例包括(但不限于)组氨酸标签、FLAG标签、myc标签、HA标签或GST标签。用于细菌、真菌、酵母及哺乳动物细胞宿主的适当克隆及表达载体可见于Cloning Vectors:ALaboratory Manual,(Elsevier,NewYork,1985)中,该文献的相关公开内容以引用的方式并入本文中。
使用适合于宿主细胞的方法将表达构建体引入宿主细胞中,这是本领域技术人员容易想到的。将核酸引入宿主细胞中的各种方法是本领域中已知的,包括(但不限于)电穿孔;使用氯化钙、氯化铷、磷酸钙、DEAE-葡聚糖或其它物质转染;微粒轰击;脂质转染;及感染(其中载体为感染剂)。
适合的宿主细胞包括原核生物、酵母、哺乳动物细胞或细菌细胞。适合的细菌包括革兰氏阴性(gram negative)或革兰氏阳性(gram positive)生物体,例如大肠杆菌或芽孢杆菌属(Bacillus spp)。酵母,优选的来自酵母属(Saccharomyces)物种诸如酿酒酵母(S.cerevisiae),亦可用于产生多肽。亦可使用各种哺乳动物或昆虫细胞培养系统来表达重组蛋白质。用于在昆虫细胞中产生异源蛋白质的杆状病毒系统由Luckow及Summers(Bio/Technology,6:47,1988)综述。在一些情况下,需要在脊椎动物细胞中产生蛋白质,诸如用于糖基化,而在培养中繁殖脊椎动物细胞(组织培养)已成为常规程序。适合的哺乳动物宿主细胞系的实例包括内皮细胞、COS-7猴肾脏细胞、CV-1、L细胞、C127、3T3、中国仓鼠卵巢(CHO)、人类胚肾细胞、海拉(HeLa)、293、293T及BHK细胞系。对于许多应用而言,本文所述的蛋白质多聚体的小尺寸将使得大肠杆菌成为优选的表达方法。
蛋白质产生
用本文所述用于产生蛋白质的表达或克隆载体转化宿主细胞,并将该宿主细胞培养于视情况调整的常规营养培养基中以诱导启动子、选择转化体或扩增编码所需序列的基因。
可将用于产生本发明的蛋白质的宿主细胞培养于各种培养基中。诸如哈姆氏F10(Ham's F10)(Sigma)、最低必需培养基((MEM),Sigma)、RPMI-1640(Sigma)及杜尔贝科氏改良伊格尔培养基((DMEM),Sigma)的市售培养基适合于培养宿主细胞。此外,Ham等人,Meth.Enz.58:44(1979),Barnes等人,Anal.Biochem.102:255(1980);美国专利第4,767,704号;第4,657,866号;第4,927,762号;第4,560,655号;或第5,122,469号;WO 90/03430;WO87/00195;或美国专利第Re.30,985号中所述的任何培养基可用作宿主细胞的培养基。任何这些培养基均可视需要补充激素及/或其它生长因子(诸如胰岛素、转铁蛋白或表皮生长因子)、盐(诸如氯化钠、钙、镁及磷酸盐)、缓冲液(诸如HEPES)、核苷酸(诸如腺苷及胸苷)、抗生素(诸如GENTAMYCINTM药物)、痕量元素(定义为无机化合物,通常以在微摩尔范围内的最终浓度存在)及葡萄糖或等效能源。亦可包括适当浓度的本领域技术人员已知的任何其它必要的补充剂。培养条件,诸如温度、pH值等,为先前用于选择用于表达的宿主细胞的那些条件,且对于本领域普通技术人员而言是容易想到的。
本文所公开的蛋白质亦可使用细胞翻译系统产生。为了此类目的,编码蛋白质的核酸必须经修饰,以允许体外转录产生mRNA并允许mRNA在所用的特定无细胞系统中进行无细胞翻译。例示性的真核无细胞翻译系统包括例如哺乳动物或酵母无细胞翻译系统,而例示性的原核无细胞翻译系统包括例如细菌无细胞翻译系统。
本文所公开的蛋白质亦可藉由化学合成产生(例如藉由Solid PhasePeptideSynthesis,第2版,1984,The Pierce Chemical Co.,Rockford,IL中所述的方法)。蛋白质的修饰亦可藉由化学合成产生。
本文所公开的蛋白质可藉由蛋白质化学领域中通常已知的用于蛋白质的分离/纯化方法来纯化。非限制性实例包括萃取、重结晶、盐析(例如使用硫酸铵或硫酸钠)、离心、透析、超滤、吸附层析、离子交换层析、疏水层析、正相层析、反相层析、凝胶过滤、凝胶渗透层析、亲和层析、电泳、逆流分配或这些方法的任何组合。纯化后,可藉由本领域已知的各种方法中的任意方法(包括但不限于过滤及透析)将蛋白质交换至不同缓冲液中及/或浓缩。
经纯化蛋白质优选为至少85%纯,更优选为至少95%纯,且最优选为至少98%纯。不考虑纯度的精确数值,蛋白质的纯度足以用作医药产品。
成像、诊断及其它应用
基于与SABA融合的异源分子的身份,本文所提供的SABA融合物可用于治疗各种疾病及病症。SABA融合物的应用可由本领域技术人员根据本领域的知识及本文所提供的信息来判定。本文详细描述各种SABA融合蛋白的用途。SABA融合物可施用给任何哺乳动物受试者或患者,包括人类与非人类生物体。
可以将本文所述的血清白蛋白结合物及融合分子可检测地标记,并用来接触例如表达融合分子所结合的蛋白质的细胞,以用于成像或诊断性应用。可使用本领域中已知的用于使蛋白质结合于可检测部分的任何方法,包括以下所述的那些方法:Hunter等人,Nature 144:945(1962);David等人,Biochemistry 13:1014(1974);Pain等人,J.Immunol.Meth.40:219(1981);及Nygren,J.Histochem.and Cytochem.30:407(1982)。
在某些实施方式中,本文所述的血清白蛋白结合物及融合分子进一步连接于能够被检测的标记物(例如该标记物可为放射性同位素、荧光化合物、酶或酶辅因子)。标记物可为放射剂,诸如放射性重金属,诸如铁螯合物,钆或锰的放射性螯合物,氧、氮、铁、碳或镓的正电子发射体,43K,52Fe,57Co,67Cu,67Ga,68Ga,123I,125I,131I,132I或99Tc。固定于此类部分的血清白蛋白结合物或融合分子可用作成像剂且以有效用于哺乳动物(诸如人类)中的诊断性用途的量施用,然后检测成像剂的定位及积累。成像剂的定位及积累可藉由放射性闪烁摄影术、核磁共振成像、计算机断层摄影术或正电子发射断层摄影法来检测。如本领域技术人员容易想到的,放射性同位素的施用量视放射性同位素而定。本领域技术人员可容易基于用作活性部分的特定放射性核素的特定活性及能量来调配成像剂的施用量。
血清白蛋白结合物及融合分子亦适用作亲和纯化剂。在此方法中,使用本领域中熟知的方法将蛋白质固定于适合的载体(诸如Sephadex树脂或滤纸)上。蛋白质可用于任何已知测定方法中,诸如竞争性结合测定、直接及间接夹心检定及免疫沉淀测定(Zola,Monoclonal Antibodies:A Manual ofTechniques,第147-158页(CRC Press,Inc.,1987))。
SABA-FGF21融合物的例示性用途
本文所提供的SABA-FGF21融合物可用于治疗或预防一或多种以下疾病:糖尿病、高血糖症、葡萄糖耐受障碍、妊娠期糖尿病、胰岛素抗性、高胰岛素血症、视网膜病、神经病、肾病、伤口愈合、动脉粥样硬化及其后遗症(急性冠状动脉综合征、心肌梗塞、心绞痛、外周血管疾病、间歇性跛行、心肌缺血、中风、心脏衰竭)、代谢综合征、高血压、肥胖、血脂异常、高脂血症、高甘油三酯血症、高胆固醇血症、低HDL、高LDL、血管再狭窄、外周动脉疾病、脂质失调、骨病(包括骨质疏松症)、PCOS、HIV蛋白酶相关脂质营养不良、青光眼及炎性疾病,诸如银屑病、类风湿性关节炎及骨关节炎;及治疗来自皮质类固醇治疗的与糖尿病、脂肪代谢障碍及骨质疏松症有关的副作用。在某些实施方式中,本文所提供的SABA-FGF21融合物可用于治疗或预防受试者的肥胖或减轻体重或预防体重增加。在一个例示性实施方式中,SABA-FGF21融合物可用于减轻BMI为25-29.9的受试者的体重或预防体重增加。在另一例示性实施方式中,SABA-FGF21融合物可用于减轻BMI≥30的受试者的体重或预防体重增加。在另一个实施方式中,SABA-FGF21融合物可用于治疗总胆固醇水平≥200mg/dL及/或甘油三酯水平≥150mg/dL的受试者。在其它实施方式中,SABA-FGF21融合物可用于治疗或降低胰岛素抗性及/或增加脂肪组织中的葡萄糖摄取。在其它实施方式中,SABA-FGF21融合物可用于减慢糖尿病前期受试者的糖尿病进展。在其它实施方式中,SABA-FGF21融合物可用于降低受试者的血糖水平,降低甘油三酯水平,降低胆固醇水平,增加能量消耗,增加脂肪利用及/或增加脂质排泄。
如本文中所使用,“预防”疾病或病症指相对于未经处理的对照样品降低统计样品中疾病状况的发生概率,或相对于未经处理的对照样品延迟该疾病或病症的一或多种症状的发作或降低其严重程度。可基于已知与普通群体相比增加罹患临床疾病状况的风险的因素选择患者进行预防性疗法。如本文中所使用,术语“治疗”包括(a)抑制疾病状况,亦即停止其发展;及/或(b)缓解疾病状况,亦即一旦其确立后使疾病状况消退。
在某些实施方式中,本申请提供药物组合物,其包含作为活性成分的治疗有效量的SABA-FGF21融合物,所述融合物单独存在或与药用担载体组合。视情况,可使用单独的SABA-FGF21融合物,该融合物与本文所述的其它融合物的组合,或与一或多种其它治疗剂(例如抗糖尿病剂或其它医药活性物质)的组合。
在某些实施方式中,SABA-FGF21融合物可单独施用或与一或多种其它治疗剂组合施用。“组合施用”或“组合疗法”意谓SABA-FGF21融合物与一或多种其它治疗剂同时(concurrently)施用给所治疗的哺乳动物。当组合施用时,各组分可在相同时间施用或以任何次序在不同时间点依序施用。因此,各组分可以足够接近的时间分开施用以提供所需治疗效果。
本文所提供的SABA-FGF21融合物可与以下药剂组合使用:抗糖尿病剂、抗高血糖剂、抗高胰岛素血症剂、抗视网膜病剂、抗神经病剂、抗肾病剂、抗动脉粥样硬化剂、抗缺血剂、抗高血压剂、抗肥胖剂、抗血脂异常剂、抗血脂异常剂、抗高脂质血症剂、抗高甘油三酯血症剂、抗高胆固醇血症剂、抗再狭窄剂、抗胰剂(anti-pancreatic agent)、降脂剂、食欲减退剂、记忆增强剂、抗痴呆剂或认知促进剂、食欲抑制剂、心脏衰竭治疗、外周动脉疾病治疗及抗炎剂。
与SABA-FGF21融合物组合使用的抗糖尿病剂包括但不限于胰岛素促泌素或胰岛素增敏剂、GPR40受体调节剂或其它抗糖尿病剂。这些药剂包括(但不限于)二肽基肽酶IV(DP4)抑制剂(例如西他列汀(sitagliptin)、萨格列汀(saxagliptin)、阿洛利停(alogliptin)、维格列汀(vildagliptin)及其类似物)、双胍(例如二甲双胍、苯乙双胍及其类似物)、磺酰脲(例如格列本脲(gliburide)、格列美脲(glimepiride)、格列吡嗪(glipizide)及其类似物)、葡糖苷酶抑制剂(例如阿卡波糖(acarbose)、米格列醇(miglitol)及其类似物)、PPARγ激动剂(诸如噻唑啶二酮,例如罗格列酮(rosiglitazone)、吡格列酮(pioglitazone)及其类似物)、PPARα/γ双重激动剂(例如莫格列扎(muraglitazar)、替格列扎(tesaglitazar)、阿格列扎(aleglitazar)及其类似物)、葡糖激酶活化因子(如Fyfe,M.C.T.等人,Drugs ofthe Future,34(8):641-653(2009)所述,且将其通过引用并入本文)、GPR119受体调节剂(MBX-2952、PSN821、APD597及其类似物)、SGLT2抑制剂(达格列净(dapagliflozin)、卡格列净(canagliflozin)、雷格列净(remagliflozin)及其类似物)、胰淀素类似物(诸如普兰林肽)及/或胰岛素。用于治疗糖尿病的现有及新兴疗法的评述可见于以下文献中:Mohler,M.L等人,Medicinal ResearchReviews,29(1):125-195(2009),及Mizuno,C.S等人,Current Medicinal Chemistry,15:61-74(2008)中。
SABA-FGF21融合物亦可视情况与一或多种降低食欲剂组合使用,诸如安非拉酮(diethylpropion)、苯甲曲秦(phendimetrazine)、芬特明(phentermine)、奥利司他(orlistat)、西布曲明(sibutramine)、罗卡色林(lorcaserin)、普兰林肽、托吡酯(topiramate)、MCHR1受体拮抗剂、胃泌酸调节素(oxyntomodulin)、纳曲酮(naltrexone)、胰淀素肽、NPY Y5受体调节剂、NPY Y2受体调节剂、NPYY4受体调节剂、西替利斯他(cetilistat)、5HT2c受体调节剂等。SABA-FGF21融合物亦与胰高血糖素样肽-1受体(GLP-1R)的激动剂组合使用,诸如艾塞那肽(exenatide)、利戈鲁泰(liraglutide)、GPR-1(1-36)酰胺、GLP-1(7-36)酰胺、GLP-1(7-37)(如Habener的美国专利第5,614,492号中所公开,该专利的公开内容以引用的方式并入本文中),其可经由注射、鼻内或藉由经皮或经颊装置来施用。用于治疗肥胖的现有及新兴疗法的评述可见于以下文献中:Melnikova,I等人,Nature Reviews Drug Discovery,5:369-370(2006);Jones,D.,Nature Reviews:DrugDiscovery,8:833-834(2009);Obici,S.,Endocrinology,150(6):2512-2517(2009);及Elangbam,C.S.,Vet.Pathol.,46(1):10-24(2009)。
