CN104507966B - 基于补体组分c5a的疫苗 - Google Patents
基于补体组分c5a的疫苗 Download PDFInfo
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Abstract
本发明涉及一种包含至少一种肽的疫苗,所述肽组成为由以下氨基酸序列组成的7至19个氨基酸残基:(X3)mKDX2QLGX1 (SEQ ID No.99),其中X1是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、酪氨酸和缬氨酸,X2是选自下组的氨基酸残基:丙氨酸、精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苏氨酸、酪氨酸和缬氨酸,X3是(X4)nANISX5(SEQ ID No.100)或其由1至4个氨基酸残基组成的N端截短的片段,X4是VVASQLR(SEQ ID No.101)或其由1至6个氨基酸残基组成的N端截短的片段,X5是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、谷氨酸、组氨酸、精氨酸、异亮氨酸、赖氨酸、甲硫氨酸、丝氨酸和苏氨酸,m是0或1,且n是0或1,其中所述至少一种肽与包含至少一种T细胞表位的载体偶联或融合。
Description
本发明涉及一种要在医学、免疫学、和分子生物学领域中使用以预防和/或治疗补体组分C5a诱导的慢性炎性疾病的药物。
补体是先天免疫系统的一种中心组分,其针对微生物,诸如病毒,细菌和其他外来的及异常的细胞为宿主提供保护。然而,补体系统的不适当或过多的活化可以导致针对宿主自身的破坏能力。不受控制的补体活化参与许多慢性炎性疾病,诸如阿尔茨海默(Alzheimer)氏病,帕金森(Parkinson)氏病,亨丁顿(Huntington)氏病,年龄相关性黄斑变性(age-related macular degeneration),类风湿性关节炎(rheumatoid arthritis)系统性红斑狼疮(systemic lupus erythematosus),抗磷脂综合征(antiphospholipidsyndrome),哮喘,血管炎(vasculitis),动脉粥样硬化(atherosclerosis),多发性硬化(multiple sclerosis),炎性皮炎(inflammatory dermatitis),诸如银屑病(psoriasis)和慢性荨麻疹(chronic urticaria),格巴二氏综合征(Guillain-Barre syndrome),和溶血尿毒综合征(hemolytic uremic syndrome)。
不受控制的补体活化也可以在癌症,妊娠并发症(pregnancy complication),诸如先兆子痫(preeclampsia)和抗磷脂综合征中,以及在急性病理状况,包括败血症(sepsis),急性肺损伤(acute lung injury),急性呼吸窘迫综合征(acute respiratorydistress syndrome,ARDS),和缺血-再灌注损伤下发生。大面积的补体活化也存在于人工表面上,导致血液透析关联的血栓形成(hemodialysis-associated thrombosis)。
这些状况中看到的许多毒性效应可归因于促进炎性反应并使其永久存在的过敏毒素C5a的过多生成。C5a的主要功能是粒细胞、柱状细胞、和巨噬细胞的趋化性和活化,其介导可溶性免疫因子的释放。因此,多年来已经公认对补体活性的抑制或调控是一种有希望的治疗策略。
大多数补体蛋白质以无活性前体形式存在于血浆中,该无活性前体响应三种不同机制而在蛋白水解级联中彼此切割并活化:经典途径,凝集素诱导,和旁路途经。所有三种活化级联的最终结果是应答的大幅放大和过敏毒素C3a和C5a及细胞杀伤膜攻击复合物(MAC)(一种引起细胞裂解的孔)的形成。
补体组分C5是一种190kDa蛋白质,并且包含两条链(α115kDa和β75kDa)。任一种补体途径的活化可以生成酶C5转化酶,其能够切割C5为C5b和有力的过敏毒素C5a。在C5的切割后,C5a片段上的C端新表位(neoepitope)被暴露。
人C5a是一种具有12-14.5kDa分子量的长74个氨基酸的糖蛋白。该分子由通过三个内部二硫键稳定的4个α-螺旋构成。天冬酰胺位于64位,其具有对于生物学活性而言不是必需,但是非常可能调节C5体内活性的N-连接的碳水化合物模块(moiety)。在C5a片段被C5转化酶切割后不久,长74个氨基酸的C5a蛋白的恰好C末端精氨酸残基被血清和细胞表面羧基肽酶除去,并且形成活性较小的C5a desARG分子。C5a蛋白的两种形式C5a ARG和C5adesARG都结合7次跨膜域受体C5aR(CD88)和特征较少的C5L2(gpr77),其在极其多种细胞上遍在表达,但是尤其在免疫细胞,如巨噬细胞,嗜中性粒细胞,柱状细胞,和T细胞的表面上表达。C5aR的配体结合位点是复杂的,并且由至少两个物理上可分开的结合域组成。一个结合二硫化物连接的C5a核心(氨基酸15-46),而第二个结合C5a羧基端末端(氨基酸67-74)。C5aR与其配体C5a的结合亲和力是非常高的,解离常数(KD)为约1nM。
本发明的一个目的是提供用于治疗补体组分C5a诱导的疾病或病理学的手段和方法。
本发明涉及一种包含至少一种肽的疫苗,所述肽组成为由以下氨基酸序列组成的7至19个,优选7至14个氨基酸残基:
(X3)mKDX2QLGX1 (SEQ ID No.99),
其中
X1是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、酪氨酸和缬氨酸,
X2是选自下组的氨基酸残基:丙氨酸、精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苏氨酸、酪氨酸和缬氨酸,
X3是(X4)nANISX5(SEQ ID No.100)或其由1至4个,优选1、2、3或4个氨基酸残基组成的N端截短的片段,
X4是VVASQLR(SEQ ID No.101)或其由1至6个,优选1、2、3、4、5或6个氨基酸残基组成的N端截短的片段,
X5是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、谷氨酸、组氨酸、精氨酸、异亮氨酸、赖氨酸、甲硫氨酸、丝氨酸和苏氨酸,
m是0或1,且
n是0或1,
其中所述至少一种肽与包含至少一种T细胞表位的载体偶联或融合。
本发明涉及针对在各种慢性炎性疾病中上调的身体自身的C5a的自动免疫。在C5a的C端在C5分子切割后变得易接近的新表位是本发明的免疫靶物。因此,C5b片段(其在宿主防御中发挥主要作用)的生成和功能不会受到影响。
更详细地,本发明涉及基于偶联或融合于包含至少一种T细胞表位的载体的初始hC5a C端表位的肽变体(所谓的VARIOTOPES)的疫苗,其中VARIOTOPES相对于hC5a的初始C端序列包含至少1处氨基酸残基交换。
VARIOTOPES模拟感兴趣的表位而不与其相同,因此VARIOTOPE疫苗的优点是躲避对自身抗原的自身耐受性。此外,VARIOTOPES的使用减轻由于使用自身抗原而普遍的无意副作用的风险。
例如,可以使用“丙氨酸扫描”法鉴定并选择hC5a C端表位的VARIOTOPES。丙氨酸扫描诱变指将某个蛋白质或肽区内的各个氨基酸用丙氨酸残基系统性取代以测定某些位置的功能作用。丙氨酸由于其消除β碳上的侧链并且不改变主链构象且它也不强加极端的静电或空间效应而成为选择的取代残基。
使用此技术,可以鉴定hC5a C端表位中对于hC5a体液免疫应答的诱导至关重要或必不可少的氨基酸残基。在下一步中,可以将在不损害hC5a体液免疫应答的诱导的前提下证明为可交换的位置用具有不同特性的氨基酸残基系统性取代以确定VARIOTOPES,其在与初始表位相比时能够诱导具有更高或至少相等的针对人C5a的抑制活性的抗体。随后,可以对在hC5a的C端表位内的两个或三个氨基酸交换的组合测试其免疫原性和功能活性。
VARIOTOPES是本发明的目的,其与初始C端表位相比能够诱导显示更高或至少相等的针对人C5a的抑制活性的抗体。
令人惊讶地,证明了为了能够引发令人满意的免疫应答,肽需要SEQ ID No.99中分别在2、3、5、6和7位的至少赖氨酸、天冬氨酸、谷氨酰胺、亮氨酸和甘氨酸残基的存在(图1A和1B)。甚至更令人惊讶的是如下的实情:在最后一位上具有氨基酸交换的肽(SEQ IDNO.99的X1;X1在野生型C5a C端区中是精氨酸残基,参见SEQ ID No.1至4)能够诱导的针对C5a蛋白的体液免疫应答显著高于由包含SEQ ID No.1至4的野生型C5a的片段诱导的免疫应答(图1A至1D)。重要地,如图2A至2D中描绘的,较高的体液免疫应答还导致显著较高的对C5a活性的抑制。在使用含有野生型C5a C端区的最后第5位M残基的氨基酸交换的肽(参见例如SEQ ID No.10或18)或含有野生型C5a C端表位的最后第8位H残基的氨基酸交换的肽(参见例如SEQ ID No.7或17)免疫时也可以观察到类似的结果(图1和图2)。图3至图6中显示的结果支持这种令人惊讶的效应,即源自上述氨基酸(分别在野生型C5a末端表位的最后,最后第5和最后第8位的R、M或H;参见例如SEQ ID No.1至4)的氨基酸交换的肽具有诱导C5a特异性抗体免疫应答的能力,该C5a特异性抗体免疫应答比包含SEQ ID No.1至4的野生型C5a片段诱导的免疫应答更高且更有力。本文描述了与相应的野生型C5a片段相比显示高得多的C5a抑制能力的肽。
