CN116710484A - Wars中和抗体及其用途 - Google Patents
Wars中和抗体及其用途 Download PDFInfo
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- CN116710484A CN116710484A CN202180076632.4A CN202180076632A CN116710484A CN 116710484 A CN116710484 A CN 116710484A CN 202180076632 A CN202180076632 A CN 202180076632A CN 116710484 A CN116710484 A CN 116710484A
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Abstract
本发明涉及与色氨酰tRNA合成酶(Tryptophanyl‑tRNA Syntheta se，WARS)特异性结合的抗体或其片段。本发明的抗体或其片段与WARS特异性结合的能力非常优秀，而且与其他ARS类不具有交叉反应性，WARS检测及活性抑制能力突出，因此可以有效用于感染性疾病的诊断和/或治疗用途。
Description
技术领域
本发明涉及与WARS蛋白特异性结合的抗体及其用途。
背景技术
氨基酰tRNA合成酶(Aminoacyl-tRNA Synthetase，ARS)为介导氨基酸特异性地与tRNA(tRNA)结合的反应的酶，在蛋白质生成中起到中枢性作用。近来，已知ARS除其本质功能以外，还与细胞凋亡(Apoptosis)、血管生成(Angiogenesis)、炎症反应等多种生命现象相关。尤其，人色氨酰tRNA合成酶1(Tryptophanyl-tRNA Synthetase1，WARS1)的通常功能为与识别色氨酸的tRNA(tRNA)连接来合成蛋白质的氨基酰tRNA合成酶，近来的关注点是WARS1在宿主对感染的防御机制方面所起的作用。过去，本发明人报告了在感染后几分钟内单核细胞在不从头(de novo)合成的情况下立刻向细胞外空间分泌WARS1(Young HaAhn.et al.Secreted Tryptophanyl-tRNA Synth etase as a primary defence systemagainst infection.Nature Microbio logy 2:16191(2016))。
TLR4和TLR2通过作为耐性配体的功能来分泌的WARS1通过激活巨噬细胞来诱导先天性的免疫激活。并且，WARS1启动包括肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)、巨噬细胞炎性蛋白1α(MI P-1α)、白细胞介素8(IL-8)及γ干扰素(IFN-γ)在内的前炎症细胞因子及趋化因子的生成，诱发中性粒细胞的浸润。然后，WARS1基因表达被γ干扰素激活而保持WARS1的持续分泌。与该发现一致的是，WARS1在败血症患者的血液中升得很高，但在无菌慢性炎症障碍中却非如此，确认到无关乎革兰氏阳性及阴性细菌、病毒及霉菌等抗原体类型地分泌。
为了治疗由上述细菌、病毒和/或霉菌引起的感染性炎症疾病，可以考虑开发对它们的抗体的战略，但包括WARS1在内的ARS在蛋白质结构上有太多的相似点，通过免疫反应获得的抗体对其他ARS也显出交叉反应，因此无法生产高敏感度的抗体的情况很多。
因此，切实需要开发可以在不与其他ARS发生交叉反应的情况下只与WARS1特异性结合来有效中和WARS1的抗体。
上述背景技术中说明的事项仅用于增进对本发明的背景的理解，但不应认为上述事项相当于本发明所属技术领域的普通技术人员已知的现有技术。
发明内容
技术问题
本发明人多次致力于发掘在败血症等感染性疾病患者中显著增加表达量的与WARS特异性结合的抗体或其片段，结果发掘出与WARS特异性结合且不与其他ARS类发生交叉反应的WARS检测及表达抑制能力突出的抗体，从而完成本发明。
因此本发明的目的在于，提供与色氨酰tRNA合成酶(Tryptopha nyl-tRNASynthetase，WARS)特异性结合的抗体或其片段。
本发明的再一目的在于，提供编码上述抗体或其片段的多核苷酸。
本发明的另一目的在于，提供包含上述多核苷酸的载体。
本发明的还有一目的在于，提供由上述载体转化的细胞。
本发明的又一目的在于，提供与WARS特异性结合的抗体或其片段的制备方法，包括在表达多核苷酸的条件下培养细胞来回收多肽的步骤。
本发明的又一目的在于，提供WARS的特异性检测方法，包括使上述抗体或其片段、多核苷酸、载体或细胞与试样接触的步骤。
本发明的又一目的在于，提供WARS的特异性检测用组合物，包含上述抗体或其片段、多核苷酸、载体或细胞。
本发明的又一目的在于，提供用于诊断感染性疾病的组合物，包含上述抗体或其片段、多核苷酸、载体或细胞。
本发明的又一目的在于，提供用于预防或治疗感染性疾病的药物组合物，包含上述抗体或其片段、多核苷酸、载体或细胞。
本发明的又一目的在于，提供用于预防或治疗感染性疾病的药物组合物，包含上述抗体或其片段、多核苷酸、载体或细胞以及额外的抗生素。
本发明的其他目的及优点将通过下述详细说明、发明要求保护范围以及附图得到进一步明确。
技术方案
根据本发明的一实施方式，本发明提供与色氨酰tRNA合成酶特异性结合的抗体或其片段。
本发明人多次致力于发掘在败血症等感染性疾病患者中显著增加表达量的与WARS特异性结合的抗体或其片段，结果发掘出与WARS特异性结合且不与其他ARS类发生交叉反应的WARS检测及活性抑制能力突出的抗体。
本说明书中的术语“WARS”是指色氨酰tRNA合成酶(Tryptoph anyl-tRNASynthetase)，也称为色氨酸tRNA连接酶(Tryptophan-tRN A Ligase)、TrpRS、WRS等。WARS为介导氨基酸色氨酸与tRNA的氨酰化(aminoacylation)反应的酶。WARS在人体中通过WARS基因来编码，蛋白质的氨基酸序列与信使核糖核酸(mRNA)碱基序列公知为国际基因库登陆号(Genbank accession Number)NP_004175.2(蛋白质)、国际基因库登陆号NM_004184.3(信使核糖核酸(mRNA)碱基序列)等。WARS具有细胞质形式(Cytoplasmic form)(WARS1或色氨酰tRNA合成酶1(Tryptophanyl-tRNA Synthetase 1)，细胞质(C ytoplasmic))与线粒体形式(Mitochondrial form)(WARS2或色氨酰t RNA合成酶2(Tryptophanyl-tRNASynthetase 2)，线粒体(Mitochon drial))的两种同型(Isoform)。
根据本发明的优选实例，本发明的WARS为WARS1。
本说明书中的术语“抗体”只要是本发明所属技术领域的术语就可以在本说明书中交换来使用，是指具有与抗原特异性结合的抗原结合部位的分子。本说明书中使用的术语包括所有抗体以及任意片段(即，“抗原结合部分”)或其单链。根据本发明的一实例，“抗体”是指包含通过二硫键相结合的至少两个重链(H)与两个轻链(L)的糖蛋白或其抗原结合部分。根据本发明的再一实例，“抗体”是指包含单一可变区(结构域)，例如包含VH结构域的单链抗体。各重链由重链可变区(VH)与重链恒定区组成。通常，重链恒定区包含CH1、CH2及CH3三个结构域，各轻链包含轻链可变区(简称为VL)与轻链恒定区。轻链恒定区包含一个结构域，即，包含CL。
VH及VL区域还可以细分为命名为互补决定区(CDR)的超可变区，它位于命名为骨架区(FR)的进一步加固的区域之间。各个VH及VL由三个CDR与四个FR组成，它们以FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4的顺序从氨基-末端向羧基-末端排列。重链及轻链的可变区包含与抗原相互作用的结合结构域。抗体的恒定区介导免疫系统的多种细胞(例如效应细胞)及包括经典补体系统的第一成分(C1q)在内的免疫球蛋白与宿主组织或因子的结合。
本说明书中的术语“Fc”是指介导包括与位于免疫系统的多种细胞(例如效应细胞)上的Fc受体或经典补体系统的第一成分(C1q)的结合在内的免疫球蛋白与宿主组织或因子的结合的抗体重链的C-末端区域。因此Fc包含除第一恒定区免疫球蛋白结构域(例如CH1或C L)以外的抗体的恒定区。在IgG、IgA及IgD抗体同型中，Fc区域包含源自抗体的两个重链的第二(CH2)及第三(CH3)恒定区的两个相同的蛋白质片段，IgM及IgE的Fc区域在各个多肽链中包含三个重链恒定区(CH结构域2-CH结构域4)。本说明书中提及的Fc可以为包括任意的同种异性变异体在内的自生序列Fc或Fc变异体(例如非自然产生的Fc)。并且，Fc还可以为称作“Fc融合蛋白”(例如，抗体或免疫偶联物)的“包含Fc区域的结合蛋白”等包含Fc的蛋白质多肽。
抗体可以具有免疫球蛋白分子的任意类型(例如，IgG、IgE、Ig M、IgD、IgA或IgY)或任意亚型(例如人类中的IgG1、IgG2、IgG3及IgG4或小鼠中的IgG1、IgG2a、IgG2b及IgG3等)。免疫球蛋白，例如IgG1以几个氨基酸相异的几种同种异型的方式存在。本说明书中提及的抗体可以任意源自通常已知的同型、类型、亚型或同种异型中。在特定具体例中，本说明书提及的抗体属于IgG1、IgG2、IgG3或IgG4亚型或它们的任意同种异型。在特定具体例中，抗体属于IgG2、IgG4或IgG2/IgG4亚型。