在某些实施方式中,SABA-FGF21融合物的施用剂量为约10ng至20mg、10ng至5mg、10ng至2mg、10ng至1mg、100ng至20mg、100ng至5mg、100ng至2mg、100ng至1mg、1μg至20mg、1μg至5mg、1μg至2mg、1μg至1mg、10μg至20mg、10μg至5mg、10μg至2mg、10μg至1mg、0.01至20mg、0.01至10mg、0.1至20mg、0.1至10mg、0.01至5mg、0.1至5mg或0.7至5mg、或约10ng、100ng、1μg、10μg、100μg、或约1、2、2.5、3、4、5、6、7、8、9、10mg。在某些实施方式中,SABA-FGF21融合物的施用剂量为约100pg/kg至200μg/kg、100pg/kg至50μg/kg、100pg/kg至20μg/kg、100pg/kg至10μg/kg、1ng/kg至200μg/kg、1ng/kg至50μg/kg、1ng/kg至20μg/kg、1ng/kg至10μg/kg、10ng/kg至200μg/kg、10ng/kg至50μg/kg、10ng/kg至20μg/kg、10ng/kg至10μg/kg、100ng/kg至200μg/kg、100ng/kg至50μg/kg、100ng/kg至20μg/kg、100ng/kg至10μg/kg、0.1至200μg/kg、0.1至100μg/kg、1至200μg/kg、1至100μg/kg、0.1至50μg/kg、1至50μg/g或7至50μg/kg、或约100pg/kg、1ng/kg、10ng/kg、100ng/kg、或1、2、5、10、20、25、30、40、50、60、75、100、125、150、200或250μg/kg。SABA-FGF21融合物可每天(例如每天一次、两次、三次或四次)或频率较小地(例如每隔一天一次、每周一或两次或每月)给与。在例示性实施方式中,SABA-FGF21融合物的施用剂量为以每周计约0.01至20mg、约0.01至10mg、约0.1至20mg、约0.1至10mg、约0.01至5mg、约0.1至5mg或约0.7至5mg、或约1、2、2.5、3、4、5、6、7、8、9、10mg。在例示性实施方式中,SABA-FGF21融合物的施用剂量为以每周计约0.1至200μg/kg、约0.1至100μg/g、约1至200μg/kg、约1至100μg/kg、约0.1至50μg/kg、约1至50μg/kg或约7至50μg/kg、或约1、2、5、10、20、25、30、40、50、60、75、100、125、150、200或250μg/kg。在例示性实施方式中,SABA-FGF21融合物的施用剂量为以每天计约10ng至20mg、约10ng至5mg、约10ng至2mg、约10ng至1mg、约10ng至500μg、约10ng至200μg、约100ng至20mg、约100ng至5mg、约100ng至2mg、约100ng至1mg、约100ng至500μg、约100ng至200μg、约1μg至20mg、约1μg至5mg、约1μg至2mg、约1μg至1mg、约1μg至500μg、约1μg至200μg、约10μg至20mg、约10μg至5mg、约10μg至2mg、约10μg至1mg、约10μg至500μg、约10μg至200μg、或约10ng、100ng、1μg、10μg、100μg、200μg、500μg、1mg、1.5mg、2mg、2.5mg、3mg或5mg。在例示性实施方式中,SABA-FGF21融合物的施用剂量为以每天计约100pg/kg至200μg/kg、约100pg/kg至50μg/kg、约100pg/kg至20μg/kg、约100pg/kg至5μg/kg、约100pg/kg至2μg/kg、约1ng/kg至200μg/kg、约1ng/kg至50μg/kg、约1ng/kg至20μg/kg、约1ng/kg至5μg/kg、约1ng/kg至2μg/kg、约10ng/kg至200μg/kg、约10ng/kg至50μg/kg、约10ng/kg至20μg/kg、约10ng/kg至5μg/kg、约10ng/kg至2μg/kg、约100ng/kg至200μg/kg、约100ng/kg至50μg/kg、约100ng/kg至20μg/kg、约100ng/kg至5μg/kg、约100ng/kg至2μg/kg、约1μg/kg至200μg/kg、约1μg/kg至50μg/kg、约1μg/kg至20μg/kg、约1μg/kg至5μg/kg、约1μg/kg至2μg/kg、约10μg/kg至200μg/kg、约10μg/kg至50μg/kg、或约10μg/kg至20μg/kg、或约100pg/kg、1ng/kg、10ng/kg、100ng/kg、500ng/kg、1μg/kg、5μg/kg、10μg/kg、20μg/kg、50μg/kg、100μg/kg或200μg/kg。另外,如本领域中所已知,可能需要针对年龄以及体重、一般健康状况、性别、膳食、投药时间、药物相互作用及疾病严重程度进行调整,此类调整可由本领域技术人员使用常规实验来确定。
治疗制剂及施用模式
本申请提供施用与SABA融合的治疗性部分的方法,其中当与SABA融合时,该治疗性部分的半衰期延伸。施用融合构建体的技术及剂量将视与SABA融合的治疗性部分的类型及所治疗的特定病状而变化,但可由本领域技术人员容易地确定。一般而言,管理机构要求将欲用作治疗剂的蛋白质试剂调配至具有可接受低水平的热原。因此,治疗性制剂通常将如下区别于其它制剂:其实质上无热原,或至少含有不超过如适当管理机构(例如FDA)所测定的可接受水平的热原。在某些实施方式中,SABA及其融合分子的药物制剂包含例如1-20mM琥珀酸、2-10%山梨糖醇及1-10%甘氨酸(4.0-7.0)。在一个例示性实施方式中,SABA及其融合分子的药物制剂包含例如10mM琥珀酸、8%山梨糖醇及5%甘氨酸(pH 6.0)。
在一些实施方式中,SABA及其融合物对于哺乳动物(尤其人类)是可药用的。“可药用的”多肽指施用给动物而无显著不良医学结果的多肽。可药用的SABA及其融合物的实例包括缺乏整联蛋白结合域(RGD)的10Fn3结构域及基本上无内毒素或具有极低内毒素水平的SABA或SABA融合物的组合物。
治疗性组合物可以单位剂型与可药用的稀释剂、担载体或赋形剂一起施用。作为非限制性实例,施用可非经肠(例如静脉内、皮下)、经口或表面进行。组合物可呈以下形式:用于经口投药的丸剂、片剂、胶囊、液体或持续释放片剂;用于静脉内、皮下或非经肠投药的液体;或用于局部投药的凝胶、洗剂、软膏、乳膏或聚合物或其它持续释放媒剂。
本领域中熟知的用于制备制剂的方法例如见于“Remington:The ScienceandPractice of Pharmacy”(第20版,A.R.Gennaro AR.编,2000,LippincottWilliams&Wilkins,Philadelphia,PA)中。用于非经肠投药的制剂可例如含有赋形剂、无菌水、盐水、聚亚烷基二醇(诸如聚乙二醇)、植物来源油类或氢化萘。生物相容性、生物可降解丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可用于控制化合物的释放。纳米粒子制剂(例如生物可降解纳米颗粒、固体脂质纳米颗粒、脂质体)可用于控制化合物的生物分布。其它潜在适用的非经肠投递系统包括乙烯-乙酸乙烯共聚物颗粒、渗透泵、可植入输注系统及脂质体。制剂中化合物的浓度视许多因素而变化,包括所施用的药物剂量及施用途径。
多肽任选以可药用的盐形式施用,诸如常用于制药工业中的无毒酸加成盐或金属络合物。酸加成盐的实例包括有机酸,诸如乙酸、乳酸、扑酸、顺丁烯二酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、棕榈酸、辛二酸、水杨酸、酒石酸、甲磺酸、甲苯磺酸或三氟乙酸等;聚合酸,诸如鞣酸、羧甲基纤维素等;及无机酸,诸如盐酸、氢溴酸、硫酸、磷酸等。金属络合物包括锌、铁等。在一实例中,在乙酸钠存在下调配多肽以增加热稳定性。
适于口服使用的制剂包括含有活性成分与无毒可药用的赋形剂的混合物的片剂。这些赋形剂可例如为惰性稀释剂或填充剂(例如蔗糖及山梨糖醇)、润滑剂、助流剂及抗黏着剂(例如硬脂酸镁、硬脂酸锌、硬脂酸、二氧化硅、氢化植物油或滑石)。
适于口服使用的制剂亦可以咀嚼片剂形式,或以活性成分与惰性固体稀释剂混合的硬明胶胶囊形式,或以活性成分与水或油介质混合的软明胶胶囊形式提供。
治疗有效剂量指对所施用对象产生施用所追求的治疗效果的剂量。精确剂量将视欲治疗的病症而定,且可由本领域技术人员使用已知技术来确定。一般而言,SABA或SABA融合物依每天约0.01μg/kg至约50mg/kg、优选的每天0.01mg/kg至约30mg/kg、最优选每天0.1mg/kg至约20mg/kg施用。多肽可每天(例如每天一次、两次、三次或四次)或依更低频率(例如每隔一天一次、每周一或两次或每月)给与。另外,如本领域中所已知,可能需要针对年龄以及体重、一般健康状况、性别、膳食、投药时间、药物相互作用及疾病严重程度作调整,且将可由本领域技术人员使用常规实验来确定。
实施例
正被概述的本发明可较容易地藉由参考以下实施例来了解,记载这些实施例仅出于说明本发明的某些方面及实施方式的目的,且不欲以任何方式限制本发明。
序列概要
本申请中所提及的许多序列概示于以下表2中。除非另作说明,否则所有N端延伸均以单下划线表示,所有C端尾部/延伸均以双下划线表示,且对接头序列加框。对各核心SABA序列的环区BC、DE及FG加阴影。
表2.例示性序列概要
表3.某些例示性核酸序列(SEQ ID NO:176-214及397-407)。
A.血清白蛋白结合性AdnectinsTM(SABA)
实施例A1.候选血清白蛋白结合性AdnectinTM的筛选及选择
概要
将称为PROfusion的选择技术(参见例如Roberts及Szostak,Proc Natl AcadSciU S A.94(23):12297-302,1997及WO 2008/066752)应用于具有经设计成10Fn3的BC、DE及FG环的可变区的DNA文库。自此设计形成超过1013个分子的随机文库,且对HSA的生物素化形式施加选择压力以分离具有所需结合性质的候选血清白蛋白结合性AdnectinTM(SABA)。
高产量蛋白质产生(HTTP)方法
使用高产量蛋白质产生方法(HTPP)纯化各种HSA结合AdnectinsTM。将所选结合物克隆至含有HIS6标签的pET9d载体中且转化至大肠杆菌BL21(DE3)pLysS细胞中。按24孔格式将转化细胞接种于5ml含有50μg/mL卡那霉素的LB培养基中且在37℃下生长过夜。通过自过夜培养物中吸出200μl且将其分配于适当孔中来制备新鲜5ml LB培养基(50μg/mL卡那霉素)培养物以用于诱导型表达。使培养物在37℃下生长直至A6000.6-0.9。用1mM异丙基-β-硫代半乳糖苷(IPTG)诱导后,使培养物在30℃下再生长4小时且通过在4℃下在3220×g下离心10分钟来收集。将细胞离心沉淀冷冻于-80℃。
通过再悬浮于450μl溶解缓冲液(50mM NaH2PO4、0.5M NaCl、1×CompleteTM蛋白酶抑制剂混合物-无EDTA(Roche)、1mM PMSF、10mMCHAPS、40mM咪唑、1mg/ml溶菌酶、30μg/mlDNA酶、2μg/ml抑肽酶,pH 8.0)中来溶解离心沉淀(24孔格式)且在室温下振荡1小时。使溶解物澄清,并通过转移至装备有96孔650μl收集盘的96孔Whatman GF/D Unifilter中来重置成96孔格式,并在200×g下离心5分钟。将澄清的溶解物转移至已用平衡缓冲液(50mMNaH2PO4、0.5M NaCl、10mM CHAPS、40mM咪唑,pH 8.0)平衡的96孔Ni螯合培养板中且温育5分钟。移除未结合物质。用1号洗涤缓冲液(50mM NaH2PO4、0.5M NaCl、5mM CHAPS、40mM咪唑,pH8.0)以每孔2×0.3ml洗涤树脂。随后,用PBS以每孔3×0.3ml洗涤树脂。在洗脱之前,用50μl洗脱缓冲液(PBS+20mM EDTA)洗涤各孔,温育5分钟且利用真空弃去此洗液。通过再向各孔施加100μl洗脱缓冲液来洗脱蛋白质。在室温下温育30分钟后,在200×g下离心培养板5分钟且将洗脱的蛋白质收集于含有5μl0.5M MgCl2且固定于Ni培养板的底部的96孔收集盘中。使用BCA蛋白质测定,用SGE(对照AdnectinTM)作为蛋白质标准物来定量洗脱的蛋白质。SGEAdnectin为野生型10Fn3结构域(SEQ ID NO:1),其中整联蛋白结合域(位置78-80的氨基酸RGD)已经置换为SGE。
HSA、RhSA及MuSA直接结合ELISA
为了测定对HSA的直接结合物,在4℃下用含10μg/mL HSA(Sigma,St.Louis,MO)的PBS包被MaxiSorpTM培养板(Nunc International,Rochester,NY)过夜,随后在室温下在酪蛋白封闭缓冲液(Thermo Scientific,Rockford,IL)中封闭1-3小时。对于单点筛选测定,用酪蛋白封闭缓冲液按1:20稀释经纯化的HTPP AdnectinsTM且在室温下使其结合于各孔中的HSA持续1小时。对于剂量反应测定,使用范围为0.1nM至1μM的浓度。在用PBST洗涤以移除未结合的AdnectinsTM后,在室温下将用酪蛋白封闭缓冲液按1:2500稀释的抗HismAb-HRP缀合物(R&D Systems,MN)添加至所结合的带His标签的AdnectinsTM中1小时。通过用PBST洗涤移除过量缀合物且根据制造商的说明书,使用TMB检测试剂(BD Biosciences)检测所结合的AdnectinsTM。
通过分析型大小排阻层析法进行聚集测定
对自HTPP获得的SABA进行大小排阻层析(SEC)。使用Superdex 2005/150或Superdex 755/150柱(GE Healthcare),在Agilent 1100或1200HPLC系统上对得自HTPP的物质进行SEC,并在A214nm及A280nm下进行UV检测及进行荧光检测(激发=280nm、发射=350nm)。使用100mM硫酸钠、100mM磷酸钠、150mM氯化钠(pH 6.8)的缓冲液,依SEC柱的适当流速。使用凝胶过滤标准物(Bio-Rad Laboratories,Hercules,CA)进行分子量校准。