对于本发明而言无关的是在WO 90/09162中,公开了几种肽,其显示与人野生型C5a片段的一些同源性,并且其用作C5a活性激动剂。然而,其中公开的肽以可溶性肽应用,该可溶性肽尚未与载体蛋白偶联,并且因此不能用于本发明的目的,因为它们不能诱导抑制C5a活性的抗体的形成。例如,在WO 90/09162的实施例426中,公开了在1位包含苯丙氨酸残基的肽。在本发明中,可以显示此类取代导致显著降低的C5a抑制活性(参见例如SEQ IDNo.54,图4)。
本发明疫苗中包含的至少一种肽包含或组成为(consist of)7个,优选8个,优选9个,优选10个,优选11个,优选12个,优选13个,优选14个,优选15个,优选16个,优选17个,优选18个,优选19个氨基酸残基。
根据本发明,X3是(X4)nANISX5(SEQ ID No.100)或其N端截短的片段。因此,此N端截短的片段可以由ANISX5(SEQ ID No.102),NISX5(SEQ ID No.103),ISX5,SX5或X5组成。这意味着本发明的疫苗可以包含至少一种肽,若m=1,则该肽具有氨基酸序列ANISX5KDX2QLGX1(SEQ ID No.104),NISX5KDX2QLGX1(SEQ ID No.105),ISX5KDX2QLGX1(SEQID No.106),SX5KDX2QLGX1(SEQ ID No.107)或X5KDX2QLGX1(SEQ ID No.108)。
根据本发明,X4是VVASQLR(SEQ ID No.101)或其N端截短的片段。VVASQLR的片段可以由下列一项氨基酸序列组成:VASQLR(SEQ ID No.109),ASQLR(SEQ ID No.110),SQLR(SEQ ID No.111),QLR,LR,或R。因此,若m和n是1,则本发明疫苗中使用的至少一种肽可以具有下列一项氨基酸序列:VVASQLRANISX5KDX2QLGX1(SEQ ID No.112),VASQLRANISX5KDX2QLGX1(SEQ ID No.113),ASQLRANISX5KDX2QLGX1(SEQ ID No.114),SQLRANISX5KDX2QLGX1(SEQ ID No.115),QLRANISX5KDX2QLGX1(SEQ ID No.116),LRANISX5KDX2QLGX1(SEQ ID No.117),或RANISX5KDX2QLGX1(SEQ ID No.118)。
本发明的疫苗可以包含超过一种依照SEQ ID No.99的肽。特别优选的是,疫苗包含至少一种具有氨基酸序列SEQ ID No.99的肽。然而,本发明的疫苗还可以包含至少2种,至少3种,至少4种,或甚至至少5种具有氨基酸序列SEQ ID No.99的肽。当然,也有可能组合本发明的至少一种肽与可以用于治疗与本发明状况相同的状况的其他肽或活性成分。
肽/载体组合是重要的,因为本发明的肽在不与载体偶联的情况下注射时没有诱导相关量的抗体的能力。此外,载体有助于持久抗体应答的诱导。因此,针对hC5a的主动免疫的本发明相对于采用用于治疗基于C5a的疾病的单克隆抗体疗法提供优势。因此,可以避开单克隆C5a抗体疗法的缺点,包括需要重复输注大量的抗体、患者的频繁医院访视,和人源化抗体的高生产成本。
可以通过本领域中公知的化学合成法,以分离的肽或以另一种肽或多肽的一部分以合成方式生成本发明的至少一种肽。或者,至少一种肽可以在在微生物,诸如细菌,酵母或真菌中,在真核细胞,诸如哺乳动物或昆虫细胞中,或在重组病毒载体,诸如腺病毒,痘病毒,疱疹病毒,Simliki森林病毒(Simliki forest virus)、杆状病毒、噬菌体、辛德比斯病毒(sindbis virus)或仙台病毒(sendaivirus)中生成,其生成化合物/肽,然后,将所述化合物/肽分离,并且在期望时进一步纯化。适合于生成化合物/肽的细菌包括大肠杆菌(E.coli)、枯草芽孢杆菌(B.subtilis)或任何其它能表达肽的细菌。适合于表达所述化合物/肽的酵母类型包括酿酒酵母(Saccharomyces cerevisiae)、粟酒裂殖酵母(Schizosaccharomyces pombe)、假丝酵母属菌种(Candida spp.)、巴斯德毕赤酵母(Pichia pastoris)或任何其它能表达肽的酵母。相应的方法是本领域中公知的。还有,用于纯化并分离重组生成的肽的方法是本领域中公知的,且包括例如凝胶过滤、亲和层析、离子交换层析等。
为了有助于分离化合物/肽,可以生成融合多肽,其中将所述化合物/肽与异源多肽在翻译上融合(共价融合),所述异源多肽使得能够通过亲和层析来进行分离。典型的异源多肽是His标签(例如His6;6个组氨酸残基)、GST标签(谷胱甘肽-S-转移酶)等。融合多肽不仅帮助化合物/肽的纯化,还能预防纯化步骤期间化合物/肽的降解。如果期望在纯化后移除异源多肽,那么该融合多肽可在化合物/肽和异源多肽之间的接合处包含切割位点。所述切割位点可由用酶(例如蛋白酶)切割的氨基酸序列组成,所述酶对于该位点处的氨基酸序列是特异性的。
X1可以是非极性脂肪族氨基酸残基,诸如A、G、V、L、M或I;极性、不带电荷的氨基酸残基,诸如S、T、N或Q;带正电荷的氨基酸残基,诸如K或H;或极性芳香族氨基酸残基,诸如Y。X2可以是选自下组的氨基酸残基:A、M、V、L、I、K、R、H、T和Y。X5可以是非极性脂肪族氨基酸残基,诸如A、M、I;极性不带电荷的氨基酸残基,诸如S、T、N或Q;或带电荷的氨基酸残基,诸如K、R、H或E。
根据本发明的一个优选的实施方案,X1是选自下组的氨基酸残基:苏氨酸、谷氨酰胺、酪氨酸、甲硫氨酸、丙氨酸、甘氨酸、和缬氨酸。
本发明的又一个优选的实施方案,若m是1且X5是选自下组的氨基酸残基:丙氨酸、组氨酸、甲硫氨酸和苏氨酸,和/或X2是选自下组的氨基酸残基:甲硫氨酸、丙氨酸、赖氨酸和缬氨酸,则X1是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、组氨酸、赖氨酸、甲硫氨酸、丝氨酸、和苏氨酸(Xl is an amino acid residue selected from the groupconsisting of alanine,asparagine,glutamine,histidine,lysine,methionine,serine,and threonine if m is1 and Xs is an amino acid residue selected fromthe group consisting of alanine,histidine,methionine and threonine,preferablyalanine,threonine or methionine,and/or X2 is an ami no acid residue selectedfrom the group consisting of methionine,alanine,lysine and valine)。
根据本发明的一个特别优选的实施方案,m是1,且X5是选自下组的氨基酸残基:丙氨酸、甲硫氨酸和苏氨酸。
根据本发明的一个优选的实施方案,X2是选自下组的氨基酸残基:甲硫氨酸、丙氨酸、赖氨酸和缬氨酸。
根据本发明的又一个优选的实施方案,至少一种肽选自下组:
ISHKDMQLGA(SEQ ID No.14),ANISHKDMQLGA(SEQ ID No.21),KDMQLGA(SEQ IDNo.22),VVASQLRANISHKDMQLGA(SEQ ID No.23),ANISHKDMQLGT(SEQ ID No.24),ANISHKDMQLGQ(SEQ ID No.25),ANISHKDMQLGY(SEQ ID No.26),ANISHKDMQLGM(SEQ IDNo.27),ANISHKDMQLGG(SEQ ID No.28),ANISHKDMQLGV(SEQ ID No.29),ANISHKDMQLGK(SEQID No.30),ANISHKDMQLGS(SEQ ID No.31),ANISHKDMQLGH(SEQ ID No.32),ANISHKDMQLGN(SEQ ID No.33),ANISHKDMQLGL(SEQ ID No.34),ANISTKDMQLGA(SEQ ID No.70),ANISTKDMQLGQ(SEQ ID No.71),ANISTKDMQLGS(SEQ ID No.72),ANISTKDMQLGM(SEQ IDNo.73),ANISMKDMQLGN(SEQ ID No.74),ANISTKDKQLGM(SEQ ID No.75),ANISTKDMQLGH(SEQID No.76),ANISAKDMQLGA(SEQ ID No.77),ANISMKDMQLGA(SEQ ID No.78),ANISTKDKQLGA(SEQ ID No.79),ANISTKDAQLGA(SEQ ID No.80),ANISMKDMQLGS(SEQ ID No.81),ANISTKDVQLGA(SEQ ID No.82),ANISTKDMQLGN(SEQ ID No.83),ANISTKDMQLGK(SEQ IDNo.84),ANISMKDMQLGM(SEQ ID No.85),ANISTKDMQLGT(SEQ ID No.86),ANISHKDKQLGK(SEQID No.87),ANISMKDMQLGH(SEQ ID No.88),和ANISAKDAQLGA(SEQ ID No.89)。
