CN108367056B - 用于内化酶的组合物和方法 - Google Patents
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Abstract
本发明公开了用于治疗溶酶体贮积病的组合物和方法。本发明公开了含有内化效应物结合结构域和溶酶体替代酶活性的生物治疗复合物。生物治疗复合物能够进入细胞,隔离到溶酶体内,并且将替代酶活性递送到溶酶体。
Description
技术领域
本专利申请大体上涉及用于治疗溶酶体贮积病的组合物和方法。本专利申请特别涉及含有替代酶的靶向蛋白质复合物及其在治疗溶酶体贮积病中的用途。
背景技术
溶酶体贮积病是影响溶酶体中无数底物降解的一类罕见疾病。那些底物包括鞘脂、粘多糖、糖蛋白、糖原和寡糖,它们可在患有疾病的那些人的细胞中累积,导致细胞死亡。受溶酶体贮积病影响的器官包括中枢神经系统(CNS)、外周神经系统(PNS)、肺、肝、骨、骨骼肌和心肌、以及网状内皮系统。
治疗溶酶体贮积病的选项包括酶替代疗法(ERT)、底物减少疗法、药物分子伴侣介导疗法、造血干细胞移植疗法和基因疗法。底物减少疗法的例子包括使用美格鲁特或依利格鲁司特治疗1型戈谢病。这些药物通过阻断合酶活性起作用,所述合酶减少了后续底物产生。例如,造血干细胞疗法(HSCT)用于改善和减缓患有某些形式的MPS的患者中的负中枢神经系统表型。参见R.M.Boustany,"Lysosomal storage diseases--the horizonexpands,"9(10)Nat.Rev.Neurol.583-98,2013年10月。表1列出了一些溶酶体贮积病及其相关酶或其它蛋白质。
表1:溶酶体贮积病
两种最常见的LSD是庞贝氏症和法布里病。庞贝氏症由有缺陷的溶酶体酶α-葡糖苷酶(GAA)引起,这导致溶酶体糖原的加工缺陷。溶酶体糖原的累积主要发生在骨骼、心脏和肝脏组织中。婴儿发作型庞贝氏症通常在2岁前导致心脏扩张、张力减退、肝肿大和由于心肺衰竭的死亡。成人发作型庞贝氏症晚至二十至六十年发生,并且通常只涉及骨骼肌。
法布里病由缺陷型溶酶体酶α-半乳糖苷酶A(GLA)引起,其导致球形三脂酰基鞘氨醇在血管及其它组织和器官内的累积。与法布里病相关的症状包括来自神经损伤和/或小血管阻塞的疼痛,肾功能不全和最终的衰竭,心脏并发症如高血压和心肌病,皮肤病症状如血管角化瘤的形成、无汗症或多汗症,以及眼部问题如角膜涡状营养不良、轮辐状白内障、以及结膜和视网膜血管异常。
用于溶酶体贮积病的目前治疗不太理想。例如,ERT一般必须以高频率和高剂量施用,例如每两周一次和高达40mg/kg。另外,一些替代的酶可为免疫学交叉反应性的(CRIM),刺激受试者中IgG的产生并且因此阻碍酶经由甘露糖-6-磷酸(M6P)受体递送至溶酶体。IgG可屏蔽替代酶的M6P残基,并且抗原-IgG-抗体复合物可经由Fc受体摄取到细胞溶酶体内,从而优先将替代酶分流至巨噬细胞。
将替代酶递送至适当的受累组织也是无效的(参见表2和Desnick&Schuchman,“Enzyme replacement therapy for lysosomal diseases:lessons from 20years ofexperience and remaining challenges,”13Annu.Rev.Genomics Hum.Genet.307-35,2012)。例如,经历用于婴儿型庞贝氏症的长期酶替代治疗的患者仍然可能患有言语鼻音过重、残余肌肉无力、上睑下垂、骨量减少、听力丧失、误吸风险、咽下困难、心律失常和吞咽困难。替代酶的剂量通常必须随着时间过去增加至每周一次或每两周一次40mg/kg。
表2:ERT的无效组织靶向
内源性甘露糖-6-磷酸受体(MPR)介导大多数重组酶至溶酶体的转运。存在两种互补形式的MPR:阳离子非依赖性(CI-MPR)和阳离子依赖性(CD-MPR)。任一种形式的敲除都具有错位的(missorted)溶酶体酶。溶酶体水解酶在内质网中合成,并且移动到顺面高尔基体网络,在其中它们通过添加甘露糖-6-磷酸(M6P)基团进行共价修饰。这种标记物的形成取决于两种溶酶体酶的序贯效应:UDP-N-乙酰葡糖胺-l-磷酸转移酶(G1cNac-磷酸转移酶)和N-乙酰葡糖胺-l-磷酸二酯-α-N-乙酰氨基葡糖苷酶(外显酶)。GlcNac-磷酸转移酶催化G1cNAc-1-磷酸盐残基从UDP-G1cNAc到水解酶的高甘露糖型寡糖中所选择的甘露糖的C6位置的转移。然后,外显酶去除末端G1cNAc,暴露M6P识别信号。在反面高尔基体网络中,M6P信号允许通过选择性结合M6P受体,将溶酶体水解酶与所有其它类型的蛋白质隔离。所产生的网格蛋白-包被的囊泡从反面高尔基体网络出芽脱落,并且与次级内体融合。在次级内体的低pH下,水解酶从M6P受体解离,并且空受体被循环到高尔基体用于更多轮转运。
除了经由甘露糖受体递送的β-葡糖脑苷脂酶之外,重组溶酶体酶包含M6P糖基化并且主要经由CI-MPR/IGF2R递送至溶酶体。然而,糖基化/CI-MPR介导的酶替代递送并未达到所有临床相关组织(表2)。酶替代疗法的改善已集中于通过以下方式改善CI-MPR递送:(i)使用β2-激动剂克仑特罗增加CI-MPR的表面表达(Koeberl等人,“Enhanced efficacyof enzyme replacement therapy in Pompe disease through mannose-6-phosphatereceptor expression in skeletal muscle,”103(2)Mol.Genet.Metab.107-12,2011),(ii)增加酶上M6P残基的量(Zhu等人,“Conjugation of mannose-6-phosphate-containing oligosaccharides to acid alpha-glucosidase improves the clearanceof glycogen in Pompe mice,”279(48)J.Biol.Chem.50336-41,2004),或(iii)将IGF-II结构域与酶融合(Maga等人,“Glycosylation-independent lysosomal targeting ofacid alpha-glucosidase enhances muscle glycogen clearance in Pompe mice,”288(3)J.Biol.Chem.1428-38,2013)。
大量溶酶体贮积病无法通过酶替代疗法或基因治疗充分治疗,主要是由于替代酶对相关组织或器官的弱靶向。存在改善的酶替代疗法的需要,所述改善的酶替代疗法增强且促进酶的更佳组织生物分布和溶酶体摄取。申请人已开发了改善的酶替代疗法,其使用CI-MPR不依赖性抗体引导的酶对靶受累组织的溶酶体的递送。
发明内容
申请人已发现当与细胞表面靶向实体结合时,替代酶可有效地递送至特定靶细胞的溶酶体。这种酶和靶向实体组合被称为生物治疗复合物。因此,在一个方面,本发明提供了组合物,即包含酶和抗原结合蛋白的生物治疗复合物。该酶与溶酶体贮积病(LSD)相关,并且抗原结合蛋白结合内化效应物。内化效应物介导细胞结合和摄入溶酶体区室内。
在一些实施例中,酶是以下中的任何一种:α-半乳糖苷酶、β-半乳糖苷酶、α-葡糖苷酶、β-葡糖苷酶、鞘脂激活蛋白C激活因子、神经酰胺酶、鞘磷脂酶、β-氨基己糖苷酶、GM2激活蛋白、GM3合酶、芳基硫酸酯酶、鞘脂激活因子、α-艾杜糖醛酸酶、艾杜糖醛酸酶-2-硫酸酯酶、肝素N-硫酸酯酶、N-乙酰-α-氨基葡糖苷酶、α-葡糖酰胺N-乙酰转移酶、N-乙酰葡糖胺-6-硫酸酯酶、N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶、N-乙酰半乳糖胺-4-硫酸酯酶、β-葡萄糖醛酸酶和透明质酸酶。在一些实施例中,酶是与上文列出的那些酶中的任何一种或多种具有相同或相似的活性的同工酶。在一些实施例中,α-葡糖苷酶活性可由同工酶如蔗糖酶-异麦芽糖酶(SI)、麦芽糖酶-葡糖淀粉酶(MGAM)、葡糖苷酶II(GANAB)或中性α-葡糖苷酶(CGNAC)提供。在另一个实施例中,α-半乳糖苷酶A活性可通过被改造为获得GLA活性的同工酶(例如α-N-乙酰半乳糖胺酶)提供。
在一些实施例中,抗原结合蛋白是可结合一种或多种内化效应物的任何蛋白质。在更具体的实施例中,抗原结合蛋白是以下中的任何一种或多种:受体-融合分子、陷阱分子、受体-Fc融合分子、抗体、Fab片段、F(ab')2片段、Fd片段、Fv片段、单链Fv(scFv)分子、dAb片段、经分离的互补决定区(CDR)、CDR3肽、受限的FR3-CDR3-FR4肽、结构域特异性抗体、单抗结构域抗体、结构域缺失抗体、嵌合抗体、CDR移植抗体、双抗体、三抗体、四抗体、微型抗体、纳米抗体、单价纳米抗体、二价纳米抗体、小模块免疫药物(SMIP)、骆驼科抗体(VHH重链同型二聚体抗体)、鲨鱼可变IgNAR结构域等等。在一个特定实施例中,抗原结合蛋白是与内化效应物和酶结合的双特异性抗体。
在一些实施例中,内化效应物是受体蛋白或结合受体蛋白的配体,所述受体蛋白位于细胞膜内、细胞膜上或细胞膜处,并且可被内吞。在更具体的实施例中,内化效应物是以下中的任何一种或多种:CD63、MHC-I、Kremen-1、Kremen-2、LRP5、LRP6、LRP8、转铁蛋白受体、LDL-受体、LDL-相关蛋白1受体、ASGR1、ASGR2、淀粉样前体蛋白样蛋白-2(APLP2)、爱帕琳(apelin)受体(APLNR)、PRLR(促乳素受体)、MAL(髓鞘和淋巴细胞蛋白,又名VIP17)、IGF2R、液泡型H+ATP酶、白喉毒素受体、叶酸受体、谷氨酸受体、谷胱甘肽受体、瘦素受体、清道夫受体、SCARA1-5、SCARB1-3和CD36。在某些实施例中,内化效应物是肾特异性内化剂(internalizer)例如CDH16(Cadheri-16)、CLDN16(Claudn-16)、KL(Klotho)、PTH1R(甲状旁腺激素受体)、SLC22A13(溶质载体家族22成员13)、SLC5A2(钠/葡萄糖协同转运蛋白2)和UMOD(尿调节蛋白)。在其它某些实施例中,内化效应物是肌肉特异性内化剂,例如BMPR1A(骨形态发生蛋白受体1A)、M-钙粘蛋白、CD9、MuSK(肌肉特异性激酶)、LGR4/GPR48(G蛋白偶联受体48)、胆碱能受体(烟碱)α1、CDH15(Cadheri-15)、ITGA7(整联蛋白α-7)、CACNG1(L-型钙通道亚基γ-1)、CACNAlS(L-型钙通道亚基α-15)CACNG6(L-型钙通道亚基γ-6)、SCN1B(钠通道亚基β-1)、CHRNA1(ACh受体亚基α)、CHRND(ACh受体亚基δ)、LRRC14B(富含亮氨酸重复序列的蛋白质14B)、和POPDC3(含Popeye结构域的蛋白质3)。在一些具体实施例中,内化效应物是ITGA7、CD9、CD63、APLP2或PRLR。在一些具体实施例中,内化效应物是巨噬细胞优先内化剂,包括例如VSIG4(CRIG)、MSR1(CD204)和MMR1(MCR1,CD206)。
生物治疗复合物可具有几种形式中的任何一种。在一些实施例中,酶与抗原结合蛋白共价连接。在一个特定实施例中,抗原结合蛋白包含半抗体(即,单个重链和单个轻链),该酶与免疫球蛋白Fc-结构域共价连接,并且与酶共价连接的Fc-结构域与抗原结合蛋白的Fc结构域结合。在另一个特定实施例中,抗原结合蛋白是抗体,并且酶与该抗体的重链(或轻链)的C末端共价连接。在又一个特定实施例中,抗原结合蛋白是抗体,并且酶与该抗体的重链(或轻链)的N末端共价连接。
在其它实施例中,酶不与抗原结合蛋白共价连接。在一个实施例中,抗原结合蛋白结合内化效应物和酶两者。在一个具体实施例中,抗原结合蛋白是结合内化效应物和酶的双特异性抗体。
在一些实施例中,酶是GAA或具有GAA活性的同工酶,并且内化效应物是CD9、ITGA7、CD63、APLP2或PRLR。在其它实施例中,酶是GLA或具有GLA活性的同工酶,并且内化效应物是CD9、ITGA7、CD63、APLP2或PRLR。
在另一个方面,本发明提供了治疗患有溶酶体贮积病(LSD)的受试者的方法,所述方法包括向受试者施用生物治疗复合物(如上所述)的步骤,其中所述生物治疗复合物进入受试者细胞的溶酶体,并且提供替代与LSD(“内源性酶”)相关的酶活性(“替代酶”)。LSD包括鞘酯类代谢障碍、粘多糖贮积病和糖原贮积病。更具体地,可治疗的LSD是表1中列出的疾病中的任何一种或多种,并且替代酶具有表1中列出的相应酶的活性。在一个具体实施例中,LSD是庞贝氏症,并且相关酶是α-葡糖苷酶(GAA)。在另一个具体实施例中,LSD是法布里病,并且相关酶是α-半乳糖苷酶A(GLA)。在又一个具体例子中,LSD是溶酶体酸性脂肪酶缺乏症(LAL-D),并且相关酶是溶酶体酸性脂肪酶(LIPA)。