抗体的例包括：自然产生或非自然产生的抗体；单克隆或多克隆抗体；嵌合或人类化抗体；人或非人抗体；完全合成抗体；单链抗体；但特异性抗体；多特异性抗体(包括双特异性抗体或三特异性抗体)。
本说明书中的术语“中和抗体”是指当抗原体或感染性粒子浸透身体时通过中和在生物学上带来的影响来防御细胞的抗体。中和抗体为对于病毒、细菌、霉菌及微生物毒素的后天免疫系统的免疫反应的一部分。中和抗体以特化于感染性粒子的表面结构的形态生成，通过结合来防止感染性抗原与宿主细胞之间的相互作用，从而实现免疫。
本说明书中的术语“片段”解释为包括保有与抗原特异性结合能力的抗体的一个以上片段或上述“保有与抗原特异性结合能力的抗体的一个以上片段”与其他分子(相同或包含其他抗体的一部分(Fc等))结合的所有形态。片段的例包括：由VL、VH、CL及CH1结构域构成的一价片段(Fab片段)；在铰链区包含通过二硫键连接的两个Fab片段的二价片段(F(ab')2片段)；由VH及CH1结构域构成的Fd片段；由抗体一个臂(arm)的VL及VH结构域以及二硫键连接的Fv(sdFv)构成的Fv片段；由VH结构域构成的dAb片段；以及可以通过分离的互补决定区(CDR)或接头选择性地连接的两个以上的互补决定区的组合。并且，VL与VH区域形成对可以通过接头连接来组成形成一价分子(单链Fv(scFv))的单蛋白质链。这样的单链抗体也包括在抗体的片段内。并且，上述抗体或抗体的片段包括：包含两个重链分子与两个轻链分子的四聚体抗体；抗体轻链单体；抗体重链单体；抗体轻链二聚体、抗体重链二聚体；细胞内抗体；一价抗体；骆驼抗体；以及单结构域抗体抗体(sdAb)。
根据本发明的优选实例，本发明的抗体的片段为选自由Fab、F(a b')2、Fd、sdFv、Fv、dAb、scFv、sdAb及四聚体组成的组中的片段或上述片段与Fc的结合形式。
根据本发明的优选实例，本发明的抗体或其片段包含重链可变区(VH)，上述重链可变区包含序列表中序列3的重链CDR1、序列表中序列4的重链CDR2及序列表中序列5的重链CDR3。
根据本发明的优选实例，本发明的抗体或其片段包含轻链可变区(VL)，上述轻链可变区包含序列表中序列6的轻链CDR1、序列表中序列7的轻链CDR2及序列表中序列8的轻链CDR3。
根据本发明的优选实例，本发明的由上述CDR序列构成的抗体(包括其片段)与WARS特异性结合，与扩ARS家族(family)在内的其他蛋白质不具有交叉反应性。
根据本发明的优选实例，本发明的抗体或其片段包含序列表中序列1的重链可变区及序列表中序列2的轻链可变区。
根据本发明的优选实例，本发明的抗体或其片段包含选自由序列表中序列21的CL序列、序列表中序列22的CH1序列、序列表中序列23的铰链(Hinge)序列、序列表中序列24的CH2序列及序列表中序列25的CH3序列组成的组中的一种以上序列。
根据本发明的优选实例，本发明的抗体或其片段包含序列表中序列21的CL序列、序列表中序列22的CH1序列、序列表中序列23的铰链序列、序列表中序列24的CH2序列及序列表中序列25的CH3序列。
根据本发明的再一实施方式，本发明提供编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞。
本说明书中的术语“多核苷酸”或“核酸分子”包括脱氧核糖核酸(DNA)分子及核糖核酸(RNA)分子。本发明的多核苷酸或核酸分子可以为单离的或重组的，不仅包括单链及双链形态的脱氧核糖核酸和核糖核酸，还包括与之对应的互补序列。在天然生成原则下的单离的核酸的情况下，“单离的核酸”是指从存在于核酸单离的个体的基因组的周边基因序列中分离的核酸。在从模板上通过酶或化学方法合成的核酸，例如聚合酶链式反应(PCR)产物、互补脱氧核糖核酸(c DNA)分子或寡核苷酸的情况下，通过这样的过程产生的核酸可以理解为单离的核酸分子。单离的核酸分子示出单独的片段形态或更大的核算结构物的核酸分子。当核酸与其他核酸序列以功能关系配制时，形成“可操作地连接”。例如，当前序列或分泌前导序列(leader)的脱氧核糖核酸表达为分泌多肽前的形态的前蛋白(preprotein)时，与多肽的脱氧核糖核酸可操作地连接，当给多肽序列的转录带来影响时，启动子或增强子与编码序列可操作地连接，或者当核糖体接合部分以促进翻译的方式配置时，与编码序列可操作地连接。通常，“可操作地连接”是指以相邻的方式设置连接的脱氧核糖核酸序列，在分泌前导序列的情况下，是指相邻来存在于相同的阅读框架内。但增强子没有必要相邻来设置。连接可以在便利的限制酶部位通过结扎来实现。若不存在这样的部位，则可以根据通常的方法使用合成寡核苷酸适配器或接头。
本说明书中的术语“载体”是指为了向能够复制上述多核苷酸(核酸)序列的细胞导入而能够插入多核苷酸序列的传输体。多核苷酸序列为外源性的(Exogenous)或异种(Heterologous)。载体可以为质粒、粘粒载体及病毒载体(逆转录病毒、腺病毒及腺相关病毒载体等)，但不限定于此。相关从业者可以通过标准的重组技术构筑载体(Maniatis,etal.,Molecular Cloning,A Laboratory Manual,Cold Spring Harbo r Press,ColdSpring Harbor,N.Y.,1988；及Ausubel et al.,In:Curren t Protocols in MolecularBiology,John,Wiley&Sons,Inc,NY,1994等)。
本说明书中的术语“表达载体”是指包含编码所要转录的基因产物中的至少一部分的核苷酸序列的载体。在部分情况下，其后核糖核酸分子翻译为蛋白质、多肽或肽。表达载体中可以包含多种调节序列。除调节转录及翻译的调节序列以外，载体及表达载体中还可以同时包含提供其他功能的核酸序列。
本说明书中的术语“细胞”包括真核细胞和原核细胞，是指能够复制上述载体的载体或者能够可以表达通过上述载体编码的基因的任意能够转化的细胞。细胞可以通过上述载体被转染(Transfected)、转导(Transduced)或转化(Transformed)，这是指外源性多核苷酸(核酸分子)向宿主细胞内传输或导入的过程。本说明书中的术语“转化”以包括上述转染和转导的含义来使用。
本发明的(宿主)细胞不受限制，优选地，可以利用细菌细胞、昆虫细胞或哺乳动物细胞，更优选地，昆虫细胞的可以利用Sf9，哺乳动物细胞可以利用HEK293细胞、HeLa细胞、ARPE-19细胞、RPE-1细胞、HepG2细胞、Hep3B细胞、Huh-7细胞、C8D1a细胞、Neuro2A细胞、CHO细胞、MES13细胞、BHK-21细胞、COS7细胞、COP5细胞、A549细胞、MCF-7细胞、HC70细胞、HCC1428细胞、BT-549细胞,PC3细胞、LNCaP细胞、Capan-1细胞、Panc-1细胞、MIA PaCa-2细胞、SW480细胞、HCT166细胞、LoVo细胞、A172细胞、MKN-45细胞、MKN-74细胞、Kato-III细胞、NCI-N87细胞、HT-144细胞、SK-MEL-2细胞、SH-SY5Y细胞、C6细胞、HT-22细胞、PC-12细胞、NIH3T3细胞等。
优选地，本发明的(宿主)细胞为除胚胎干细胞以外的细胞。
根据本发明的优选实例，本发明的宿主细胞为单离或分离的宿主细胞。
根据本发明的还有一实施方式，本发明提供制备与WARS特异性结合的抗体或其片段的方法，包括在表达多核苷酸的条件下培养上述细胞来回收多肽的步骤。
在本发明的制备方法的内容中，有关抗体或其片段、核苷酸、载体、细胞等的内容与上述内容相同。上述制备方法的多肽可以为本发明的抗体或其片段(抗原结合片段)或者包含本发明的抗体或其片段。
根据本发明的优选实例，本发明的制备方法包括：步骤(a)，使用包含上述多核苷酸的表达载体(重组表达载体)转化宿主细胞；步骤(b)，培养转化的宿主细胞来生产抗体或其片段；以及(c)回收从宿主细胞中生产的抗体或其片段。
根据本发明的另一实施方式，本发明提供WARS的特异性检测方法，包括使上述抗体或其片段、多核苷酸、载体或细胞与试样接触的步骤。
根据本发明的还一实施方式，本发明提供WARS的特异性检测用组合物，包含上述抗体或其片段、多核苷酸、载体或细胞。
本发明的抗体或其片段与WARS特异性结合，例如，在检测特定细胞、组织或血清内WARS蛋白表达并定量的诊断分析中有效。
本说明书中的术语“试样”可以为从受试者(例如要诊断是否患有感染性疾病或感染并发症的受试者)中采集的细胞，或者也可以为组织、血液、全血、血清、血浆、脑脊髓液等。利用上述抗体或其片段、多核苷酸、载体或细胞来检测蛋白质的方法有蛋白质印迹法、免疫印迹法、斑点印迹法、免疫组织化学染色(Immunohistochemistry)、酶联免疫分析(ELISA)、放射免疫测定法(Radioimmunoassay)、竞争结合分析、免疫沉淀法等，但不限定于此。
根据本发明的又一实施方式，本发明提供用于诊断感染性疾病的组合物，包含上述抗体或其片段、多核苷酸、载体或细胞
根据本发明的又一实施方式，本发明提供感染性疾病的诊断试剂盒，包含上述抗体或其片段、多核苷酸、载体或细胞
根据本发明的又一实施方式，本发明提供用于预防或治疗感染性疾病的药物组合物，包含上述抗体或其片段、多核苷酸、载体或细胞。
根据本发明的又一实施方式，本发明提供用于治疗由WARS的过度表达引起的疾病的药物组合物，包含上述抗体或其片段、多核苷酸、载体或细胞。
在本发明的诊断用组合物或药物组合物的内容中，有关抗体或其片段、核苷酸、载体、细胞等的内容与上述内容相同。
本发明要预防、改善或治疗的疾病不受限制，优选地，包括与W ARS的表达或活性相关的所有疾病。
上述与WARS的表达或活性相关的疾病不受限制，优选地，包括感染性疾病。