根据一个特别优选的实施方案,至少一种由氨基酸序列SEQ ID No.99组成的肽在其N和/或C端包含与其直接或经由间隔物序列结合的至少一个半胱氨酸残基。
此半胱氨酸残基可以充当反应基团以使肽与另一种分子或载体结合。例如,可以使用此基团使肽与载体蛋白结合。可以将半胱氨酸残基直接与本发明的肽结合或者经由间隔物序列结合。优选地,间隔物序列包含至少1个,优选至少2个,更优选至少3个,甚至更优选至少4个,且任选最多10个,优选最少5个小的非极性氨基酸残基,诸如甘氨酸。
根据本发明的一个优选的实施方案,载体选自下组:匙孔虫戚血蓝蛋白(KLH)、CRM197、破伤风类毒素(TT)、白喉毒素(DT)、蛋白D或含有T细胞表位的任何其他蛋白质或肽。
根据本发明,将肽与药学可接受载体,优选KLH(匙孔虫戚血蓝蛋白)、破伤风类毒素、清蛋白结合蛋白、牛血清清蛋白、树枝状聚合物(dendrimer)、肽接头(或侧翼区)及Singh等(Singh等,Nat.Biotech.17,(1999):1075-1081(特别是所述文件表1中的那些佐剂物质)),及O’Hagan等(O’Hagan and Valiante,Nature Reviews,Drug Discovery 2(9);(2003):727-735(特别是其中描述的内源免疫加强化合物和投递系统))中描述的佐剂物质,或其混合物偶联或融合。此背景中的偶联化学(例如经由异双功能化合物如GMBS,以及当然还有其他化合物,如在“Bioconjugate Techniques”,Greg T.Hermanson中描述的化合物)可以选自本领域技术人员已知的反应。
或者,也可能通过本领域中已知的方法将本发明的至少一种肽与蛋白质载体融合。此类蛋白质包含如本文中描述的肽以及无关的免疫原性蛋白质。优选地,免疫原性蛋白质能够引发回忆应答。此类蛋白质的例子包括破伤风、肺结核、肝炎蛋白和蛋白D,即革兰氏阴性细菌乙型流感嗜血菌(Haemophilus influenza B)的表面蛋白(WO 91/18926)。优选地,使用蛋白D衍生物,其包含所述蛋白质的大致第一个三分之一(例如N端的前100-110个氨基酸),并且可以是脂质化的。可以用于提供融合蛋白的另一种载体可以是称为LYTA的蛋白质,或其部分(优选C端部分)。LYTA源自肺炎链球菌(Streptococcus pneumonia),其合成称为酰胺酶LYTA的N-乙酰基-L-丙氨酸酰胺酶(其由LytA基因编码;Gene 43;(1986):265-292)。LYTA是一种特异性降解肽聚糖主链中的某些键的自溶素。在一个优选的实施方案内,可以将LYTA的重复部分掺入融合蛋白中。重复部分存在于开始于残基178A的C端区中。一个特别优选的重复部分掺入残基188-305。
根据本发明的一个优选的实施方案,肽是与佐剂一起配制的,优选吸附至明矾(alum)。
依照本发明的疫苗可以与佐剂,优选低可溶性铝组合物,特别是氢氧化铝一起配制。当然,也可以使用如下的佐剂,如MF59、磷酸铝、磷酸钙、细胞因子(例如IL-2、IL-12、GM-CSF)、皂苷类(例如QS21)、MDP衍生物、CpG寡聚物、LPS、MPL、聚磷腈(polyphosphazene)、乳剂(例如弗氏(Freund’S)、SAF)、脂质体、病毒颗粒(virosome)、Iscoms、Cochleate、PLG微粒、泊洛沙姆(poloxamer)颗粒、病毒样颗粒、热不稳定性肠毒素(LT)、霍乱毒素(CT)、突变体毒素(例如LTK63和LTR72)、微粒和/或聚合的脂质体。
例如,合适的佐剂以AS01B,AS02A,AS15,AS-2及其衍生物(GlaxoSmithKline,Philadelphia,PA);CWS,TDM,Leif,铝盐,诸如氢氧化铝凝胶(明矾)或磷酸铝;钙、铁或锌的盐;酰化酪氨酸的不溶性悬浮液;酰化糖类;阳离子或阴离子衍生化多糖;聚磷腈(polyphosphazene);生物降解性微球体;单磷酰脂质A和Quil A可购得。细胞因子,诸如GM-CSF或白介素-2、-7或-12也可以用作佐剂。
在本文中提供的疫苗内,佐剂组合物优选设计为主要诱导Th1型的免疫应答。高水平的Th1型细胞因子(例如IFN-y、TNFct、IL-2和IL-12)趋向于有利于诱导细胞介导的对施用抗原的免疫应答。比较而言,高水平的Th2型细胞因子(例如IL-4、IL-5、IL-6和IL-10)趋向于有利于诱导体液免疫应答。
在如本文中提供的疫苗应用后,患者会支持包括Th1和Th2型应答在内的免疫应答。在一个优选的实施方案内,其中应答主要是Th1型,Th1型细胞因子的水平会升高至比Th2型细胞因子的水平大的程度。可以使用标准测定法容易评估这些细胞因子的水平。对于细胞因子家族的综述,参见Janeway等,Immunobiology,第5版,2001。
在引发主要Th1型应答中使用的优选佐剂包括例如单磷酰脂质A,优选3-O-脱酰化单磷酰脂质A(3D-MPL),任选与铝盐的组合(参见例如Ribi等,Immunology andImmunopharmacology of Bacterial Endotoxins,Plenum Publ.Corp.,NY,(1986):407-419;GB 2122204B;GB 2220211;及US 4,912,094)。一种优选的3D-MPL形式是具有直径小于0.2mm的小粒径的乳剂,并且其制备方法公开于WO 94/21292。包含单磷酰脂质A和表面活性剂的水性配制剂已经记载于WO 98/43670中。例示性的优选佐剂包括AS01B(脂质体配制剂中的MPL和QS21),脂质体配制剂中的3D-MPL和QS21,AS02A(MPL和QS21及水包油乳剂),3D-MPL和QS21和水包油乳剂,及AS 15,可购自GlaxoSmithKline。MPL佐剂可购自GlaxoSmithKline,Seattle,WA(参见US4,436,727;US 4,877,611;US 4,866,034及US 4,912,094)。
含有CpG的寡核苷酸(其中CpG二核苷酸是未甲基化的)也诱导主要Th1应答。CpG是存在于DNA中的胞苷-鸟苷二核苷酸基序的缩写。此类核苷酸是公知的,并且记载于例如WO96/02555,WO 99/33488,US 6,008,200和US5,856,462。例如,Sato等,Science 273;(1996):352也描述了免疫刺激性DNA序列。CpG在配制成疫苗时通常与游离的抗原一起以游离的溶液施用(WO96/02555;McCluskie和Davis,见上文)或与抗原共价缀合(WO 98/16247),或与载体诸如氢氧化铝一起配制((肝炎表面抗原)Davis等,见上文;
Brazolot-Millan等,PNAS USA,95(26),(1998):15553-8)。本领域中已知CpG为可以通过系统和粘膜路径两者施用的佐剂(WO 96/02555,EP 0468520,Davis等,J.lmmunol,160(2),(1998):870-876;McCluskie和Davis,J.Immunol.,161(9),(1998):4463-6)。
另一种优选的佐剂是皂苷或皂苷模拟物或衍生物,优选QS21(AquilaBiopharmaceuticals Inc.),其可以单独或与其他佐剂组合使用。例如,增强的系统牵涉单磷酰脂质A和皂苷衍生物的组合,诸如如WO 94/00153中描述的QS21和3D-MPL的组合,或反应原性较小的(less reactogenic)组合物,其中QS21用胆固醇淬灭,如记载于WO 96/33739的。其他优选的配制剂包含水包油乳剂和生育酚。一种牵涉水包油乳剂中的QS21、3D-MPL和生育酚的特别有力的佐剂配制剂记载于WO 95/17210。本发明中使用的额外皂苷佐剂包括QS7(记载于WO 96/33739和WO 96/11711)和QS17(记载于US 5,057,540和EP0362279B1)。
其他优选的佐剂包括Montanide ISA 720(Seppic,France)、SAF(Chiron,California,United States)、ISCOMS(CSL)、MF-59(Chiron)、SBAS佐剂序列(例如SBAS-2、AS2’、AS2、SBAS-4、或SBAS6,可购自GlaxoSmithKline)、Detox(Corixa)、RC-529(Corixa,Hamilton,MT)和其他氨基-烷基氨基葡糖苷4-磷酸(AGP)。其他佐剂例子包括合成的MPL和基于志贺毒素(Shiga toxin)B亚基的佐剂(参见WO 2005/112991)。
本发明的疫苗可以皮下,肌肉内,皮内,静脉内施用(参见例如“Handbook ofPharmaceutical Manufacturing Formula-tions”,Sarfaraz Niazi,CRC Press Inc,2004)。根据施用路径,药物可以包含相应的载体、佐剂、和/或赋形剂。
依照本发明的疫苗含有0.1ng至10mg,优选10ng至1mg,特别是100ng至100μg,或备选例如100fmol至10μmol,优选10pmol至1μmol,特别是100pmol至100nmol量的依照本发明的化合物。以优选每剂100ng至1mg,更优选1μg至500μg,甚至更优选10μg至100μg,特别是20至40或30μg的量对哺乳动物施用本发明的化合物或肽。通常,疫苗还可以含有辅助物质,例如缓冲剂,稳定剂,等等。依照本发明的疫苗在2周直至2个月的时间间隔中应用3至6次。在存在抗C5a抗体后,以约6个月的定期时间间隔应用疫苗。