对HTPP纯化SABA所作的SEC的结果显示主要为单体,且在相对于球状凝胶过滤标准物(BioRad)为10kDa的大致范围内洗脱。
5.鉴定候选血清白蛋白结合性AdnectinTM(SABA)
作为针对HSA/RhSA/MuSA结合及生物物理学标准的筛选的结果,鉴定及选择了四种独特血清白蛋白结合性AdnectinsTM(SABA)以在小鼠中评估其半衰期。为进行体外及体内表征,对四种SABA采用中等规模制备(midscale)。表2提供自PROfusion鉴定的26种独特SABA核心序列(指定为SABA 1-26)的序列。SABA4具有一个支架突变,在中等规模制备之前将其修复(fixed)。SABA4的支架完好形式为SABA5。SABA4及SABA5在BC、DE及FG环中具有相同序列。
实例A2.候选SABA的产生及配制
SABA的中等规模蛋白质产生
将实施例A1中所述的选定SABA,后面带有His6标签,克隆至pET 9d载体中且在大肠杆菌BL21(DE3)pLysS细胞中表达(关于命名为SABA1.1、SABA2.1、SABA3.1及SABA5.1的各个带His标签的SABA序列,参见表2)。使用20ml接种培养物(自单个铺板菌落产生)接种1升含有50μg/mL卡那霉素的LB培养基。使培养物在37℃下生长直至A6000.6-1.0。在用1mM异丙基-β-硫代半乳糖苷(IPTG)诱导后,使培养物在30℃下再生长4小时且通过在4℃下≥10,000×g离心30分钟来收集。将细胞离心沉淀冷冻于-80℃下。在冰上使用Ultra-turrax均质仪(IKA works)将细胞离心沉淀重悬浮于25mL溶解缓冲液(20mM NaH2PO4、0.5M NaCl、1×CompleteTM蛋白酶抑制剂混合物-无EDTA(Roche),pH 7.4)中。通过高压均质化(≥18,000psi),使用M-110S型号的微流化机(Microfluidics)来实现细胞溶解。通过在4℃下在23,300×g下离心30分钟来分离可溶级分。经由0.45μm过滤器使上清液澄清。将澄清的溶解物上样于用20mM NaH2PO4、0.5M NaCl(pH 7.4)预平衡的HisTrap柱(GE)上。随后依序用25个柱体积的20mM NaH2PO4、0.5M NaCl(pH 7.4)、20个柱体积的20mM NaH2PO4、0.5M NaCl、25mM咪唑(pH 7.4)及35个柱体积的20mMNaH2PO4、0.5M NaCl、40mM咪唑(pH 7.4)洗涤柱。用15个柱体积的20mMNaH2PO4、0.5M NaCl、500mM咪唑(pH 7.4)洗脱蛋白质,基于A280下的吸光度合并级分,且相对于1×PBS、50mM Tris、150mM NaCl(pH 8.5)或50mMNaOAc、150mM NaCl(pH4.5)进行透析。通过0.22μm过滤来移除任何沉淀。
中等规模表达及纯化得到具有高纯度及活性的AdnectinsTM,其以可溶形式表达且自细菌细胞溶质的可溶部分中纯化出来。在Superdex 200或Superdex 7510/30GL上用100mM NaPO4、100mM NaSO4、150mM NaCl(pH6.8)(GE Healthcare)的流动相所作的SEC分析显示主要是单体AdnectinsTM。
SABA1.2的配制
选择一种特定SABA,即SABA1.2(SEQ ID NO:80)用于初步配制筛选。SABA1.2包含10Fn3的“核心1”序列上的(ED)5延伸。对于SABA1.2鉴定了一种稳定制剂,即10mM琥珀酸、8%山梨糖醇、5%甘氨酸,pH 6.0,产物浓度5mg/mL。在此制剂中,如通过差示扫描量热测定法(DSC),使用1.25mg/mL的蛋白质浓度所测定的,蛋白质熔解温度为75℃。该制剂提供在4℃及25℃下令人满意的物理及化学稳定性,且初始聚集体水平为1.2%。在稳定一个月后,聚集水平极低(在4℃下为1.6%且在25℃下为3.8%)。在自-80℃及-20℃转变至环境温度的五个冻融循环后,蛋白质在此制剂中也是稳定的。另外,在此制剂中,SABA1.2可在4℃及环境温度下溶解至至少20mg/mL蛋白质浓度而无沉淀析出或聚集增加。
实例A3.候选SABA的生物物理学表征
大小排阻层析
对自中等规模制备过程得到的候选SABA进行标准大小排阻层析(SEC)。使用Superdex 20010/30或Superdex 7510/30柱(GE Healthcare),在Agilent1100或1200HPLC系统上对中等规模制备的材料进行SEC,并在A214nm及A280nm下进行UV检测及进行荧光检测(激发=280nm、发射=350nm)。在SEC柱上依适当流速使用100mM硫酸钠、100mM磷酸钠、150mM氯化钠(pH 6.8)的缓冲液。使用凝胶过滤标准物(Bio-Rad Laboratories,Hercules,CA)进行分子量校准。
对中等规模制备的纯化的SABA所作的SEC的结果显示主要为单体AdnectinTM,且在相对于如图所示的球状凝胶过滤标准物(BioRad)为10kDa的大致范围内洗脱。
热稳定性
进行中等规模制备SABA的差示扫描量热测定法(DSC)分析以测定它们各自的Tm。对于1mg/ml溶液,通过在3个大气压下使温度以每分钟1度的速率自5℃匀变至95℃,用N-DSC II热量计(Calorimetry Sciences Corp)进行扫描。相对于适当缓冲液的对照运行,使用最佳拟合,使用Orgin软件(OrginLabCorp)分析数据。SEC及DSC分析的结果总结于表4中。
表4.对候选SABA所作的SEC及DSC分析的总结。
实例A4.结合血清白蛋白的候选SABA1的表征
通过将各种血清白蛋白(HSA/RhSA/MuSA)固定于Biasensor CM5芯片表面上,并使一系列浓度的SABA流过参考流动室与固定的白蛋白两者,来测定自实施例A1及实施例A2中所述的HTPP及/或中等规模制备材料纯化出的选定SABA克隆的动力学。另外,在范围为pH5.5至pH 7.4的各种pH值条件下进行白蛋白结合。HSA结合性AdnectinsTM SABA2.1、SABA3.1、SABA4.1(SABA5.1)及SABA1.1与RhSA交叉反应,但不与MuSA交叉反应。SABA2及SABA4结合具有pH敏感性,然而克隆SABA3在低至pH 6.0仍显示具有pH值抗性的HSA结合。SABA1.1在低至pH 5.5仍符合pH值抗性及亲和力/动力学的生物化学标准。
通过Biacore确定结构域定位。通过将HSA或仅由HSA-结构域I及II或HSA-结构域III组成的构建体固定于Biasensor CM5芯片表面上,且使一系列浓度的SABA流过参考流动室与固定的白蛋白两者,来测定自HTPP及/或中等规模制备材料纯化的选定SABA克隆。克隆SABA2及SABA1结合于HSA及HSA-结构域I-II构建体,但不结合HSA-结构域III构建体。克隆SABA3及SABA4结合于HSA,但不结合HSA-结构域I-II或HSA-结构域III构建体。结果总结于下表5中。
表5.候选SABA(SABA1.1、2.1、3.1及4.1)的结合亲和力及动力学。
实例A5.候选SABA的体内t1/2的检查
测定小鼠中的HSA的半衰期以允许在小鼠中评估HSA结合性AdnectinsTM,因为HSA结合性AdnectinsTM不与MuSA交叉反应。将HSA以20mg/kg(图1A)及50mg/kg剂量(图1B)注入约6周龄的Ncr裸雌性小鼠的尾静脉中,且通过ELISA测定注射后每隔一段时间获取的血液样品中HSA的浓度。使用WinNonlin软件及非隔室建模,分别测得依20mg/kg及50mg/kg注射入小鼠中的HSA的t1/2为约24小时及约20小时。
小鼠中的SABA1-4的半衰期测定
制备一升大肠杆菌生长量的HSA结合克隆SABA1.1、SABA2.1、SABA3.1及SABA4.1,加以纯化并移除内毒素。在有或无HSA情况下将各SABA变体注入小鼠尾静脉中,且使用一种开发用于检测血浆样品中的AdnectinTM的基于定量ELISA的测定法来测定注射后每隔一段时间获取的血液样品中的浓度。使用非隔室建模,用WinNonlin软件来确定每种AdnectinTM的药物动力学参数。
在约6周龄的Ncr裸雌性小鼠中在存在或不存在has的条件下比较各SABA的药物动力学概况。对于共注射HSA的小鼠,HSA与各SABA预混合(HSA为3-4摩尔过量),因为该结合克隆对HSA及RhSA具有选择性且不结合小鼠血清白蛋白。小鼠血浆中的SABA1.1的半衰期为0.56小时,而与HSA共注射的SABA1.1的半衰期为5.6小时,半衰期增加约10倍(图2A)。小鼠血浆中的SABA2.1的半衰期为0.24小时,而与HSA共注射的SABA2.1的半衰期为2.8小时,半衰期增加约12倍(图2B)。小鼠血浆中的SABA3.1的半衰期为0.28小时,而与HSA共注射的SABA3.1的半衰期为0.53小时,半衰期增加约2倍(图2C)。小鼠血浆中的SABA4.1的半衰期为0.66小时,而与HSA共注射的SABA4的半衰期为4.6小时,半衰期增加约7倍(图2D)。本实施例总结展示于图3中。表6总结SABA1.1、SABA2.1、SABA3.1、SABA4.1及SABA5.1的类似数据;当可用时,与食蟹猴中的半衰期进行比较。
表6.小鼠及猴中的SABA1.1、SABA2.1、SABA3.1、SABA4.1及SABA5.1的数据。
食蟹猴中的SABA1.1及SABA5.1的半衰期测定
在食蟹猴中进行SABA1.1(图4A)及SABA5.1(图4B)的三周单剂量构思验证研究以评估2只食蟹猴中1mg/kg(mpk)静脉内剂量下的药物动力学。使用开发用于检测血浆样品中的AdnectinTM的基于定量ELISA的测定法来评估药物动力学。SABA1.1的半衰期在96-137小时的范围内(图4A及表7)。SABA5.1的半衰期为约12小时,且在ELISA中仅在不晚于120小时时可测量(图4B及表8)。表7总结SABA1.1的数据;表8总结SABA5.1的数据。
表7:SABA1.1的数据。
表8:SABA5.1的数据。
实施例A6.结合血清白蛋白的SABA1的表征
SABA1.1和1.2结合SA及RhSA
SABA1.2,一种包含(ED)5延伸的“核心1”10Fn3(SEQ ID NO:90),在中性pH值及25℃下结合人血清白蛋白(HSA)的平均缔合速率常数(ka)为8.21E+03M-1s-1,且平均解离速率常数(kd)为4.43E-04s-1,算得的平均KD为55.3nM(表9)。对于猕猴血清白蛋白(RhSA)而言,测得的平均缔合速率常数为6.6E+03M-1s-1,且解离速率常数为3.78E-03s-1,从而算得的平均KD为580nM。直到高达1μM为止,SABA1.2与小鼠或大鼠血清白蛋白之间观察不到可测量的相互作用(表9及图5)。在37℃下,ka及kd增加2至5倍,从而使得对HSA的亲和力增加约2倍及对RhSA的亲和力增加1/2(表9)。
表9.在HBS-P缓冲液中SABA1.2结合白蛋白的动力学参数。
另外,进行量热滴定以确定SABA1与HSA之间的化学计量。在此项研究中,使用SABA1.1,一种包含His6延伸的“核心1”10Fn3(SEQ ID NO:89)。将HSA(每次注射10μl 115μM蛋白质溶液)注入含有浓度为8.1μM的SABA1.1的量热小室中。在37℃下在PBS缓冲液(pH7.4)中进行实验。图6展示SABA1.1以1:1的化学计量结合HSA。
SABA1.2在低pH值下强结合HSA
白蛋白的长半衰期(例如HSA的t1/2为19天)在很大程度上归因于以下事实:其通过在内体中存在的低pH值条件下结合新生Fc受体FcRn而自内吞路径再循环。如表10中所示,SABA1.2在5.5的内体pH值下有效地结合HSA,这表明一旦结合于HSA,SABA1的t1/2亦将得益于FcRn再循环机制。
表10.在MES缓冲液中在pH 7.4及5.5的白蛋白结合动力学的比较。
SABA1.2结合HSA的结构域I及II,但不结合结构域III
白蛋白上的结合位点SABA1.2使用重组HSA片段被定位于N端结构域I或II,且与结构域III无可检测的结合(图7)。因为结构域III是HSA中主要与FcRn相互作用的结构域,所以SABA1.2不太可能会与FcRn竞争HSA结合,这又提高了充分利用再循环机制来延伸半衰期的可能性。
实施例A7.SABA1.2的活体内药理学
在食蟹猴中进行SABA1.2的四周单剂量预毒理学研究以评估两个不同剂量下的药物动力学。还在包括静脉内与皮下投药组的三周单剂量预毒理学研究中评估药物动力学及生物利用度。在这些研究的每一项中,使用开发用于检测血浆样品中的SABA1.2的基于定量ELISA的测定法结合使用WinNonlin软件的非隔室模型化来评估SABA1.2的药物动力学。
向猴子静脉内施用1mpk及10mpk的SABA1.2。使用WinNonlin软件进行非隔室分析以评估药物动力学参数。如图20及下文所述的参数所示,SABA1.2在此项研究中展现剂量依赖性药物动力学,如通过浓度-时间曲线下面积(AUC)评估所测定的。10mpk的SABA1.2清除率(CL)为0.15ml/hr/kg,β相半衰期(t1/2)为143小时,分布体积(Vz)为30mL/kg,且总药物暴露(AUCall)为5,609,457hr*nmol/L(表11)。1mpk的SABA1.2清除率(CL)为0.4ml/hr/kg,半衰期(t1/2)为124小时,分布体积(Vz)为72mL/kg,且总药物暴露(AUCall)为214,636hr*nmol/L(表11)。