在一个实施例中,替代酶在受试者中不诱导免疫反应。在一些情况下,替代酶是同工酶。例如,当内源性酶是α-葡糖苷酶时,同工酶是提供与α-葡糖苷酶相同或相似的酶促活性的不同蛋白质,例如蔗糖酶-异麦芽糖酶(SI)、麦芽糖酶-葡糖淀粉酶(MGAM)、葡糖苷酶II(GANAB)或中性α-葡糖苷酶(C GNAC)。当内源性酶是α-半乳糖苷酶A(GLA)时,同工酶是提供与α-半乳糖苷酶A相同或相似的酶促活性的不同蛋白质,例如被改造为获得GLA活性的α-N-乙酰半乳糖胺酶。
在一个方面,本发明提供了用于选择或筛选含有酶和抗原结合蛋白的生物治疗复合物的方法,所述生物治疗复合物有效替代有此需要的患者中的酶。在一个实施例中,将生物治疗复合物施用于模型系统,并且评价模型系统的替代酶活性。在一个实施例中,模型系统是缺乏酶表达并且表达抗原结合蛋白的抗原同源物的动物。在一个实施例中,动物模型是表达抗原结合蛋白的人源化同源物和具有编码该酶的基因敲除的小鼠。
附图说明
图1示意性地表示了生物治疗复合物。小图A描绘了包含双特异性抗体(ii)和替代酶(i)的生物治疗复合物。小图B描绘了与内化效应物特异性半体(ii)结合的酶-Fc融合多肽(i),以形成生物治疗复合物。小图C描绘了与抗内化效应抗体的重链的C末端共价连接的替代酶(六边形)。小图D描绘了与抗内化效应抗体的重链的N末端共价连接的替代酶(六边形)。小图E描绘了与抗内化效应物抗体的轻链的C末端共价连接的替代酶(六边形)。小图F描绘了与抗内化效应物抗体的轻链的N末端共价连接的替代酶(六边形)。小图C、D、E和F中的曲线表示接头。
图2描绘了表达内化效应结合蛋白(IE-BP)或溶酶体贮积病替代蛋白(LSD-RP)的CHO细胞上清液的抗hFc非还原型蛋白质印迹。泳道1装载有抗CD63IgG4,泳道2装载有GAA-Fc旋钮,泳道3装载有抗CD63IgG4GAA,并且泳道4装载有GAA抗CD63IgG4。
图3描绘了代表如使用荧光底物4-甲基伞形酮基-α-葡糖苷确定的近似GAA活性的条形图。小图A和小图B的Y轴是每小时每摩尔蛋白质水解的底物的摩尔数。X轴列出了每种GAA融合蛋白。
图4描绘了表示由HEK细胞内化的GAA构建体的近似GAA活性的线图。小图A和B的Y轴指示每小时每mg细胞裂解产物水解的底物纳摩尔。X轴指示GAA构建体浓度的增加。小图A,正方形(■)表示在5mM甘露糖-6-磷酸(M6P)(MPR介导的溶酶体靶向的竞争剂)的存在下,对HEK细胞施用抗CD63-GAA,并且圆圈(D)表示单独施用于HEK细胞的抗CD63-GAA。小图B,圆圈(D)表示施用于HEK细胞的抗CD63-GAA,正方形(■)表示施用于HEK细胞的不结合CD63的突变型抗CD63-GAA,并且三角形(▲)表示施用于不表达CD63的A CD63HEK细胞的抗CD63-GAA。
图5描绘了表示被人(小图A)或鼠(小图B)成肌细胞内化的GAA构建体的近似GAA活性的线图。小图A和B的Y轴指示每小时每mg细胞裂解产物水解的底物纳摩尔。X轴指示在M6P的存在或不存在下,GAA构建体(抗CD63-GAA或mycGAA)浓度的增加。
图6描绘了与GAA野生型新生儿人皮肤成纤维细胞(NHDF)相比,三种庞贝氏症细胞系(GM20089、GM20090和GM20091)的GAA水平(小图A)和糖原含量(小图B)。小图A是描绘了庞贝氏症细胞系中的残余GAA蛋白和NHDF中GAA蛋白的野生型水平的抗hGAA蛋白质印迹。小图B是描绘了在葡萄糖饥饿以减少细胞质糖原后,作为微克/百万细胞的糖原含量的条形图。
图7以条形图形式描绘了通过200nM抗-CD63-GAA或200nM myc-GAA援救庞贝氏症细胞系GM20089(小图A)、GM20090(小图B)和GM20091(小图C)的糖原累积缺乏症。Y轴表示以毫克/毫克细胞裂解产物的糖原含量。
图8描绘了含有抗CD63-GLA(泳道1)、GLA-Fc旋钮(泳道2)、GLA-抗-CD63(泳道3)、抗-myc旋钮(泳道4)、抗CD63洞(泳道5)的CHO细胞提取物上清液以及含有抗myc旋钮和抗CD63洞(泳道6)的上清液混合物的抗hFc非还原型蛋白质印迹。
图9以条形图形式描绘了含有GLA的融合蛋白的GLA酶促活性(每小时每纳摩尔融合蛋白水解的纳摩尔底物中的Y轴),从左到右在X轴上包括抗CD63-GLA(重链C末端构建体)、GLA-Fc、GLA-抗CD63(重链N末端构建体)、GLA-myc-FLAG和GLA 6-his。
图10描绘了表示在含有被HEK细胞内化的GLA构建体的HEK细胞提取物中发现的近似GLA活性的线图。Y轴指示以每小时每毫克细胞裂解产物水解的底物纳摩尔的GLA活性。X轴指示GAA构建体浓度的增加。顶线代表GLA-抗CD63,中线代表GLA-myc加上抗myc/抗-CD63双特异性抗体,并且底线代表GLA-myc。
图11描绘了表示加上pHrodo标签的蛋白质摄入HEK细胞(小图A)、PC-3细胞(小图B)和HepG2细胞(小图3)的低pH级分(即溶酶体级分)内的线图。圆圈(D)表示加上pHrodo标签的抗CD63抗体,正方形(■)表示加上pHrodo标签的抗APLP2抗体,并且三角形(▲)表示加上pHrodo标签的GLA。
图12描绘了含有内化的抗CD63-GAA的细胞裂解产物的还原型蛋白质印迹。每条泳道代表在蛋白质内化后的特定日时制备的细胞提取物。小图A是用抗GAA抗体探测的蛋白质印迹。150kDa抗CD63-GAA在标记←a处可见。GAA的溶酶体76kDa活性形式在标记←b处可见。小图B是用抗hIgG抗体探测的蛋白质印迹。150kDa抗CD63-GAA在标记c→处可见。抗体重链(50kDa)在标记d→处可见。抗体轻链(23kDa)在标记e→处可见。
图13描述了抗hGAA抗体蛋白质。76kDa带代表成熟的GAA。泳道1含有来自给予抗CD63-GAA的人源化CD63小鼠的肝提取物,泳道2肾,泳道3心脏,泳道4腓肠肌,泳道5四头肌并且泳道6膈肌。
图14描绘了以50mg/kg给予抗hCD63-GAA后24小时来自野生型(+/+)小鼠和人源化CD63(hu/hu)小鼠的组织提取物的抗-hGAA抗体蛋白质印迹。显现了GAA的溶酶体76kDa活性形式。泳道1和2分别是来自野生型和人源化小鼠的心脏提取物。泳道3和4是来自野生型和人源化小鼠的腓肠肌提取物。泳道5和6是来自野生型和人源化小鼠的膈肌提取物。
图15是描述了对肝中发现的水平标准化的,在腓肠肌、四头肌、膈肌、心脏、肝、肾和脾内发现的抗整联蛋白α7抗体、抗CD9抗体和抗肌营养不良蛋白聚糖抗体的相对量的直方图。
图16是表示加上pHrodo标签的抗体的溶酶体靶向的直方图。Y轴表示标准化的囊泡荧光。X轴从左到右代表每种抗体:抗myc、抗CD63、抗肌营养不良蛋白聚糖、抗M-钙粘蛋白、抗CD9和抗整联蛋白α7。
图17是描绘了以毫克糖原/毫克组织表示的糖原水平的点图。组织在X轴上从左到右描绘为心脏、四头肌、腓肠肌、膈肌和三头肌。圆圈(●)表示未处理的GAA敲除(KO)小鼠中的糖原水平,正方形(■)表示用抗mCD63-GAA处理的GAA KO小鼠中的糖原水平,向上的三角形(▲)表示用hGAA处理的GAA KO小鼠中的糖原水平,并且向下的三角形(▼)表示未处理的野生型小鼠中的糖原水平。通过DNA构建体的流体动力学递送施用处理。
图18是描绘了以毫克糖原/毫克组织表示的糖原水平的点图。组织在X轴上从左到右描绘为心脏、四头肌、腓肠肌、膈肌和三头肌。圆圈(●)表示未处理的GAA敲除(KO)小鼠中的糖原水平,正方形(■)表示用抗mCD63-GAA处理的GAA KO小鼠中的糖原水平,向上的三角形(▲))表示用抗hCD63-GAA处理的GAA KO小鼠中的糖原水平,并且向下的三角形(▼))表示未处理的野生型小鼠中的糖原水平。通过DNA构建体的流体动力学递送施用处理。
图19是描绘了脂肪酶活性的直方图,所述脂肪酶活性表示为通过抗myc抗体、天然溶酶体酸性脂肪酶(LIPA)、抗myc-LIPA融合蛋白(重链C末端融合物)和LIPA抗myc(重链N末端融合物)每小时水解的底物(4-甲基伞形酮基油酸酯)的纳摩尔(Y-轴)。
图20是描绘了以毫克糖原/毫克组织表示的糖原水平的点图。组织在X轴上从左到右描绘为心脏、三头肌、四头肌、腓肠肌和膈肌。圆圈(●)表示未处理的GAA敲除(KO)小鼠中的糖原水平,正方形(■)表示用抗mCD63-GAA处理的GAA KO小鼠中的糖原水平,向上的三角形(▲)表示用抗hCD63-GAA处理的GAA KO小鼠中的糖原水平,并且向下的三角形(▼)表示未处理的野生型小鼠中的糖原水平。通过DNA构建体的流体动力学递送(HDD)施用处理。
具体实施方式
本发明并不限于所述的特定实施例、组合物、方法和实验条件,因为这样的实施例、组合物、方法和条件可变化。本文使用的术语仅为了描述特定实施例的目的,而不预期是限制性的,因为本发明的范围仅受所附权利要求限制。
尽管现在描述一些优选的方法和材料,但与本文所述那些相似或等价的任何方法和材料都可用于本发明的实践或测试中。本文引用的所有出版物都以引用的方式并入本文以全文描述。除非另有定义,否则本文使用的所有技术和科学术语都具有与本发明所属领域的普通技术人员通常理解相同的含义。
“溶酶体贮积病”包括来源于溶酶体功能缺陷的任何病症。目前,已鉴定了大约50种病症,其中最众所周知包括Tay-Sachs、戈谢病和尼曼-匹克病。这些疾病的发病机制归于溶酶体中不完全降解产物的积累,通常是由于蛋白质功能的丧失。溶酶体贮积病由其正常功能是降解或协调溶酶体内容物降解的蛋白质中的功能丧失或减弱变体引起。与溶酶体贮积病有关联的蛋白质包括酶、受体和其它跨膜蛋白(例如NPC1)、翻译后修饰蛋白(例如硫酸酯酶)、膜转运蛋白、以及非酶促辅因子和其它可溶性蛋白(例如GM2神经节苷脂激活因子)。因此,溶酶体贮积病涵盖超过由缺陷酶本身引起的那些病症,还包括由任何分子缺陷引起的任何病症。因此,如本文使用的,术语“酶”意欲涵盖与溶酶体贮积病相关的那些其它蛋白质。
在很多情况下,分子损伤的性质影响疾病的严重程度,即完全丧失功能趋于与出生前或新生儿发作相关,并且涉及严重症状;部分功能丧失与更温和(相对)和晚发型疾病有关。一般地,仅需要恢复小百分比的活性,以纠正缺陷细胞中的代谢缺陷。表1列出了一些较常见的溶酶体贮积病及其相关的功能丧失蛋白。溶酶体贮积病通常描述在Desnick和Schuchman,2012中。
溶酶体贮积病可根据在缺陷溶酶体内累积的产物类型进行分类。鞘脂类代谢障碍是影响鞘脂类代谢的一类疾病,所述鞘脂是含有与脂肪族氨基醇连接的脂肪酸的脂质(在S.Hakomori,“Glycosphingolipids in Cellular Interaction,Differentiation,andOncogenesis,”50 Annual Review of Biochemistry 733-764,1981年7月中综述)。鞘脂类代谢障碍的累积产物包括神经节苷脂(例如Tay-Sachs病)、糖脂(例如法布里病)和葡糖脑苷脂(例如戈谢氏病)。
粘多糖贮积症是影响糖胺聚糖(GAGS或粘多糖)代谢的一组疾病,所述糖胺聚糖是帮助构建骨、软骨、腱、角膜、皮肤和结缔组织的重复二糖的长非分支链(在J.Muenzer,“Early initiation of enzyme replacement therapy for themucopolysaccharidoses,”111(2)Mol.Genet.Metab.63-72(2014年2月);Sasisekharan等人,“Glycomics approach to structure-function relationships ofglycosaminoglycans,”8(1)Ann.Rev.Biomed.Eng.181-231(2014年12月)中综述)。粘多糖的累积产物包括硫酸乙酰肝素、硫酸皮肤素、硫酸角蛋白、各种形式的硫酸软骨素和透明质酸。例如,莫奎欧综合征A是由于溶酶体酶半乳糖-6-硫酸酯硫酸酯酶中的缺陷,其导致硫酸角蛋白和6硫酸软骨素的溶酶体累积。
糖原贮积病(又名糖原累积病)来源于细胞代谢(产生或分解)糖原的无能。糖原代谢由各种酶或其它蛋白质调节,包括葡萄糖-6-磷酸酶、酸性α-葡糖苷酶、糖原脱支酶、糖原分支酶、肌糖原磷酸化酶、肝糖原磷酸化酶、肌磷酸果糖激酶、磷酸化酶激酶、葡萄糖转运蛋白、醛缩酶A、β-烯醇酶和糖原合酶。示例性的溶酶体贮积病/糖原贮积病是庞贝氏症,其中缺陷型酸性α-葡糖苷酶引起糖原在溶酶体中累积。症状包括肝肿大、肌无力、心力衰竭,并且在婴儿变体的情况下,到2岁时的死亡(参见DiMauro和Spiegel,“Progress andproblems in muscle glycogenosis,”30(2)Acta Myol.96-102(2011年10月))。
