CN111683687A - 靶向edb的il-12组合物 - Google Patents
靶向edb的il-12组合物 Download PDFInfo
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- CN111683687A CN111683687A CN201980012247.6A CN201980012247A CN111683687A CN 111683687 A CN111683687 A CN 111683687A CN 201980012247 A CN201980012247 A CN 201980012247A CN 111683687 A CN111683687 A CN 111683687A
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Abstract
本发明涉及组合物,其包含具有第一及第二亚基的IL‑12蛋白、EDB结合结构域,及介于IL‑12蛋白与EDB结合结构域之间的接头。
Description
技术领域
本申请涉及包含细胞因子、抗原结合结构域及改良的接头的组合物。
背景技术
IL-12为包含两种经二硫键连接的亚基(p35及p40)的异二聚细胞因子。IL-12刺激从T细胞及自然杀伤细胞产生IFNγ,且也诱导Th1辅助细胞分化。IL-12为先天性免疫及细胞介导性免疫的关键介质,其具有抗癌及抗转移活性的潜能。
然而,与许多其他细胞因子类似,施用IL-12与严重毒性相关(Car等人,1999),即使剂量低至每天每公斤1μg,这阻碍其作为抗癌药物的开发。
发明内容
本发明尤其提供可用于有效治疗与EDB纤连蛋白表达相关的各种疾病及病症的经改良的组合物及方法。
具体而言,本发明提供具有优于已知重组IL-12构建体的优选治疗特性的IL-12连接型EDB结合结构域。本文所述的组合物惊人地优于先前已知的为了靶向EDB而设计的IL-12构建体,并解决了安全且有效施用IL-12以靶向治疗疾病或病症(例如癌症)的长期已知问题。本文所述的组合物及方法通过增强其生物分布谱、其耐受性、其治疗窗及其到达疾病位点的效力中的一或多个来提供改良的IL-12的治疗潜力。本文所述的构建体也惊人地展现优异的可制造性。
本领域中仍需要改良免疫细胞因子治疗对组织的渗透。本领域中也需要改良免疫细胞因子治疗的制造,因为这些是难以生产的高度复合蛋白质。
因此,本发明的一个目标为提供改良版免疫细胞因子,例如包含IL-12及EDB纤连蛋白结合结构域的蛋白质治疗剂(therapeutics)。本发明的另一目标为提供展现更高生产效率的免疫细胞因子。本发明的另一目标为提供具有改良的体内表现(例如靶结合或组织渗透)的免疫细胞因子。
本发明提供包含抗原结合结构域及具有此类优越特性的细胞因子的组合物。本发明及其特征的总体优势,包括适合的接头,将在下文详细论述。
根据本发明的一个方面,提供一种组合物,其包含
a.包含第一IL-12亚基及第二IL-12蛋白亚基的IL-12蛋白;
b.包含EDB结合结构域的肽或蛋白质;及
c.介于IL-12蛋白与包含EDB结合结构域的肽或蛋白质之间的接头。
优选地,IL-12的两个亚基是通过指定接头、根据以下方案(N→C方向)彼此连接:p40-接头1-p35。
优选地,IL-12为人类IL-12。根据本发明的一些实施方案,单链双抗体结合纤连蛋白的剪接同种型。优选地,纤连蛋白的所述外结构域(extra-domain)B(ED-B)为人类纤连蛋白的外结构域B(UniProt:P02751)。
在一些实施方案中,介于IL-12蛋白与包含EDB结合结构域的肽或蛋白质之间的接头包含GSADGGSSAGGSDAG(SEQ ID NO:4)。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含scFv。在一些实施方案中,包含EDB结合结构域的肽或蛋白质是双抗体。在一些实施方案中,包含EDB结合结构域的肽或蛋白质是单链双抗体。
在一些实施方案中,IL-12蛋白的第一亚基为p40且第二亚基为p35。
在一些实施方案中,IL-12蛋白的第一亚基为包含与SEQ ID NO:1中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列的p40或其片段,其中该IL-12蛋白可以活化IL-12受体。