WARS的表达水平通过细菌、病毒或霉菌(Fungi)等的感染从感染初期即急速增加，据报告，在表现出肺炎或败血症等感染并发症的情况下，相对于正常人对照组，表达水平显著增加。进而，在败血症患者的情况下，WARS的表达水平与败血症的疾病严重程度及预后有着很高的关联性，由于WARS只在感染性炎症中增加，因此可以迅速正确地将感染性炎症疾病与非感染性炎症疾病区分开来，作为新发的感染性疾病及感染并发症的诊断标记物的价值很高。尤其，在由细菌或霉菌感染引起的败血症或败血症休克患者的血清中，WARS的量比健康的正常人对照组的血清显著增加，在分别由革兰氏阴性细菌、革兰氏阳性细菌感染引起的败血症患者中，WARS的增加倾向在统计学上没有显著差异，因此WAR均可在由革兰氏阴性细菌、革兰氏阳性细菌或霉菌感染引起的败血症诊断中有效使用。并且，比起败血性休克患者，WARS的水平在败血症患者中更为增加，因此WARS的表达水平与败血症的疾病严重程度相关。即，WARS的表达水平越高，可判断为败血症的症状越严重(韩国公开专利第10-2017-0027313)。即，在利用本发明的WARS特异性抗体的情况下，可以通过在生物学试样中以高准确率检测WARS的表达程度来给感染性疾病或感染并发症的诊断提供有效信息，从而可以预测其预后。
本发明的抗体或其片段可以提供为分析试剂盒或诊断试剂盒，上述试剂盒只要是本发明所属技术领域中已知的提供具有抗体或特定结合结构域的肽作为构成品的分析试剂盒，其种类就不受特别限制，例如，包括蛋白质印迹法、酶联免疫吸附测定(ELISA)、放射免疫分析法、放射免疫扩散法、双向免疫扩散法、火箭免疫电泳、组织免疫染色、免疫沉淀分析法、补体结合试验、流式细胞荧光粉选(FACS)或蛋白芯片用试剂盒等。
本发明的感染性疾病有肺炎、肺结核、结核、败血症(Sepsis)、败血性休克(SepticShock)、沙门氏菌病(Salmonellosis)、食物中毒、伤寒、尿路感染、膀胱炎、肾盂肾炎、尿道炎、前列腺炎、上呼吸道感染、中耳炎、获得性免疫缺陷综合征(AIDS)病毒及冠状病毒等病毒性感染性疾病等，但不限定于此。
上述冠状病毒包括重症急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)、作为新型冠状病毒肺炎(C OVID-19，corona virus disease 19)的病原体的严重急性呼吸系统综合征冠状病毒2型(SARS-CoV-2)、传染性支气管炎病毒(Infectious bronchitis virus，IBV)、猪传染性胃肠炎病毒(TGE)、猪流行性腹泻病毒(PED)、牛冠状病毒(BCoV)、猫/狗冠状病毒(FCoV/CCoV)、小鼠肝炎病毒(MHV)等，但不限定于此。
根据本发明的优选实例，上述感染性疾病为感染性炎症疾病。
感染性炎症疾病为伴有炎症的感染性疾病，可以通过抑制感染的病原抗原体(病毒、细菌、霉菌等)的增殖，或者通过调节炎症来实现预期的治疗效果。
根据本发明的优选实例，上述感染性炎症疾病为败血症或败血性休克。
上述败血症包括初期败血症、重症败血症、败血症性休克及败血症并发的多器官功能障碍综合征(Multiple Organ Dysfunction Syndro me，MODS)、弥散性血管内凝血(DIC)、急性呼吸窘迫综合征(AR DS)或急性肾衰竭(AKI)的发病，但不限定于此。
本发明的组合物不仅能够以高敏感度检测出WARS，还可以显著降低因感染增加的WARS的量，可以降低炎性细胞因子(例如白细胞介素8、白细胞介素6、巨噬细胞炎性蛋白1α、肿瘤坏死因子α等)的表达量，从而具有可以同时实现诊断和治疗的优点。
本说明书中的术语“细胞因子”是指从免疫细胞中分泌的蛋白质免疫调节剂，以包括趋化因子(Chemokine)在内的含义来使用。
上述细胞因子包括白细胞介素8、白细胞介素6、巨噬细胞炎性蛋白1α、γ干扰素、肿瘤坏死因子α、白细胞介素1β(IL-1β)、白细胞介素10(IL-10)等。
根据本发明的优选实例，上述药物组合物包含药剂学上可接受的载体。
根据本发明的优选实例，本发明的药物组合物包含上述抗体或其片段、多核苷酸、载体或细胞以及额外的抗生素。
优选地，上述抗生素包括庆大霉素(Gentamycin)、氨苄青霉素(A mpicillin)、卡那霉素(Kanamycin)、氯霉素(Chloramphenicol)、链霉素(Streptomycin)、四环素(Tetracycline)、红霉素(Erythromycin)、万古霉素(Vancomycin)、青霉素(Penicillin)、奇霉素(Spectinomyci n)、氯霉素(Chloramphenicol)、磺胺嘧啶(Sulfadiazine)、甲氧苄啶(Trimethoprim)，但不限定于此。
根据本发明的一实施例，可以通过给药抗生素后给药本发明的W ARS特异性抗体一次以上，或者与抗生素组合来给药，或者给药上述抗体后给药抗生素的方式来增加患有感染性疾病的个体的存活率。
本发明的药物组合物中包含的药剂学上可接受的载体为配制时通常使用的载体，包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油，但不限定于此。除上述成分以外，本发明的药物组合物还可以包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、助悬剂、保存剂等。适当的药剂学上可接受的载体及制剂在Remington's Pharmaceutical Sciences(19th ed.,1995)中有详细记载。
本发明的药物组合物可以口服或胃肠外给药，优选地，可以胃肠外给药，例如，可以通过静脉内注射、经皮给药、皮下注射、肌肉内注射、玻璃体内注射(IntravitrealInjection)、视网膜下注射(Subretin al Injection)、脉络膜上腔注射(SuprachoroidalInjection)、滴眼给药(Eye Drop Administration)、脑室内注射(Intracerebroventricular Inj ection)、脊髓腔内注射(Intrathecal Injection)、羊膜内注射(Intraamn iotic Injection)、动脉内注射(Intraarterial Injection)、关节腔内注射(I ntraarticular Injection)、心脏内注射(Intracardiac Injection)、阴茎海绵体内注射(Intracavernous Injection)、脑内注射(Intracerebral Inject ion)、脑池内注射(Intracisternal Injection)、冠状动脉内注射(Intraco ronary Injection)、颅内注射(Intracranial Injection)、硬膜内注射(Int radural Injection)、硬膜外注射(Epidural Injection)、海马内注射(In trahippocampal Injection)、鼻腔内注射(Intranasal Injection)、骨髓腔内注射(Intraosseous Injection)、腹腔内注射(Intraperitoneal Injectio n)、胸腔内注射(Intrapleural Injection)、椎管内注射(Iintraspinal Inj ection)、胸廓内注射(Intrathoracic Injection)、胸腺内注射(Intrathy mic Injection)、子宫内注射(Intrauterine Injection)、阴道内注射(Intravaginal Injection)、心室内注射(Intraventricular Injection)、膀胱内注射(Intravesical Injection)、结膜下注射(Subconjunctival Injection)、肿瘤内注射(Intratumoral Injection)、病灶注射及腹腔注射(Intraperit oneal Injection)等来给药。
本发明的药物组合物的适当给药剂量根据配制方法、给药方式、患者的年龄、体重、性别、疾病状态、饮食、给药时间、给药途径、代谢速度及反应敏感度等多种因素的不同而不同，通常熟练的医生可以轻易决定及处方希望获得的治疗或预防的有效的给药剂量。
能够以诊断、或预防、改善、治疗为目的向对象给药药剂学上的有效量的本发明的组合物。上述“药剂学上的有效量”是指能够显出相对于阴性对照组更为以上的反应的量。可以通过单剂量(Single Do se)向患者给药本发明的抗体或其片段的总有效量，也可以通过以多剂量(Multiple Dose)长期给药的分次治疗方案(Fractionated Treatmen tProtocol)来给药。本发明的抗体或其片段向人体给药的一日给药剂量通常为0.0001mg/kg-100mg/kg。但是，上述本发明的抗体或其片段的剂量不仅是考虑药物组合物的给药途径及治疗次数，还使考虑患者的年龄、体重、健康状态、性别、疾病的严重程度、饮食及代谢率等多种因素后确定的对患者的有效给药剂量，从这些方面考虑时，本发明所属技术领域的普通技术人员可以根据本发明的特定用途来确定上述本发明的抗体或其片段的有效给药剂量。
本发明的药物组合物可以根据本发明所属技术领域的普通技术人员轻易实施的方法，利用药剂学上可接受的载体和/或赋形剂配制来制备为单位剂量形态或者装入多剂量容器内制备。在此情况下，剂型可以为油或水性溶剂中的溶液、悬浊液或乳化液形态，或者也可以为提取剂、粉末剂、颗粒剂、片剂或胶囊剂形态，还可以包含分散剂或稳定剂。
根据本发明的又一实施方式，本发明提供上述抗体或其片段、多核苷酸、载体或细胞的治疗用途(for use in therapy)。