依照本发明的一个优选的实施方案,在补体介导的病症的治疗中使用疫苗(参见例如Allegretti M等,Curr Med Chem 12(2005):217-236)。因此,本发明还涉及用于治疗患有补体介导的病症的个体的方法,其通过施用依照本发明的疫苗进行。
补体介导的病症优选是炎性疾病,优选慢性炎性疾病。
优选地,炎性疾病选自下组:年龄相关性黄斑变性(AMD),神经变性性病症,优选阿尔茨海默氏病,帕金森氏病或亨丁顿氏病,变应性哮喘(allergic asthma),动脉粥样硬化,格巴二氏综合征,血管炎,炎性皮炎,优选银屑病和荨麻疹,类风湿性关节炎,抗磷脂综合征(APS),多发性硬化,溶血尿毒综合征,和系统性红斑狼疮(SLE)。
补体介导的病症优选是缺血-再灌注损伤,急性肺损伤,急性呼吸窘迫综合征(ARDS),败血症,癌症,妊娠并发症,诸如先兆子痫,反复性自然流产,宫内生长迟缓和APS。
根据本发明,补体介导的病症也是一种牵涉不想要的或不适当的补体活性的病症,诸如血液透析关联的血栓形成。此活性可以通过本领域中已知的方法测定。可以用依照本发明的疫苗治疗的病症以升高的C5a活性为特征。
AMD是一种通常影响老年成人并且由于对视网膜的损害而导致视场中心(视网膜中区)的视觉丧失的医学状况。它以“干性”和“湿性”形式发生,而干性形式占到所有AMD情况的90%。湿性和干性AMD的最早的临床标志之一是在与视网膜色素上皮接近的区域中细胞外积累的无定形脂蛋白性沉积物的出现。这些病原性组分称作Drusen。最近的研究已经在Drusen(干性AMD的标志)的形成中暗示局部炎性和补体级联的活化。这与显示除了其他分子外补体组分C5在这些Drusen内积累的其它研究一致。
此外,已经显示了除了VEGF(C5a参与VEGF的释放)外,C5a在诱导脉络膜新血管化(其在AMD的湿性形式中发生)中发挥关键作用。最重要地,可以显示针对C5a的中和性抗体能够在动物模型中停止疾病的进展。
总之,在AMD的湿性和干性形式中存在有补体介导的疾病的强烈支持,因此C5a似乎是治疗这两种AMD形式的最佳靶物。
提出了补体介导的炎症(其主要由C5a引起)在阿尔茨海默氏病的加速或进展中发挥作用。阿尔茨海默症脑中的纤维状Aβ斑块引发长时间的补体激活,并且该疾病的许多表现是由于C5a募集和激活的促进炎性事件的神经胶质。类似的事件可以也适用帕金森氏症和亨廷顿氏病。此外,初步数据表明补体C5激活片段(C5a)在运动神经元病中的特定病理作用,所述运动神经元病是一组造成进行性运动神经元死亡,最终导致瘫痪和死亡的退行性疾病。
在实验性过敏性哮喘中,阻断C5aR明显减轻了气道发炎和气道高反应性。但是,补体成分C5在哮喘中的作用仍然有争议。C5曾被描述为能够在实验性过敏性哮喘中促进或者对抗气道高反应性,说明C5a在过敏性哮喘中可能有双重作用。一种假设是C5aR信号转导在过敏原致敏过程中有保护免于肺过敏发展的作用,但在效应期期间增强发炎的肺环境的过敏表型。因此C5aR阻断对已建立哮喘的处置可以有治疗上的益处。
C5a还在动脉粥样硬化中发挥作用。C3a和C5a在人冠状动脉斑块中表达。此外,最近已经显示在晚期动脉粥样硬化患者中C5a预示了心血管事件,升高的C5a血清水平与股浅动脉气囊血管成形术后再狭窄的形成有关。
血管炎是血管的炎性过程,其组织病理学特征在于血管壁的发炎或纤维蛋白样坏死。这种形式的血管炎的临床范围从紫癜到重度增殖性肾小球肾炎变化,并且提出了补体系统关键地参与这些过程。例如,C5a在抗嗜中性粒细胞胞浆自身抗体(ANCA)相关性血管炎这种相对不常见但可能会危及生命的系统性自身免疫疾病中发挥重要作用。ANCA诱导的坏死性新月体性肾小球肾炎需要补体参与其发病机制。C5a和嗜中性粒细胞C5aR可能给ANCA介导的嗜中性粒细胞激活构成一个放大循环。C5aR可能提供了ANCA诱导的坏死性新月体性肾小球肾炎的一个新的治疗靶点。
补体激活参与自身免疫性皮炎(包括大疱性类天疱疮(BP)、寻常性银屑病和慢性荨麻疹)的炎性改变的发病机制。在天疱疮中,似乎是表皮中天疱疮抗体引起的补体激活造成了被称为嗜酸细胞性海绵层水肿的特征性炎性改变的发生。在银屑病鳞屑中发现了高水平C5a,表明该疾病中涉及到补体激活。银屑病已知是T细胞介导的疾病,但是嗜中性粒细胞和肥大细胞可能也参与了该病的发病机制。T细胞和嗜中性粒细胞受到C5a的化学吸引,因此C5a可以作为银屑病治疗的重要治疗靶点。
补体激活还对自身免疫炎性疾病类风湿性关节炎有作用。过敏毒素C5a似乎是补体激活中造成类风湿性关节炎组织损伤的主要产物,虽然膜攻击复合物的沉积以及C3b片段的调理作用也是重要的。
补体在系统性红斑狼疮(SLE)的发病机制中的作用仍然有争议。一方面,补体成分似乎介导自身抗体引发的组织损伤。另一方面,补体系统似乎具有保护性特性,因为某些补体的遗传性缺乏与增加的SLE风险相关。已知SLE患者往往患有低补体血症(hypocomplementemia)。此外,证明了C5a/C5aR信号传导通过调节血脑屏障的完整性在中枢神经系统狼疮的发病机制中扮演重要角色。突出显示了C5a/C5aR阻断有潜力成为SLE的有前景的治疗策略。
似乎组织再灌注(R),而不是局部缺血(I)激活了补体,造成炎症诱导的损伤。虽然补体激活在I/R损伤中的确切参与情况还不清楚,多项实验性研究表明补体与I/R损伤的发病机制之间存在联系,并且已经提出补体抑制作为强力疗法。例如,在鼠心肌I/R损伤模型中,再灌注前30分钟系统性C5抑制显著保护小鼠免于心肌I/R损伤。
在许多形式的急性肺损伤中证明了存在补体激活。C5a浓度在酸灌注诱发的急性肺损伤中的支气管肺泡灌洗液(BALF)中是增加的,并且C5a浓度在人移植肺中也是升高的。C5a将嗜中性粒细胞吸引到肺中,并直接激活嗜中性粒细胞、巨噬细胞和内皮细胞。抗C5a的保护性作用与BALF中TNF-α水平的剧烈下降,以及肺血管胞间粘附分子ICAM-1表达的极大减少有关,表明C5a对于炎症网络的建立、调节炎性介质的表达和调节粘附分子的表达是至关重要的。
急性肺损伤和急性呼吸窘迫综合征(ARDS)特征在于肺泡内空间中存在富含纤维蛋白的炎性渗出物以及嗜中性粒细胞广泛迁移到肺泡内。对来自健康志愿者的嗜中性粒细胞中的TNF-α和C5a信号传导进行的药学阻断能够显著消除这些否则正常的细胞的BALF诱导的前凝血剂活性,造成同时丧失组织因子(TF)的表达。这些结果表明C5a和TNF-α信号传导对受到AFDS影响的肺泡中累积的嗜中性粒细胞中TF表达的诱导有作用。
在败血症的开始期间,炎性系统变得极度活跃,包括细胞和体液防御机制两者。已经显示人败血症过程中的补体激活,特别是反映为C5a水平提高的补体激活,当与较不严重的败血症患者和存活者相比时,与明显下降的存活率以及多器官衰竭相关联。而且,对C5a或C5aR的阻断显著改善啮齿动物中进行的实验性败血症期间的存活。因此,C5似乎是败血症发展的关键因素,对C5a/C5aR结合进行干扰可能给有较高的形成败血症的风险的患者提供一种用于预防性处理的有力临床方法。
在心肺分流术和血透析中,当人血液与心肺机或者肾透析仪的人工表面发生接触时旁路补体途径被激活,从而产生了C5a。C5a导致毛细血管通透性提高和水肿、支气管收缩、肺血管收缩、白细胞和血小板激活并渗滤到组织,特别是肺中。显示了施用抗C5a单克隆抗体降低心肺分流和心脏麻痹诱发的冠状动脉内皮官能障碍。
肿瘤驱动的补体激活可以提供肿瘤生长优势。补体C5a在肿瘤微环境中的产生通过抑制抗肿瘤CD8+T细胞介导的反应增强肿瘤生长。使用小鼠肿瘤生长模型揭示了C5aR的缺乏或者阻断与延迟的肿瘤生长有关。因此补体抑制被认为是抗癌疗法中有效和有前景的办法。
显著增加的补体激活与不同病理性怀孕后果,即先兆子痫(preeclampsia)、反复性自然流产、宫内发育迟缓和抗磷脂综合征(APS)有关。患有先兆子痫的女性比正常怀孕女性显示升高的C5a血浆浓度。对于APS,抗磷脂抗体和补体激活(经由C3a、C5a和MAC)可能合作引发局部的炎性过程,最终导致胎盘血栓、缺氧症和嗜中性粒细胞渗滤。组织因子(TF)代表了抗磷脂抗体诱发的胎儿损伤中C5a和嗜中性粒细胞激活之间的连接。
总之,肽诱导的抗C5a免疫反应提供了对C5a介导的(慢性炎性)疾病的有效疗法,所述疾病包括神经变性性疾病,比如阿尔茨海默症(参见例如Fonseca,M.I.等(2009),JImmunol“Treatment with a C5aR Antagonist Decreases Pathology and EnhancesBehavioral Performance in Murine Models of Alzheimer's Disease.”和Klos,A等(2009),Mol Immunol“The role of the anaphylatoxins in health and disease.”)、帕金森氏症(参见例如McGeer,P.L.等(2004),Parkinsonism Relat Disord“Inflammationand neurodegeneration in Parkinson’s disease.”)、亨廷顿氏病(参见例如Singhrao,S.K.等(1999),Exp Neurol“Increased complement biosynthesis by microglia andcomplement activation on neurons in Huntington’s disease.”)和年龄相关性黄斑变性(参见例如Nozaki,M.等(2006),Proc Natl Acad Sci“Drusen complement componentsC3a and C5a promote choroidal neovascularization.”)