在皮下或静脉内施用SABA1.2后,β相药物动力学概况相似(图9)。静脉内1mpk的SABA1.2清除率(CL)为0.22ml/hr/kg,β相半衰期(t1/2)为125小时,分布体积(Vz)为40mL/kg,且总药物暴露(AUCall)为357,993hr*nmol/L(表11)。皮下1mpk的SABA1.2清除率(CL)为0.32ml/hr/kg,β相半衰期(t1/2)为134小时,分布体积(Vz)为62mL/kg,且总药物暴露(AUCall)为251,339hr*nmol/L(表11)。与静脉内相比,皮下相对生物利用度(F)为0.7。
表11.猴中的SABA1.2的药物动力学参数。
实施例A8.人血清白蛋白与SABA1.2的复合物的结构
通过Proteros Biostructures GmbH,自100mM乙酸钠(pH 4.75)、100mMNaCl及28%PEG200使人血清白蛋白与SABA1.2的复合物结晶。使用自由安装系统(Free MountingSystem,FMS)使晶体衍射最优化且在油下急速冷却。
通过Proteros Biostructures GmbH,在瑞士光源(Swiss Light Source)PXI/X06SA束线收集数据,其间将晶体维持于100K。波长为且检测器为Pilatus 6M(Dectris)。用XDS及XSCALE处理数据(W.Kabsch(2010),XDS.Acta Crystallogr.Sect.D66,125-132;W.Kabsch(2010),Integration,scaling,space-group assignment andpost-refinement,Acta Crystallogr.Sect.D 66,133-144)并得到以下统计数据:空间群:P212121;单位晶胞:
表12.结构数据的总结。
分辨率 | 测量值 | 独特值 | 冗余度 | 完成% | R值 | I/σI | |
总体 | 50.00-1.96 | 330257 | 55260 | 6.0 | 99.0 | 0.039 | 23.1 |
第一壳层 | 50.00-4.30 | 30746 | 5523 | 5.6 | 99.2 | 0.024 | 56.1 |
最后壳层 | 2.03-1.96 | 32596 | 5527 | 5.9 | 98.6 | 0.681 | 2.7 |
使用分子置换程序MOLREP(Vagin,A.及Teplyakov,A.(1997),MOLREP:anAutomated Program for Molecular Replacement.J.App.Crystallogr.,30,1022-1025)及使用PDB输入1BM0作为检索模型来确定人血清白蛋白的结构。根据基于PDB输入1FNF残基1423-1502的检索模型,使用分子置换程序PHASER来确定Adnectin部分的结构(A.J.McCoy,R.W.Grosse-Kunstleve,P.D.Adams,M.D.Winn,L.C.Storoni &R.J.Read(2007),PhaserCrystallographic Software,J.Appl.Crystallogr.40,658-674)。
使用BUSTER/TNT(Blanc,E.,Roversi,P.,Vonrhein,C.,Flensburg,C.,Lea,S.M.及Bricogne,G.(2004),Refinement of severely incomplete structureswith maximumlikelihood in BUSTER/TNT,Acta Crystallogr.Sect.D 60,2210-2221)进行模型优化,并且用COOT进行模型建立(Emsley,P.及Cowtan,K.(2004),Coot:model-building tools formolecular graphics,Acta CrystallogrSect.D 60:2126-2132;Emsley,P.,Lokhamp,B.,Scott,W.G.&Cowtan,K.(2010),Features and Development of Coot,Acta CrystallogrSect.D 66:486-501)。用PyMol(DeLano,W.L.(2002),The PyMol MoleculargraphicsSystem,DeLano Scientific,San Carlos,CA,US;可在万维网上在pymol.org上得到)制备显示图。
最后一轮优化得到表13中所示的统计数据。
表13.来自最后一轮优化的统计数据。
结构的描述
SABA1.2的结合位点严格地位于人血清白蛋白(HuSA)的结构域1上(图17A及17B)。HuSA的以下残基与Adnectin接触(编号基于成熟HuSA序列,减去信号及前肽区):Pro 35、Phe 36、Glu 37、Pro 113、Arg 114、Leu 115、Arg 117、Pro 118、Glu 119、Val 122、Met123、Phe 134、Lys 137、Tyr 140、Glu 141、Arg 144、Arg 145及Tyr 161。(Sheriff,S.,Hendrickson,W.A.及Smith,J.L.(1987),Structure of Myohemerythrin in theAzidomet State at 1.7/1.3Resolution,J.Mol.Biol.197,273-296;Sheriff,S.(1993),Some methods forexamining the interactions between two molecules,Immunomethods 3,191-196)。相互作用残基的更宽泛的定义可以为:至少部分被包埋的那些残基,除上文所列的处于接触中的残基外,其还包括以下残基:Asp 38、Thr 125、Ala126、Asp 129、Thr 133、Tyr 138及Leu 182。
Adnectin经由BC、DE及FG环相互作用且具有与HuSA接触的以下残基:His 25、Ser26、Tyr 27、Glu 29、Gln 30、Asn 31、Pro 53、Tyr 54、Ser 55、Thr 57、Tyr 78、Tyr 83及Tyr84(属于SABA1.2,例如SEQ ID NO:90)。除先前所列的残基外,以下残基至少部分因相互作用而被包埋:Trp 24、Ser 32、Tyr 33、Gln 56、Gly 79及Lys 81(属于SABA1.2,例如SEQ IDNO:90)。
实施例A9.SABA安全性研究的I期设计
将在健康男性志愿者中进行静脉内施用的SABA1.2的1期、部分不知情、安慰剂对照的药物动力学研究。志愿者将为18岁至60岁的健康成年男性受试者,他们当前未接受处方或非处方药物治疗并符合规程对健康及器官功能规定的限制。SABA1.2为对人血清白蛋白(HSA)具有结合亲和力的非治疗性Adnectin。其意欲当与原本将被快速消除的其他治疗性Adnectin或其它蛋白质一起整合至单一多肽链中时充当白蛋白结合物以延伸血清半衰期(T-HALF)。将用0.1mg/kg、0.3mg/kg或1.0mg/kg SABA1.2或安慰剂处理各群组受试者,每两周处理一次,总共施用药物两次。
研究设计。志愿者受试者将随机化接受SABA1.2或安慰剂,且将间隔14天接受两个剂量的其随机化治疗,每次为1小时输注,随后为2周样品收集及观察期;在第二观察期后,将针对安全性再追踪受试者4周。将在第1及15天施用治疗(SABA1.2或安慰剂)。
将在渐增剂量的SABA1.2下招募三个连续群组。各个别剂量群组将另外分成3个亚组,其以部分不知情(受试者及研究人员将对输注物的身份不知情;而药剂师并非不知情)方式依序暴露于SABA1.2或安慰剂(参见图18)。各群组的第一亚组将仅含有1位经活性药物处理的受试者以使风险减至最小。
在第1群组的所有受试者均已完成其第29天就诊,且已评估PK所见(预期不晚于第4周)后,第2群组将开始研究,假设第1群组不符合超越所规定的未观察到不良事件的水平(no observed adverse event level,NOAEL)的标准(参见下文)。同样,第3群组直至第2群组完成及PK评估后才开始,假设未超越NOAEL。
NOAEL将被定义为低于最低剂量1个水平的剂量,其中a)2个或2个以上经有效处理(非安慰剂)的受试者经受了任何2级国家癌症研究所(NationalCancer Institute,NCI;US)不良事件常用术语标准(Common TerminologyCriteria for Adverse Events)(CTCAEv4.03)SABA1.2相关毒性;或b)至少1个经有效处理的受试者经受了任何≥3级SABA1.2相关毒性。NOAEL将为不符合任一这些标准时所达成的最高剂量。在第2或3群组超越NOAEL标准的情况下,下一较低群组将被宣布达到NOAEL,且所有剩余受试者将以NOAEL处理,以便在研究中处理总共37个受试者(28个接受SABA1.2及9个接受安慰剂)。这是为了维持为了支持药物动力学(PK)及免疫原性评估的而寻求的统计精确度,以及在安全性观察下支持适当数目的受试者。若发现第1群组的剂量超过NOAEL,则将不对其他受试者进行给药并结束研究。
研究评估及主要终点。研究的主要终点将为PK且将包括所有剂量的平均T-HALF、最大血浆浓度(Cmax)、全身清除率(CL)、自给药起至给药间隔结束的浓度-时间曲线下面积(AUCtlast)及稳态下的分布体积(VSS)。将在研究第1及15天开始每次输注的前及的后0.5(输注中途)、1(输注结束)、1.5、2、3、5、7、24、48、72、96或120及168小时收集用于PK分析的连续样品。另外,将在第29(第15天给药后的336小时试样)、36、43、50及57天收集用于SABA1.2血浆浓度测定的单一随机样品。
安全性评估将包括生命征象、身体检查、心电图、临床实验室评估及不良事件。另外,将通过测量抗药物抗体(ADA)、自体免疫性的血清指示物(抗核抗体[ANA]、C3及C4)及临床观察(例如皮疹、输注反应、肌肉或关节疼痛等)来评估免疫原性。将进行HLA分类及T细胞刺激测定以试图了解任何观察到的免疫原性的机制。
统计方法。在25个受试者中,所观察到的133.159小时或更久的T-HALF的单侧95%信赖区间(CI)的下限将不会延伸至120小时。为获得25个经积极处理的完成者,每个给药群组将包括额外1个受试者,总共28个经积极处理的受试者。
将血浆PK参数依据剂量及在剂量范围内变化的汇总统计数据列成表格。将使用非隔室方法,自SABA1.2血浆浓度相对于时间得出PK参数。若有必要,则隔室方法可用于进一步了解体内分布(disposition)。将由95%CI估算平均T-HALF。将报导Cmax、AUCtlast、R及CL的几何平均值及CV;Tmax的中值(最小、最大);及其它参数的平均值与标准偏差。将评估SABA1.2的剂量比例。将使用线性混合效应模型化将对数转换的AUC及Cmax拟合成对数转换的剂量。将构建关系斜率的对称、渐近95%CI。若95%CI包括1.0的值,则作出剂量均衡的结论。相反地,若95%CI不包括1.0的值,则将作出非均衡的结论。
将依据剂量及总体描述性地概括安全性结果。
起始剂量基本原理。当每周给与两次达到5个剂量时,食蟹猴的NOEL(未观察到作用的水平)为静脉内30mg/kg。基于以体表面积表示的剂量,此人体临床试验中的SABA1.2的起始剂量(0.1mg/kg)代表安全系数为猴的NOEL的1/100;而此研究中的最高计划剂量(1mg/kg)代表安全系数为1/10或更低。基于预计的人Cmax及AUC,此临床研究中的起始剂量代表相对于猴NOEL下的第15天猴Cmax及AUC而言分别为约600倍及200倍的安全系数;而基于此研究中的最高计划剂量,预计的人Cmax及AUC表示相对于第15天猴参数而言分别为约50倍及20倍的安全系数。因此,已对此研究中的给药水平考虑到足够的安全系数。
B.FGF21-SABA融合分子
实施例B1.制备FGF21-SABA融合分子
概要
将本文所公开的所有FGF21-SABA DNA序列置于市售表达载体pET29b(EMDBiosciences,San Diego,CA,USA)中。将序列适当地置于质粒载体中恰好位于核糖体结合位点下游的NDEI与XHOI限制性核酸内切酶位点之间(图10)。
将表达载体转化至宿主菌株BL21(DE3)(EMD Biosciences)中,且以包涵体形式表达至不同水平。或者,可将其转化至大肠杆菌菌株的氧化性菌株中,诸如“OrigamiTM”(EMDBiosciences)。后述宿主菌株含有硫氧还蛋白还原酶(trxB)与谷胱甘肽还原酶(gor)基因的突变,这大大增强大肠杆菌细胞质中的二硫键形成。在适当注意下表达各种FGF21-SABA融合物,诸如表2中所述的那些融合物。
通过本领域技术人员通常已知的标准转化方法,将经纯化的质粒DNA表达载体组入或“转化”至以上所述的大肠杆菌宿主中。简言之,在冰上解冻商业上制备的转化态细胞(EMD biosciences)并轻轻混合以确保细胞均匀地悬浮。将这些细胞的20μl等分试样吸移至在冰上经冰预冷却的1.5ml聚丙烯微量离心管中。将约1μl经纯化的质粒DNA(1-10ng/μl质粒)直接添加至细胞中并轻轻搅拌而混合。将管保持于冰上5分钟,随后在42℃水浴中加热正好30秒。将经加热的管立即置于冰上并静置2分钟。向各管中添加80μl室温SOC或LB培养基。通过涂板于含有卡那霉素的培养基上来完成对转化体的选择以获得pET 29b质粒编码的抗药性。
可溶FGF21-SABA融合多肽在Origami 2细胞株中的表达通过使转化细胞的过夜起始培养物(starter culture)生长来起始。使用细胞接种各含有1升LB培养基(LuriaBroth)的2升摇瓶,且在37℃下在250-300RPM剧烈振荡下生长直至达到0.6至0.8的O.D.600nm。此时,添加0.1mM IPTG(异丙基β-D-1-硫代哌喃半乳糖苷)以引发T7RNA聚合酶诱导,且使振荡培养箱的温度降低至18℃。持续发酵12-16小时,通过离心收集细胞并以压积的湿细胞糊状物形式冷冻于-80℃下。