根据本发明的又一实施方式，本发明提供疾病的治疗方法，包括向对象(subject)给药有效量的上述抗体或其片段、多核苷酸、载体或细胞的步骤。
在本发明中，“对象”是指需要给药本发明的组合物的个体，给要对象可以不受限地为哺乳类、鸟类、爬虫类、两栖类、鱼类等。
根据本发明的优选实例，本发明的治疗方法还可以包括给药抗生素的步骤。
根据本发明的优选实例，本发明的治疗方法包括与上述抗体或其片段、多核苷酸、载体或细胞同时给药抗生素，或者在给药抗生素之前或之后给药一次以上的步骤。
优选地，上述抗生素包括庆大霉素、氨苄青霉素、卡那霉素、氯霉素、链霉素、四环素、红霉素、万古霉素、青霉素、奇霉素、氯霉素、磺胺嘧啶、甲氧苄啶，但不限定于此。
根据本发明的一实施例，可以通过给药抗生素后给药本发明的W ARS特异性抗体一次以上，或者与抗生素组合来给药，或者给药上述抗体后给药抗生素等方式来增加患有感染性疾病的个体的存活率。
发明的效果
本发明的特征及优点简述如下：(i)本发明提供与色氨酰tRNA合成酶特异性结合的抗体或其片段。(ii)本发明的抗体或其片段与WAR S特异性结合的能力非常优秀且与其他ARS类不具有交叉反应性，WA RS检测及活性抑制能力突出，因此可以有效用于感染性疾病的诊断和/或治疗用途。
附图说明
图1a及图1b为用于将GKB101转化为IgG抗体的载体的示意图。图1a为重链载体，图1b为轻链载体。
图2a及图2b为测量GKB101的靶向结合力的结果。图2a为使用GE Biacore T200来测量GKB101对人及小鼠的WARS1的结合力的结果，图2b为通过酶联免疫吸附测定的吸光度测量结果。
图3a及图3b为利用GKB101在体外(in vitro)检验中和能力的结果。图3a示出减少肿瘤坏死因子α的分泌的结果，图3b示出减少m CXCL2(人白细胞介素8的同源物)的分泌的结果。
图4a至图4k为确认WARS1特异性抗体给细菌感染的小鼠的存活率带来影响的结果。图4a为向通过向小鼠的腹腔注入盲肠浆液来诱发重症败血症的小鼠注射磷酸盐缓冲溶液(PBS)或GKB101后分析存活率的结果。图4b及图4c为给药GKB101后确认WARS1浓度减少的结果(图4b：血浆(Plasma)，图4c：腹腔液)。图4d至图4g为给药G KB101后确认腹腔液内分泌的白细胞介素8(图4e)、白细胞介素6(图4f)、巨噬细胞炎性蛋白1α(图4d)、肿瘤坏死因子α(图4g)的浓度减少的结果。图4h至图4k为给药GKB101的后确认谷丙转氨酶(AL T)(图4h)、谷草转氨酶(AST)(图4i)、尿素氮(BUN)(图4j)、肌酐(Creatinine)(图4k)的浓度相对减少的结果(圆形表示正常(Nor mal)组；方块表示磷酸盐缓冲溶液组；三角形表示GKB101组)。
图5a至图5k为确认WARS1特异性抗体给细菌感染的小鼠的存活率带来影响的结果。图5a为向通过向小鼠的腹腔注入盲肠浆液(Ceca l Slurry，CS)来诱发重症败血症的小鼠注射同型(Isotype)IgG或G KB101后分析存活率的结果。图5b及图5c为给药GKB101后确认W ARS1浓度减少的结果(图5b：血浆，图5c：腹腔液)。图5d至图5g为给药GKB101后确认腹腔液内分泌的白细胞介素8(图5e)、白细胞介素6(图5f)、巨噬细胞炎性蛋白1α(图5d)、肿瘤坏死因子α(图5g)的浓度减少的结果。图5h至图5k为给药GKB101的后确认谷丙转氨酶(图5h)、谷草转氨酶(图5i)、尿素氮(图5j)、肌酐(图5k)的浓度相对减少的结果。
图6a及图6b为利用重症败血症小鼠模型来检验GKB101与抗生素的联合用药效果的结果。图6a示出庆大霉素与GKB101的注射方案，图6b示出注射庆大霉素与GKB101后随时间的存活率曲线图。
图7a至图7g为利用狨猴内毒素血症模型(Endotoxemia model)验证GKB101的功效的结果。图7a示出注射磷酸盐缓冲溶液和GKB101的方案，图7b至图7e示出使用脂多糖(LPS)诱导后磷酸盐缓冲溶液给药组或GKB101给药组随时间的体温(图7b)、体重(图7c)、血液内白细胞(WBC)(图7d)及中性粒细胞(Neutrophil)(图7e)的变化。图7f示出随着GKB101的给药的血浆内WARS1的水平，图7g为测量肿瘤坏死因子α的水平的结果。
具体实施方式
以下，通过实施例更为详细地说明本发明。这些实施例仅用于更为具体地说明本发明，本发明所属技术领域的普通技术人员应该自明的是，根据本发明的要旨，本发明的范围不限定于这些实施例。
实施例
实施例1.scFv抗体向IgG1抗体的转换
将包含含有重链CDR1(序列表中序列3)、重链CDR2(序列表中序列4)、重链CDR3(序列表中序列5)的重链可变区(Heavy chain variable region，序列表中序列1)及含有轻链CDR1(序列表中序列6)、轻链CDR2(序列表中序列7)、轻链CDR3(序列表中序列8)的序列表中序列2的轻链可变区(Light chain variable region)的scFv抗体筛选为与WARS1(序列表中序列26)特异性结合的scFv抗体。向重链载体(Heavy chain vector)(图1a)和轻链载体(Light chainvector)(图1b)插入(insertion)筛选的scFv抗体来克隆(cloing)质粒脱氧核糖核酸载体(plasmid DNA vector)。首先通过聚合酶链式反应扩增编码scFv的多核苷酸。用来扩增上述scFv的CDR区域的基因的引物的碱基序列如下：正向(Forward)(gtggccacagcggccgatgtccactcggaagtacagttggtcgaaagtggc，序列表中序列9)，反向(Reverse)(gaagaccgatgggcccttggtgctagccgatgagacggtcactaaagtgcc，序列表中序列10)。
用来扩增scFv的VL区域的基因的引物的碱基序列如下：正向(gccacagcggccgatgtccactcggacattcaaatgacgcagagtccctc，序列表中序列11)，反向(gaagacagatggtgcagccacagatcttttaatttccactttagttccctgcc，序列表中序列12)。
用于制备利用上述scFv抗体的单克隆抗体(以下命名为GKB101)的IgG转换(conversion)方法如下。
用于GKB101的IgG转换的重链(Heavy chain)和轻链(Lightchain)分别在作为表达赫赛汀(Herceptin)的母载体的pOptiVEC和pcDNA 3.3中扩增各自的基因(图1a及图1b)。在上述CH(VH3-23)与CL区域的基因的扩增过程中使用的引物碱基序列如下：CH正向(ggcactttagtgaccgtctcatcggctagcaccaagggcccatcggtcttc，序列表中序列13)，CH反向(gccactttcgaccaactgtacttccgagtggacatcggccgctgtggccac，序列表中序列14)，CL正向(ggcagggaactaaagtggaaattaaaagatctgtggctgcaccatctgtcttc，序列表中序列15)，CL反向(gagggactctgcgtcatttgaatgtccgagtggacatcggccgctgtggc，序列表中序列16)。
用于GKB101的IgG转换的Fab2(VH-1-69)通过聚合酶链式反应来扩增，插入(Insert)其利用VH1-69_正向(gtggccacagcggccgatgtccactcgcaagttcagctggtccagagcggc，序列表中序列17)，VH1-69_反向(gaagaccgatgggcccttggtgctagccgatgagacggtaaccagagtaccc，序列表中序列18)，载体(Vector)利用CH1-69_正向(gccgctctggaccagctgaacttgcgagtggacatcggccgctgtggccacc，序列表中序列19)，CH1-69_反向(gggtactctggttaccgtctcatcggctagcaccaagggcccatcggtcttc，序列表中序列20)。
各个载体模板(Vector template)(pcDNA3.3-Herceptin_CL、pOptiVEC-Herceptin_CH)与插入模板(Insert template)(scFv,Fabphage vector)利用上述引物(各10pmol)在95℃/3min；95℃/30sec；60℃/30sec；72℃/30sec；30次循环(cycles)；72℃/5min的条件下进行聚合酶链式反应来扩增用于GKB101转换的GKB101的VH、VL、赫赛汀表达载体的CH、CL以及VH1-69基因。利用DpnI限制酶向用来生产IgG的载体插入聚合酶链式反应产物。将上述内容中制备的包含编码包含scFv的可变区的IgG的轻链和重链的脱氧核糖核酸的载体共同转化到Expi293F细胞中来使轻链和重链在细胞内一同表达。
实施例2.利用瞬时转染和柱(Transient transfection and column)的分离纯化