、类风湿性关节炎(参见例如Okroj,M.等(2007),Ann Med“Rheumatoid arthritis and the complement system.”)、系统性红斑狼疮(SLE)(参见例如Chen,M.等(2009),J Autoimmun“complement system insystemic autoimmune disease.”;Jacob,A.等(2010),J Neuroimmunol“Inhibition ofC5a receptor alleviates experimental CNS lupus.”和Jacob,A,等(2010),FASEB J“C5a alters blood-brain barrier integrity in experimental lupus.”)、哮喘(参见例如Kohl,J.等(2006),J Clin Invest“A regulatory role for the C5a anaphylatoxinin type 2 immunity in asthma.”)、血管炎、抗磷脂综合征(APS)、动脉粥样硬化、炎性皮炎,比如银屑病和慢性荨麻疹、格巴二氏综合征、溶血尿毒症综合征和多发性硬化症。因为失控的hC5a释放也会促进其他病理状况,比如局部缺血和再灌注损伤、败血症、急性肺损伤、与血液透析相关的并发症、癌症、怀孕并发症(比如先兆子痫和APS),通过主动免疫将C5a中和也可能给这些病理并发症提供有效的疗法。
如本文中使用的,“治疗/处理”指提供处理,即对受试者提供任何类型的医学或手术管理。可以提供治疗以反转、减轻、抑制疾病,病症,或状况的进展,阻止或降低疾病、病症或状况的可能性,或以反转、减轻、抑制或阻止疾病、病症或状况的进展,阻止或降低疾病、病症或状况的一种或多种症状或表现的可能性。“预防”指在至少一些个体中使疾病、病症、状况、或其症状或表现在至少一段时间不发生。治疗可以包括在指示补体介导的状况的一种或多种症状或表现形成后对受试者施用药剂,例如以反转、减轻、降低状况的严重性,和/或抑制或阻止状况的进展和/或以反转、减轻、降低状况的一种或多种症状或表现的严重性,和/或抑制状况的一种或多种症状或表现。可以对受试者施用本发明的组合物,所述受试者已经形成补体介导的病症或者相对于一般群体的成员有增加的形成此类病症的风险。可以预防性施用本发明的组合物,即在形成状况的任何症状或表现前。通常,在此情况下,受试者会有形成状况的风险。
本发明的另一个方面涉及组成为由以下氨基酸序列组成的7至19个氨基酸残基的肽:
(X3)mKDX2QLGX1 (SEQ ID No.99),
其中:
X1是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、酪氨酸和缬氨酸,
X2是选自下组的氨基酸残基:丙氨酸、精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苏氨酸、酪氨酸和缬氨酸,
X3是(X4)nANISX5(SEQ ID No.100)或由1至4个氨基酸残基组成的其N端截短的片段,
X4是VVASQLR(SEQ ID No.101)或由1至6个氨基酸残基组成的其N端截短的片段,
X5是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、谷氨酸、组氨酸、精氨酸、异亮氨酸、赖氨酸、甲硫氨酸、丝氨酸和苏氨酸,
m是0或1,且
n是0或1,
其中所述至少一种肽与包含至少一种T细胞表位的载体偶联或融合。
依照本发明的一个优选的实施方案,X1是选自下组的氨基酸残基:苏氨酸、谷氨酰胺、酪氨酸、甲硫氨酸、丙氨酸、甘氨酸、和缬氨酸。
优选地,若m是1且X5是选自下组的氨基酸残基:丙氨酸、组氨酸、甲硫氨酸和苏氨酸,优选丙氨酸、苏氨酸或甲硫氨酸,和/或X2是选自下组的氨基酸残基:甲硫氨酸、丙氨酸、赖氨酸和缬氨酸,则X1是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、组氨酸、赖氨酸、甲硫氨酸、丝氨酸、和苏氨酸。
依照本发明的一个特别优选的实施方案,m是1,且X5是选自下组的氨基酸残基:丙氨酸、组氨酸、甲硫氨酸和苏氨酸,优选丙氨酸、苏氨酸、或甲硫氨酸。
依照本发明的另一个优选的实施方案,X2是选自下组的氨基酸残基:甲硫氨酸、丙氨酸、赖氨酸和缬氨酸。
依照本发明的一个特别优选的实施方案,肽选自下组:ISHKDMQLGA(SEQ IDNo.14),ANISHKDMQLGA(SEQ ID No.21),KDMQLGA(SEQ ID No.22),VVASQLRANISHKDMQLGA(SEQ ID No.23),ANISHKDMQLGT(SEQ ID No.24),ANISHKDMQLGQ(SEQ ID No.25),ANISHKDMQLGY(SEQ ID No.26),ANISHKDMQLGM(SEQ ID No.27),ANISHKDMQLGG(SEQ IDNo.28),ANISHKDMQLGV(SEQ ID No.29),ANISHKDMQLGK(SEQ ID No.30),ANISHKDMQLGS(SEQID No.31),ANISHKDMQLGH(SEQ ID No.32),ANISHKDMQLGN(SEQ ID No.33),ANISHKDMQLGL(SEQ ID No.34),ANISTKDMQLGA(SEQ ID No.70),ANISTKDMQLGQ(SEQ ID No.71),ANISTKDMQLGS(SEQ ID No.72),ANISTKDMQLGM(SEQ ID No.73),ANISMKDMQLGN(SEQ IDNo.74),ANISTKDKQLGM(SEQ ID No.75),ANISTKDMQLGH(SEQ ID No.76),ANISAKDMQLGA(SEQID No.77),ANISMKDMQLGA(SEQ ID No.78),ANISTKDKQLGA(SEQ ID No.79),ANISTKDAQLGA(SEQ ID No.80),ANISMKDMQLGS(SEQ ID No.81),ANISTKDVQLGA(SEQ ID No.82),ANISTKDMQLGN(SEQ ID No.83),ANISTKDMQLGK(SEQ ID No.84),ANISMKDMQLGM(SEQ IDNo.85),ANISTKDMQLGT(SEQ ID No.86),ANISHKDKQLGK(SEQ ID No.87),ANISMKDMQLGH(SEQID No.88)和ANISAKDAQLGA(SEQ ID No.89)。
本发明的另一个方面涉及包含至少一种肽的疫苗,所述肽组成为由以下氨基酸序列组成的7至19个氨基酸残基:
(X3)mKDX2QLGX1 (SEQ ID No.99),
其中
X1是选自下组的氨基酸残基:精氨酸、丙氨酸、天冬酰胺、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、酪氨酸和缬氨酸,最优选精氨酸,
X2是选自下组的氨基酸残基:丙氨酸、精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、苏氨酸、酪氨酸和缬氨酸,优选丙氨酸、缬氨酸、苏氨酸、酪氨酸或亮氨酸,更优选缬氨酸,
X3是(X4)nANISX5(SEQ ID No.100)或由1至4个氨基酸残基组成的其N端截短的片段,
X4是VVASQLR(SEQ ID No.101)或由1至6个氨基酸残基组成的其N端截短的片段,
X5是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、谷氨酸、组氨酸、精氨酸、异亮氨酸、赖氨酸、甲硫氨酸、丝氨酸和苏氨酸,最优选组氨酸,
m是0或1,且
n是0或1,
其中所述至少一种肽与包含至少一种T细胞表位的载体偶联或融合。
本发明的又一个方面涉及包含至少一种肽的疫苗,所述肽组成为由以下氨基酸序列组成的7至19个氨基酸残基:
(X3)mKDX2QLGX1 (SEQ ID No.99),
其中
X1是选自下组的氨基酸残基:精氨酸、丙氨酸、天冬酰胺、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、酪氨酸和缬氨酸,最优选精氨酸,
X2是选自下组的氨基酸残基:丙氨酸、精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苏氨酸、酪氨酸和缬氨酸,优选甲硫氨酸,
X3是(X4)nANISX5(SEQ ID No.100)或由1至4个氨基酸残基组成的其N端截短的片段,
X4是VVASQLR(SEQ ID No.101)或由1至6个氨基酸残基组成的其N端截短的片段,
X5是选自下组的氨基酸残基:丙氨酸、天冬酰胺、谷氨酰胺、谷氨酸、精氨酸、异亮氨酸、赖氨酸、甲硫氨酸、丝氨酸和苏氨酸,优选苏氨酸、谷氨酰胺、谷氨酸、丝氨酸、赖氨酸或天冬酰胺,更优选苏氨酸或谷氨酰胺,
m是0或1,且
n是0或1,
其中所述至少一种肽与包含至少一种T细胞表位的载体偶联或融合。
依照本发明的一个优选的实施方案,X3是(X4)nANISX5(SEQ ID No.100)或其N端截短的片段,且X1是精氨酸。因此,此N端截短的片段可以由ANISX5(SEQ ID No.102)、NISX5(SEQ ID No.103)、ISX5、SX5或X5组成。这意味着若m=1,则本发明的疫苗可以包含至少一种具有氨基酸序列ANISX5KDX2QLGR(SEQ ID No.119)、NISX5KDX2QLGR(SEQ ID No.120)、ISX5KDX2QLGR(SEQ ID No.121)、SX5KDX2QLGR(SEQ ID No.122)或X5KDX2QLGR(SEQ IDNo.123)的肽。