在一些实施方案中,IL-12蛋白的第二亚基为包含与SEQ ID NO:3中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列的p35或其片段,其中该IL-12蛋白可以活化IL-12受体。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质具单特异性或双特异性。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质结合纤连蛋白的外结构域B(ED-B)。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含与SEQ ID NO:28至33中所示的氨基酸序列中的一或多个具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含SEQ ID NO:28至33的氨基酸序列中的每一个。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含与SEQ ID NO:7及5中所示的氨基酸序列中的一或多个具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含SEQ ID NO:7及5的氨基酸序列中的每一个。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含以下中的至少一个
a)根据以上描述的序列对,其条件为结构域中的至少一个相对于SEQ ID NO 7或SEQ ID NO 5分别具有≥80%的序列相同性,和/或
b)根据以上描述的序列对,其条件为结构域中的至少一个相对于SEQ ID NO 7或SEQ ID NO 5分别具有最多10个氨基酸取代,
同时维持其结合至纤连蛋白的外结构域B(ED-B)的能力。
在一些实施方案中,该肽或蛋白质包含至少一个氨基酸取代,其中所述至少一个氨基酸取代为保守氨基酸取代。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质
·与如上文所述的包含抗EDB结合结构域的肽或蛋白质之一相比,对纤连蛋白的外结构域B(ED-B)具有≥50%的靶结合亲和力,和/或
·与如上文所述的包含EDB结合结构域的肽或蛋白质之一竞争结合至纤连蛋白的外结构域B(ED-B)。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含两个L19VH结构域及两个L19VL结构域。
在一些实施方案中,两个L19VH结构域具有相同氨基酸序列;
·两个L19VH结构域具有不同氨基酸序列;
·两个L19VL结构域具有相同氨基酸序列;或
·两个L19VL结构域具有不同氨基酸序列。
在一些实施方案中,包含EDB结合结构域的肽或蛋白质包含一个L19VH结构域及一个L19VL结构域。
在一些实施方案中,组合物包含:
·p40结构域,其通过第一接头(也称为“接头1”)连接至p35结构域;
·第一L19VH结构域,其通过SAD接头连接至p35结构域;
·第一L19VL结构域,其通过第三接头(也称为“接头3”)连接至第一L19VH结构域;
·第二L19VH结构域,其通过第四接头(也称为“接头4”)连接至第一L19VL结构域;
·第二L19VL结构域,其通过第五接头(也称为“接头5”)连接至第二L19VH结构域。
在一些实施方案中,第三接头和第五接头包含相同的氨基酸序列,和/或可以被彼此替换。
在一些实施方案中,p40结构域包含与SEQ ID NO:1中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列或其片段。
在一些实施方案中,p35结构域包含与SEQ ID NO:3中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列或其片段。
在一些实施方案中,第一接头(“接头1”)为GS接头。
在一些实施方案中,第一接头包含与SEQ ID NO:2中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第一L19VH结构域、第二L19VH结构域或两者均包含与SEQ IDNO:28-30中所示的至少一个氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第一L19VL结构域、第二L19VL结构域或两者均包含与SEQ IDNO:31-33中所示的至少一个氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第一L19VH结构域、第二L19VH结构域或两者均包含与SEQ IDNO:7中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第一L19VL结构域、第二L19VL结构域或两者均包含与SEQ IDNO:5中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,SAD接头包含与SEQ ID NO:4中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第三接头(“接头3”)为GS接头。