“生物治疗复合物”包括(i)含有超过一个功能结构域的单一蛋白质,(ii)含有超过一条多肽链的蛋白质,和(iii)超过一种蛋白质或超过一种多肽的混合物。术语多肽一般视为意指经由肽键连接在一起的单链氨基酸。术语蛋白质涵盖术语多肽,但还包括更复杂的结构。即,单个多肽是蛋白质,并且蛋白质可含有以更高级结构结合的一种或多种多肽。例如,血红蛋白是含有四种多肽的蛋白质:两种α珠蛋白多肽和两种β珠蛋白多肽。肌红蛋白也是蛋白质,但它仅含有单一肌红蛋白多肽。
生物治疗复合物包含一种或多种多肽和至少两种功能。这些功能之一是替代与溶酶体贮积病有关的缺陷蛋白质活性。这些功能中的另一种是与内化效应物的结合。因此,提供溶酶体蛋白质活性(例如,酶促活性或转运蛋白活性;又名溶酶体疾病相关蛋白(LSD-RP)活性)以及与内化效应物结合的能力(又名内化效应物结合蛋白(IE-BP活性)的单个多肽是生物治疗复合物。另外,其中一种蛋白质具有溶酶体蛋白质功能,并且另一种蛋白质具有内化效应物结合活性的蛋白质混合物是生物治疗复合物。图1描绘了生物治疗复合物的各种范例。在一个例子中(图1,小图A),生物治疗复合物含有溶酶体替代蛋白(以六边形表示的LSD-RP)和双特异性抗体(1E-BP),所述双特异性抗体结合溶酶体替代蛋白(虚线)和内化效应物(实线)。此处,双特异性抗体的一个臂非共价结合LSD-RP,并且另一个臂非共价结合内部效应物,从而使得替代蛋白(LSD-RP)能够内化到溶酶体内。在另一个例子中(小图B),生物治疗复合物包含含有两种多肽的单一蛋白质,一种多肽具有LSD-RP功能,并且另一种具有IE-BP功能。此处,LSD-RP融合至免疫球蛋白Fc结构域或重链恒定区,其与LSD-RP半抗体的Fc结构域结合,以形成双功能生物治疗复合物。除了LSD-RP共价附着至半抗体之一,而不是通过在半抗体的免疫球蛋白可变结构域处的抗原-抗体相互作用之外,小图B中描绘的实施例与小图A中的那种类似。
在其它例子中,生物治疗复合物由与IE-BP共价连接(直接或通过接头间接地)的LSD-RP组成。在一个实施例中,LSD-RP附着至免疫球蛋白分子(例如,重链或可替代的轻链)的C末端。在另一个实施例中,LSD-RP附着至免疫球蛋白分子(例如重链或轻链)的N末端。在这些范例中,免疫球蛋白分子是IE-BP。
“溶酶体贮积病相关蛋白质”或“LSD-RP”指示与溶酶体贮积病的病因学或生理效应相关的任何蛋白质。LSD-RP包括实际的酶、转运蛋白、受体或其它蛋白质,其是有缺陷的,并且归于引起疾病的分子损害。LSD-RP还包括可提供类似或足够的生化或生理活性的任何蛋白质,以替代或避开疾病的分子损害。例如,“同工酶”可用作LSD-RP。溶酶体贮积病相关蛋白的例子包括表1中列为“涉及的酶/蛋白质”的那些和任何已知或以后发现的蛋白质或其它分子,其避开溶酶体贮积病的分子缺陷。
在其中分子缺陷是α-葡糖苷酶活性缺陷的庞贝氏症的情况下,LSD-RP包括人α-葡糖苷酶和“同工酶”,例如其它α-葡糖苷酶、经改造的重组α-葡糖苷酶、其它葡糖苷酶、重组葡糖苷酶、经改造为水解末端非还原性1-4连接的α-葡萄糖残基以释放单个α-葡萄糖分子的任何蛋白质、任何EC 3.2.1.20酶、用于糖原或淀粉的天然或重组的低pH碳水化合物水解酶和葡糖基水解酶如蔗糖酶异麦芽糖酶、麦芽糖酶葡糖淀粉酶、葡糖苷酶II和中性α-葡糖苷酶,。
“内化效应物”包括能够被内化到细胞内或者以其它方式参与或促成逆梯度膜运输的蛋白质。在一些情况下,内化效应物是经历转胞吞作用的蛋白质;即,蛋白质在细胞的一侧上被内化并且转运到细胞的另一侧(例如,顶端至基底)。在许多实施方案中,内化效应蛋白是细胞表面表达的蛋白质或可溶解的胞外蛋白质。然而,本发明也考虑了其中内化效应蛋白在细胞内区室如内体、内质网、高尔基体、溶酶体等中表达的实施例。例如,参与逆梯度膜运输(例如,从早期/再循环型内体至反-高尔基体网的途径)的蛋白质可以在本发明的多个实施方案中充当内化效应蛋白。无论如何,IE-BP与内化效应蛋白的结合导致整个生物治疗复合物以及与其相关的任何分子(例如LSD-RP)也变得内化到细胞内。如下文解释,内化效应蛋白包括直接内化至细胞中的蛋白质,以及间接地内化至细胞中的蛋白质。
直接内化至细胞中的内化效应蛋白包括经历细胞内化并且优选地由胞内降解和/或再循环途径加工的具有至少一个胞外结构域的膜结合分子(例如,跨膜蛋白、GPI-锚定蛋白等)。直接内化到细胞内的内化效应蛋白的具体非限制性例子包括例如CD63、MHC-I(例如HLA-B27)、Kremen-1、Kremen-2、LRP5、LRP6、LRP8、转铁蛋白受体、LDL-受体、LDL-相关蛋白1受体、ASGR1、ASGR2、淀粉样前体蛋白样蛋白-2(APLP2)、爱帕琳受体(APLNR)、MAL(髓鞘和淋巴细胞蛋白,又名VIP17)、IGF2R、液泡型H+ATP酶、白喉毒素受体、叶酸受体、谷氨酸受体、谷胱甘肽受体、瘦素受体、清道夫受体(例如SCARA1-5、SCARB1-3和CD36)等等。
在某些实施例中,内化效应物是促乳素受体(PRLR)。发现PRLR不仅是某些治疗应用的靶标,而且是基于其高内化速率和翻转率的有效内化效应蛋白。W02015/026907中示出了例如PRLR作为内化效应蛋白的潜力,其中尤其证实抗PRLR抗体在体外被PRLR表达细胞有效内化。
在某些实施例中,内化效应物是肾特异性内化剂,例如CDH16(Cadheri-16)、CLDN16(Claudn-16)、KL(Klotho)、PTH1R(甲状旁腺激素受体)、SLC22A13(溶质载体家族22成员13)、SLC5A2(钠/葡萄糖协同转运蛋白2)和UMOD(尿调节蛋白)。在其它某些实施例中,内化效应物是肌肉特异性内化剂,例如BMPR1A(骨形态发生蛋白受体1A)、m-钙粘蛋白、CD9、MuSK(肌肉特异性激酶)、LGR4/GPR48(G蛋白偶联受体48)、胆碱能受体(烟碱)α1、CDH15(Cadheri-15)、ITGA7(整联蛋白α-7)、CACNG1(L-型钙通道亚基γ-1)、CACNAlS(L-型钙通道亚基α-15)CACNG6(L-型钙通道亚基γ-6)、SCN1B(钠通道亚基β-1)、CHRNA1(ACh受体亚基α)、CHRND(ACh受体亚基δ)、LRRC14B(富含亮氨酸重复序列的蛋白质14B)、和POPDC3(含Popeye结构域的蛋白质3)。在一些具体实施例中,内化效应物是ITGA7、CD9、CD63、ALPL2或PPRLR。
在其中内化效应物(IE)直接内化到细胞内的那些实施例中,IE-BP可为例如特异性结合IE的抗体或抗体的抗原结合片段,或者与IE特异性相互作用的配体或配体的一部分。例如,如果IE是Kremen-1或Kremen-2,则IE-BP可包含下述或由下述组成:Kremen配体(例如DKK1)或其Kremen结合部分。作为另一个例子,如果IE是受体分子例如ASGR1,则IE-BP可包含下述或由下述组成:对于受体特异性的配体(例如脱唾液酸血清类粘蛋白[ASOR]或β-Ga1NAc)或其受体结合部分。
间接内化至细胞中的内化效应蛋白包括本身不内化,但与直接内化至细胞中的第二蛋白质或多肽结合或以其他方式缔合后变成内化至细胞中的蛋白质和多肽。间接内化至细胞中的蛋白质包括例如能够与内化性细胞表面表达受体分子结合的可溶性配体。通过可溶性配体与内化性细胞表面表达受体分子相互作用(间接)内化至细胞中的可溶性配体的非限制性示例是转铁蛋白。在其中IE是转铁蛋白(或另一种间接内化蛋白质)的实施例中,IE-BP与IE的结合以及IE与转铁蛋白受体(或另一种内化的细胞表面表达的受体分子)的相互作用,导致整个IE-BP以及与其结合的任何分子(例如LSD-RP)与IE及其结合配偶体的内化同时变得内化到细胞内。
在IE被间接内化到细胞内的那些实施例中,IE-BP可为例如特异性结合IE的抗体或抗体的抗原结合片段、或者与可溶性效应蛋白特别相互作用的受体或受体的一部分。例如,如果IE是细胞因子,则IE-BP可包含下述或由下述组成:相应的细胞因子受体或其配体结合部分。
示例性的IE是CD63,其是跨越细胞膜四次的细胞表面蛋白的四次跨膜蛋白超家族的成员。CD63在实际上所有组织中表达,并且被认为涉及形成和稳定化信号传导复合物。CD63定位于细胞膜、溶酶体膜和次级内体膜。已知CD63与整联蛋白结合并且可涉及上皮-间充质转化。参见H.Maecker等人,“The tetraspanin superfamily:molecularfacilitators,”11(6)FASEB J.428-42,May 1997;和M.Metzelaar等人,“CD63antigen.Anovel lysosomal membrane glycoprotein,cloned by a screening procedure forintracellular antigens in eukaryotic cells,”266J.Biol.Chem.3239-3245,1991。
另一个示例性的IE是淀粉样β(A4)前体样蛋白2(“APLP2”),其是APP(淀粉样前体蛋白)家族的遍在表达的成员。APLP2是已知与主要组织相容性复合体(MHC)I类分子(例如Kd)相互作用的膜结合蛋白。它在细胞表面处结合Kd,并且紧随其后以网格蛋白N-依赖性方式与Kd一起内化。参见Tuli等人,“Mechanism for amyloid precursor-like protein2enhancement of major histocompatibility complex class I moleculedegradation,”284 The Journal of Biological Chemistry 34296-34307(2009)。
另一个IE范例是促乳素受体(PRLR)。促乳素受体是I型细胞因子受体家族的成员,并且在配体结合和后续二聚化后激活“酪氨酸激酶Jak2、Fyn和Tec,磷酸酶SHP-2,鸟嘌呤核苷酸交换因子Vav和信号传导抑制因子SOCS”(参见Clevenger和Kline,“Prolactinreceptor signal transduction,”10(10)Lupus 706-18(2001),摘要)。促乳素受体经历内吞再循环并且可在溶酶体级分中发现。参见Genty等人,“Endocytosis and degradationof prolactin and its receptor in Chinese hamster ovary cells stablytransfected with prolactin receptor cDNA,”99(2)Mol.Cell Endocrinol.221-8(1994);和Ferland等人,“The effect of chloroquine on lysosomal prolactinreceptors in rat liver,”115(5)Endocrinology 1842-9(1984)。
如本文使用的,“免疫反应”一般意指患者对外部或‘非自身’蛋白质的免疫应答。这种免疫应答包括变态反应和干扰替代酶效力的抗体的发展。一些患者可能不产生任何无功能的蛋白质,因此致使替代酶成为“外来”蛋白质。例如,对缺乏GLA的那些法布里病患者重复注射重组GLA(rGLA)频繁导致变态反应。在其它患者中,针对rGLA的抗体的产生已显示降低替代酶在治疗疾病中的有效性。参见例如Tajima等人(“Use of a Modified α-N-Acetylgalactosaminidase(NAGA)in the Development of Enzyme Replacement Therapyfor Fabry Disease,”85(5)Am.J.Hum.Genet.569-580(2009)),其讨论了经修饰的NAGA作为替代GLA的“同工酶”的用途。经修饰的NAGA与GLA没有免疫交叉反应性,并且“不与来自用重组GLA重复治疗的法布里病患者的血清反应”。同上,摘要