为了通过临时表达系统的蛋白质纯化，使用了ExpiHEK293(赛默飞世尔公司(Thermofisher))细胞株和Freestype293表达系统(expression media)(赛默飞世尔公司)。转染(Transfection)使用了Expifectamine 293(赛默飞世尔公司)试剂(reagent)和GKB101的重链与轻链的比例为1∶1的质粒脱氧核糖核酸(plasmid DNA)。转染后，振荡培养细胞5天，通过离心分离细胞培养液来只回收上清液来在蛋白质的分离及纯化过程中使用。将回收的上清液上样到Hitrap MabselectSure柱子(selectSure column)(GE医疗生命科学公司(GE Healt hcare Life Sciences))后，使用磷酸盐缓冲溶液洗涤(wash)来去除非特异性结合后，使用100mM的柠檬酸盐缓冲液(Citrate buffer)(p H3.0)+50mM的氯化钠(NaCl)一次分离特异性地结合在柱(column)的蛋白质。将通过快速蛋白液相色谱(FPLC)获得的洗脱产物(Elute)上样到体积排除色谱(Size Exclusion Chromatography)(GE医疗生命科学公司)来获得高纯度的GKB101。通过临时表达系统的最佳条件获得的GKB101的最终收率以500ml的细胞培养液为基准为总37mg，内毒素为0.002EU/g的水平。
通过上述过程制备的GKB101抗体的序列如下。
表1.GKB101抗体的序列
实施例3.测定GKB101的靶向结合力
1)表面等离子共振：利用S系列传感器CM5芯片(Series S Sensor CM5 Chip)(GE医疗生命科学公司)和GE Bioacore T200来测定结合力。缓冲溶液使用HBS-EP(GE医疗生命科学公司)，以30μl/min的流速注入GKB101或缓冲液的连续稀释液1分钟-10分钟后，根据分析物洗涤20分钟。
2)酶联免疫吸附测定：以1μg/ml的浓度将GKB101涂敷在96孔培养板(Maxisorp牌，赛默飞世尔公司)后，使用包含1％的牛血清白蛋白(BSA)的磷酸盐缓冲溶液在常温下封闭1小时。将重组WARS1蛋白浓度依赖地稀释并放入涂敷的各孔中在常温下反应1小时后，使用磷酸盐吐温缓冲溶液(PBST，磷酸盐缓冲溶液+吐温(Tween)20)洗涤4次。向各孔中放入抗WARS1抗体(Abfrontier公司)在常温下反应1小时后，使用磷酸盐吐温缓冲溶液洗涤4次。使用附着有辣根过氧化物酶(HRP)的二抗(抗人IgG(anti-Human IgG)，细胞信号传导公司(cell-signaling))反应1小时后，使用磷酸盐吐温缓冲溶液洗涤。使用3,3',5,5'-四甲基联苯胺底物(TMB substrate)(BD公司)显色后，在490nm的波长处测量吸光度(VersaMax酶标仪(Microplate reader))。
3)免疫印迹法(Immunoblot)：将分别使用20ng的WARS1人及小鼠重组蛋白和脂多糖刺激24小时的人单核细胞细胞株THP-1与小鼠巨噬细胞株J774.1A的细胞培养上清液各30μg上样到8％的十二烷基磺酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)后，转移到(transfer)到聚偏二氟乙烯膜(PVDF membrane)(密理博公司(Millipore))。使用1ug/ml的GKB101反应1小时后，使用磷酸盐吐温缓冲溶液(磷酸盐缓冲溶液+吐温20)洗涤膜(Membrane)三次。使用二抗(抗人IgG辣根过氧化物酶(anti-human IgG HRP)，密理博公司)反应一小时后，使用磷酸盐吐温缓冲溶液洗涤三次。使用增强型化学发光试剂(ECL)(bright ECL，爱德万塔公司(Advanta))显色(LAS-4000，富士公司(Fujifilm))。
4)结果：测量并比较GKB101对重组WARS1蛋白的结合力的结果，在酶联免疫吸附测定和表面等离子共振(SPR)中都对人WARS1表现出强的结合力，在人重组蛋白中显出约0.2nM水平的结合力，在小鼠重组蛋白中显出约3.76nM的高结合力(图2a)。并且，在免疫印迹实验中，不仅是重组蛋白，也可以通过GKB101有效检测出人单核细胞及小鼠巨噬细胞株的培养上清液内的WARS1(图2b)。
实施例4.在体外检验WARS1特异性抗体的中和能力
为了确认作为WARS1特异性抗体的GKB101在体外是否具有中和能力，利用小鼠巨噬细胞株J774.1A进行实验。使用包含10％的胎牛血清(FBS)、1％的青霉素-链霉素(penicillin-streptomycin)的高葡萄糖杜氏改良伊戈尔培养基(high Glucose DMEM)(赛默飞世尔公司(Gibco))作为小鼠巨噬细胞的培养液。一天前，在48孔细胞培养板(纽恩科公司(Nunc))的每孔中放入8×104数量的细胞，在向细胞处理抗原-抗体混合物2小时前，更换为纯杜氏改良伊戈尔培养基。按照不同浓度混合200nM的重组蛋白WARS1与GKB101，在37℃的恒温箱中混合2小时后，分别向放入有各细胞的孔中追加放入混合物。约15小时后通过离心分离培养液来获得上清液，将其用在趋化因子配体2(CXCL2)(R&D公司)及肿瘤坏死因子α(Biolegend公司)的测量中。酶联免疫吸附测定根据各生产公司的说明书来进行。
在小鼠巨噬细胞中，GKB101对200nM的WARS1摩尔数比例依赖性地在肿瘤坏死因子α的分泌为1∶2.5和1∶5的比例中显著减少(图3a)。在mCXCL2(小鼠白细胞介素8的同源物(mouse IL-8homolog))中，在1:5与1∶2.5的比例中显出减少的倾向，在1∶2.5的比例中示出统计学上显著的差异(图3b)。所有结果均使用ANOVA统计软件进行分析。
实施例5.WARS1特异性抗体给细菌感染的小鼠的存活率带来的影响
向小鼠注入盲肠浆液(CS)来诱发重症败血症后，在腹腔注射盲肠浆液的4小时及20小时后分别静脉注射(i.v)2.5mg/kg的磷酸盐缓冲溶液或GKB101两次，实施直至60小时的存活分析。
WARS1及细胞因子分析：为了确认GKB101的WARS1中和能力，分别采取第5小时、第11小时、第18小时、第20小时的腹腔液及血液，利用其通过酶联免疫吸附测定测量WARS1(室内(in house))及肿瘤坏死因子α(Biolegend公司)、巨噬细胞炎性蛋白1α(R&D公司)、小鼠白细胞介素6(Biolegend公司)、mCXCL2(小鼠白细胞介素8的同源物，R&D公司)。除WARS1以外的细胞因子酶联免疫吸附测定根据生产公司的说明书进行。WARS1的测量如下：将GKB101以1μg/ml的浓度涂敷在96孔培养板(Maxisorp牌，赛默飞世尔公司)后，使用包含1％的牛血清白蛋白的磷酸盐缓冲溶液在常温下封闭1小时。将稀释血浆、腹腔液样品及小鼠重组蛋白的标准溶液放入各封闭的孔中在常温下反应1小时后，使用磷酸盐吐温缓冲溶液(磷酸盐缓冲溶液+吐温20)洗涤4次。向各孔中放入抗WARS1抗体(Abfrontier公司)在常温下反应1小时后，使用磷酸盐吐温缓冲溶液洗涤4次。使用附着有辣根过氧化物酶的二抗(抗人IgG，细胞信号传导公司)反应1小时后，使用磷酸盐吐温缓冲溶液洗涤。使用3,3',5,5'-四甲基联苯胺底物(BD公司)显色后，在490nm的波长处测量吸光度(VersaMax酶标仪)。
利用血液的生物化学检查：将一部分血液注入装有凝血激活剂(clot activator)的真空采血管(vacutainer)中后在常温下放置10分钟至15分钟来凝固。然后，通过血液生物化学分析仪(7180，日立公司(Hitachi)，日本(Japan))利用以3000rpm的转速离心分离10分钟获得的血清测量谷草转氨酶(aspartate aminotransferase，AST)、谷丙转氨酶(alanine aminotransferase，ALT)、血尿素氮(blood urea nitrogen，BUN)、肌酐。
为了确认GKB101给小鼠的存活率带来的影响，根据图4a的实验钙盐利用小鼠进行动物实验来实施存活分析。向小鼠注入盲肠浆液来诱发重症败血症后，在腹腔注射盲肠浆液的4小时及20小时后分别静脉注射磷酸盐缓冲溶液或GKB101。示出直至感染后60小时的小鼠的存活率。结果，盲肠浆料+磷酸盐缓冲溶液(诱发重症败血症后注射磷酸盐缓冲溶液)在第29小时的存活率为50％，在第41小时的存活率为20％，而盲肠浆料+GKB101(诱发重症败血症后注射GKB101)在第29小时的存活率为80％，在第41小时的存活率为50％，存活率比磷酸盐缓冲溶液增加。确认到腹腔液(图4c)及血浆(图4b)中的WARS1浓度通过GKB101在第11小时或第18小时显著减少，腹腔液内分泌的白细胞介素8(图4e)、白细胞介素6(图4f)、巨噬细胞炎性蛋白1α(图4d)、肿瘤坏死因子α(图4g)也在第11小时或第18小时显著减少。在谷丙转氨酶(图4h)、谷草转氨酶(图4i)、血尿素氮(图4j)、肌酐(图4k)中示出相对减少的倾向，与磷酸盐缓冲溶液相比，GKB101注射组中的谷丙转氨酶、血尿素氮在第11小时显出显著减少的倾向。所有结果均使用ANOVA统计软件分析(*，P＜0.05；**，P＜0.01；***，P＜0.001)。
实施例6.WARS1特异性抗体给细菌感染的小鼠带来的影响2
在向小鼠注射盲肠浆料诱发重症败血症后，分别在第4小时、第8小时、第12小时各腹腔注射(i.p)5mg/kg、2.5mg/kg、2.5mg/kg的同型IgG或GKB101，在三次注射中每只小鼠共注射10mg/kg，实施直至72小时的存活分析。