依照本发明的一个优选的实施方案,X4是VVASQLR(SEQ ID No.101)或其N端截短的片段。VVASQLR的片段可以由下列氨基酸序列之一组成:VASQLR(SEQ ID No.109)、ASQLR(SEQ ID No.110)、SQLR(SEQ ID No.111)、QLR、LR、或R。因此,若m和n是1,则本发明的疫苗中使用的至少一种肽可以具有下列氨基酸序列之一:VVASQLRANISX5KDX2QLGR(SEQ IDNo.124)、VASQLRANISX5KDX2QLGR(SEQ ID No.125)、ASQLRANISX5KDX2QLGR(SEQ IDNo.126)、SQLRANISX5KDX2QLGR(SEQ ID No.127)、QLRANISX5KDX2QLGR(SEQ ID No.128)、LRANISX5KDX2QLGR(SEQ ID No.129)、或RANISX5KDX2QLGR(SEQ ID No.130)。
在本发明的一个特别优选的实施方案中,若X2是如上文限定的氨基酸残基而非甲硫氨酸,则SEQ ID No.119至130的X5是组氨酸。
在本发明的一个进一步优选的实施方案中,若X5是如上文限定的氨基酸残基而非组氨酸,则SEQ ID No.119至130的X2是甲硫氨酸。
依照本发明的一个具体的优选实施方案,肽选自下组:
ANISHKDVQLGR(SEQ ID No.56),ANISHKDTQLGR(SEQ ID No.57),ANISHKDYQLGR(SEQ ID No.58),ANISHKDLQLGR(SEQ ID No.59),ANISHKDAQLGR(SEQ ID No.18),ANISTKDMQLGR(SEQ ID No.39),ANISQKDMQLGR(SEQ ID No.40),ANISEKDMQLGR(SEQ IDNo.41),ANISSKDMQLGR(SEQ ID No.42),ANISKKDMQLGR(SEQ ID No.43)和ANISNKDMQLGR(SEQ ID No.44),优选选自下组:ANISHKDVQLGR(SEQ ID No.56),ANISTKDMQLGR(SEQ IDNo.39)和ANISQKDMQLGR(SEQ ID No.40)。
本发明的又一个方面涉及选自下组的肽:ANISHKDVQLGR(SEQ ID No.56),ANISHKDTQLGR(SEQ ID No.57),ANISHKDYQLGR(SEQ ID No.58),ANISHKDLQLGR(SEQ IDNo.59),ANISHKDAQLGR(SEQ ID No.18),ANISTKDMQLGR(SEQ ID No.39),ANISQKDMQLGR(SEQID No.40),ANISEKDMQLGR(SEQ ID No.41),ANISSKDMQLGR(SEQ ID No.42),ANISKKDMQLGR(SEQ ID No.43)和ANISNKDMQLGR(SEQ ID No.44),优选选自下组:ANISHKDVQLGR(SEQ IDNo.56),ANISTKDMQLGR(SEQ ID No.39)和ANISQKDMQLGR(SEQ ID No.40)。
本发明通过以下图和实施例进一步例示,然而并不受限于此。
图1显示了hC5a的各种长度的C端片段(SEQ ID No:1-4)的丙氨酸扫描(SEQ IDNo:5-23)以限定可以在不消除免疫原性和诱导针对hC5a的抗体的能力的情况下交换的位置。图1(A)显示了初始表位hC5a位置65-74(SEQ ID No:1)及其VARIOTOPES,(B)初始表位hC5a位置63-74(SEQ ID No:2)及其VARIOTOPES,(C)初始表位hC5a位置68-74(SEQ ID No:3)及其VARIOTOPE,(D)初始表位hC5a位置55-74(SEQ ID No:4)及其VARIOTOPE的免疫原性(以滴度描绘)。
图2显示了相对于初始表位序列(其描绘为100%(SEQ ID No:1-4))的用VARIOTOPES SEQ ID No:5-23接种疫苗的小鼠的免疫血清的抑制活性。图2(A)显示了由初始表位hC5a位置65-74(SEQ ID No:1)及其VARIOTOPES,(B)初始表位hC5a位置63-74(SEQID No:2)及其VARIOTOPES,(C)初始表位hC5a位置68-74(SEQ ID No:3)及其VARIOTOPE,(D)初始表位hC5a位置55-74(SEQ ID No:4)及其VARIOTOPE诱导的免疫血清的抑制。
图3显示了由hC5a的长12个氨基酸的C端片段(SEQ ID No:2)的VARIOTOPES诱导的抗体的抑制活性的评估,其中hC5a的74位R用不同特征的氨基酸残基交换(SEQ ID No:21,24-38)。
图4显示了由hC5a的长12个氨基酸的C端片段(SEQ ID No:2)的VARIOTOPES诱导的抗体的抑制活性的评估,其中hC5a的67位H用不同特征的氨基酸残基交换(SEQ ID No:17,39-55)。
图5显示了由hC5a的长12个氨基酸的C端片段(SEQ ID No:2)的VARIOTOPES诱导的抗体的抑制活性的评估,其中hC5a的67位H用不同特征的氨基酸残基交换(SEQ ID No:18,56-69)。
图6显示了由hC5a的长12个氨基酸的C端片段(SEQ ID No:2)的VARIOTOPES诱导的抗体的抑制活性,其中hC5a的74位R和67或70位的一个或两个额外的氨基酸用其他氨基酸残基交换(SEQ ID No:70-98)。
实施例
本发明的一个目的是开发针对过多的人C5a的中和性活性免疫应答以避免其在慢性炎性疾病或急性病理学情况中的病理学活性。
为了实现此目的,设计所谓的VARIOTOPES并将其用于免疫,以诱导针对人C5a分子的C端新表位的抗体。在C5蛋白被C5转化酶切割从而产生较小的过敏性片段C5a和C5b(膜攻击复合物的一部分)后,C5a上的此新表位变得易接近。VARIOTOPES是能够通过模仿靶定蛋白上的表位诱导针对感兴趣蛋白质的体液免疫应答的免疫原性肽。因此,VARIOTOPE疫苗的优点是避免对自身抗原的自身耐受性并且降低由于使用自身抗原而普遍的不想要的副作用的风险。
将所有肽经由N端的半胱氨酸残基与蛋白质载体匙孔虫戚血蓝蛋白(KLH)化学连接,并与作为佐剂的明矾一起对小鼠施用。对自用hC5a的初始C端序列或VARIOTOPES免疫的小鼠获得的所有免疫血清分析其诱导针对hC5a的功能性活性抗体和抗体滴度的能力。
材料和方法:
小鼠的免疫
使用BALB/c小鼠作为hC5a-VARIOTOPE免疫实验的模型系统。用缀合有KLH的VARIOTOPE疫苗(磷酸盐缓冲液pH=7.4中200μl,皮下)激发6至8周龄的雌性BALB/c小鼠,并以每二周的时间间隔加强免疫四次。使用铝水凝胶作为佐剂。使用5至6只小鼠进行用相应VARIOTOPE疫苗的免疫。
免疫原性测定法
使用酶联免疫吸附测定法(ELISA)对接种疫苗的小鼠的免疫血清分析其对注射肽(数据未显示)及对人C5a蛋白的抗体应答。抗体滴度以给出半最大结合的血清稀释(即ODmax/2)确定,并且呈现每组的所有小鼠的均值滴度。
C5a抑制测定法
使用人U937细胞通过葡糖醛酸糖苷酶酶释放测定法评估肽或VARIOTOPE诱导的针对hC5a的抗体的抑制活性。用环状腺苷3’:5’-单磷酸分化U937细胞,并且在用人重组C5a蛋白刺激后,β-葡糖醛酸糖苷酶被释放。此效果可以通过添加hC5a特异性抗体或肽诱导的抗hC5a免疫血清阻断。
更为详细地,将U937细胞用RPMI,10%FCS中的0.5mM环状腺苷3’:5’-单磷酸(cAMP)分化5天。在第5天,将细胞于37℃用细胞松弛素B(2.5μg/ml)预处理10分钟。对于每种方法,用总体积120μl HAG-CM缓冲液(20mM HEPES pH=7.4,125mM NaCl,5mM KCl,0.5mM葡萄糖,1mM CaCl2,1mM MgCl2,0.25%BSA)中单独的10nM hC5a或10nM hC5a加上8%源自用不同肽或VARIOTOPES(SEQ ID No:1-98,如表1和2中指示的)免疫的小鼠的热灭活血清(于56℃进行1h)刺激1.8x 105个经预处理的细胞。在于37℃温育10分钟后,将细胞沉淀,将上清液转移至96孔微量滴定板,并在总体积150μl中用0.01M P-硝基苯基-β-D-葡糖苷酸(溶解于0.1M乙酸钠pH=4.0)以1:1稀释。将微量滴定板在黑暗中于37℃温育1h。然后,通过添加0.4M甘氨酸缓冲液(pH=10.0)停止反应。β-葡糖醛酸糖苷酶将P-硝基苯基-β-D-葡糖苷酸转化成微黄色颜色,将该颜色于405nm测量。
表1:用作生成VARIOTOPES的模板的人C5a C端表位。
序列标识号 | 序列 |
SEQ ID No:1 | ISHKDMQLGR |
SEQ ID No:2 | ANISHKDMQLGR |
SEQ ID No:3 | KDMQLGR |
SEQ ID No:4 | VVASQLRANISHKDMQLGR |
表2:hC5a C端片段(SEQ ID No:1-4)的VARIOTOPES的列表,其中单个多个氨基酸用不同氨基酸残基替换(加下划线并用粗体标示)。