术语“蛋白质”意指具有经由酰胺键共价连接的超过约20个氨基酸的任何氨基酸聚合物。蛋白质含有一个或多个氨基酸聚合物链,在本领域中一般称为“多肽”。因此,多肽可为蛋白质,并且蛋白质可含有多重多肽以形成单一功能性生物分子。二硫桥(即在半胱氨酸残基之间以形成胱氨酸)可存在于一些蛋白质中。这些共价键可在单个多肽链内,或在两个个别多肽链之间。例如,二硫桥对于胰岛素、免疫球蛋白、鱼精蛋白等等的适当结构和功能是必需的。关于二硫键形成的最近综述,参见Oka和Bulleid,“Forming disulfides inthe endoplasmic reticulum,”1833(11)Biochim Biophys Acta 2425-9(2013)。
除二硫键形成之外,蛋白质还可经受其它翻译后修饰。这些修饰包括脂化(例如肉豆蔻酰化、棕榈酰化、法尼基化、香叶基香叶基化(geranylgeranylation)和糖基磷脂酰肌醇(GPI)锚形成)、烷基化(例如甲基化)、酰化、酰胺化、糖基化(例如在精氨酸、天冬酰胺、半胱氨酸、羟赖氨酸、丝氨酸、苏氨酸、酪氨酸和/或色氨酸处添加糖基基团)、以及磷酸化(即,磷酸团对丝氨酸、苏氨酸、酪氨酸和/或组氨酸的添加)。关于真核生物中产生的蛋白质的翻译后修饰的最近综述,参见Mowen和David,“Unconventional post-translationalmodifications in immunological signaling,”15(6)Nat Immunol 512-20(2014);以及Blixt和Westerlind,“Arraying the post-translational glycoproteome(PTG),”18CurrOpin Chem Biol.62-9(2014)。
免疫球蛋白是具有多重多肽链和广泛的翻译后修饰的蛋白质。经典免疫球蛋白(例如IgG)包含四条多肽链-两条轻链和两条重链。每条轻链经由胱氨酸二硫键与一条重链连接,并且两条重链经由两个胱氨酸二硫键彼此结合。在哺乳动物系统中产生的免疫球蛋白在不同残基处(例如,在天冬酰胺残基处)由各种多糖糖基化,并且可因物种不同而不同,这可影响治疗性抗体的抗原性(参见Butler和Spearman,“The choice of mammalian cellhost and possibilities for glycosylation engineering”,30 Curr Opin Biotech107-112(2014))。
如本文使用的,“蛋白质”包括生物治疗性蛋白质、用于研究或疗法中的重组蛋白质、陷阱蛋白质和其它Fc-融合蛋白、嵌合蛋白、抗体、单克隆抗体、人抗体、双特异性抗体、抗体片段、纳米抗体、重组抗体嵌合体、细胞因子、趋化因子、肽激素等等。可使用基于重组细胞的生产系统如昆虫杆状病毒系统、酵母系统(例如毕赤酵母属物种(Pichia sp.))、哺乳动物系统(例如CHO细胞和CHO衍生物如CHO-K1细胞)来产生蛋白质。关于讨论生物治疗性蛋白质及其产生的最近综述,参见Ghaderi等人,“Production platforms forbiotherapeutic glycoproteins.Occurrence,impact,and challenges of non-humansialylation,”28Biotechnol Genet Eng Rev.147-75(2012)。
如本文使用的,术语“抗体”包括包含通过二硫键相互连接的四条多肽链(两条重链(H)和两条轻链(L))的免疫球蛋白分子。每条重链包含重链可变区(本文中缩写为HCVR或VH)和重链恒定区。重链恒定区包含三个结构域:CH1、CH2和CH3。每条轻链包含轻链可变区(本文中缩写为LCVR或VL)和轻链恒定区。轻链恒定区包含一个结构域CL。VH和VL区还可细分成称为互补决定区(CDR)的高变区,其间插有称为构架区(FR)的更保守区域。每个VH和VL由从氨基末端到羧基末端按照下述次序排列的三个CDR和四个FR组成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4(重链CDR可缩写为HCDR1、HCDR2和HCDR3;轻链CDR可缩写为LCDR1、LCDR2和LCDR3。术语“高亲和力”抗体指对于其靶具有至少10-9M、至少10-10M;至少10-11M;或至少10-12M的结合亲和力的那些抗体,如通过表面等离振子共振例如BIACORETM或溶液亲和ELISA测量的。
短语“双特异性抗体”包括能够选择性结合两个或更多个表位的抗体。双特异性抗体一般包含两条不同的重链,其中每条重链特异性结合不同表位—或在两个不同分子(例如抗原)上或在相同分子上(例如在相同抗原上)。如果双特异性抗体能够选择性结合两个不同的表位(第一表位和第二表位),则第一重链对于第一表位的亲和力一般比第一重链对于第二表位的亲和力低至少一个到两个或三个或四个数量级,并且反之亦然。由双特异性抗体识别的表位可在相同或不同的靶上(例如在相同或不同的蛋白质上)。双特异性抗体可例如通过组合识别相同抗原的不同表位的重链来制备。例如,编码识别相同抗原的不同表位的重链可变序列的核酸序列可与编码不同重链恒定区的核酸序列融合,并且这样的序列可在表达免疫球蛋白轻链的细胞中表达。通常的双特异性抗体具有两条重链以及免疫球蛋白轻链,所述两条重链各自具有三个重链CDR,随后为(N末端至C末端)CH1结构域、铰链、CH2结构域和CH3结构域,所述免疫球蛋白轻链不赋予抗原结合特异性,但可与每条重链结合,或者可与每条重链结合并且可结合由重链抗原结合区结合的一个或多个表位,或者可与每条重链结合并且使得重链之一或两者能够与一个或两个表位结合。
短语“重链”或“免疫球蛋白重链”包括来自任何生物的免疫球蛋白重链恒定区序列,并且除非另有说明,否则包括重链可变结构域。除非另有说明,否则重链可变结构域包括三个重链CDR和四个FR区。重链片段包括CDR、CDR和FR及其组合。通常的重链在可变结构域之后具有(从N末端到C末端)CH1结构域、铰链、CH2结构域和CH3结构域。重链的功能片段包括能够特异性识别抗原的片段(例如,以在微摩尔、纳摩尔或皮摩尔范围内的KD识别抗原),其能够由细胞表达且分泌,并且包含至少一个CDR。
短语“轻链”包括来自任何生物的免疫球蛋白轻链恒定区序列,并且除非另有说明,否则包括人κ和λ轻链。除非另有说明,否则轻链可变(VL)结构域通常包括三个轻链CDR和四个构架(FR)区。一般地,全长轻链从氨基末端到羧基末端包括包含FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4的VL结构域和轻链恒定结构域。可用于本发明的轻链包括例如不选择性结合由抗原结合蛋白选择性结合的第一抗原或第二抗原的那些。合适的轻链包括可通过在现有抗体文库(湿文库或在计算机芯片上)中筛选最常用的轻链来鉴定的那些,其中所述轻链基本上不干扰抗原结合蛋白的抗原结合结构域的亲和力和/或选择性。合适的轻链包括可结合被抗原结合蛋白的抗原结合区结合的一个或两个表位的那些。
短语“可变结构域”包括免疫球蛋白轻链或重链(根据需要进行修饰)的氨基酸序列,其从N末端到C末端序贯包含下述氨基酸区(除非另有说明):FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。“可变结构域”包括能够折叠成具有双重β片层结构的经典结构域(VH或VL)的氨基酸序列,其中β片层通过第一β片层和第二β片层的残基之间的二硫键连接。
短语“互补决定区”或术语“CDR”包括由生物的免疫球蛋白基因的核酸序列编码的氨基酸序列,其通常(即在野生型动物中)出现在免疫球蛋白分子(例如抗体或T细胞受体)的轻链或重链的可变区中的两个构架区之间。CDR可由例如种系序列或者重排或未重排序列,以及例如天然或成熟的B细胞或T细胞编码。在一些情况下(例如对于CDR3),CDR可由两个或更多个序列(例如种系序列)编码,所述两个或更多个序列是不邻接的(例如未重排的核酸序列中),但例如由于剪接或连接序列(例如,V-D-J重组以形成重链CDR3)在B细胞核酸序列中是邻接的。
术语“抗体片段”指保留特异性结合抗原的能力的抗体的一个或多个片段。在术语“抗体片段”内涵盖的结合片段的例子包括(i)Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')2片段,包含通过在铰链区处的二硫键连接的两个Fab片段的二价片段;(iii)由VH和CH1结构域组成的Fd片段;(iv)由抗体单臂的VL和VH结构域组成的Fv片段,(v)由VH结构域组成的dAb片段(Ward等人(1989)Nature 241:544-546),(vi)经分离的CDR,和(vii)scFv,其由Fv片段的两个结构域VL和VH组成,所述两个结构域VL和VH通过合成接头连接以形成单条蛋白质链,其中VL和VH区配对以形成单价分子。其它形式的单链抗体例如双抗体也涵盖在术语“抗体”下(参见例如Holliger等人(1993)PNAS USA 90:6444-6448;Poljak等人(1994)Structure 2:1121-1123)。
短语“含Fc的蛋白质”包括抗体、双特异性抗体、免疫粘附素和其它结合蛋白,其包含免疫球蛋白CH2和CH3区的至少一个功能部分。“功能部分”指可结合Fc受体(例如FcγR;或FcRn,即新生儿Fc受体)和/或可参与补体活化的CH2和CH3区。如果CH2和CH3区含有致使其不能与任何Fc受体结合并且也不能激活补体的缺失、置换和/或插入或其它修饰,则CH2和CH3区是无功能的。
含Fc的蛋白质可包含免疫球蛋白结构域中的修饰,包括影响结合蛋白的一种或多种效应子功能的修饰(例如影响FcγR结合、FcRn结合和因此的半衰期和/或CDC活性的修饰)。参考免疫球蛋白恒定区的EU编号,这样的修饰包括但不限于下述修饰及其组合:238、239、248、249、250、252、254、255、256、258、265、267、268、269、270、272、276、278、280、283、285、286、289、290、292、293、294、295、296、297、298、301、303、305、307、308、309、311、312、315、318、320、322、324、326、327、328、329、330、331、332、333、334、335、337、338、339、340、342、344、356、358、359、360、361、362、373、375、376、378、380、382、383、384、386、388、389、398、414、416、419、428、430、433、434、435、437、438和439。
例如,但不作为限制,结合蛋白是含有Fc的蛋白质,并且显示出增强的血清半衰期(与没有所述修饰的相同的含有Fc的蛋白质相比),并且具有位置250(例如E或Q);250和428(例如L或F);252(例如L/Y/F/W或T)、254(例如S或T)和256(例如S/R/Q/E/D或T)处的修饰;或在428和/或433(例如L/R/SI/P/Q或K)和/或434(例如H/F或Y)处的修饰;或在250和/或428处的修改;或在307或308(例如308F、V308F)和434处的修饰。在另一个例子中,修饰可包括428L(例如M428L)和434S(例如N434S)修饰;428L、2591(例如V259I)和308F(例如V308F)修饰;433K(例如H433K)和434(例如434Y)修饰;252、254和256(例如252Y、254T和256E)修改;250Q和428L修改(例如T250Q和M428L);307和/或308修改(例如308F或308P)。
如本文使用的,术语“抗原结合蛋白”指特异性识别抗原上的表位的多肽或蛋白质(在功能单元中复合的一种或多种多肽),所述抗原例如细胞特异性抗原和/或本发明的靶抗原。抗原结合蛋白可为多特异性的。关于抗原结合蛋白的术语“多特异性”意指蛋白质识别不管是在相同的抗原上还是在不同的抗原上的不同表位。本发明的多特异性抗原结合蛋白可为单个多功能多肽,或者它可为彼此共价或非共价结合的两个或更多个多肽的多聚复合物。术语“抗原结合蛋白”包括可与另一种功能分子(例如另一种肽或蛋白质)连接或共表达的本发明的抗体或其片段。例如,抗体或其片段可与一个或多个其它分子实体例如蛋白质或其片段功能性连接(例如通过化学偶联、基因融合、非共价结合或其它方式),以产生具有第二结合特异性的双特异性或多特异性抗原结合分子。
如本文使用的,术语“表位”指被多特异性抗原结合多肽识别的抗原的一部分。单个抗原(例如抗原性多肽)可具有超过一个表位。表位可被定义为结构或功能的。功能表位一般是结构表位的子集,并且定义为直接促成抗原结合多肽与抗原之间相互作用的亲和力的那些残基。表位也可为构象的,即由非线性氨基酸组成。在某些实施例中,表位可包括决定簇,所述决定簇是分子的化学活性表面分组,例如氨基酸、糖侧链、磷酰基或磺酰基,并且在某些实施例中,可具有特定的三维结构特征,和/或特定的电荷特征。由邻接氨基酸形成的表位通常在暴露于变性溶剂时保留,而通过三级折叠形成的表位通常在用变性溶剂处理时丢失。