WARS1及细胞因子分析：为了确认GKB101的WARS1中和能力，分别采取第2小时、第6小时、第10小时、第14小时的腹腔液及血液，利用其通过酶联免疫吸附测定测量WARS1(室内)及肿瘤坏死因子α(Biolegend公司)、巨噬细胞炎性蛋白1α(R&D公司)、小鼠白细胞介素6(Biolegend公司)、mCXCL2(小鼠白细胞介素8的同源物，R&D公司)。除WARS1以外的细胞因子酶联免疫吸附测定根据生产公司的说明书进行。WARS1的测量如下：将GKB101以1μg/ml的浓度涂敷在96孔培养板(Maxisorp牌，赛默飞世尔公司)后，使用包含1％的牛血清白蛋白的磷酸盐缓冲溶液在常温下封闭1小时。将稀释血浆、腹腔液样品及小鼠重组蛋白的标准溶液放入各封闭的孔中在常温下反应1小时后，使用磷酸盐吐温缓冲溶液(磷酸盐缓冲溶液+吐温20)洗涤4次。向各孔中放入抗WARS1抗体(Abfrontier公司)在常温下反应1小时后，使用磷酸盐吐温缓冲溶液洗涤4次。使用附着有辣根过氧化物酶的二抗(抗人IgG，细胞信号传导公司)反应1小时后，使用磷酸盐吐温缓冲溶液洗涤。使用3,3',5,5'-四甲基联苯胺底物(BD公司)显色后，在490nm的波长中测量吸光度(VersaMax酶标仪)。
为了确认GKB101给小鼠的存活率带来的影响，根据图5a的实验大纲利用小鼠进行动物实验来实施存活分析。向小鼠注入盲肠浆液来诱发重症败血症后，在腹腔注射盲肠浆液的4小时、8小时及12小时后分别静脉注射同型IgG或GKB101。示出直至感染后72小时的小鼠的存活率。结果，盲肠浆料+同型IgG(诱发重症败血症后注射同型IgG)在第28小时的存活率为20％，在第36小时的存活率为10％，而盲肠浆料+GKB101(诱发重症败血症后注射GKB101)在第28小时的存活率为80％，在第36小时的存活率为70％，存活率比同型IgG增加(图5a)。确认到腹腔液(图5c)及血浆(图5b)中的WARS1浓度通过GKB101在第6小时、第10小时、第14小时减少，腹腔液内分泌的白细胞介素8(图5e)、白细胞介素6(图5f)、巨噬细胞炎性蛋白1α(图5d)、肿瘤坏死因子α(图5g)也注入GKB101后显出减少的倾向，尤其，第14小时时白细胞介素8、巨噬细胞炎性蛋白1α、肿瘤坏死因子α中显著减少。在谷丙转氨酶(图5h)、谷草转氨酶(图5i)、血尿素氮(图5j)、肌酐(图5k)中显出相对减少的倾向，与同型IgG相比，GKB101注入组的谷丙转氨酶、血尿素氮在第14小时示出显著减少的倾向。所有结果均使用ANOVA统计软件分析(*，P＜0.05；**，P＜0.01；***，P＜0.001)。
实施例7.WARS1特异性抗体及抗生素给细菌感染的小鼠的存活率带来的影响
在向注射盲肠浆料诱发重症败血症的小鼠给药抗生素(庆大霉素)后，分别在第4小时、第8小时、第20小时各腹腔注射(i.p)5mg/kg、2.5mg/kg、2.5mg/kg的同型IgG或GKB101，在三次注射中每只小鼠共注射10mg/kg，实施直至72小时的存活分析。
在盲肠浆料诱发小鼠中分析GKB101与抗生素联合用药效果的结果，GKB101给药组在第24小时的存活率为80％，在72小时的存活率为70％，显出与同型IgG给药组的存活率间的显著差异。所有结果均使用ANOVA统计软件分析(图6)。
实施例8.利用狨猴内毒素血症模型检验GKB101的功效
从五松尖端医疗产业振兴财团实验动物中心(忠清北道，韩国)获得狨猴(Callithrix jacchus)。所有的狨猴都在不锈钢笼中饲育。在SPF动物饲育室中以12小时凌晨和12小时黄昏的条件，在27±2℃的温度、30％至70％的湿度中向普通狨猴任意提供标准狨猴饲料(维持非人灵长类管理，#0639；阿尔特罗敏公司(Altromin)，拉格(Lage)，德国(Germany))与水。所有的实验方案都得到了五松尖端医疗产业振兴财团实验动物中心动物保护委员会的认可。向狨猴注射脂多糖来诱发内毒素血症后，分别在第0.2小时、2小时静脉注射两次共2mg/kg的磷酸盐缓冲溶液磷酸盐缓冲溶液或GKB101后，观察24小时。
在狨猴内毒素血症模型中确认免疫细胞的数量的结果，在给药抗WARS1抗体的组中，白细胞与中性粒细胞在第12小时显著增加(*，P＜0.05，**，P＜0.01)。并且，在血液中比较给药GKB101给WARS1、细胞因子及趋化因子的表达带来的影响的结果，在给药作为血液蛋白质内抗WARS1抗体的GKB101实验组中，WARS1在第0.5小时、第1小时、第2小时、第4小时、第8小时显著减少(****，P＜0.0001)，肿瘤坏死因子α在第1小时、第2小时显著减少(2小时，****，P＜0.0001)。所有结果均使用ANOVA统计软件分析(图7)。
上述实施例的结果表明GKB101对WARS1具有单(single)nM以下的强结合力，在体内(in vivo)及体外具有减少通过WARS1表达的细胞因子的表达的中和能力。如上所述，本发明的组合物特异性地检测出作为在感染初期诱发过度炎症的最上位物质的WARS1，可以将其用于开发靶向抑制的抗体药品的目的，因此可以高度期待其产业上的可应用性。
以上说明了本发明的实施例，但本发明所属技术领域的普通技术人员可以在不脱离发明要求保护范围中记载的本发明的思想的范围内通过结构要素的附加、变更、删除或追加来多种多样地修正及变更本发明，因此，这些也应包括在本发明的权力范围内。
<110> 株式会社美琳基因
<120> WARS 中和抗体及其用途
<130> PCT787
<150> KR 10-2020-0140371
<151> 2020-10-27
<150> KR 10-2021-0136547
<151> 2021-10-14
<160> 26
<170> KoPatentIn 3.0
<210> 1
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VH
<400> 1
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Ser Gly Gly Ser Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Ala Trp Asp Met Leu Gly Asp Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VL
<400> 2
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asn Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Asp Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val
100 105
<210> 3
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VH CDR1
<400> 3
Ser Tyr Asp Met Ser
1 5
<210> 4
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VH CDR2
<400> 4
Ala Ile Ser Ser Gly Gly Ser Ser Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 5
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VH CDR3
<400> 5
Asp Val Ala Trp Asp Met Leu Gly Asp Phe Asp Tyr
1 5 10
<210> 6
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VL CDR1
<400> 6
Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr
1 5 10
<210> 7
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VL CDR2
<400> 7
Ala Asn Ser His Arg Pro Ser
1 5
<210> 8
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - VL CDR3
<400> 8
Gly Ala Trp Asp Asp Ser Leu Ser Ala
1 5
<210> 9
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> CDR_primer_F
<400> 9
gtggccacag cggccgatgt ccactcggaa gtacagttgg tcgaaagtgg c 51
<210> 10
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> CDR_primer_R
<400> 10
gaagaccgat gggcccttgg tgctagccga tgagacggtc actaaagtgc c 51
<210> 11
<211> 50
<212> DNA
<213> Artificial Sequence
<220>
<223> VL_primer_F
<400> 11
gccacagcgg ccgatgtcca ctcggacatt caaatgacgc agagtccctc 50
<210> 12
<211> 53
<212> DNA
<213> Artificial Sequence
<220>
<223> VL_primer_R
<400> 12
gaagacagat ggtgcagcca cagatctttt aatttccact ttagttccct gcc 53
<210> 13
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> CH_primer_F
<400> 13
ggcactttag tgaccgtctc atcggctagc accaagggcc catcggtctt c 51