在一些实施方案中,第三接头包含与SEQ ID NO:6中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第五接头(“接头5”)为GS接头。
在一些实施方案中,第五接头包含与SEQ ID NO:6中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,第三接头(“接头3”)与第五接头(“接头5”)包含相同氨基酸序列,和/或可被彼此替换。
在一些实施方案中,第四接头(“接头4”)为GS接头。
在一些实施方案中,第四接头包含与SEQ ID NO:8中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,组合物包含与SEQ ID NO:16中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
在一些实施方案中,组合物由与SEQ ID NO:16中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列组成。
根据本发明的另一方面,提供了根据前述权利要求中任一项所述的组合物在(制备)治疗人类或动物对象(的药物)中的用途,所述人类或动物对象
·诊断有发展赘生性疾病,
·患有发展赘生性疾病,或
·面临发展赘生性疾病风险,
或在(制备)预防这种状况(的药物)中的用途。
在一些实施方案中,赘生性疾病(neoplastic disease)选自恶性黑素瘤、非小细胞肺癌(NSCLC)、肾细胞癌、尿路上皮癌、头颈部鳞状细胞癌(HNSCC)、微卫星高不稳定性(MSI-H)或错配修复缺陷(dMMR)转移性结直肠癌、肝细胞癌、胃癌、皮肤鳞状细胞癌、子***及弥漫性大B细胞淋巴瘤(DLBCL)。
根据本发明的另一方面,提供了根据前述公开的组合物在(制备)用于抑制人类或动物对象中血管生成(的药物)中的用途。
根据本发明的另一方面,提供了一种药物组合物,其至少包含根据以上描述的组合物及任选包含一或多种药学上可接受的赋形剂。
根据本发明的另一方面,提供了一种组合,其包含(i)根据以上描述的组合物或根据以上描述的药物组合物,及(ii)一或多种治疗活性化合物。
根据本发明的另一方面,提供了一种治疗或预防与ED-B纤连蛋白的表达或过表达相关的病症或状况的方法,其包含向有需要的对象施用有效量的根据以上描述的组合物、根据以上描述的药物组合物或根据以上描述的组合。
根据本发明的另一方面,提供了一种治疗试剂盒,其包含:
a)根据以上描述的组合物、根据以上描述的药物组合物,或根据以上描述的组合,
b)用于施用该组合物、组合物或组合的装置,及
c)使用说明书。
附图说明
图1A-1B:蛋白质表达实验的结果。关于材料及方法,参见下文。
图1A:具有氨基酸序列SEQ ID NO:4的15聚体接头(本文中命名为“SAD”)迄今展示所有变体(本文中也称为“克隆”)的最佳产量。产量比第2最佳变体DDS更优异几乎100%。
系(line)AKKAS中的两个序列为SEQ ID NO 9及18,系AP7中的两个序列为SEQ IDNO 15及19,系DDS中的两个序列为SEQ ID NO 10及20,系AP6中的两个序列为SEQ ID NO 14及21,系G4S中的两个序列为SEQ ID NO 11及22,系SES中的两个序列为SEQ ID NO 12及23,系α3中的两个序列为SEQ ID NO 13及24,系SAD中的两个序列为SEQ ID NO 4及25。
图1中的N端及C端残基(或5'-核苷酸或3'-核苷酸)以灰色展示。这些不属于本申请的公开内容,因为这些需要检索。其仅展示各个接头可嵌入其中的框架。
图1B:SDS-PAGE表征显示所有变体的分子量为约120kDa。
图2:ELISA实验。所有变体均在10μg/ml及1μg/ml浓度结合至人类纤连蛋白的结构域7B89。
图3:Biacore实验。所有变体展示针对人类纤连蛋白的结构域7B89的类似结合行为。
图4:尺寸排阻层析(SEC)。所有变体均展示相当的聚集谱,其中13ml时的主峰对应于单体免疫细胞因子,且10ml时的较小峰对应于聚集体。
图5:免疫荧光染色实验。相较于阴性对照,所有变体均特异性地将冷冻的同基因F9畸胎癌试样的血管结构染色。