术语“结构域”指具有特定功能或结构的蛋白质或多肽的任何部分。优选地,本发明的结构域结合细胞特异性抗原或靶抗原。如本文使用的,细胞特异性抗原或靶抗原结合结构域等等包括任何天然存在的、可酶促获得的、合成的或遗传改造的特异性结合抗原的多肽或糖蛋白。
可互换使用的术语“半体”或“半抗体”指抗体的一半,其基本上含有一条重链和一条轻链。抗体重链可形成二聚体,因此一个半体的重链可与和不同分子(例如另一个半体)或另一个含Fc多肽结合的重链结合。两个略微不同的Fc-结构域可“异源二聚化”,如在双特异性抗体或其它异源二聚体、-三聚体、-四聚体等等形成中。参见Vincent和Murini,“Current strategies in antibody engineering:Fc engineering and pH-dependentantigen binding,bispecific antibodies and antibody drug conjugates,”7Biotechnol.J.1444-1450(20912);和Shimamoto等人,“Peptibodies:A flexiblealternative format to antibodies,”4(5)MAbs 586-91(2012)。
在一个实施例中,半体可变结构域特异性识别内化效应物,并且半体Fc-结构域与包含替代酶(例如肽体)的Fc-融合蛋白二聚化,同上,586。
“α-葡糖苷酶(Alpha-glucosidase)”(或“α-葡糖苷酶(α-glucosidase)”)、“α-葡糖苷酶活性”、“GAA”和“GAA活性”可互换使用,并且指促进糖原和淀粉的1,4-α键水解成葡萄糖的任何蛋白质。GAA尤其还称为EC 3.2.1.20、麦芽糖酶、葡糖转化酶、葡糖苷蔗糖酶、麦芽糖酶-葡糖淀粉酶、α-吡喃葡糖苷酶、葡糖苷转化酶、α-D-葡糖苷酶、α-葡糖苷水解酶、α-1,4-葡糖苷酶和α-D-葡糖苷葡糖水解酶。GAA可在溶酶体中和小肠的刷状缘处发现。患有庞贝氏症的患者缺乏功能性溶酶体α-葡糖苷酶。参见S.Chiba,“Molecular mechanism in alpha-glucosidase and glucoamylase,”61(8)Biosci.Biotechnol.Biochem.1233-9(1997);和Hesselink等人,“Lysosomal dysfunction in muscle with special reference toglycogen storage disease type II,”1637(2)Biochim.Biophys.Acta.164-70(2003)。
“α-半乳糖苷酶A(Alpha-galactosidase A)”(或“α-半乳糖苷酶A(α-galactosidase A)”)、“α-半乳糖苷酶A活性”、“α-半乳糖苷酶”、“α-半乳糖苷酶活性”、“GLA”和“GLA活性”是可互换使用,并且指促进来自糖脂和糖蛋白的末端α-半乳糖基部分水解,且还水解α-D-岩藻糖苷的任何蛋白质。GLA尤其也称为EC3.2.1.22、蜜二糖酶、α-D-半乳糖苷酶、α-半乳糖苷酶A、α-半乳糖苷半乳糖水解酶、α-D-半乳糖苷半乳糖水解酶。GLA是由X连锁GLA基因编码的溶酶体酶。GLA中的缺陷可导致法布里病,其中称为球形三脂酰基鞘氨醇(又名Gb3、GL-3或三己糖苷神经酰胺)的糖脂在血管内累积(即显著的血管病变),导致肾心脏、皮肤和/或脑血管组织及其它组织和器官的疼痛和功能受损。参见例如Prabakaran等人“Mannose6-phosphate receptor and sortilin mediated endocytosis of α-galactosidase Ain kidney endothelial cells,”7(6)PLoS One e39975第1-9页(2012)。
在一个方面,本发明提供了通过向患者施用“生物治疗复合物”来治疗患有溶酶体贮积病(LSD)的患者(或受试者)的方法。生物治疗复合物进入患者的细胞,并且对溶酶体递送替代与LSD相关的酶或酶促活性(即“内源性酶”)的酶或酶促活性(即“替代酶”)。
LSD包括鞘脂类代谢障碍、粘多糖贮积病和糖原贮积病。在一些实施例中,LSD是法布里病、I型戈谢病、II型戈谢病、III型戈谢病、A型尼曼-皮克病、B型尼曼-皮克病、GM1-神经节苷脂贮积症、桑德霍夫病、Tay-Sachs病、GM2-激活因子缺乏症、GM3-神经节苷脂贮积症、异染性脑白质营养不良、鞘脂激活因子缺乏症、Scheie病、Hurler-Sceie病、Hurler病、Hunter病、Sanfilippo A、Sanfilippo B、Sanfilippo C、Sanfilippo D、莫奎欧综合征A、莫奎欧综合征B、Maroteaux-Lamy病、Sly病、MPS IX和庞贝氏症。在一个具体实施例中,LSD是法布里病。在另一个实施例中,LSD是庞贝氏症。
在一些实施例中,生物治疗复合物包含(a)替代酶,和(b)结合内化效应物的分子实体。在一些情况下,替代酶是以下中的一种或多种:α-半乳糖苷酶、β-半乳糖苷酶、α-葡糖苷酶、β-葡糖苷酶、鞘脂激活蛋白C激活因子、神经酰胺酶、鞘磷脂酶、β-氨基己糖苷酶、GM2激活蛋白、GM3合酶、芳基硫酸酯酶、鞘脂激活因子、α-艾杜糖醛酸酶、艾杜糖醛酸酶-2-硫酸酯酶、肝素N-硫酸酯酶、N-乙酰-α-氨基葡糖苷酶、α-葡糖酰胺N-乙酰转移酶、N-乙酰葡糖胺-6-硫酸酯酶、N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶、N-乙酰半乳糖胺-4-硫酸酯酶、β-葡萄糖醛酸酶和透明质酸酶。
在一些情况下,患者无法制备足够的蛋白质,使得替代酶被患者识别为“非自身的”,并且免疫反应在施用替代酶后跟着发生。这是不期望的。因此,在一些实施例中,以避免在受试者中诱导免疫反应的方式设计或生产替代酶。一种这样的解决方案是使用“同工酶”作为替代酶。同工酶足够接近于患者的“自身”蛋白质,但具有足以改善LSD症状的替代酶活性。
在其中LSD是庞贝氏症并且内源性酶是α-葡糖苷酶(GAA)的一个特定实施例中,同工酶可为酸性α-葡糖苷酶、蔗糖酶-异麦芽糖酶(SI)、麦芽糖酶-葡糖淀粉酶(MGAM)、葡糖苷酶II(GANAB)和中性α-葡糖苷酶(C GNAC)中的任何一种。在其中LSD是法布里病并且内源性酶是α-半乳糖苷酶A(GLA)的另一个特定实施例中,同工酶可为经改造为具有GLA活性的α-N-乙酰半乳糖胺酶。
生物治疗复合物具有内化效应结合蛋白组分,其使得能够摄取替代酶进入细胞。因此,在一些实施例中,内化效应物可为CD63、MHC-I、Kremen-1、Kremen-2、LRP5、LRP6、LRP8、转铁蛋白受体、LDL-受体、LDL-相关蛋白1受体、ASGR1、ASGR2、淀粉样前体蛋白样蛋白-2(APLP2)、爱帕琳受体(APLNR)、PRLR(促乳素受体)、MAL(髓鞘和淋巴细胞蛋白,又名VIP17)、IGF2R、液泡型H+ATP酶、白喉毒素受体、叶酸受体、谷氨酸受体、谷胱甘肽受体、瘦素受体、清道夫受体、SCARA1-5、SCARB1-3和CD36。在某些实施例中,内化效应物是肾特异性内化剂(internalizer)例如CDH16(Cadheri-16)、CLDN16(Claudn-16)、KL(Klotho)、PTH1R(甲状旁腺激素受体)、SLC22A13(溶质载体家族22成员13)、SLC5A2(钠/葡萄糖协同转运蛋白2)和UMOD(尿调节蛋白)。在其它某些实施例中,内化效应物是肌肉特异性内化剂,例如BMPR1A(骨形态发生蛋白受体1A)、m-钙粘蛋白、CD9、MuSK(肌肉特异性激酶)、LGR4/GPR48(G蛋白偶联受体48)、胆碱能受体(烟碱)α1、CDH15(Cadheri-15)、ITGA7(整联蛋白α-7)、CACNG1(L-型钙通道亚基γ-1)、CACNAlS(L-型钙通道亚基α-15)CACNG6(L-型钙通道亚基γ-6)、SCN1B(钠通道亚基β-1)、CHRNA1(ACh受体亚基α)、CHRND(ACh受体亚基δ)、LRRC14B(富含亮氨酸重复序列的蛋白质14B)、和POPDC3(含Popeye结构域的蛋白质3)。在一些具体实施例中,内化效应物是ITGA7、CD9、CD63、APLP2或PRLR。
在一些实施例中,内化效应物结合蛋白包含抗原结合蛋白,其包括例如受体-融合分子、陷阱分子、受体-Fc融合分子、抗体、Fab片段、F(ab')2片段、Fd片段、Fv片段、单链Fv(scFv)分子、dAb片段、经分离的互补决定区(CDR)、CDR3肽、受限的FR3-CDR3-FR4肽、结构域特异性抗体、单抗结构域抗体、结构域缺失抗体、嵌合抗体、CDR移植抗体、双抗体、三抗体、四抗体、微型抗体、纳米抗体、单价纳米抗体、二价纳米抗体、小模块免疫药物(SMIP)、骆驼科抗体(VHH重链同型二聚体抗体)和鲨鱼可变IgNAR结构域。
在一个实施例中,结合内化效应物的分子实体是抗体、抗体片段或其它抗原结合蛋白。例如,分子实体可为双特异性抗体,其中一个臂结合内化效应物(例如ITGA7、CD9、CD63、PRLR、APLP2),并且另一个臂结合替代酶。此处,生物治疗复合物包含双特异性抗体和替代酶(图1A)。在一个具体实施例中,所治疗的疾病是法布里病,并且生物治疗复合物包含GLA以及结合GLA和CD63的双特异性抗体。在另一个具体实施例中,所治疗的疾病是庞贝氏症,并且生物治疗复合物包含GAA以及结合GAA和CD63的双特异性抗体。
在另一个实施例中,结合内化效应物的分子实体包含半抗体,并且替代酶含有Fc结构域(酶-Fc融合多肽)。在一个实施例中,酶-Fc融合多肽的Fc结构域与内化效应物特异性半体的Fc结构域结合,以形成生物治疗复合物(图1B)。
在其它实施例中,替代酶与内化效应物结合蛋白共价连接。由于Fc二聚体可经由一个或多个二硫桥固定,所以在先前段落中描述的酶-Fc融合物:半体实施例(也参见图1B)落入该类别内。酶活性结构域或多肽与内化-结合结构域或多肽之间的共价连接可为任何类型的共价键,即涉及共享电子的任何键。在一些情况下,共价键是两个氨基酸之间的肽键,使得替代酶和内化效应物结合蛋白全部或部分形成如融合蛋白中的连续多肽链。在一些情况下,替代酶部分和内化效应物结合蛋白直接连接。在其它情况下,使用接头来栓系两个部分。参见Chen等人,“Fusion protein linkers:property,design andfunctionality,”65(10)Adv Drug Deliv Rev.1357-69(2013)。
在一个特定实施例中,替代酶共价连接至抗内化效应物抗体的重链的C末端(参见图1C)或轻链的C末端(图1E)。在另一个特定实施例中,替代酶共价连接至抗内化效应抗体的重链的N末端(参见图1D)或轻链的N末端(图1F)。
在一些情况下,尤其是替代酶在溶酶体中通常不被蛋白酶解加工的情况下,将可切割接头加入包含抗体-酶融合物的生物治疗复合物的那些实施例中。在一些实施例中,将组织蛋白酶可切割接头插入抗体和替代酶之间,以促进溶酶体中抗体的去除,以便a)可能通过去除空间上大的抗体来帮助保存酶促活性,和b)可能增加溶酶体酶的半衰期。
在另一个方面,本发明提供了包含酶活性和抗原结合蛋白的组合物,其中所述酶与溶酶体贮积病(LSD)和内化效应物结合蛋白相关。与溶酶体贮积病相关的酶(其包括本身并非催化性的蛋白质)包括例如α-半乳糖苷酶、β-半乳糖苷酶、α-葡糖苷酶、β-葡糖苷酶、鞘脂激活蛋白C激活因子、神经酰胺酶、鞘磷脂酶、β-氨基己糖苷酶、GM2激活蛋白、GM3合酶、芳基硫酸酯酶、鞘脂激活因子、α-艾杜糖醛酸酶、艾杜糖醛酸酶-2-硫酸酯酶、肝素N-硫酸酯酶、N-乙酰-α-氨基葡糖苷酶、α-葡糖酰胺N-乙酰转移酶、N-乙酰葡糖胺-6-硫酸酯酶、N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶、N-乙酰半乳糖胺-4-硫酸酯酶、β-葡萄糖醛酸酶、透明质酸酶等等。
内化效应物结合蛋白例如包括受体-融合分子、陷阱分子、受体-Fc融合分子、抗体、Fab片段、F(ab')2片段、Fd片段、Fv片段、单链Fv(scFv)分子、dAb片段、经分离的互补决定区(CDR)、CDR3肽、受限的FR3-CDR3-FR4肽、结构域特异性抗体、单抗结构域抗体、结构域缺失抗体、嵌合抗体、CDR移植抗体、双抗体、三抗体、四抗体、微型抗体、纳米抗体、单价纳米抗体、二价纳米抗体、小模块免疫药物(SMIP)、骆驼科抗体(VHH重链同型二聚体抗体)、鲨鱼可变IgNAR结构域、其它抗原结合蛋白等等。