<210> 14
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> CH_primer_R
<400> 14
gccactttcg accaactgta cttccgagtg gacatcggcc gctgtggcca c 51
<210> 15
<211> 53
<212> DNA
<213> Artificial Sequence
<220>
<223> CL_primer_F
<400> 15
ggcagggaac taaagtggaa attaaaagat ctgtggctgc accatctgtc ttc 53
<210> 16
<211> 50
<212> DNA
<213> Artificial Sequence
<220>
<223> CL_primer_R
<400> 16
gagggactct gcgtcatttg aatgtccgag tggacatcgg ccgctgtggc 50
<210> 17
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> VH1-69_Forward
<400> 17
gtggccacag cggccgatgt ccactcgcaa gttcagctgg tccagagcgg c 51
<210> 18
<211> 52
<212> DNA
<213> Artificial Sequence
<220>
<223> VH1-69_Reverse
<400> 18
gaagaccgat gggcccttgg tgctagccga tgagacggta accagagtac cc 52
<210> 19
<211> 52
<212> DNA
<213> Artificial Sequence
<220>
<223> CH1-69_Forward
<400> 19
gccgctctgg accagctgaa cttgcgagtg gacatcggcc gctgtggcca cc 52
<210> 20
<211> 52
<212> DNA
<213> Artificial Sequence
<220>
<223> CH1-69_Reverse
<400> 20
gggtactctg gttaccgtct catcggctag caccaagggc ccatcggtct tc 52
<210> 21
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - CL
<400> 21
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
1 5 10 15
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
20 25 30
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
35 40 45
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
50 55 60
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
65 70 75 80
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
85 90 95
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 22
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - CH1
<400> 22
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val
<210> 23
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - Hinge
<400> 23
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro
20
<210> 24
<211> 103
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - CH2
<400> 24
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
1 5 10 15
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
20 25 30
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
35 40 45
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
50 55 60
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
65 70 75 80
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
85 90 95
Thr Ile Ser Lys Ala Lys Gly
100
<210> 25
<211> 100
<212> PRT
<213> Artificial Sequence
<220>
<223> GKB101 - CH3
<400> 25
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
1 5 10 15
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
20 25 30
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
35 40 45
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
50 55 60
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
65 70 75 80
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
85 90 95
Ser Leu Ser Leu
100
<210> 26
<211> 471
<212> PRT
<213> Artificial Sequence
<220>
<223> WARS
<400> 26
Met Pro Asn Ser Glu Pro Ala Ser Leu Leu Glu Leu Phe Asn Ser Ile
1 5 10 15
Ala Thr Gln Gly Glu Leu Val Arg Ser Leu Lys Ala Gly Asn Ala Ser
20 25 30
Lys Asp Glu Ile Asp Ser Ala Val Lys Met Leu Val Ser Leu Lys Met
35 40 45
Ser Tyr Lys Ala Ala Ala Gly Glu Asp Tyr Lys Ala Asp Cys Pro Pro
50 55 60
Gly Asn Pro Ala Pro Thr Ser Asn His Gly Pro Asp Ala Thr Glu Ala
65 70 75 80
Glu Glu Asp Phe Val Asp Pro Trp Thr Val Gln Thr Ser Ser Ala Lys
85 90 95
Gly Ile Asp Tyr Asp Lys Leu Ile Val Arg Phe Gly Ser Ser Lys Ile
100 105 110
Asp Lys Glu Leu Ile Asn Arg Ile Glu Arg Ala Thr Gly Gln Arg Pro
115 120 125
His His Phe Leu Arg Arg Gly Ile Phe Phe Ser His Arg Asp Met Asn
130 135 140
Gln Val Leu Asp Ala Tyr Glu Asn Lys Lys Pro Phe Tyr Leu Tyr Thr
145 150 155 160
Gly Arg Gly Pro Ser Ser Glu Ala Met His Val Gly His Leu Ile Pro
165 170 175
Phe Ile Phe Thr Lys Trp Leu Gln Asp Val Phe Asn Val Pro Leu Val
180 185 190
Ile Gln Met Thr Asp Asp Glu Lys Tyr Leu Trp Lys Asp Leu Thr Leu
195 200 205
Asp Gln Ala Tyr Ser Tyr Ala Val Glu Asn Ala Lys Asp Ile Ile Ala
210 215 220
Cys Gly Phe Asp Ile Asn Lys Thr Phe Ile Phe Ser Asp Leu Asp Tyr
225 230 235 240
Met Gly Met Ser Ser Gly Phe Tyr Lys Asn Val Val Lys Ile Gln Lys
245 250 255