图6:体内肿瘤靶向。所有变体及阳性对照均用125I进行放射性碘标记且注射(4-9μg蛋白质/动物)至皮下带有移植的F9鼠类畸胎癌的免疫活性(immunocompetent)小鼠中。注射的后24小时计数的放射性展示所有变体在肿瘤中的聚积。然而,相较于其他七种克隆,“SAD”变体在肿瘤中展示优异的聚积(~2.9%ID/g(=注射剂量/克组织)vs.第二最佳者((G4S)3且展示~2.4%ID/g)))。
图7及8:使用IL-12及抗纤连蛋白抗体的例示性免疫细胞因子形式。
图9:对不同融合蛋白(A)huIL-12L19L19“SAD”批次A、(B)huIL-12L19L19“SAD”批次B、(C)huIL-12L19L19“Old”批次A、(D)huIL-12L19L19“Old”批次B的SEC分析。
图10:Biacore实验。相较于具有针对纤连蛋白7B89结构域的“Old”接头的变体,“SAD”变体展示具有改良的表面亲和力(3.8nM vs 6.7nM)。此惊人的结果出人意料,因为接头的变异可影响蛋白质的稳定性,但通常不影响对其靶的亲和力。
图11:体内肿瘤靶向实验。“SAD”及“Old”变体用125I进行放射性碘标记且注射(10-11μg蛋白质/动物)至皮下带有移植的F9鼠类畸胎癌的免疫活性小鼠中。相较于“Old”接头变体,“SAD”变体展示具有改良的肿瘤靶向能力。
具体实施方式
定义
“抗体”是指包含四聚结构单元的免疫球蛋白家族的分子。各四聚体由两条相同的多肽链对构成,各对具有经由二硫键连接的一条“轻”链(约25kD)及一条“重”链(约50-70kD)。识别的免疫球蛋白基因包括κ、λ、α、γ、δ、ε及μ恒定区基因以及多种免疫球蛋白可变区基因。轻链分类为κ或λ。重链分类为γ、μ、α、δ或ε,其又分别限定免疫球蛋白类别IgG、IgM、IgA、IgD及IgE。抗体可为任何同种型/类别(例如IgG、IgM、IgA、IgD及IgE)或任何子类(例如IgG1、IgG2、IgG3、IgG4、IgA1、IgA2)。
轻链与重链分成结构及功能同源区。术语“恒定”及“可变”是在结构上及功能上使用的。各链的N端限定约100至110个或更多个氨基酸的可变(V)区或结构域,其主要负责抗原识别。术语可变轻链(VL)及可变重链(VH)分别指轻链及重链的这些区域。VH与VL的配对一起形成单一抗原结合位点。除V区外,重链与轻链均含有恒定(C)区或结构域。免疫球蛋白C区的分泌形式是由三个C结构域CH1、CH2、CH3、任选的CH4(Cμ)及铰链区构成。免疫球蛋白C区的膜结合形式也具有膜及胞内结构域。各轻链在N端具有VL,然后在其另一端具有恒定结构域(C)。轻链(CL)及重链(CH1、CH2或CH3)的恒定结构域赋予重要生物特性,诸如分泌、经胎盘迁移、Fc受体结合、补体结合等。按照惯例,恒定区结构域的编号随着它们距离抗体的抗原结合位点或氨基端愈远而增大。N端为可变区且C端为恒定区;CH3及CL结构域实际上分别包含重链及轻链的羧基端结构域。将VL与VH比对,且将CL与重链的第一恒定结构域比对。如本文所用,“抗体”涵盖常规抗体结构及抗体变体。因此,在此概念的范畴内为全长抗体、嵌合抗体、人源化抗体、人类抗体及其抗体片段。
抗体以完整免疫球蛋白链存在或以多种经充分表征的抗体片段存在,所述抗体片段是通过各种肽酶消化而产生。如本文所用,术语“抗体片段”是指抗体的一或多个部分,其保留与抗原的表位特异性相互作用(例如结合、立***阻、稳定化/去稳定化、空间分布)的能力。因此,举例而言,胃蛋白酶在铰链区中的二硫键下方消化抗体而产生F(ab)'2,即Fab'的二聚体,Fab'自身为经二硫键连接至VH-CH1的轻链。F(ab)'2可以在温和条件下还原以使铰链区中的二硫键断裂,从而将F(ab)'2二聚体转化成Fab'单体。Fab'单体基本上为具有铰链区的一部分的Fab。Paul,Fundamental Immunology第3版(1993)。尽管各种抗体片段的定义是依据完整抗体的消化,但本领域技术人员应了解此类片段可以化学方法或通过使用重组DNA方法从头合成。如本文所用,“抗体片段”是指通过修饰整个抗体而产生的抗体的一或多个部分,或使用重组DNA方法从头合成的抗体的一或多个部分,其保留结合特异性及功能活性。抗体片段的实例包括Fv片段、单链抗体(ScFv)、Fab、Fab'、Fd(Vh及CH1结构域)、dAb(Vh及分离的CDR);双抗体及单链双抗体;及具有相同结合特异性的这些片段的多聚体形式(例如F(ab')2)。抗体片段也可掺入细胞因子移植的蛋白质中以获得本公开所提供的结合特异性及活性。