内化效应物包括例如CD63、MHC-I、Kremen-1、Kremen-2、LRP5、LRP6、LRP8、转铁蛋白受体、LDL-受体、LDL-相关蛋白1受体、ASGR1、ASGR2、淀粉样前体蛋白样蛋白-2(APLP2)、爱帕琳受体(APLNR)、PRLR(促乳素受体)、MAL(髓鞘和淋巴细胞蛋白,又名VIP17)、IGF2R、液泡型H+ATP酶、白喉毒素受体、叶酸受体、谷氨酸受体、谷胱甘肽受体、瘦素受体、清道夫受体、SCARA1-5、SCARB1-3和CD36。在某些实施例中,内化效应物是肾特异性内化剂(internalizer)例如CDH16(Cadheri-16)、CLDN16(Claudn-16)、KL(Klotho)、PTH1R(甲状旁腺激素受体)、SLC22A13(溶质载体家族22成员13)、SLC5A2(钠/葡萄糖协同转运蛋白2)和UMOD(尿调节蛋白)。在其它某些实施例中,内化效应物是肌肉特异性内化剂,例如BMPR1A(骨形态发生蛋白受体1A)、m-钙粘蛋白、CD9、MuSK(肌肉特异性激酶)、LGR4/GPR48(G蛋白偶联受体48)、胆碱能受体(烟碱)α1、CDH15(Cadheri-15)、ITGA7(整联蛋白α-7)、CACNG1(L-型钙通道亚基γ-1)、CACNAlS(L-型钙通道亚基α-15)CACNG6(L-型钙通道亚基γ-6)、SCN1B(钠通道亚基β-1)、CHRNA1(ACh受体亚基α)、CHRND(ACh受体亚基δ)、LRRC14B(富含亮氨酸重复序列的蛋白质14B)、和POPDC3(含Popeye结构域的蛋白质3)。在一些具体实施例中,内化效应物是ITGA7、CD9、CD63、ALPL2或PPRLR。
在一些实施例中,酶共价连接(即,跨越原子共享的电子)至抗原结合蛋白。在一个特定实施例中,内化效应物结合蛋白由半体组成或包含半体;该酶与Fc-融合结构域融合(例如在C末端处);并且与酶共价连接的Fc结构域与抗原结合蛋白的Fc结构域结合,使得结合含有一个或多个二硫桥。图1B中示意性地描绘了该特定实施例。
在另一个特定实施例中,内化效应物结合蛋白(IE-BP)由抗体或抗体片段组成或者包含抗体或抗体片段,并且该酶共价连接至抗体或抗体片段。在一个具体实施例中,IEBP是抗体,并且该酶共价连接(通过肽键直接地,或经由接头间接地)至抗体的重链或轻链的C末端(分别为图1C或1E)。在另一个具体实施例中,IEBP是抗体,并且该酶共价连接(通过肽键直接地,或经由接头间接地)至抗体的重链或轻链的N末端(分别为图1D或1F)。
在一些实施例中,酶和IEBP不是共价连接的,而是在混合物中组合。IEBP和酶可通过非共价力结合以形成复合物。例如,在一个特定实施例中,IEBP是双特异性抗体,其中抗体的一个臂结合内化效应物,并且另一个臂结合酶。图1A中示意性地描绘了该实施例。
在一些实施例中,酶是GAA或包含GAA活性(例如具有GAA活性的同工酶),并且内化效应物是ITGA7、CDH15、CD9、CD63、APLP2或PRLR。在一个特定实施例中,酶是GAA或包含GAA活性,内化结构域是CD63,并且IEBP是对于CD63和GAA具有特异性的双特异性抗体。
在一些实施例中,酶是GLA或包含GLA活性(例如具有GAA活性的同工酶),并且内化效应物是ITGA7、CD9、CD63、APLP2或PRLR。在一个特定实施例中,酶是GLA或包含GLA活性,内化结构域是CD63,并且IEBP是对于CD63和GLA具有特异性的双特异性抗体。
在另一个方面,本发明提供了用于选择或筛选含有酶和抗原结合蛋白的生物治疗复合物的方法,所述生物治疗复合物有效替代有此需要的患者中的酶。在一个实施例中,将生物治疗复合物施用于模型系统,并且评价模型系统的替代酶活性。在一个实施例中,模型系统是缺乏酶表达并且表达抗原结合蛋白的抗原同源物的动物。在一个实施例中,动物模型是表达抗原结合蛋白的人源化同源物和具有编码该酶的基因敲除的小鼠。
在一个实施例中,小鼠含有溶酶体酶的敲除,所述溶酶体酶例如α-半乳糖苷酶A、神经酰胺酶、β-葡糖苷酶、鞘脂激活蛋白C激活因子、鞘磷脂酶、β-半乳糖苷酶、β-氨基己糖苷酶A和B、β-氨基己糖苷酶A、GM2-激活蛋白、GM3合酶、芳基硫酸酯酶A、鞘脂激活因子、α-艾杜糖醛酸酶、艾杜糖醛酸酶-2-硫酸酯酶、乙酰肝素N-硫酸酯酶、N-乙酰-α-氨基葡糖苷酶、乙酰CoA;α-葡糖酰胺N-乙酰转移酶、N-乙酰葡糖胺-6-硫酸酯酶、N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶、β-半乳糖苷酶、N-乙酰半乳糖胺-4-硫酸酯酶(芳基硫酸酯酶B)、β-葡萄糖醛酸酶、透明质酸酶、α-葡糖苷酶2或溶酶体酸性脂肪酶。在一个实施例中,敲除小鼠还表达内化效应物的人或人源化形式(即,抗原结合蛋白的同源性)。人内化效应物包括CD63、MHC-I、Kremen-1、Kremen-2、LRP5、LRP6、LRP8、转铁蛋白受体、LDL-受体、LDL-相关蛋白1受体、ASGR1、ASGR2、淀粉样前体蛋白样蛋白-2(APLP2)、爱帕琳受体(APLNR)、PRLR(促乳素受体)、MAL(髓鞘和淋巴细胞蛋白,又名VIP17)、IGF2R、液泡型H+ATP酶、白喉毒素受体、叶酸受体、谷氨酸受体、谷胱甘肽受体、瘦素受体、清道夫受体、SCARA1-5、SCARB1-3、CD36、CDH16(Cadheri-16)、CLDN16(Claudn-16)、KL(Klotho)、PTH1R(甲状旁腺激素受体)、SLC22A13(溶质载体家族22成员13)、SLC5A2(钠/葡萄糖协同转运蛋白2)、UMOD(尿调节蛋白)、BMPR1A(骨形态发生蛋白受体1A)、M-钙粘蛋白、CD9、MuSK(肌肉特异性激酶)、LGR4/GPR48(G蛋白偶联受体48)、胆碱能受体(烟碱)α1、CDH15(Cadheri-15)、ITGA7(整联蛋白α-7)、CACNG1(L-型钙通道亚基γ-1)、CACNAlS(L-型钙通道亚基α-15)CACNG6(L-型钙通道亚基γ-6)、SCN1B(钠通道亚基β-1)、CHRNA1(ACh受体亚基α)、CHRND(ACh受体亚基δ)、LRRC14B(富含亮氨酸重复序列的蛋白质14B)、和POPDC3(含Popeye结构域的蛋白质3)。
制备表达人受体的小鼠的方法是本领域已知的。参见例如Ma等人,DrugMetab.Dispos.2008 Dec;36(12):2506-12;和美国专利号8,878,001 B2,所述参考文献因表达人受体的转基因小鼠而并入本文。制造酶剔除小鼠的方法也是本领域已知的。参见例如Kuemmel等人,Pathol.Res.Pract.1997;193(10):663-71,所述小鼠因小鼠溶酶体贮积酶的敲除而并入本文。
提供下述实例以进一步说明本发明的方法。这些实例仅是说明性的,并不预期以任何方式限制本发明的范围。
实例
实例1:溶酶体α-葡糖苷酶融合蛋白
CI-MPR不依赖性抗体引导的递送系统设计为将酶递送至溶酶体。表3列出了分子构建体,连同其在CHO细胞中的表达水平(参见图2),如使用荧光底物4-甲基伞形酮基-α-葡糖苷测定的近似GAA活性(参见图3),以及溶酶体靶向、内化和活性状态(参见图4和5)。
实例2:GAA构建体内化
通过测量细胞裂解产物中的酶活性来确定GAA构建体的内化。将各种重组GAA(SEQID NO:1)构建体加入HEK293、人骨骼肌成肌细胞(Lonza,Walkersville,MD)或C2C12小鼠成肌细胞中。在加入酶构建物之前24小时,将细胞在24孔板中铺平板。将酶构建体加入细胞培养基中18小时。然后将细胞在冰冷的PBS中充分洗涤,并且在测定缓冲液(0.2M乙酸钠、0.4M氯化钾,pH 4.3)中的冰冷的0.5%NP-40中裂解。将裂解产物在4℃下以15,000x g离心15分钟,并且将上清液与GAA底物4-甲基伞形酮基α-D-葡糖苷一起在测定缓冲液中在96孔板中温育1小时。使用以pH 10.7的甘氨酸-碳酸盐缓冲液停止反应。在360nm激发和450nm发射下在板阅读器上读取荧光。使用二辛可宁酸测定试剂盒测定裂解产物蛋白质浓度。使用4-甲基伞形酮作为标准。GAA活性报告为每mg纯化蛋白质每小时释放的nmol 4-甲基伞形酮。参见Fuller等人,“Isolation and characterisation of a recombinant,precursor formof lysosomal acid alpha-glucosidase,”234(3)European Journal of Biochemistry903-909(1995)。
在甘露糖6-磷酸(M6P)的存在或不存在下(图4A),以及在CD63的存在或不存在下,评价GAA活性的内化。一些溶酶体酶经由与甘露糖6-磷酸受体(MPR)结合的附着的M6P部分靶向溶酶体。因此,通过在抗CD63-GAA摄取期间,在HEK培养基中包含5mM M6P(其竞争MPR结合)来评价CI-MPR对抗CD63-GAA内化的牵涉。M6P的包括对抗CD63-GAA的摄取没有作用,如通过细胞溶解产物中的4-甲基伞形酮的检测测定的(图4A)。然而,抗CD63-GAA的摄取取决于CD63的存在(图4B)。抗CD63·GAA被表达CD63的HEK细胞吸收,但不被携带CD63基因敲除的HEK细胞吸收(图4B)。
表3
NA=不适用;NT=未测试
实例3:GAA构建体被成肌细胞的摄取
测试了骨骼肌成肌细胞吸收各种GAA构建体的能力,所述骨骼肌成肌细胞是庞贝氏症中的目的组织类型。在各种浓度(即25nM、50nM和200nM)的(1)抗CD63-GAA、(2)抗CD63-GAA加上5mM M6P、(3)myc-GAA、以及(4)myc-GAA加上5mM M6P的存在下,培养人骨骼肌成肌细胞。评价GAA构建体的内化从细胞裂解产物中检测到的GAA活性水平推断,如通过4-甲基伞形酮的累积所示。其为MPR非依赖性的200nM抗-CD63-GAA的摄取比依赖于MPR的myc-GAA的摄取高超过五倍(图5A)。
为了确定抗CD63-GAA构建体的亚细胞定位,将人骨骼肌成肌细胞用抗人IgG抗体(以检测抗CD63-GAA构建体的抗CD63部分)和抗LAMP抗体(以标记溶酶体)染色。LAMP或溶酶体相关膜糖蛋白包括对溶酶体特异的整合膜蛋白。共标记实验证实抗CD63-GAA与抗LAMP共定位,指示抗CD63-GAA定位于溶酶体。
类似地,在各种浓度(即25nM、50nM和200nM)的(1)抗CD63-GAA、(2)抗CD63-GAA加上5mM M6P、(3)myc-GAA、以及(4)myc-GAA加上5mM M6P的存在下,培养小鼠C2C12成肌细胞。评价GAA构建体的内化从细胞裂解产物中检测到的GAA活性水平推断,如通过4-甲基伞形酮的累积所示。未受M6P不利影响的200nM抗-CD63-GAA的摄取比myc-GAA的摄取多约六倍至约九倍(图5B)。
实例4:抗CD63-GAA对糖原累积的作用
评价了抗CD63-GAA对三种不同庞贝氏症细胞系的溶酶体中的糖原累积的作用。庞贝氏症细胞系源自得自严重发作的婴儿庞贝氏症受害者的成纤维细胞,并且在GAA基因中含有敲除或击倒突变。使用的细胞系是GM20089(外显子18缺失)、GM20090(外显子14和16中的复合杂合子)和GM20090(外显子2中的复合杂合子)。这些系得自Coriell Institute,Camden,NJ。参见Huie等人,“Increased occurrence of cleft lip in glycogen storagedisease type II(GSDII):exclusion of a contiguous gene syndrome in twopatients by presence of intragenic mutations including a novel nonsensemutation Gln58Stop,”85(1)Am.J.Med.Genet.5-8(1999);Huie等人,“Glycogen storagedisease type II:identification of four novel missense mutations(D645N,G648S,R672W,R672Q)and two insertions/deletions in the acid alpha-glucosidase locusof patients of differing phenotype,”244(3)