His Val Thr Phe Asn Gln Val Lys Gly Ile Phe Gly Phe Thr Asp Ser
260 265 270
Asp Cys Ile Gly Lys Ile Ser Phe Pro Ala Ile Gln Ala Ala Pro Ser
275 280 285
Phe Ser Asn Ser Phe Pro Gln Ile Phe Arg Asp Arg Thr Asp Ile Gln
290 295 300
Cys Leu Ile Pro Cys Ala Ile Asp Gln Asp Pro Tyr Phe Arg Met Thr
305 310 315 320
Arg Asp Val Ala Pro Arg Ile Gly Tyr Pro Lys Pro Ala Leu Leu His
325 330 335
Ser Thr Phe Phe Pro Ala Leu Gln Gly Ala Gln Thr Lys Met Ser Ala
340 345 350
Ser Asp Pro Asn Ser Ser Ile Phe Leu Thr Asp Thr Ala Lys Gln Ile
355 360 365
Lys Thr Lys Val Asn Lys His Ala Phe Ser Gly Gly Arg Asp Thr Ile
370 375 380
Glu Glu His Arg Gln Phe Gly Gly Asn Cys Asp Val Asp Val Ser Phe
385 390 395 400
Met Tyr Leu Thr Phe Phe Leu Glu Asp Asp Asp Lys Leu Glu Gln Ile
405 410 415
Arg Lys Asp Tyr Thr Ser Gly Ala Met Leu Thr Gly Glu Leu Lys Lys
420 425 430
Ala Leu Ile Glu Val Leu Gln Pro Leu Ile Ala Glu His Gln Ala Arg
435 440 445
Arg Lys Glu Val Thr Asp Glu Ile Val Lys Glu Phe Met Thr Pro Arg
450 455 460
Lys Leu Ser Phe Asp Phe Gln
465 470
Claims (28)
1.一种与色氨酰tRNA合成酶特异性结合的抗体或其片段，其特征在于，包含序列表中序列1的重链可变区及序列表中序列2的轻链可变区。
2.一种与色氨酰tRNA合成酶特异性结合的抗体或其片段，其特征在于，包含：
重链可变区，包含序列表中序列3的重链CDR1、序列表中序列4的重链CDR2及序列表中序列5的重链CDR3；以及
轻链可变区，包含序列表中序列6的轻链CDR1、序列表中序列7的轻链CDR2及序列表中序列8的轻链CDR3。
3.根据权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段，其特征在于，上述抗体或其片段包含选自由序列表中序列21的CL序列、序列表中序列22的CH1序列、序列表中序列23的铰链序列、序列表中序列24的CH2序列及序列表中序列25的CH 3序列组成的组中的一种以上序列。
4.根据权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段，其特征在于，上述片段为选自由Fab、F(ab')2、Fd、sdFv、Fv、dAb、scFv、sdAb及四聚体组成的组中的片段或者为上述片段与Fc的结合形式。
5.一种多核苷酸，其特征在于，编码权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段。
6.一种载体，其特征在于，包含权利要求5所述的多核苷酸。
7.一种细胞，其特征在于，由权利要求6所述的载体转化。
8.一种与色氨酰tRNA合成酶特异性结合的抗体或其片段的制备方法，其特征在于，包括在表达多核苷酸的条件下培养权利要求7所述的细胞来回收多肽的步骤。
9.一种色氨酰tRNA合成酶的特异性检测方法，其特征在于，包括使权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段、编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞与试样接触的步骤。
10.一种色氨酰tRNA合成酶的特异性检测用组合物，其特征在于，包含权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段、编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞。
11.一种用于诊断感染性疾病的组合物，其特征在于，包含权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段、编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞。
12.根据权利要求11所述的用于诊断感染性疾病的组合物，其特征在于，上述感染性疾病为感染性炎症疾病。
13.根据权利要求12所述的用于诊断感染性疾病的组合物，其特征在于，上述感染性炎症疾病为败血症或败血性休克。
14.一种用于预防或治疗感染性疾病的药物组合物，其特征在于，包含权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段、编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞。
15.根据权利要求14所述的用于预防或治疗感染性疾病的药物组合物，其特征在于，上述药物组合物还包含抗生素。
16.根据权利要求14所述的用于预防或治疗感染性疾病的药物组合物，其特征在于，上述药物组合物与抗生素同时给药，或者在给药抗生素之前或之后给药一次以上。
17.根据权利要求14所述的用于预防或治疗感染性疾病的药物组合物，其特征在于，上述感染性疾病为感染性炎症疾病。
18.根据权利要求17所述的用于预防或治疗感染性疾病的药物组合物，其特征在于，上述感染性炎症疾病为败血症或败血性休克。
19.一种疾病的治疗方法，其特征在于，包括向对象给药有效量的权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段、编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞的步骤。
20.根据权利要求19所述的疾病的治疗方法，其特征在于，上述治疗方法还包括给药抗生素的步骤。
21.根据权利要求20所述的疾病的治疗方法，其特征在于，上述抗生素选自由庆大霉素、氨苄青霉素、卡那霉素、氯霉素、链霉素、四环素、红霉素、万古霉素、青霉素、奇霉素、氯霉素、磺胺嘧啶及甲氧苄啶组成的组中。
22.根据权利要求19所述的疾病的治疗方法，其特征在于，上述疾病为感染性疾病。
23.根据权利要求22所述的疾病的治疗方法，其特征在于，上述感染性疾病为感染性炎症疾病。
24.根据权利要求23所述的疾病的治疗方法，其特征在于，上述感染性炎症疾病为败血症或败血性休克。
25.一种治疗用途，其特征在于，上述治疗用途为权利要求1或2所述的与色氨酰tRNA合成酶特异性结合的抗体或其片段、编码上述抗体或其片段的多核苷酸、包含上述多核苷酸的载体或由上述载体转化的细胞的治疗用途。
26.根据权利要求25所述的治疗用途，其特征在于，上述治疗用途为感染性疾病的治疗用途。
27.根据权利要求26所述的治疗用途，其特征在于，上述感染性疾病为感染性炎症疾病。
28.根据权利要求27所述的治疗用途，其特征在于，上述感染性炎症疾病为败血症或败血性休克。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2020-0140371 | 2020-10-27 | ||
| KR10-2021-0136547 | 2021-10-14 | ||
| KR1020210136547A KR20220056116A (ko) | 2020-10-27 | 2021-10-14 | Wars 중화항체 및 이의 용도 |
| PCT/KR2021/014301 WO2022092644A1 (ko) | 2020-10-27 | 2021-10-15 | Wars 중화항체 및 이의 용도 |
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| Publication Number | Publication Date |
|---|---|
| CN116710484A true CN116710484A (zh) | 2023-09-05 |
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| CN202180076632.4A Pending CN116710484A (zh) | 2020-10-27 | 2021-10-15 | Wars中和抗体及其用途 |
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| Country | Link |
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| CN (1) | CN116710484A (zh) |
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