表3:所有氨基酸的缩写及其侧链特性:
实施例1:hC5a的C端表位SEQ ID No:1-4(表1)的丙氨酸扫描以限定可以被交换为 使得免疫原性和诱导针对hC5a的中和性抗体的能力得到维持或甚至增加的位置。
将hC5a C端表位的各个氨基酸用丙氨酸残基取代,并且测试其与初始表位序列相比的免疫原性。所有VARIOTOPES明显诱导结合注射肽的特异性抗体,然而,针对蛋白hC5a的滴度有所不同。hC5a 66位(S66A),68位K(K68A),71位Q(Q71A),72位L(L72A),和73位G(G73A)的丙氨酸交换明显消除识别hC5a的抗体的诱导(图1A和1B;SEQ ID No:6,8,11,12,13,19,和20)。初始序列SEQ ID No:1-3诱导相对较高的滴度,而由VARIOTOPES SEQ ID No:6,8,11,12,13,19,和20诱导的滴度下降至小于13.000ODmax/2,这指示氨基酸S,K,Q,L,和G(hC5a 66、68、71、72、和73位)对于诱导hC5a特异性抗体是至关重要的(图1A和1B,表1-2)。
比较而言,74位R的丙氨酸取代揭示了抗hC5a反应性抗体的强增加。这不仅对于hC5a的长10和12个氨基酸的C端片段(图1A和1B;SEQ ID No:14,21),而且对于测试的具有不同长度和交换R74A的所有C端hC5a VARIOTOPES(图1C和1D,SEQ ID No:22-23)得到显现。VARIOTOPES R74A的滴度范围为56.000至88.000,并且在与通过初始序列得到的滴度相比时达到多达5.5倍增加(图1D,SEQ ID No:4和23)。具有交换N64A、I65A、H67A、D69A、和M70A的VARIOTOPES(SEQ ID No:5,7,9,10,15-18)与初始表位SEQ ID No:1-2以类似的程度展现出针对hC5a的相关滴度(图1A和1B,表1和2)。总之,多个长度的hC5a C端表位内的单个氨基酸的取代产生类似的发现,这指示特定氨基酸残基对针对hC5a的免疫原性的影响仅较小程度受到肽长度的影响。特别地,用其中74位R用A交换的hC5a C端片段的免疫导致在与初始表位相比时显著升高的针对hC5a的滴度。用于疫苗接种的肽片段至少包含hC5a的最后7个C端氨基酸以保证免疫原性,并且可能不超过19个氨基酸,即hC5a C端新表位的限定长度。
通过葡糖醛酸糖苷酶酶释放测定法评估其中的单个氨基酸用丙氨酸残基取代的VARIOTOPES的抑制活性。简言之,在用hC5a刺激后,从分化的人U937细胞释放β-葡糖醛酸糖苷酶,并且此效果可以通过添加抗hC5a免疫血清阻断。
由VARIOTOPES R74A诱导的免疫血清显示了最佳的抑制活性,并且与初始序列(SEQ ID No:1-4)相比,获得多达2倍的抑制活性增加(图2A-D,SEQ ID No:14,21,22,和23)。此外,由SEQ ID No:5,7,10,17,和18诱导的免疫血清揭示了超过由初始表位获得的信号或与该信号相当的抑制活性(图2A和2B)。因此,交换H67A(SEQ ID No:7,17),M70A(SEQID No:10,18),和I65A在这里仅对长10个(SEQ ID No:5)而非12个氨基酸(SEQ ID No:16)的hCa C端VARIOTOPE看到,似乎对于诱导针对hC5a的功能性活性抗体是有利的,然而,交换R74A占统治地位,尽管VARIOTOPES的长度不同(图2A-D)。
获得的针对hC5a的蛋白质滴度和基于葡糖醛酸糖苷酶释放测定法的功能性活性数据显示良好的关联。在随后的实施例中,仅显示了由初始表位及其VARIOTOPES诱导的免疫血清(抗体)的抑制活性,其在原则上比单独的抗体滴度在效力上更具预测性。
实施例2:
通过丙氨酸扫描法鉴定的关键氨基酸是hC5a 74位的R,其导致对hC5a的抑制升高多达2倍(参见图2)。因此,在接着的实验中,将此位置用与精氨酸残基具有相似或相反特征的多种氨基酸系统性交换(参见表3)。对于此实验,选择长12个氨基酸的C端表位作为模板,因为此片段(图1B)比长10或20个氨基酸的片段诱导更高的针对hC5a的滴度(图1A和D),并且比长7个氨基酸的hC5a C端片段显示更好的抑制活性。
对hC5a的长12个氨基酸的C端表位的16个VARIOTOPES R74X测试其免疫原性和其诱导功能性活性抗体的能力。从具有交换R74T和R74Q的VARIOTOPES获得的免疫血清在葡糖醛酸糖苷酶释放测定法中显示最佳抑制(图3,SEQ ID No:24和25),接着是交换R74Y(图3,SEQ ID No:26)和用非极性,脂肪族氨基酸残基M、A、G、和V替换R(图3,SEQ ID No:27、21、28、29)。其中的R被带负电荷的氨基酸(以R74D)或芳香族非极性氨基酸(W和F)和P(其是一种结构破坏氨基酸)替换的VARIOTOPES不利于诱导hC5a抑制抗体(图4,SEQ ID No:35-38)。
实施例3:
hC5a的67位组氨酸是通过丙氨酸扫描方法鉴定的另一种有利的可交换位置。将此位置再次用与组氨酸残基具有相似或相反特性的多种氨基酸系统性交换(参见表3)。对hC5a的长12个氨基酸的C端表位的18个VARIOTOPES H67X测试其免疫原性及其诱导功能性活性抗体的能力(SEQ ID No:17,39-55)。
从具有交换H67T和H67Q的VARIOTOPES获得的免疫血清在葡糖醛酸糖苷酶释放测定法的背景中显示最佳的抑制(图4,SEQ ID No:39和40),与初始序列(SEQ ID No:2)相比时升高20%(图4)。由VARIOTOPES SEQ ID No:41-47诱导的免疫血清相对于初始序列SEQID No:2展现出略高或相当的抑制活性。对由VARIOTOPES SEQ ID No:51-55诱导的免疫血清看到对hC5a抑制的明显负影响,以与初始序列(SEQ ID No:2)相比时降低20%及更多指示(图4)。
实施例4:
hC5a的70位甲硫氨酸是系统性交换以限定能够比hC5a的长12个氨基酸的初始C端表位诱导更高的针对hC5a的抑制性活性的VARIOTOPES的下一氨基酸。通过葡糖醛酸糖苷酶释放测定法对15个VARIOTOPES测试并分析其功能性活性。由VARIOTOPES SEQ ID No:18和56-62诱导的免疫血清显示比由初始表位SEQ ID No:2诱导的免疫血清更好或相当的抑制信号(图5)。然而,VARITOPES SEQ ID No:63-60显示抑制活性的逐步下降,并且不利于诱导针对hC5a的功能性活性抗体。
实施例5:
hC5a的74位氨基酸交换确实对C端hC5a片段的免疫原性及因此也对诱导抗体的功能性活性具有极大的影响(参见图3)。然而,在74位有利交换外hC5a C端表位的67或70位或这两个位置交换时,此效果甚至是更明显的。在以下实验中,生成分别含有交换R74X和67或70位,或这两个位置的额外交换的VARIOTOPES,并对其测试其免疫原性。与用小的非极性(A、M)、极性不带电荷(Q、S、N)、和带正电荷的H氨基酸残基替换74位R一起的交换H67T、H67M、和H67A在与初始表位SEQ ID No:2相比时获得高的滴度和超过1.5倍的针对hC5a的反应性抗体(图6,SEQ ID No:70-80)。与67位的有利交换,诸如H67T、H67M、和H67A,或70位的有利交换,诸如M70K、M70A、和M70V组合的74位有利交换在与初始序列SEQ ID No:2相比时产生更高的抑制活性(图6)。由VARIOTOPES SEQ ID No:90-98诱导的免疫血清在与初始序列相比时不是有利的,其以降低的抑制活性指示(图6)。
Claims (22)
1.包含至少一种肽的疫苗,所述至少一种肽选自下组:ISHKDMQLGA(SEQ ID No.14),ANISHKDMQLGA(SEQ ID No.21),KDMQLGA(SEQ ID No.22),VVASQLRANISHKDMQLGA(SEQ IDNo.23),ANISHKDMQLGT(SEQ ID No.24),ANISHKDMQLGQ(SEQ ID No.25),ANISHKDMQLGY(SEQID No.26),ANISHKDMQLGM(SEQ ID No.27),ANISHKDMQLGG(SEQ ID No.28),ANISHKDMQLGV(SEQ ID No.29),ANISHKDMQLGK(SEQ ID No.30),ANISHKDMQLGS(SEQ ID No.31),ANISHKDMQLGH(SEQ ID No.32),ANISHKDMQLGN(SEQ ID No.33),ANISHKDMQLGL(SEQ IDNo.34),ANISTKDMQLGA(SEQ ID No.70),ANISTKDMQLGQ(SEQ ID No.71),ANISTKDMQLGS(SEQID No.72),ANISTKDMQLGM(SEQ ID No.73),ANISMKDMQLGN(SEQ ID No.74),ANISTKDKQLGM(SEQ ID No.75),ANISTKDMQLGH(SEQ ID No.76),ANISAKDMQLGA(SEQ ID No.77),ANISMKDMQLGA(SEQ ID No.78),ANISTKDKQLGA(SEQ ID No.79),ANISTKDAQLGA(SEQ IDNo.80),ANISMKDMQLGS(SEQ ID No.81),ANISTKDVQLGA(SEQ ID No.82),ANISTKDMQLGN(SEQID No.83),ANISTKDMQLGK(SEQ ID No.84),ANISMKDMQLGM(SEQ ID No.85),ANISTKDMQLGT(SEQ ID No.86),ANISHKDKQLGK(SEQ ID No.87),ANISMKDMQLGH(SEQ ID No.88),和ANISAKDAQLGA(SEQ ID No.89),