Biochem.Biophys.Res.Commun.921-7(1998);和Nishiyama等人,“Aktinactivation induces endoplasmic reticulum stress-independent autophagy infibroblasts from patients with Pompe disease,”107Molecular genetics andmetabolism 490-5(2012)。新生儿人皮肤成纤维细胞(NHDF,Lonza)用作对照。即使存在残留(<0.1%)GAA活性(图6,分别为小图A和B),所有庞贝氏症细胞系也显示溶酶体糖原累积(在葡萄糖饥饿以减少细胞质糖原72小时后)。使用糖原测定试剂盒(Sigma-Aldrich,St.Louis,MO)测量糖原。
在裂解以去除细胞质糖原之前将细胞葡萄糖饥饿约96小时(参见Umapathysivam等人,“Correlation of acid alpha-glucosidase and glycogen content in skinfibroblasts with age of onset in Pompe disease,”361(1-2)Clin Chim Acta.191-8(2005))。在裂解之前用抗CD63-GAA(200nM)或myc-GAA(200nM)处理细胞72小时。对于所有三种庞贝氏症细胞系,用抗CD63-GAA处理导致溶酶体糖原累积中的显著减少(图7),指示外源给药的抗CD63-GAA到达溶酶体并且是酶促活性的。
实例5:GAA的同工酶
为了避免庞贝氏症患者对GAA(即交叉反应性免疫材料或CRIM)的可能免疫应答,研究了援救GAA活性的其它人葡糖苷酶的递送。与GAA(又名酸性α-葡糖苷酶)具有相似糖原水解活性的非溶酶体酶处于研究中。这些酶包括蔗糖酶-异麦芽糖酶(SI)、麦芽糖酶-葡糖淀粉酶(MGAM)、葡糖苷酶II(GANAB)或中性α-葡糖苷酶(C GNAC)。这些酶和各种重组实施例在以下中描述:Dhital等人,“Mammalian mucosal α-glucosidases coordinate with α-amylase in the initial starch hydrolysis stage to have a role in starchdigestion beyond glucogenesis,”8(4)PLoS One e625462013 Apr 25(2013);Sim等人,“Human intestinal maltase-glucoamylase:crystal structure of the N-terminalcatalytic subunit and basis of inhibition and substrate specificity,”375(3)J.Mol.Biol.782-92(2008);和Quezada-Calvillo等人,“Luminal starch substrate“brake”on maltase-glucoamylase activity is located within the glucoamylasesubunit,”138(4)J.Nutr.685-92(2008)。
制备下述同工酶构建体并且在CHO细胞中表达:(1)抗CD63、(2)抗CD63-NtMGAM(即,与抗CD63抗体重链的C末端连接的麦芽糖酶-葡糖淀粉酶的N末端亚基)、以及(3)抗CD63-CtMGAM。参见Dhital,2013。还改造了表达与小鼠麦芽糖-葡糖淀粉酶的C末端亚基融合的抗小鼠CD63重链(抗mCD63-mctMGAM)的另一种构建体,用于小鼠模型中(参见实例11)。
实例6:溶酶体α-半乳糖苷酶A (GLA)融合蛋白
构建含有人GLA(SEQ ID NO:2)的各种融合蛋白并且在CHO细胞中表达。那些构建体包括(i)与抗CD63重链的C末端融合的GLA(抗CD63-GLA),(ii)与免疫球蛋白Fc融合的GLA(例如Fc“旋钮”),(iii)GLA-抗CD63(即,与抗CD63重链的N末端融合的GLA),以及(iv)GLA-myc融合物(图8)。没有GLA部分的内化效应结合蛋白(IEBP)也被改造且表达。在一种情况下,IEBP是双特异性抗体,其中一半具有对CD63的结合特异性,并且另一半具有对于myc的结合特异性。评价每种GLA融合蛋白的GLA酶促活性(即,4-甲基伞形酮酰-β-吡喃半乳糖苷的水解),其结果呈现于图9中。除了C末端抗-CD63-GLA融合物之外,所有构建体都显示α-半乳糖苷酶活性(图9)。Fc旋钮在Ridgway等人,“'Knobs-into-holes'engineering ofantibody CH3domains for heavy chain heterodimerization,”9(7)Protein Eng.617-621(1996)中描述。
通过测量来自酶催化的4-甲基伞形酮酰-β-吡喃半乳糖苷水解的甲基伞形酮形成来确定每种构建体(或IEBP和GLA-myc的组合)到HEK细胞内的内化。将各种构建体加入HEK293细胞中,然后将所述HEK293细胞温育以允许胞吞作用,然后洗涤并且在pH 4下裂解。将GLA底物加入每种细胞裂解产物中,并且允许α-半乳糖苷酶反应进行。结果显示于图9中,所述图9显示GLA-抗CD63融合蛋白被内化到HEK细胞内。单独的GLA-myc,即在不存在IEBP元件的情况下,不被HEK细胞吸收。然而,它在结合CD63且结合myc表位的双特异性抗体的存在下被吸收(图10)。
实例7:内化效应物结合蛋白的摄取
抗CD63或抗APLP2抗体内化到低pH细胞级分内与具有高M6P含量的重组人GLA(rhGLA)内化到低pH级分内进行比较。用低pH敏感染料(Invitrogen,Calsbad,CA)标记GLA、抗CD63和抗APLP2各自。将HEK细胞、HepG2细胞(肝癌)和PC-3细胞(前列腺癌)与标记的蛋白质接触,并且温育过夜或约16小时。然后将细胞成像并且计数荧光囊泡。根据每种蛋白质的标记程度将荧光输出标准化。HEK、PC-3和HepG2细胞证实相对于rhGLA更高的抗CD63和抗APLP2摄取(图11)。
实例8:融合蛋白在溶酶体中的加工
通过庞贝氏症细胞裂解产物的蛋白质印迹分析测试抗CD63-GAA构建体是否在溶酶体中被蛋白酶解加工。GM20089庞贝氏症细胞在抗CD63-GAA的存在下进行培养,使后续细胞裂解产物经受使用抗GAA抗体(图12,小图A)或抗hIgG抗体(图12,小图B)的还原型免疫印迹分析。
将来自Coriell的GM20089庞贝氏症成纤维细胞系在6孔板内铺平板,并且与抗CD63-GAA一起温育18小时,然后用培养基充分洗涤。在各种时间点,即去除抗CD63-GAA后的0、24、48、72小时,使孔在RIPA缓冲液中裂解。通过使用抗人GAA抗体(ab113021,Abcam LTD,Cambridge,UK;图12)的蛋白质印迹测定裂解产物的GAA。在早期时间点检测到完全的抗CD63-GAA和较小的中间产物,并且在用抗CD63-GAA给药后的所有时间点检测到GAA的成熟溶酶体76kDa形式。这证实抗CD63-GAA在患者细胞中内化,并且被正确加工成GAA的成熟溶酶体形式。此外,细胞中76kDa形式的半衰期与GAA内化的其它研究相匹配(Maga,J.A.等人Glycosylation-independent lysosomal targeting of acidα-glucosidase enhancesmuscle glycogen clearance in Pompe mice.Journal of Biological Chemistry 288,1428-1438(2013).)。
实例9:抗CD63-GAA的组织分布和加工
在CD63基因座处人源化的小鼠(参见Valenzuela等人,“High-throughputengineering of the mouse genome coupled with high-resolution expressionanalysis,”21Nature Biotechnology 652-659(2003))施用抗CD63-GAA。获取组织样品并且经由蛋白质印迹分析评价GAA。在肝、膈肌、肾、心脏、以及四头肌和腓肠肌中检测到GAA(图13)。
简言之,通过将人CD63基因座敲入小鼠CD63基因座内,产生人源化CD63小鼠。通过以50mg/kg对2月龄的人源化CD63小鼠或缺乏人CD63的野生型小鼠的尾静脉注射,施用抗CD63-GAA或抗CD63。在不同的时间点,例如注射后的0、6、24小时,执行尾部放血。执行抗人Fc ELISA以确定抗CD63-GAA的血清浓度。抗CD63-GAA从血清中快速清除,并且比亲本抗CD63抗体更快。注射的小鼠也在不同的时间点处死,并且解剖组织并在液氮中快速冷冻。组织在RIPA缓冲液中裂解,并且通过蛋白质印迹测定GAA。测定的大多数组织中存在76kDa成熟溶酶体形式,证实抗CD63-GAA内化到组织内的细胞中(图13)。人源化CD63小鼠在骨骼肌(心脏、腓肠肌、四头肌)中内化抗CD63-GAA,但野生型小鼠未显示任何摄取。这证实抗-CD63-GAA由CD63介导内化到骨骼肌细胞内。
经由尾静脉注射将抗CD63-GAA以50mg/kg施用于CD63人源化小鼠(CD63hu/hu)和对照小鼠(CD63+/+)。在24小时时间点,提取组织,并且装载200μg裂解产物/泳道。蛋白质印迹用抗hGAA抗体和抗GAPDH作为装载对照进行探测。图14描绘了蛋白质印迹,并且证实CD63介导的抗-hCD63-GAA在CD63hu/hu而不是WT CD63+/+小鼠中的肌肉组织内的摄取。抗hCD63-GAA被加工为成熟的76kDa hGAA。
实例10:肌肉特异性内化效应物
将针对肌肉特异性抗原的抗体(其包括抗整联蛋白α7、抗CD9和抗肌营养不良蛋白聚糖)施用于GAA敲除小鼠。这些抗体的组织分布通过蛋白质印迹分析确定。图15描绘了在骨骼肌(腓肠肌、四头肌和膈肌)、心肌、肝脏(充当正常化的基线)、肾和脾内发现的抗体水平的直方图。在骨骼肌和心脏中发现抗整联蛋白α7抗体(水平超过肝中的水平)。在骨骼肌和心脏以及肾和脾中发现抗CD9抗体(水平超过肝中的水平)(图15)。
为了确定那些选择的肌肉特异性抗体是否可靶向溶酶体,用pHrodo-红标记抗体,然后以10μg/mL与鼠C2C12成肌细胞温育过夜。将囊泡荧光定量且对抗体上荧光团的标记程度标准化。结果在图16中描绘,所述图16显示靶向C2C12成肌细胞的低pH溶酶体级分的抗CD63、抗肌营养不良蛋白聚糖、抗M-钙粘蛋白、抗CD9和抗整联蛋白α7。
实例11:肌糖原水平的恢复
使具有天然小鼠CD63表达的2-3个月龄的GAA敲除(KO)小鼠经受质粒构建体的流体动力学递送(HDD),所述质粒构建体编码全长人α-葡糖苷酶(hGAA)、抗mCD63-GAA(抗小鼠CD63)及其相关轻链,或抗hCD63-GAA(抗人CD63)及其相关轻链。所有构建体都使用由遍在蛋白启动子和SV40聚A尾部组成的相同质粒主链。简言之,将40μg每种质粒(即40μg重链和轻链,或仅hGAA)在2-3mL无菌盐水中稀释,并且快速注射到GAA KO小鼠的尾静脉内。每3天的尾部放血证实~10天的hGAA或抗体-GAA构建体的血清水平。小鼠在HDD后3周处死,并且将组织在液氮中快速冷冻。组织在蒸馏水中匀浆化,煮沸且向下旋转。使用荧光糖原测定试剂盒(MAK016,Sigma Aldrich,St.Louis,MO)测定上清液的糖原。
在野生型小鼠、GAA KO小鼠和用流体动力学递送且表达的hGAA或抗mCD63-GAA处理的GAA KO小鼠中,测定心脏、膈肌和骨骼肌(包括三头肌、腓肠肌和四头肌)中的糖原水平。结果在图17中描绘,所述图17显示了在抗mCD63-GAA处理的小鼠中糖原恢复到接近野生型水平。糖原恢复效应对于抗-mCD63-GAA比单独的hGAA更显著,所述抗-mCD63-GAA显示接近于100%的野生型肌糖原水平的恢复,所述单独的hGAA仅显示在GAA KO小鼠中的骨骼肌或膈肌中糖原水平的约10%至35%降低(参见图17)。