FGF21-SABA融合多肽以包涵体(IB)形式在BL21(DE3)细胞株中的表达亦通过使转化细胞的过夜起始培养物生长来起始。使用细胞接种各含有1升Overnight ExpressTM培养基(EMD Biosciences及Nature Methods 2,233-235,2005)的2升摇瓶。出于形成包涵体的目的,不需要降低发酵温度,而是使细胞在37℃下生长12-16小时,随后通过离心收集。将所收集的细胞以压积的湿细胞糊状物形式冷冻于-80℃下。
所述FGF21-SABA变体的纯化视所用的确切的序列变体及蛋白质是否以细胞溶质可溶形式在Origami细胞株中表达或以包涵体形式在BL21细胞株中表达而变化。方法亦视序列是否含有有助于纯化的6×组氨酸标签而定。然而,一般而言,纯化方法共享本领域技术人员所熟悉的常见技术。以下为纯化方法的详细描述。
细胞溶解及制备包涵体(IB)离心沉淀
依8-10份缓冲液比1份压积的细胞糊状物的稀释度将细胞悬浮于溶解缓冲液中。使用Avestin C-5均质机(Avestin Inc.Ottawa,Ontario,Canada),通过在2000PSI下通过两次来以机械方式溶解细胞。溶解后,离心溶解物(4,000RPM,20-30分钟)并丢弃可溶部分。用0.5%Triton X-100洗涤包涵体离心沉淀以移除细胞碎片,并再次离心悬浮液。重复此过程(通常2或3次)直至离心沉淀显现为均匀白色。随后用PBS缓冲液洗涤所得的富集的IB制备物离心沉淀以移除过量去污剂。
溶解包涵体
随后将经洗涤且去除去污剂的IB离心沉淀溶解于经50mM Tris-HCl(pH8.0)及500mM NaCl缓冲的6M胍-HCl中。大部分以此方式制备的物质自由进入液相,然而有少量细胞碎片残留且通过在16,000RPM下用SS-34转子离心1小时来移除。保留上清液以进行重折叠及氧化步骤。或者在此阶段可使用金属螯合层析步骤(IMAC)捕捉含有6×His标签的蛋白质融合物变体并进一步精细纯化。可将经离液剂变性的材料结合于柱且洗去污染物,随后在补充有咪唑的变性缓冲液存在下洗脱。
重折叠及氧化
将胍-HCl溶解的材料稀释至约1mg/mL蛋白质(由280nM下的吸光度估计)且置于3.5MWCO透析管中。随后将透析装置中的样品漂浮于4L重折叠缓冲液(50mM Tris、150mMNaCl、1mM EDTA,pH 9.0)中在4℃轻柔搅拌下过夜。第二天早晨,用新鲜的重折叠缓冲液更换透析重折叠缓冲液。在此过程期间,融合蛋白的FGF21结构域中的二硫桥键容易被空气氧化。这种简单的透析方法是方便的,且需要时可一次处理若干样品。或者,可用尿素替代胍-HCl来使蛋白质变性。或者,重折叠及氧化亦可使用将分子自高离液盐浓度快速稀释至较低盐浓度来进行。或者可使用确定的还原型谷胱甘肽与氧化型谷胱甘肽的氧化还原混合物(GSH/GSSG)替代空气氧化来使系统再折叠。
或者,亦可使这些蛋白质在结合于层析树脂载体时再折叠,以替代经由如上文所述的透析或快速稀释使这些蛋白质在自由扩散阶段再折叠。此方法通常具有优点及改善的产率,因为其将重折叠期内会导致大量聚集及产率损失的蛋白质相互作用最小化。
移除沉淀物
当在这些条件下的再折叠及氧化步骤结束时,并非所有蛋白质均保持可溶。一部分分子以聚集状态存在且容易以沉淀物形式自溶液中下沉。通过在16,000RPM下用SS-34转子离心1小时来移除此沉淀物,随后通常经由0.2μm针筒过滤器过滤,随后层析。
层析分离
可通过使用Resource Q或类似离子交换介质系统(GE Healthcare,PiscatawayNJ)纯化经重折叠的FGF21-SABA融合物以移除DNA及其它污染物。用再折叠缓冲液(50mMTris(pH 9.0)加上150mM NaCl、1mM EDTA)平衡40mL Resource Q柱,且使经澄清的重折叠材料通过该柱。在这些条件下,大部分FGF21-SABA变体通过树脂床而不结合。来自经洗涤包涵体的DNA及其它细胞碎片保留于柱树脂上。或者此时可使用固定金属离子亲和层析(IMAC)步骤捕捉含有6×His标签的折叠的蛋白质融合物变体且用咪唑或组氨酸的梯度洗脱。
浓缩
随后使用XL装置及LabscaleTM切向流过滤(TFF)系统(MilliporeInc.,Billerica,MA)将第一层析步骤中富集的蛋白质样品浓缩至约4mg/mL。
大小排阻层析
随后使用经PBS缓冲液(pH 7.2)预平衡的26/60Sephacryl S100或26/60Superdex75大小排阻柱(GE Healthcare,Piscataway NJ,USA)进一步纯化FGF21-SABA融合物的约4mg/mL样品。合并对应于单体蛋白质融合物的样品,且必要时将样品稀释至1-2mg/ml,随后冷冻于-80℃下。使用此方法,每100mL由初始自动诱导培养基产生的包涵体可纯化出多达20mg的FGF21-SABA融合物。
实施例B2.结合于血清白蛋白的FGF21-SABA融合物的表征
使用等温滴定量热法,在Microcal VP-ITC仪器(Microcal Inc.AmherstMA,USA)上进行FGF21-SABA融合物变体与人血清白蛋白的结合能力及热力学表征。另外,在BiacoreT100仪器(GE Healthcare Inc,Piscataway,NJ)上进行FGF21-SABA1融合物变体与人血清白蛋白(HSA,Sigma#A3782,St.LouisMO,USA)、食蟹猴血清白蛋白(CySA,Equitech-Bio#CMSA,Kerrville,TX,USA)及鼠血清白蛋白(MuSA,Sigma#A3559)的结合能力及动力学表征。下文描述详细实验条件。
在量热测定中,使用FGF21-SABA变体SABA1-FGF21v1(SEQ ID NO:132)。37℃下的代表性滴定曲线展示于图11中且KD经计算为3.8nM。在SPR研究中,检查SABA1-FGF21v1及SABA1-FGF21v3(SEQ ID NO:134)。1000、500、250、125及62.5nM融合物与来自人(HSA)、食蟹猴(CySA)及鼠(MuSA)的血清白蛋白的结合的SPR传感图数据展示于图12中。表14概括这些融合物与HSA、CySA及MuSA的结合的动力学数据。
表14.SABA1-FGF21v1及SABA1-FGF21v3与HSA、CySA及MuSA的结合的SPR动力学数据。
详细方案
等温滴定热测量定法
将经纯化的SABA1-FGF21融合蛋白及商业制备的人血清白蛋白(HSA,Sigma#A3782,St.Louis MO,USA)在分别的3,500MW透析袋中相对于PBS缓冲液(10mM磷酸钠、130mM氯化钠,pH 7.1)进行透析以确保与实验匹配的适当溶剂。将SABA-FGF21融合蛋白加上缓冲液依范围为0.4mg/mL至1.0mg/mL蛋白质的浓度置于仪器样品小室中。将匹配缓冲液置于参考小室中。使用由纯蛋白质的蛋白质序列计算的消光系数测定浓度。在37℃平衡仪器反应小室。自注射器向反应小室中反复注射,每次10μl,且监测每摩尔HSA的过量热。将所得数据集减去基线且针对注入小室中的HSA的稀释热进行校正。使用OriginTM评估软件包(Microcal Inc.)2.0.2版拟合所得热分析图数据以估算蛋白质-蛋白质结合反应的化学计量、焓及平衡解离常数(KD)。
表面等离子共振
将血清白蛋白溶解于PBS缓冲液(10mM磷酸钠、130mM氯化钠,pH 7.1)中达至10mg/ml的浓度,且随后用10mM乙酸钠(pH 5.0)稀释至8-10μg/ml以用于固定。根据通用制造商指南,在25℃下使用标准含乙基(二甲基氨基丙基)碳二亚胺(EDC)/N-羟基丁二酰亚胺(NHS)化学的HBS-EP+操作缓冲液将血清白蛋白固定于S CM5系列感应芯片上。用EDC/NHS活化流动室1且用乙醇胺封闭。分别用EDC/NHS活化流动室2、3及4,随后固定8-10μg/ml血清白蛋白,且用乙醇胺封闭以达成700RU HSA(流动室2)、1100RU CySA(流动室3)及1050RU MuSA(流动室4)的表面密度。在25℃或37℃下在含有0.05%tween-20(操作缓冲液)的PBS缓冲液中进行动力学实验。用PBS操作缓冲液将含SABA1-FGF21v3(15.3μM)或SABA1-FGF21v1(40.6μM)的PBS(pH 7.2)的储备溶液稀释至1μM,随后连续稀释(2:1)以产生各蛋白质的1.0μM、0.5μM、0.25μM、0.125μM、0.063μM的浓度系列。将这些样品以30μl/min或60μl/min的流速注射通过流动室1-4历时300秒,其中解离时间为420秒,以检查质量传递限制。所有表面以30μl/min用10mM甘氨酸(pH 2.0)脉冲2次持续30秒来再生。通过自流动室2、3或4数据减去流动室1数据,然后自各感测图减去一个分别的缓冲液循环来对原始感测图加以“再参比”。使用Biacore T100评估软件2.0.2版将经再参比的感测图数据拟合成1:1朗格缪耳模型(Langmuirmodel)以测定缔合速率常数(ka)、解离速率常数(kd)及平衡解离常数(KD)。
实例B3.HEK-β-klotho细胞中的SABA1-FGF21融合物的体外活性
FGF21在β-klotho存在下诱导ERK磷酸化。因此,构建了本HEK-β-klotho测定系统以检查FGF21-SABA融合物的体外功能活性。具体而言,在HEKβ-Klotho表达稳定细胞pERK1/2测定法中,使用未融合且带His标签的FGF21(“FGFv1”;SEQ ID NO:125)作为比较物进行测量,测定了SABA1-FGF21v1(SEQ ID NO:132)融合蛋白的体外活性、效力(EC50)及功效(以相比于从不与SABA融合的FGF21分子观察到的最大活性的百分比表示)。
如图13中所示,SABA1-FGF21v1剂量依赖性地刺激稳定表达人β-klotho的HEK细胞中的pERK 1/2水平。效力(EC 50)相对于带His标签的FGF21右移约15倍,且功效为带His标签的FGF21的62%(参见下表15)。因此,SABA1-FGF21v1保留FGF21活性,即使当结合于人血清白蛋白时亦然。
表15.SABA-FGF21融合物与对照FGF21相比的效力。
蛋白质 | EC50(nM) | 功效(%) |
带His 6标签的FGF21 | 7±4 | 100 |
SABA1-FGF21v1 | 102±53 | 62±9 |
*在HEKβ-Klotho表达稳定细胞pERK 1/2测定中所测量的化合物的效力(EC50)及功效(相比于带His 6标签的FGF21最大活性的%)。来自N≥4个独立测定的来自多次实验的汇集数据以平均值±标准偏差给出。
在内源不表达β-klotho的亲代HEK细胞的特异性测定法中,带His标签的FGF21与SABA1-FGF21v1皆不刺激pERK 1/2水平,而阳性对照物FGF1刺激pERK 1/2水平(图14A)。在使用相同的蛋白质稀释物但使用标准测定法HEKβ-klotho稳定细胞的平行实验中,所有三种蛋白质均显示活性(图14B)。因此,SABA1-FGF21v1保留FGF21的特异性,即使当结合于白蛋白时亦然。
在本基于细胞的测定法中,有必要首先测定活化pERK磷酸化途径所必需的药物浓度。为此目的,在细胞培养基中在存在及不存在HSA下将融合蛋白滴定到细胞中。在添加HSA的情况下,其以血流中所见的生理浓度(30mg/mL至40mg/mL约500μM HSA)添加。此浓度高于使所有FGF21-SABA融合蛋白饱和所必需的浓度数千倍。FGF21-SABA-HSA溶液结合常数为约4nM(参见图11)。该测定法中,无论有无HSA存在,蛋白质融合物的活性不发生变化,此表明当融合蛋白与HSA复合时FGF21结构域的活性不改变。
以下为实验方法的详细描述。
HEK-β-klotho稳定细胞株构建
构建稳定表达人β-klotho的HEK细胞株。人β-klotho构建体在具有C端FLAG标签的CMV启动子控制下编码全长蛋白质。根据制造商方案,使用标准技术使用Lipofectamine2000(Invitrogen目录号11668027),用线性化cDNA转染HEK 293细胞。在含600μg/ml(Invitrogen目录号10131)遗传霉素及高葡萄糖并含有L-谷氨酰胺、Hepes(Invitrogen目录号12430054)及10%FBS(Hyclone目录号SH30071)的杜尔贝科氏改良伊格尔培养基中选择14天后分离阳性克隆。进一步通过Western印迹分析表征阳性稳定克隆且通过AlphaScreen(Perkin Elmer目录号TGRES50K)分析表征p-ERK活化。
HEK β-klotho pERK 1/2测定法
将稳定表达人β-klotho的HEK细胞以每孔20,000个细胞涂于96孔组织培养板中的含有10%(v/v)FBS(Hyclone)及600μg/ml G418(Gibco)的DMEM高葡萄糖培养基(Gibco)中。第二天,移除培养基且替换为无血清的DMEM高葡萄糖培养基并温育细胞过夜。第三天早晨,移除无血清培养基,且将细胞与用含有3%(w/v)无脂肪酸人血清白蛋白的PBS调制的蛋白质稀释液一起温育总共7分钟。按一式三份测试稀释液,三个培养板的每一个中各一个孔。在7分钟温育结束时,移除蛋白质稀释液且每孔添加100μl 1×AlphaScreen溶解缓冲液(Perkin-Elmer)并在振荡下温育约10-15分钟。将含有细胞溶解物的培养板冷冻于-80℃下至少30分钟或直至准备进行测定。根据制造商的指示,使用Surefire AlphaScreen pERK1/2试剂盒(Perkin Elmer),使用384孔白色Proxiplates(Perkin Elmer)分析来自每孔的4μl解冻的细胞溶解物的pERK 1/2。在室温下在黑暗中温育培养板两小时,随后在Envision2103多板读取器(Perkin Elmer)上读取。使用Graph Pad Prism软件,使用非线性回归分析分析数据。