其中所述至少一种肽与包含至少一种T细胞表位的载体偶联或融合。
2.根据权利要求1的疫苗,其中所述至少一种肽在其N端包含与其直接或经由间隔物序列结合的至少一个半胱氨酸残基。
3.根据权利要求1或2的疫苗,其特征在于所述包含至少一种T细胞表位的载体是蛋白质载体。
4.根据权利要求3的疫苗,其特征在于所述蛋白质载体选自下组:匙孔虫戚血蓝蛋白(KLH)、CRM197、破伤风类毒素(TT)、蛋白D或白喉毒素(DT)。
5.根据权利要求1或2的疫苗,其特征在于所述肽是与佐剂一起配制的。
6.根据权利要求5的疫苗,其特征在于所述肽吸附至明矾。
7.根据权利要求1或2的疫苗,其在用于治疗和/或预防补体介导的病症的方法中使用。
8.根据权利要求7的疫苗,其特征在于所述补体介导的病症是炎性疾病。
9.根据权利要求8的疫苗,其特征在于所述炎性疾病是慢性炎性疾病。
10.根据权利要求8的疫苗,其特征在于所述炎性疾病选自下组:年龄相关性黄斑变性(age-related macular degeneration,AMD),神经变性性病症,哮喘,动脉粥样硬化(atherosclerosis),血管炎(vasculitis),皮炎(dermatitis),溶血尿毒综合征(hemolytic uremic syndrome),类风湿性关节炎(rheumatoid arthritis),格巴二氏综合征(Guillain-Barre syndrome),多发性硬化(multiple sclerosis),抗磷脂综合征(antiphospholipid syndrome),溶血尿毒综合征,和系统性红斑狼疮(SLE)。
11.根据权利要求10的疫苗,其特征在于所述神经变性性病症是阿尔茨海默(Alzheimer)氏病,帕金森(Parkinson)氏病或亨丁顿(Huntington)氏病。
12.根据权利要求10的疫苗,其特征在于所述皮炎是银屑病(psoriasis)或荨麻疹(urticaria)。
13.根据权利要求7的疫苗,其特征在于所述补体介导的病症选自下组:缺血/再灌注损伤,急性肺损伤,急性呼吸窘迫综合征(acute respiratory distress syndrome),败血症(sepsis),癌症,妊娠并发症(pregnancy complication),和血液透析关联的血栓形成(hemodialysis-associated thrombosis)。
14.根据权利要求13的疫苗,其特征在于所述妊娠并发症是先兆子痫(preeclampsia),反复性自然流产(recurrent spontaneous abortion)或宫内生长迟缓(intra-uterinegrowth retardation)。
15.根据权利要求1-10中任一项的疫苗中包含的多肽或根据权利要求1-10中任一项的疫苗在制备用于治疗和/或预防补体介导的病症的组合物中的用途。
16.根据权利要求15的用途,其特征在于所述补体介导的病症是炎性疾病。
17.根据权利要求16的用途,其特征在于所述炎性疾病是慢性炎性疾病。
18.根据权利要求16的用途,其特征在于所述炎性疾病选自下组:年龄相关性黄斑变性(age-related macular degeneration,AMD),神经变性性病症,哮喘,动脉粥样硬化(atherosclerosis),血管炎(vasculitis),皮炎(dermatitis),溶血尿毒综合征(hemolytic uremic syndrome),类风湿性关节炎(rheumatoid arthritis),格巴二氏综合征(Guillain-Barre syndrome),多发性硬化(multiple sclerosis),抗磷脂综合征(antiphospholipid syndrome),溶血尿毒综合征,和系统性红斑狼疮(SLE)。
19.根据权利要求18的用途,其特征在于所述神经变性性病症是阿尔茨海默(Alzheimer)氏病,帕金森(Parkinson)氏病或亨丁顿(Huntington)氏病。
20.根据权利要求18的用途,其特征在于所述皮炎是银屑病(psoriasis)或荨麻疹(urticaria)。
21.根据权利要求15的用途,其特征在于所述补体介导的病症选自下组:缺血/再灌注损伤,急性肺损伤,急性呼吸窘迫综合征(acute respiratory distress syndrome),败血症(sepsis),癌症,妊娠并发症(pregnancy complication),和血液透析关联的血栓形成(hemodialysis-associated thrombosis)。
22.根据权利要求21的用途,其特征在于所述妊娠并发症是先兆子痫(preeclampsia),反复性自然流产(recurrent spontaneous abortion)或宫内生长迟缓(intra-uterinegrowth retardation)。
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- 2012-05-23 EP EP12169088.7A patent/EP2666785A1/en not_active Withdrawn
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2013
- 2013-05-23 WO PCT/EP2013/060618 patent/WO2013174920A1/en active Application Filing
- 2013-05-23 US US14/402,145 patent/US10344062B2/en not_active Expired - Fee Related
- 2013-05-23 CN CN201380035942.7A patent/CN104507966B/zh not_active Expired - Fee Related
- 2013-05-23 CA CA2874082A patent/CA2874082A1/en not_active Abandoned
- 2013-05-23 AU AU2013265239A patent/AU2013265239B2/en not_active Ceased
- 2013-05-23 JP JP2015513180A patent/JP6189424B2/ja not_active Expired - Fee Related
- 2013-05-23 EP EP13724587.4A patent/EP2852614B1/en not_active Not-in-force
- 2013-05-23 ES ES13724587.4T patent/ES2647138T3/es active Active
- 2013-05-23 PL PL13724587T patent/PL2852614T3/pl unknown
- 2013-05-23 DK DK13724587.4T patent/DK2852614T3/en active
- 2013-05-23 AR ARP130101796A patent/AR092836A1/es unknown
- 2013-05-23 CN CN201711326410.5A patent/CN107998386A/zh active Pending
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CN101193654A (zh) * | 2005-06-14 | 2008-06-04 | 赛托斯生物技术公司 | 抗原偶联物及其用途 |
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US20150166620A1 (en) | 2015-06-18 |
PL2852614T3 (pl) | 2018-02-28 |
JP2015518852A (ja) | 2015-07-06 |
US10344062B2 (en) | 2019-07-09 |
AR092836A1 (es) | 2015-05-06 |
CA2874082A1 (en) | 2013-11-28 |
CN107998386A (zh) | 2018-05-08 |
EP2852614A1 (en) | 2015-04-01 |
CN104507966A (zh) | 2015-04-08 |
EP2666785A1 (en) | 2013-11-27 |
WO2013174920A1 (en) | 2013-11-28 |
AU2013265239A1 (en) | 2015-01-22 |
EP2852614B1 (en) | 2017-09-13 |
AU2013265239B2 (en) | 2017-08-31 |
ES2647138T3 (es) | 2017-12-19 |
JP6189424B2 (ja) | 2017-08-30 |
DK2852614T3 (en) | 2017-10-23 |
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