在野生型小鼠、GAA KO小鼠和用流体动力学递送(HDD)且表达抗hCD63-GAA、抗mCD63-GAA或抗mCD63-mctMGAM处理的GAA KO小鼠中,测定心脏、膈肌和骨骼肌(包括三头肌、腓肠肌和四头肌)中的糖原水平。图18中描绘的结果显示了在抗mCD63-GAA处理的小鼠中糖原恢复到接近野生型水平。糖原恢复效应对于抗-mCD63-GAA比单独的抗hCD63-GAA更显著,所述抗-mCD63-GAA显示肌糖原水平恢复至野生型水平的20%内,所述单独的抗hCD63-GAA仅显示在GAA KO小鼠的骨骼肌或膈肌中糖原水平的约20%降低(参见图18)。该结果还证实GAA经由物种特异性CD63内化递送至溶酶体的增强效应。在HDD后7或12天,检查与对照(未处理的)GAA KO小鼠相比的在GAA KO小鼠经由HDD用抗-mCD63-mctMGAM的处理(参见图20)。在两个时间点用小鼠特异性抗mCD63-mctMGAM HDD构建体处理的GAA KO小鼠体内观察到糖原降低,而在其它方面相同的条件下的野生型未处理小鼠未显示糖原贮积中的变化(图20)。
实例12:溶酶体酸性脂肪酶
溶酶体酸性脂肪酶(LAL或LIPA)是分解溶酶体中胆固醇酯和甘油三酯的酶。LIPA缺陷(例如LAL-D或沃尔曼病)导致脂肪物质在肝、脾和其它器官中的积聚。LAL-D的流行率在全世界内为40,000人中的1个到300,000人中的1个。如果未经治疗,则患有LIPA缺陷的婴儿由于多器官衰竭而在6-12个月内死亡。稍大的儿童可保持未被诊断,直到他们因心脏病发作、中风或肝衰竭而死亡。
为了测试抗体栓系至LIPA对内源性脂肪酶活性的作用,制备两种LIPA抗体构建体:重链C末端融合物(抗myc-LIPA);和重链N末端融合物(LIPA-抗myc)。将人溶酶体酸性脂肪酶(SEQ ID NO:3)的氨基酸24-399的cDNA克隆到抗体重链质粒的N末端或C末端内。组织蛋白酶可切割序列用作重链和酶之间的接头。将构建体连同相应的轻链一起转染到CHO-K1细胞内。转染后5天收集CHO细胞上清液并且无菌过滤。使上清液经受蛋白质印迹分析,并且用抗LIPA抗体和抗hIgG抗体进行探测。证实了CHO细胞中LIPA、抗myc-LIPA和LIPA-抗myc的表达。
使在测定缓冲液(0.2M乙酸钠、0.4M氯化钾,pH 4.3)中的上清液稀释物与4-甲基伞形酮基油酸酯(LIPA底物)一起温育1小时。使用以pH 10.7的甘氨酸-碳酸盐缓冲液停止反应。在360nm激发和450nm发射下在板阅读器上读取荧光。相对于天然LIPA对照,抗myc-LIPA和LIPA-抗myc构建体两者均显示出显著的脂肪酶活性(图19)。
本发明的范围不受本文所述的特定实施方案限制。事实上,除本文所述的那些之外,本发明的各种修改根据前文描述书对于本领域技术人员将变得显而易见。希望这些修改属于所附权利要求书的范围内。
序列表
<110> Regeneron Pharmaceuticals, Inc.
<120> 用于内化酶的组合物和方法
<130> 10109WO01
<150> US 62/264,702
<151> 2015-12-08
<150> US 62/379,929
<151> 2016-08-25
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 883
<212> PRT
<213> 智人
<400> 1
Ala His Pro Gly Arg Pro Arg Ala Val Pro Thr Gln Cys Asp Val Pro
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Pro Asn Ser Arg Phe Asp Cys Ala Pro Asp Lys Ala Ile Thr Gln Glu
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Gln Gly Ala Gln Met Gly Gln Pro Trp Cys Phe Phe Pro Pro Ser Tyr
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Pro Ser Tyr Lys Leu Glu Asn Leu Ser Ser Ser Glu Met Gly Tyr Thr
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Ala Thr Leu Thr Arg Thr Thr Pro Thr Phe Phe Pro Lys Asp Ile Leu
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Thr Leu Arg Leu Asp Val Met Met Glu Thr Glu Asn Arg Leu His Phe
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Thr Ile Lys Asp Pro Ala Asn Arg Arg Tyr Glu Val Pro Leu Glu Thr
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Pro His Val His Ser Arg Ala Pro Ser Pro Leu Tyr Ser Val Glu Phe
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Ser Glu Glu Pro Phe Gly Val Ile Val Arg Arg Gln Leu Asp Gly Arg
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Val Leu Leu Asn Thr Thr Val Ala Pro Leu Phe Phe Ala Asp Gln Phe
165 170 175
Leu Gln Leu Ser Thr Ser Leu Pro Ser Gln Tyr Ile Thr Gly Leu Ala
180 185 190
Glu His Leu Ser Pro Leu Met Leu Ser Thr Ser Trp Thr Arg Ile Thr
195 200 205
Leu Trp Asn Arg Asp Leu Ala Pro Thr Pro Gly Ala Asn Leu Tyr Gly
210 215 220
Ser His Pro Phe Tyr Leu Ala Leu Glu Asp Gly Gly Ser Ala His Gly
225 230 235 240
Val Phe Leu Leu Asn Ser Asn Ala Met Asp Val Val Leu Gln Pro Ser
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Pro Ala Leu Ser Trp Arg Ser Thr Gly Gly Ile Leu Asp Val Tyr Ile
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Phe Leu Gly Pro Glu Pro Lys Ser Val Val Gln Gln Tyr Leu Asp Val
275 280 285
Val Gly Tyr Pro Phe Met Pro Pro Tyr Trp Gly Leu Gly Phe His Leu
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Cys Arg Trp Gly Tyr Ser Ser Thr Ala Ile Thr Arg Gln Val Val Glu
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Asn Met Thr Arg Ala His Phe Pro Leu Asp Val Gln Trp Asn Asp Leu
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Asp Tyr Met Asp Ser Arg Arg Asp Phe Thr Phe Asn Lys Asp Gly Phe
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Met Val Ala Glu Phe His Asp Gln Val Pro Phe Asp Gly Met Trp Ile
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Asp Met Asn Glu Pro Ser Asn Phe Ile Arg Gly Ser Glu Asp Gly Cys
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Ser Thr His Tyr Asn Leu His Asn Leu Tyr Gly Leu Thr Glu Ala Ile
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Val Cys Gly Phe Leu Gly Asn Thr Ser Glu Glu Leu Cys Val Arg Trp
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Thr Gln Leu Gly Ala Phe Tyr Pro Phe Met Arg Asn His Asn Ser Leu
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Claims (15)
1. 一种组合物,所述组合物包含与溶酶体贮积病(LSD)相关的酶和抗原结合蛋白,
其中所述酶是α-葡糖苷酶GAA,包含GAA活性,或者是GAA的同工酶,并且
所述抗原结合蛋白结合CD63。
2. 根据权利要求1所述的组合物,其中所述抗原结合蛋白选自抗体、Fab片段、F(ab')2片段、Fd片段、Fv片段、单链Fv (scFv)分子、dAb片段、结构域特异性抗体、单结构域抗体、嵌合抗体、CDR移植抗体、双抗体、三抗体、四抗体、微型抗体、纳米抗体、单价纳米抗体、二价纳米抗体和骆驼科抗体。
3. 根据权利要求1所述的组合物,其中所述酶与所述抗原结合蛋白共价连接,并且任选地其中:
(i) 所述抗原结合蛋白包含半抗体,所述酶与免疫球蛋白Fc-结构域共价连接,并且与所述酶共价连接的Fc-结构域与所述抗原结合蛋白的Fc-结构域结合;或
(ii) 所述抗原结合蛋白包含抗体,并且所述酶与所述抗体的重链的C末端共价连接。
4. 根据权利要求1所述的组合物,其中所述酶与所述抗原结合蛋白不是共价连接,并且任选地其中:
(i) 所述抗原结合蛋白结合CD63和所述酶二者;和/或
(ii) 所述抗原结合蛋白是结合CD63和所述酶的双特异性抗体。
5. 根据权利要求1-4中任一项所述的组合物,其中所述酶包含SEQ ID NO: l的氨基酸序列。
6. 一种生物治疗复合物在制备用于治疗患有溶酶体贮积病(LSD)的受试者的药物中的用途,其中所述生物治疗复合物进入受试者细胞的溶酶体,并且提供替代与所述LSD相关的内源性酶的酶促活性的替代酶的酶促活性,其中所述生物治疗复合物包含:
(a)替代酶,其中所述替代酶是α-葡糖苷酶GAA、包含GAA活性或是GAA的同工酶,和
(b) 结合CD63的抗原结合蛋白。
7.根据权利要求6所述的用途,其中所述LSD是庞贝氏症。
8.根据权利要求6所述的用途,其中所述替代酶在所述受试者中不诱导免疫反应。
9.根据权利要求6所述的用途,其中所述LSD是庞贝氏症,所述内源性酶是α-葡糖苷酶,并且所述替代酶选自酸性α-葡糖苷酶、蔗糖酶-异麦芽糖酶、麦芽糖酶-葡糖淀粉酶、葡糖苷酶II和中性α-葡糖苷酶。
10.根据权利要求6-8中任一项所述的用途,其中所述结合CD63的抗原结合蛋白是抗体或抗体片段。
11.根据权利要求10所述的用途,其中结合CD63的所述抗原结合蛋白包含结合所述替代酶和CD63的双特异性抗体。
12.根据权利要求11所述的用途,其中所述替代酶是GAA。
13.根据权利要求10所述的用途,其中所述生物治疗复合物包含与CD63半抗体的免疫球蛋白Fc结构域融合的替代酶。
14.根据权利要求10所述的用途,其中所述生物治疗复合物包含共价连接至抗CD63抗体的重链的C末端的所述替代酶。
15.根据权利要求10所述的用途,其中所述生物治疗复合物包含共价连接至抗CD63抗体的重链的N末端的所述替代酶。
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