如上所述使用不内源性地表达β-klotho的亲本HEK细胞株进行选择性测定法。在那些实验中使用FGF1作为阳性对照物。
实施例B4.3T3-L1脂肪细胞中的SABA1-FGF21v1的体外活性
3T3-L1细胞(ATCC#CL-173)为可分化为小鼠脂肪细胞的小鼠成纤维细胞。因为β-klotho仅在分化的3T3-L1细胞中表达,所以有必要在进行如实施例B3中所述的β-klothopERK 1/2测定法前首先使其分化。类似于其在HEK系统中的活性,SABA1-FGF21v1保留磷酸化3T3-L1脂肪细胞中的ERK的能力,且此活性与带His标签的FGF21相当。结果展示于表16中。
表16.在3T3-L1脂肪细胞中SABA1-FGF21v1活性与带His标签的FGF21相当。
化合物 | EC50(nM) | 活化倍数 |
带His标签的FGF21 | 4±2 | 2.1±0.2 |
SABA1-FGF21v1 | 11±4 | 1.8±0.2 |
以下为实验方法的详细描述。
3T3-L1脂肪细胞的分化
使细胞生长于补充有10%优级胎牛血清(characterized fetal bovine serum,Hyclone#SH30071.03)及1×抗生素-抗真菌剂(Gibco#15240-096)的DMEM培养基(Invitrogen#12430-054)中。在含5%CO2的37℃温育箱中培养细胞。随后进行如ATCC产品信息页中所述的传代培养程序,只是使用TrypLE Express(Gibco#12605)替代胰蛋白酶-EDTA溶液。
在分化前约68小时,将每孔5500个细胞(150μl培养基中)接种于96孔培养板(Falcon#353072)中;可根据接种时间及其倍增时间调整细胞数目,但在开始分化程序时细胞为100%汇合。为起始分化,小心地吸出细胞上清液且将200μl新鲜分化培养基I(含有500μM IBMX、100nM地塞米松(dexamethasone)、240nM胰岛素的生长培养基,全部均来自Sigma)添加至各细胞孔中。随后温育细胞41至48小时,随后小心地吸出细胞上清液且将200μl分化培养基II(含有240nM胰岛素的生长培养基)添加至各细胞孔中。在温育细胞第二个48小时时段后,小心地吸出细胞上清液且向各孔中添加200μl常规生长培养基。随后再温育细胞48至72小时,此时它们将充分分化为脂肪细胞。
3T3-L1脂肪细胞中pERK测定法的建立
在分化第九至第十天,自细胞中吸出生长培养基且用200μl含2%胎牛血清的DMEM(Invitrogen#12320-032)使细胞饥饿过夜。第二天,用含有测试药剂(FGF21或其一种变体)或作为对照物的PBS的100μl DMEM加上0.1%无脂肪酸BSA(Sigma#A6003)刺激饥饿细胞,其中使用Tomtec Quadra以确保同时添加至培养板的所有96孔中。随后在含95%空气/5%CO2的37℃温育箱中温育培养板7分钟。7分钟后,自细胞中移除处理培养基且向各孔中添加100μl溶解缓冲液。溶解缓冲液原液为PerkinElmer的AlphaScreen SureFire p-ERK1/2测定试剂盒(目录号TGRES10K),补充有0.5mM DTT(Sigma,D9779)、5mM焦磷酸钠(Sigma,S6422)、1mM原钒酸钠(Sigma S6508)及Roche的蛋白酶抑制剂片剂(#04693159001)。检测方案系基于测定试剂盒:在培养板振荡器上搅动含溶解缓冲液的培养板约15分钟然后冷冻于-80℃下30分钟。在室温下解冻培养板(约40分钟)且搅动溶解物(通过用移液管上下吸移20次)以确保完全溶解。随后将来自各孔的4μl溶解物转移至384孔培养板中且向各孔中添加7μl反应混合物(根据试剂盒规程混合的活化缓冲液与IgG检测供体及接受体珠子[PerkinElmer#6760617M])。密封培养板且搅动1-2分钟,随后在22℃下在遮光区中温育2小时。最后在PerkinElmer Envision 2103多标记读取器上,使用标准α筛选(Alpha Screening)设置读取培养板。
实施例B5.糖尿病ob/ob小鼠中的SABA1-FGF21v1的体内功效
已显示FGF21增加3T3-L1脂肪细胞及原代人脂肪细胞培养物中的葡萄糖摄取。因此,监测糖尿病ob/ob小鼠中的血浆葡萄糖水平是一种可评估FGF21-SABA融合蛋白的功能活性的途径。在8周龄时开始,糖尿病ob/ob小鼠接受每天皮下给药持续7天(每组n=8)。所有规程均由BMS ACUC委员会批准。第7天,自早上8点开始,在给药后24小时及3小时检查餐后葡萄糖水平(fed glucose level)。用PBS调配带His标签的FGF21及SABA1-FGF21v1,并分别以0.3mg/kg及1.0mg/kg施用。
为评估结合于人白蛋白的SABA1-FGF21v1的功效,在另外一组中将融合蛋白(1mg/kg)与摩尔过量的人血清白蛋白(6mg/kg)一起温育并注射混合物(每天皮下注射持续7天)。使用人血清白蛋白(6mg/kg)作为另一对照组。
图15中所示的结果指示在给药后3小时,与PBS媒剂对照组相比,SABA1-FGF21v1使葡萄糖降低29%,且此降低与带His标签的FGF21在第7天降低相当(图15A)。相比之下,与HSA对照组相比,SABA1-FGF21v1与人白蛋白的组合使血浆葡萄糖水平降低46%。
在给药后24小时,SABA1-FGF21v1使葡萄糖降低的幅度为7%,而SABA1-FGF21v1与HSA的组合为41%,且因此在第7天最后一次给药后持续24小时(图15B)。因此,SABA1-FGF21v1即使当结合于人血清白蛋白时亦非常有效地降低ob/ob小鼠的血浆葡萄糖水平。在人白蛋白存在及不存在下SABA1-FGF21v1的暴露展示于表17及18中。在人血清白蛋白存在下SABA1-FGF21v1的暴露比在其不存在下要大。表17.给药后3小时带His标签的FGF21及SABA1-FGF21v1的血浆浓度。
SD:标准偏差
表18.给药后24小时带His标签的FGF21及SABA1-FGF21v1的血浆浓度。
<LLOQ小于定量下限。
实施例B6.测量小鼠及猴中的SABA1-FGF21v1血浆t1/2
对小鼠及猴进行各种体内研究以表征带His标签的FGF21及SABA1-FGF21v1的药物动力学。使用基于ELISA的配体结合测定法测量所有小鼠及猴血浆样品中的带His标签的FGF21及SABA1-FGF21v1。
静脉内及皮下施用后小鼠中的带His标签的FGF21及SABA1-FGF21v1的药物动力学
带His标签的FGF21
在CD-1小鼠中静脉内施用(1mg/kg)后,带His标签的FGF21的稳态分布体积(Vss)为0.27L/kg。总身体血浆清除率(CLTp)值为12mL/min/kg。终末半衰期(T1/2)为0.5小时。皮下施用后,带His标签的FGF21被充分吸收。绝对皮下生物利用度为约100%。表观皮下终末半衰期(T1/2)为0.6小时。
SABA1-FGF21v1
在CD-1小鼠中静脉内投药(1.6mg/kg)后,SABA1-FGF21v1的稳态分布体积(Vss)为0.12L/kg。总身体血浆清除率(CLTp)值为2.9mL/min/kg。终末半衰期(T1/2)为1.9小时,比带His标签的FGF21(0.5小时)长。皮下施用后,SABA1-FGF21v1被充分吸收。表观皮下终末半衰期(T1/2)为1.9小时。
还在与人血清白蛋白(6mg/kg)预混合后向ob/ob小鼠皮下施用1mg/kg的SABA1-FGF21v1。表观皮下终末半衰期(T1/2)进一步延伸至9小时。
静脉内及皮下施用后猴中的带His标签的FGF21及SABA1-FGF21v1的药物动力学
带His标签的FGF21
在静脉内施用(0.5mg/kg)后,带His标签的FGF21的稳态分布体积(Vss)为1L/kg。总身体血浆清除率(CLTp)值为6.4mL/min/kg。终末半衰期(T1/2)为1.9小时。皮下施用后,带His标签的FGF21被充分吸收。绝对皮下生物利用度为65%。表观皮下终末半衰期(T1/2)为4.3小时。
SABA1-FGF21v1
在静脉内施用(0.08mg/kg)后,SABA1-FGF21v1的稳态分布体积(Vss)为0.08L/kg。总身体血浆清除率(CLTp)值为0.012mL/min/g。终末半衰期(T1/2)为97小时。皮下施用后,SABA1-FGF21v1被充分吸收。绝对皮下生物利用度为68%。表观皮下终末半衰期(T1/2)为67小时。
图16展示与带His标签的FGF21相比,猴中的例示性融合物SABA1-FGF21v3(SEQ IDNO:134)及FGF21-SABA1v1(其中SABA部分位于FGF21的C端)(SEQ ID NO:171)的t1/2。结果指示与单独FGF21相比,融合物使t1/2增加约27倍。数据总结于下表19中。
表19.SABA-FGF21融合物的药物动力学数据。
实施例B7.SABA1-FGF21v1降低ob/ob小鼠中的HbA1c
对糖尿病ob/ob小鼠检查SABA1-FGF21v1的其它短期及长期效应。在3周每天治疗后研究结束时,观察到血浆葡萄糖、胰岛素及总胆固醇减少。血浆丙氨酸转胺酶有减少且β-羟基丁酸水平升高。在口服葡萄糖耐受性测试中,经SABA1-FGF21v1处理的动物显示处理葡萄糖负荷的能力增加。
对接受三种不同剂量(0.01mg/kg或0.1mg/kg或1mg/kg)之一的SABA1-FGF21v1与人血清白蛋白(HSA,6mg/kg)的预混物并注射(每天皮下)达到14天的糖尿病ob/ob小鼠(每组n=8)进行另一实验。对照组仅接受HSA(6mg/kg,于PBS中)。在最后给药后24小时测量血浆样品中的HbA1c(参见图19)。对照组(仅接受HSA)显示与基线值相比HbA1c水平未有降低。最低剂量(0.01mg/kg)显示未有降低,中间剂量(0.1mg/kg)显示降低0.39%,其在统计上不显著。1mg/kg(或mpk)的最高剂量显示相对于基线降低0.9%,而HbA1c减去媒剂降低0.94%,此在统计上是显著的。因此,与人白蛋白共注射的SABA1-FGF21v1可有效降低糖尿病小鼠的HbA1c水平。
在最后给药后24小时,0.01mg/kg、0.1mg/kg及1mg/kg剂量下的SABA1-FGF21v1血浆水平分别为3.85ng/ml、2.28ng/ml及28.73ng/ml。
实施例B8.食蟹猴中的SABA1-FGF21v1的药物动力学
在静脉内(IV)施用后,SABA1-FGF21v1的稳态分布体积(Vss)为0.076L/kg。此值大于血浆体积,但小于细胞外液体积,这表明SABA1-FGF21v1大多存在于细胞外间隙中。SABA1-FGF21v1的总身体血浆清除率较低(0.71mL/h/kg),这与对猴血清白蛋白的高亲和力结合是一致的。终末半衰期(T1/2)为97小时(参见图20及表20)。此外,SABA1-FGF21v1显示在猴中有良好的皮下(SC)生物利用度(参见图20及表20)。绝对皮下生物利用度为68%。
表20.猴中的SABA1-FGF21v1的单剂量药物动力学参数(平均值±SD)。
*三种动物之一的给药后24小时的血浆样品未收集;猴:N=2(静脉内)及3(皮下)。
C.SABA-合成肽融合分子
实施例C1.用于化学衍生的间隔物连接的SABA-合成肽融合分子的SABA多肽的制备
使用下文所述的方法产生SABA1.7-(ED)5G-Cys多肽与合成衍生的肽缀合以形成SABA融合蛋白。此方法亦可用于产生经由多肽接头共价连接的SABA-肽融合物。
将编码SABA1.7(SEQ ID NO:225)与(ED)5G C端尾部(SEQ ID NO:397)及C端His残基(SABA1.7-(ED)5G-Cys)的DNA序列置于市售表达载体pET29b(EMD Biosciences,SanDiego,CA,USA)中。将序列适当地置于该质粒载体中恰好位于核糖体结合位点下游的NDEI与XHOI限制性核酸内切酶位点之间(图10)。将该表达载体转化至宿主菌株BL21(DE3)(EMDBiosciences)中且以包涵体形式表达。
通过本领域技术人员通常已知的标准转化方法,将经纯化的质粒DNA表达载体组入或“转化”至以上所述的大肠杆菌宿主中。简言之,将商业上制备的感受态细胞(EMDbiosciences)在冰上解冻且轻轻混合以确保细胞均匀地悬浮。将这些细胞的20μl等分吸移至在冰上以冰预冷却的1.5ml聚丙烯微量离心管中。将约1μl经纯化的质粒DNA(1-10ng/μl质粒)直接添加至细胞中并轻轻搅拌混合。将管保持于冰上5分钟,随后在42℃水浴中加热正好30秒。将经加热的管立即置于冰上并静置2分钟。向各管中添加80μl室温SOC或LB培养基。通过涂板于含有卡那霉素的培养基上来完成转化体的选择,以获得pET 29b质粒编码的药物抗性。
可溶性SABA1.7-(ED)5G-Cys在大肠杆菌中的表达通过使转化细胞的过夜起始培养物生长来起始。使用细胞接种2升摇瓶,每个摇瓶含有1升Overnight ExpressTM培养基(EMD Biosciences及Nature Methods 2:233-235(2005))。振荡温育箱的温度可降低至18℃以改善可溶物产率。持续发酵12-16小时,通过离心收集细胞,并以压积的湿细胞糊冷冻于-80℃。发现形成蛋白质包涵体(IB)是有利的,因为其有助于保护并使宿主细胞蛋白酶切割最小化。
细胞溶解及制备包涵体(IB)离心沉淀
解冻细胞并依8-10份缓冲液比1份压积的细胞糊状物的稀释度悬浮于溶解缓冲液中。使用Avestin C-5均质机(Avestin Inc.Ottawa,Ontario,Canada),通过在2000PSI下通过两次来以机械方式溶解细胞。溶解后,离心溶解物(4,000RPM,20-30分钟)并丢弃可溶部分。用0.5%Triton X-100洗涤包涵体离心沉淀以移除细胞碎片,且再次离心悬浮液。重复此过程(通常2或3次),之后离心沉淀显现为均匀白色。随后用PBS缓冲液洗涤所得的富集的IB制备体离心沉淀以移除过量去污剂。
溶解包涵体
随后将经洗涤且去除去污剂的IB离心沉淀溶解于经50mM Tris-HCl(pH8.0)及500mM NaCl缓冲的6M胍-HCl中。大部分以此方式制备的物质自由进入液相,然而有少量细胞碎片残留,通过在16,000RPM下用SS-34转子离心1小时来移除之。保留上清液以进行重折叠及氧化步骤。或者可在此阶段使用金属螯合层析步骤(IMAC)捕捉含有6×His标签的蛋白质并进一步精细纯化。可使经离液剂变性的材料结合于柱并洗去污染物,随后在补充有咪唑的变性缓冲液存在下洗脱。
重折叠(及控制氧化)
将胍-HCl溶解的材料稀释至约1mg/mL蛋白质(由280nM下的吸光度估计)且置于3.5MWCO透析管中。随后在4℃下在轻柔搅拌下将透析装置中的样品漂浮于4L重折叠缓冲液(50mM Tris、150mM NaCl、1mM EDTA,pH9.0)中过夜。第二天早晨,用新鲜重折叠缓冲液更换透析重折叠缓冲液。
在此过程期间,可视需要完成二硫化物氧化的调节及/或融合蛋白的桥键形成。对于需要在其多肽序列中的两个半胱氨酸残基之间形成二硫桥键以实现适当的最终形式的肽,诸如胰淀素,使系统在透析过程期间被空气氧化。对于SABA1.7-(ED)5G-Cys,其含有一个必须呈还原型以便随后使其与所关注的肽发生马来酰亚胺缀合的半胱氨酸残基,可通过在重折叠过程结束时添加还原剂(例如TCEP三[2-羧乙基]膦(TCEP)或二硫苏糖醇(DTT))使氧化减至最少。亦可通过在pH 4.5下重折叠来实现最小氧化的重折叠,在该pH下Cys氨基酸的硫醇盐阴离子不容易聚集并启动二硫桥键的形成。
这些简单的透析方法是方便的,且需要时可一次处理若干样品。或者,可用尿素替代胍-HCl来使蛋白质变性。或者,重折叠及氧化亦可使用将分子自高离液盐浓度快速稀释至较低盐浓度来进行。或者可使用确定的还原型谷胱甘肽与氧化型谷胱甘肽(GSH/GSSG)的氧化还原混合物替代空气氧化来使系统重折叠。或者,亦可在结合于层析树脂载体时使这些蛋白质重折叠,以替代在自由扩散阶段经由如上文所述的透析或快速稀释使这些蛋白质重折叠。此方法通常具有改善的产率,因为其将重折叠期内会导致大量聚集及产率损失的蛋白质相互作用最小化。
移除沉淀物
在重折叠步骤(及在需要时采用的氧化步骤)结束时,并非所有蛋白质均保持可溶。一部分蛋白质以聚集状态存在且容易以沉淀物形式自溶液中下沉。通过在16,000RPM下用SS-34转子离心1小时来移除此物质,随后通常经由0.2μm针筒过滤器过滤,随后层析。
层析分离
可通过使用Resource Q或类似离子交换介质系统(GE Healthcare,PiscatawayNJ)纯化重折叠的SABA1.7-(ED)5G-Cys以移除DNA及其它污染物。用重折叠缓冲液(50mMTris(pH 9.0)加上150mM NaCl、1mM EDTA)平衡40mL Resource Q柱且使澄清的重折叠材料通过该柱。在这些条件下,大部分多肽通过树脂床而不结合。来自经洗涤的包涵体的DNA及其它细胞碎片被保留于柱树脂上。或者此时可使用固定金属离子亲和层析(IMAC)步骤捕捉含有6×His标签的折叠的多肽,并用咪唑或组氨酸的梯度洗脱。
大小排阻层析
随后可使用经PBS缓冲液(pH 7.2)预平衡的26/60Sephacryl S100或26/60Superdex 75大小排阻柱(GE Healthcare,Piscataway NJ,USA)进一步纯化SABA1.7-(ED)5G-Cys。合并对应于单体蛋白质的样品,并且必要时将样品稀释至1-2mg/ml,随后冷冻于-80℃下。所表达及纯化的蛋白质的表达及纯化产率在本文中有变化。使用这些方法,每升由初始自动诱导培养基产生的包涵体可产生纯化产率为0.5mg至10mg或以上的经纯化蛋白质。
实施例C2.化学合成用于由化学衍生的间隔物连接的SABA-神经肽融合分子的神经肽
实施例C2-1:合成3-马来酰亚胺丙酰基-PEG20-大鼠胰淀素:Mal-(PEG)20-KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-NH2
通过固相合成,使用Liberty微波肽合成器(CEM Corp.,Matthews,NorthCarolina)制备该肽。在75℃下使用按20W的电源脉冲序列提供的微波加热进行脱除Fmoc保护及偶连步骤。用插入反应容器中的光纤探头监测反应温度。自置于50mL聚丙烯容器中的0.25mmol受Fmoc保护的PAL-PEG树脂(0.34mmol/g)开始该合成。使用由制造商提供的0.25毫摩尔规模的方法偶连氨基酸。在每个偶连步骤开始时,通过用含有0.1M HOBt的5%哌嗪的DMF溶液处理两次(每次5分钟)来移除Fmoc基团。在5次20mL DMF洗涤后,通过用0.5MHCTU(4当量)的DMF溶液及2M DIEA(8当量)的NMP溶液活化5分钟来依次偶连所需的Fmoc-氨基酸。在每次偶连结束时,用5次20mL DMF洗涤来洗涤树脂。在偶连Fmoc-PEG20之前,移除一半肽基-树脂(0.125mmol),且如上文所述使Fmoc-PEG20偶连于合成器上。将脱Fmoc保护的肽基-树脂转移至烧结聚丙烯反应器中且通过用HOAt/DIC(5当量)活化16小时来手动偶连3-马来酰亚胺丙酸。用DMF(4×5mL)及DCM(4×5mL)及再次DMF(4×5mL)洗涤肽基-树脂。添加I2(20当量)的10mL DMF溶液并搅拌混合物1小时。用DMF(5×5mL)及DCM(3×5mL)洗涤树脂,得到作为环状二硫化物产物的所需大鼠胰淀素肽衍生物Mal-(PEG)20-KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-NH2(酰胺)。
通过在室温下用TFA/水/苯酚(90:5:5;v:v:w)(15mL)处理90分钟使肽脱保护并自树脂释放。滤除废树脂且再用切割溶液(2×2.5mL)冲洗。蒸发合并的滤液至约4mL,并通过添加Et2O(35mL)使产物沉淀。通过离心收集沉淀的产物,再用Et2O洗涤并干燥,得到灰白色固体(理论值的50%)。
如下通过制备型RP-HPLC,在Shimadzu LC-8A型号液相层析仪上纯化粗肽。将该肽溶解于水/AcCN/TFA(60:40:0.1)中,经由0.45μm过滤器过滤,并每次将30mg注射至Phenomenex Luna C18柱(21.2×100mm;5μ)上。在45分钟内使用含25-45%B的A溶液的梯度以15mL/min洗脱产物,在220nm下进行UV检测。溶剂A:0.1%TFA水溶液;溶剂B:0.1%TFA的AcCN溶液。合并含有干净产物的级分(通过分析型HPLC确定)并冻干,得到呈白色冻干物形式的至少95%纯的产物。通过LC/MS分析在电喷雾模式下确认该肽的身份。以实验方式观察到的m/z离子(M+3H)3+/3=1464.0及(M+4H)4+/4=1097.9与所计算的分子量4389.9D一致。
实施例C2-2:合成3-马来酰亚胺丙酰基-(GS)5-大鼠胰淀素:Mal-GSGSGSGSGS-KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-NH2
使用实施例C2-1中所述的相同固相偶连及二硫化物环化方法制备该肽,得到作为环状二硫化物产物的所需大鼠胰淀素肽衍生物Mal-GSGSGSGSGS-KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-NH2(酰胺)。在脱保护并自树脂释放后,如实施例C2-1中所述通过制备型RP-HPLC纯化粗肽,不同之处在于在40分钟内使用含10-55%B的A溶液的梯度洗脱该肽,得到至少98%纯的产物。通过LC/MS分析在电喷雾模式下确认该肽的身份。从实验观察到的m/z离子(M+3H)3+/3=1598.3及(M+4H)4+/4=1199.3推出的分子量4792.2D在算得的分子量4791.2D的1道尔顿之内。
实施例C2-3:合成3-马来酰亚胺丙酰基-Ahx-小鼠PYY(3-36):Mal-Ahx-AKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY-NH2
使用实施例C2-1中所述的相同固相程序制备此肽,得到所需小鼠PYY(3-36)肽衍生物Mal-Ahx-AKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY-NH2。使Ala12-Ser13及Ala22-Ser23残基对偶连成Fmoc-Ala-Ser(ψMe,Mepro)-OH假脯氨酸二肽形式(EMD Chemicals,Inc.,SanDiego,CA)。在脱保护并自树脂释放后,如实施例C2-1中所述通过制备型RP-HPLC纯化粗肽,不同之处在于在45分钟内使用含5-50%B的A溶液的梯度洗脱该肽,得到至少97%纯的产物。通过LC/MS分析在电喷雾模式下确认该肽的身份。以实验方式观察到的m/z离子(M+3H)3+/3=1415.8及(M+4H)4+/4=1062.2与算得的分子量4244.7D一致。
实施例C2-4:合成3-马来酰亚胺丙酰基-PEG20-小鼠PYY(3-36):Mal-PEG20-AKPEAPGEDASPEELSRYYASL RHYLNLVTRQRY-NH2
使用实施例C2-3中所述的相同固相偶连程序制备此肽,不同之处在于偶连Fmoc-PEG20-OH以替代Fmoc-6-Ahx-OH,由此得到所需的小鼠PYY(3-36)肽衍生物Mal-PEG20-AKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY-NH2。在脱保护并自树脂释放后,如实施例C2-3中所述通过制备型RP-HPLC纯化粗肽,得到至少86%纯的产物。通过LC/MS分析在电喷雾模式下确认该肽的身份。以实验方式观察到的m/z离子(M+3H)3+/3=1484.8及(M+4H)4+/4=1113.5与算得的分子量4449.9D一致。
实施例C2-5:合成3-马来酰亚胺丙酰基-(GS)5-小鼠PYY(3-36):Mal-GSGSGSGSGS-AKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY-NH2
通过GenScript USA,Inc.,Piscataway,NJ,使用类似于实施例C2-3中所述的那些程序的固相程序定制合成此肽,得到95%纯度的所需的小鼠PYY(3-36)肽衍生物Mal-GSGSGSGSGS-AKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY-NH2。通过LC/MS分析在电喷雾模式下确认该肽的身份。以实验方式观察到的m/z离子(M+3H)3+/3=1618.5及(M+4H)4+/4=1214.1与算得的分子量4852.2D一致。
实施例C2-6:合成3-马来酰亚胺丙酰基-Ahx-小鼠PP:Mal-Ahx-APLEPMYPGDYATPEQMAQYETQLRRYINTL TRPRY-NH2
使用实施例C2-3中所述的相同固相程序制备此肽,得到所需的小鼠PP肽衍生物Mal-Ahx-APLEPMYPGDYATPEQMAQYETQLRRYINTLTRPRY-NH2(酰胺)。使Ala12-Thr13残基对偶连成Fmoc-Ala-Thr(ψMe,Mepro)-OH假脯氨酸二肽(EMD Chemicals,Inc.,San Diego,CA)。在脱除保护基及自树脂释放后,如实施例C2-3中所述通过制备型RP-HPLC纯化粗肽,得到至少99%纯的产物。通过LC/MS分析在电喷雾模式下确认该肽的身份。从实验观察到的m/z离子(M+3H)3+/3=1533.5及(M+4H)4+/4=1150.4推出的分子量4597.5D在算得的分子量4598.2D的1道尔顿内。
实施例C2-7:合成3-马来酰亚胺丙酰基-PEG20-小鼠PP:Mal-PEG20-APLEPMYPGDYATPEQMAQYETQLRR YINTLTRPRY-NH2
使用实施例C2-6中所述的相同固相程序制备此肽,不同之处在于偶连Fmoc-PEG20-OH以替代Fmoc-6-Ahx-OH,由此得到所需小鼠PP肽衍生物Mal-PEG20-APLEPMYPGDYATPEQMAQYETQLRRYINTLTRPRY-NH2(酰胺)。在脱保护并自树脂释放后,如实施例C2-3中所述通过制备型RP-HPLC纯化粗肽,得到至少91%纯的产物。通过LC/MS分析在电喷雾模式下确认该肽的身份。从实验观察到的m/z离子(M+3H)3+/3=1601.9及(M+4H)4+/4=1201.7推出的分子量4803.0D在算得的分子量4803.4D的1道尔顿内。
实施例C2-8:合成3-马来酰亚胺丙酰基-(GS)5-小鼠PP:Mal-GSGSGSGSGS-APLEPMYPGDYATPEQMAQYETQLRRYINTLTRPRY-NH2
通过GenScript USA,Inc.,Piscataway,NJ,使用类似于实施例C2-6中所述的那些程序的固相程序定制合成此肽,得到90%纯度的所需小鼠PP肽衍生物Mal-GSGSGSGSGS-APLEPMYPGDYATPEQMAQYETQLRRYINTLTRPRY-NH2(酰胺)。通过LC/MS分析在电喷雾模式下确认该肽的身份。实验观察到的m/z离子(M+4H)4+/4=1302.5及(M+5H)5+/5=1042.1与所计算的分子量5205.7D一致。
实施例C2-9:合成人骨钙蛋白:YLYQWLGAPVPYPDPLEPRREVCELNPDCDELADHIGFQEAYRRFYGPV,经由Cys23-Cys29二硫化物环化
通过GenScript USA,Inc.,Piscataway,NJ,使用类似于实施例C2-6中所述的那些程序的固相程序定制合成线性肽,得到87%纯度的人OCN的所需线性前体。通过在室温下将线性肽(0.5mg/mL;20mL)于50mM TRIS缓冲液(pH8.1)、5mM还原型谷胱甘肽及0.5mM氧化型谷胱甘肽的溶液中搅拌4天来实现该肽的氧化二硫化物环化。通过旋转蒸发浓缩该溶液至10mL,并如实施例C2-1中所述通过制备型HPLC纯化该肽,不同之处在于在40分钟内使用含20-50%B的A溶液的梯度进行洗脱。此得到纯度为99%的所需环状人OCN肽。通过LC/MS分析在电喷雾模式下确认该肽的身份。实验观察到的m/z离子(M+3H)3+/3=1933.3及(M+4H)4+/4=1449.8与算得的分子量5797.4D一致。
实施例C2-10:合成小鼠骨钙蛋白:YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI,经由Cys19-Cys25二硫化物环化
通过GenScript USA,Inc.,Piscataway,NJ,使用类似于实施例C2-9中所述的那些程序的固相程序定制合成线性肽,得到90%纯度的小鼠OCN的所需线性前体。使该肽环化且如实施例C2-9中所述通过制备型HPLC纯化,得到98%纯度的环状小鼠OCN肽。通过LC/MS分析在电喷雾模式下确认该肽的身份。实验观察到的m/z离子(M+3H)3+/3=1705.3及(M+4H)4+/4=1279.5与算得的分子量5114.7D一致。
实施例C2-11:合成大鼠骨钙蛋白:YLNNGLGAPAPYPDPLEPHREVCELNPNCDELADHIGFQDAYKRIYGTTV,经由Cys23-Cys29二硫化物环化
通过GenScript USA,Inc.,Piscataway,NJ,使用类似于实施例C2-9中所述的那些程序的固相及氧化环化程序定制合成二硫化物环肽,得到96%纯度的所需环状大鼠OCN。通过LC/MS分析在电喷雾模式下确认该肽的身份。实验观察到的m/z离子(M+3H)3+/3=1862.5及(M+4H)4+/4=1397.5与算得的分子量5586.1D一致。
实施例C3.使用马来酰亚胺缀合反应形成由化学衍生的间隔物连接的SABA-胰淀素、SABA-PYY及SABA-PP融合分子
用0.5mM TCEP还原如上文所概述在Q Sepharose柱(GE Healthcare,PiscatawayNJ)上纯化的SABA1.7-(ED)5G-Cys蛋白。移除TCEP并进一步经由大小排阻层析,在用50mM乙酸钠、150mM氯化钠(pH 5.2)平衡的Superdex75柱(GE Healthcare)上纯化该蛋白质。将洗脱的SABA1.7-(ED)5G-Cys蛋白在该缓冲液中以1:1摩尔比与马来酰亚胺-PEG20-胰淀素-CONH2、马来酰亚胺-PEG20-PYY-CONH2或马来酰亚胺-PEG20-PP-CONH2合成肽组合且在4℃下在轻柔振荡下温育过夜。在温育后,将反应混合物0.2μm过滤,且使用Superdex75SEC柱,用PBS(pH 7.4)自游离反应物分离经修饰的蛋白质SABA1.7-(ED)5G-Cys-PEG20-胰淀素-CONH2(SEQ ID NO:328)、SABA 1.7-(ED)5G-Cys-PEG20-PYY-CONH2(SEQ ID NO:344)或SABA1.7-(ED)5G-Cys-PEG20-PP-CONH2(SEQ ID NO:364)。
实施例C4.SABA-神经肽(胰淀素、PYY及PP)融合物与人血清白蛋白的结合功效
表面等离子共振(SPR)是一种可实时观察到分子间相互作用的直接结合技术。在这些实验中,使用ProteOn XPR36仪器(BioRad Laboratories)进行SPR结合研究。操作缓冲液,即磷酸盐缓冲生理盐水0.05%Tween 20(pH 7.4)购自Teknova(目录号P1192),且所有实验均在25℃下操作。根据制造商的指南,使用购自BioRad Laboratories的胺偶连试剂经由胺偶连将人血清白蛋白直接固定于BioRad GLC芯片上。人血清白蛋白购自Novozymes(RecombuminTM)。将约5000个共振单位(RU)的人血清白蛋白固定于GLC芯片表面的4个各别泳道上。对于每个分析物,将范围为15.6nM至250nM的五种浓度以30μl/min注射至表面上持续240秒。监测解离600秒。用100mM HCl再生表面。使用ProteOn管理软件(ProteOn ManagerSoftware)将所得数据拟合成朗格缪耳1:1结合模型。用不同浓度范围重复实验。在此第二实验中,将范围为500nM至32nM的5种浓度注射于表面上,且如上所述分析数据。对这些实验的结果求平均值且展示于表21中。KD为解离常数。较小数字指示与血清白蛋白有较紧密的结合。共价连接于SABA的结合血清白蛋白的分子呈现较长的体内药物动力学半衰期,如先前对于SABA-FGF-21融合物所述。
表21.SABA-神经肽融合物与人血清白蛋白结合的Kon、Koff及KD值。
实施例C5.SABA-合成肽融合物的体外活性
实施例C5-1:SABA-胰淀素融合物的体外活性
胰淀素通过活化胰淀素受体(一种Gs偶连GPCR)来诱导细胞环状单磷酸腺苷(cAMP)产生。因此,使用细胞cAMP产生来作为胰淀素激动剂的体外功能活性的显示。具体而言,测定SABA1-AMYv25(SEQ ID NO:328)蛋白的体外活性,包括效力(EC50)及功效(以相比于从胰淀素肽观察到的最大活性的百分比表示)。
如下表22中所示,SABA1-AMYv25刺激稳定表达胰淀素受体的HEK细胞中产生cAMP。SABA1-AMYv25的效力(EC50)为12.2nM且功效为胰淀素肽的约119%。因此,SABA1-AMYv25即使当其连接于SABA时亦在体外测定法中保留完全的胰淀素功能活性。在其它实验中,大鼠胰淀素与SABA1-AMYv25皆对HEK亲本细胞中的cAMP水平无显著影响,此证明其对于胰淀素受体的特异性。
胰淀素受体稳定细胞系的构建
胰淀素受体为降钙素受体(CT)及受体活性修饰蛋白(RAMP)之一的异二聚体。通过在HEK-293细胞中稳定转染黑猩猩CT(a)与人受体活性修饰蛋白3(RAMP3)来产生重组胰淀素受体细胞系。选择这些重组受体细胞系且使用若干胰淀素激动剂肽(包括大鼠胰淀素、鲑降钙素、人降钙素及人CGRP)表征。在37℃及5%CO2下将稳定细胞系培养于含10%FBS、300μg/ml新霉素及250μg/ml潮霉素的完全DMEM中。
用于评估SABA1-AMYv25活性的体外环状AMP(cAMP)功能测定法
通过使用来自Cisbio(Bedford,MA)的cAMP测定试剂盒进行cAMP测定法。在37℃及5%CO2下使胰淀素受体稳定细胞生长于BD FalconTM75cm2烧瓶(BD Biosciences,Bendford,MA)中的培养基(含10%FBS、300μg/ml新霉素及250μg/ml潮霉素的DMEM)中。使用来自Invitrogen的细胞解离缓冲液(Cell Dissociation Buffer)(不含酶)自烧瓶收集细胞。在用PBS缓冲液洗涤一次后,使细胞再悬浮于测定缓冲液(HBSS缓冲液,2.5mM HEPES(pH7.5)、100μM IBMX)中,并加样到96孔测定培养板(每孔约2,000个细胞)中。随后在37℃下将细胞与胰淀素肽或SABA-胰淀素一起温育30分钟。根据制造商的方案(Cisbio)测定细胞中的cAMP量。
实施例C5-2:SABA-PYY3-36及SABA-PP融合物的体外活性
肽YY(PYY)及胰多肽(PP)为分别回应于食物摄取而自肠道及胰脏分泌的天然饱腹感因子,且在禁食后减少。PYY与PP皆可以其全长形式分离,其全长形式为具有36个残基的肽酰胺。PYY亦可进一步由酶DPPIV切割为较短生物活性形式PYY(3-36)。在动物模型中及在人中,PYY(3-36)或PP的外周注射会引起食物摄取减少及体重降低。病态肥胖患者的基础PYY(3-36)及/或PP水平与膳食刺激的PYY(3-36)及/或PP水平都降低。相比之下,厌食症患者或旁路手术后体重减轻的患者具有高于正常的血浆PYY(3-36)及/或PP。PYY(3-36)及PP的激动作用在治疗肥胖及代谢疾病中具有极大治疗价值。NPY Y2及Y4为分别对PYY(3-36)及PP具有最高亲和力的受体。NPY受体属于G蛋白偶连受体家族。在激动剂刺激后,NPY受体可刺激下游G蛋白,从而将其结合的GDP换为GTP。使用竞争结合测定法测量SABA1-PYYv7(SEQID NO:344)及SABA1-PPv7(SEQ ID NO:364)对其各别受体的结合亲和力,且使用GTPγS结合测定法来测量在最早的受体介导事件之一时受体被占据的功能后果。
如表22中所示,在所述测定法中所测得的效力(EC50)为0.6nM(对于PYY3-36)及52nM(对于SABA1-PYYv7融合物)。在所述测定法中所测得的效力(EC50)为1.7nM(对于PP)及大于1μm(对于SABA1-PPv7融合物)。SABA1-PPv7融合物的效力降低可归因于用于缀合SABA与PP多肽的PEG20接头。该PEG20接头可能在此构建体中不是最佳的,将使用具有其他接头的构建体来改善SABA-PP融合物的效力。
受体膜制备:
使一个T150烧瓶的过表达人NPY Y2或Y4受体的重组CHO细胞生长于含0.5mg/mlG418的F-12培养基(HAM,含L-谷氨酰胺)中直至汇合。在收集之前,细胞用PBS (无Ca2+及Mg2 +)洗涤一次,随后使用细胞解离溶液脱离。离心后,使细胞离心沉淀再悬浮于1ml溶解缓冲液(20mM Tris-Cl(pH7.5)、1mM EDTA及蛋白酶抑制因子)中且使用Polytron均质机均质化(设置5,10秒×2)。在1,000g下离心均质化细胞10分钟。收集上清液且使离心沉淀再悬浮于1ml溶解缓冲液中,均质化并再次在1,000g下离心10分钟。混合两次离心的上清液且在100,000g下离心60分钟。使所得膜离心沉淀再悬浮于250μl测定缓冲液(TBS(pH 7.4)、1mMMgCl2、2.5mM CaCl2)中。测量蛋白质浓度并将等分试样储存于-80℃下直至使用。
竞争结合测定法:
在96孔培养板中在总体积为250μl的测定缓冲液(TBS(pH 7.4)、1mMMgCl2、2.5mMCaCl2)中进行该测定法。反应混合物由分析样品(SABA1-PYYv7/SABA1-PPv7、对照PP/PYY(3-36)、对照媒剂)、膜及0.025nM125I-hPYY或125I-hPP(2200Ci/mmol,PerkinElmer)组成。试剂添加次序为:150μl测定样品、50μl 125I-PYY或125I-hPP、随后为50μl膜(每孔于测定缓冲液中1-3μg)。在室温下温育结合混合物120分钟。通过使用Packard细胞收集器将反应物转移至GF/C培养板(经0.5%聚乙撑亚胺及0.1%BSA预浸透)上来结束结合反应。随后用冰冷的50mM Tris缓冲液(pH 7.4)(4×200ml)洗涤过滤板。洗涤后,向各孔中添加40μlMicroScint20且在Packard TopCount闪烁计数器上对培养板计数。
GTPγS结合测定法:
在96孔培养板上以100μl总体积进行该测定法。首先向各孔中添加10μl通用缓冲液(20mM HEPES(pH 7.4)、100mM NaCl、1mM MgCl2、10μMGDP、0.1%BSA)。随后依次添加10μl测试样品和40μl膜(每孔于测定缓冲液中1-3μg)并充分混合。在25℃下在振荡下温育反应物30分钟。随后添加40μl具有35S-GTP(0.25μCi/ml)的SPA珠(每孔0.5mg)且在25℃下在振荡下再温育60分钟。通过在1000rpm下离心5分钟来结束反应。
表22.SABA-胰淀素、SABA-PYY3-36及SABA-PP融合物的功能活性。
*以占测试化合物的天然肽配体最大活性的%呈现。结果以来自一项实验的一式三份测量的平均值±SEM表示。
D.其它SABA融合分子
实施例D1:SABA-骨钙蛋白融合物的体外活性
骨钙蛋白(OCN)刺激胰β细胞中的胰岛素分泌,因此使用来自啮齿动物胰岛的胰岛素产生作为评估骨钙蛋白(OCN)的体外生物功能的显示。用天然人OCN(hOCN)及与AdnectinSABA融合的人OCN(SABA-hOCN)处理啮齿动物胰岛,并测定与各构建体相关的胰岛素分泌的增强程度。
实施例D2:SABA-Apelin融合物
SABA-APLNv2是SABA1.6经由6×His标签及(GS)7接头与APLNv4融合的融合物。在经麻醉大鼠中,APLNv4在静脉内投递60μg/kg的条件下展现鲁棒的降血压效果。SABA-APLNv2展现15,000的分子量,其中APLNv4占融合蛋白质量的10%。将SABA-APLNv2以600μg/kg的剂量静脉内投递给经麻醉大鼠,而未影响血压。SABA-APLNv2构建体缺乏活性的可能解释可包括:由较弱产生性碰撞(productive collision)频率导致的效力减小、位阻、或肽-PKE退火。未测试SABA-APLNv2来测定其是否结合于HSA。
Claims (11)
1.一种包含纤连蛋白III型第十(10Fn3)结构域的多肽,其结合HSA,其中10Fn3结构域由以SEQ ID NO:4中所示的氨基酸序列组成。
2.权利要求1的多肽,其中该10Fn3结构域还包含由SEQ ID NO:45组成的N端序列。
3.权利要求1或2的多肽,其中该10Fn3结构域还包含由SEQ ID NO:54、59或62之任一组成的C端序列。
4.权利要求3的多肽,其中该10Fn3结构域还包含由SEQ ID NO:62组成的C端序列。
5.一种药物组合物,其包含权利要求1至4中任一项的多肽和生理学上可接受的担载体。
6.一种核酸,其编码如权利要求1-4中任一项的多肽。
7.一种载体,其包含权利要求6的核酸。
8.权利要求7的载体,其中该载体为表达载体。
9.一种宿主细胞,其包含权利要求7或8的载体。
10.权利要求9的宿主细胞,其中该细胞为细菌细胞。
11.权利要求9的宿主细胞,其中该细胞为哺乳动物细胞。
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