如本文所用,“Fab”结构域包含重链可变结构域、恒定区CH1结构域、轻链可变结构域及轻链恒定区CL结构域。结构域的相互作用是通过CH1与CL结构域之间的二硫键稳定化。在一些实施方案中,Fab的重链结构域自N端至C端依次为VH-CH,且Fab的轻链结构域自N端至C端依次为VL-CL。在一些实施方案中,Fab的重链结构域自N端至C端依次为CH-VH,且Fab的轻链结构域依次为CL-VL。尽管历史上通过木瓜蛋白酶消化完整免疫球蛋白而鉴别出Fab,但在本发明的上下文中,“Fab”通常通过任何方法重组产生。各Fab片段就抗原结合而言为单价的,即,其具有单一抗原结合位点。
“互补决定结构域”或“互补决定区”(“CDR”)可互换地指VL及VH的高变区。CDR为抗体链的靶蛋白结合位点,其对此类靶蛋白具有特异性。各人类VL或VH中存在三个CDR(CDR1-3,自N端依序编号),占可变结构域的约15-20%。CDR在结构上与靶蛋白的表位互补,并因此直接负责结合特异性。VL或VH的剩余段(stretch),所谓的框架区(FR),在氨基酸序列中展现较少的变异(Kuby,Immunology,第4版,第4章,W.H.Freeman&Co.,New York,2000)。
CDR及框架区的位置可以利用本领域中熟知的各种定义确定,例如Kabat、Chothia、国际ImMunoGeneTics数据库(IMGT)及AbM(参见例如Johnson等人,Nucleic AcidsRes.,29:205-206(2001);Chothia及Lesk,J.Mol.Biol.,196:901-917(1987);Chothia等人,Nature,342:877-883(1989);Chothia等人,J.Mol.Biol.,227:799-817(1992);Al-Lazikani等人,J.Mol.Biol.,273:927-748(1997))。抗原组合位点的定义也描述于以下文献中:Ruiz等人,Nucleic Acids Res.,28:219-221(2000);及Lefranc,M.P.,NucleicAcids Res.,29:207-209(2001);MacCallum等人,J.Mol.Biol.,262:732-745(1996);及Martin等人,Proc.Natl.Acad.Sci.USA,86:9268-9272(1989);Martin等人,MethodsEnzymol.,203:121-153(1991);及Rees等人,于Sternberg M.J.E.(编),ProteinStructure Prediction,Oxford University Press,Oxford,141-172(1996)。
根据Kabat,VH中的CDR氨基酸残基编号为31-35(HCDR1)、50-65(HCDR2)及95-102(HCDR3);且VL中的CDR氨基酸残基编号为24-34(LCDR1)、50-56(LCDR2)及89-97(LCDR3)。根据Chothia,VH中的CDR氨基酸编号为26-32(HCDR1)、52-56(HCDR2)及95-102(HCDR3);且VL中的氨基酸残基编号为26-32(LCDR1)、50-52(LCDR2)及91-96(LCDR3)。通过将Kabat与Chothia的CDR定义组合,CDR由人类VH中的氨基酸残基26-35(HCDR1)、50-65(HCDR2)及95-102(HCDR3)及人类VL中的氨基酸残基24-34(LCDR1)、50-56(LCDR2)及89-97(LCDR3)组成。
如本文所用,“抗体可变轻链”或“抗体可变重链”是指分别包含VL或VH的多肽。内源VL是由基因区段V(可变)及J(接合)编码,且内源VH是由V、D(多样)及J编码。VL或VH各包括CDR以及框架区(FR)。术语“可变区”或“V区”可互换地指包含FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4的重链或轻链。V区可为天然存在的、重组的或合成的。在本申请中,抗体轻链和/或抗体重链有时可统称为“抗体链”。如本文所提供及进一步描述,“抗体可变轻链”或“抗体可变重链”和/或“可变区”和/或“抗体链”任选的包含移植至CDR中的细胞因子多肽序列。
如本文所公开的包含例如CH2及CH3结构域的免疫球蛋白重链的C端部分为“Fc”结构域。如本文所用,“Fc区”是指抗体的恒定区,不包括第一恒定区(CH1)免疫球蛋白结构域。Fc是指IgA、IgD及IgG的最后两个恒定区免疫球蛋白结构域、以及IgE及IgM的最后三个恒定区免疫球蛋白结构域、以及这些结构域N端的柔性铰链。对于IgA及IgM而言,Fc可包括J链。对于IgG而言,Fc包含免疫球蛋白结构域Cγ2及Cγ3以及介于Cγ1与Cγ之间的铰链。在本领域中,应了解Fc区的边界可变化,然而,人类IgG重链Fc区通常经定义而包含残基C226或P230至其羧基端,其使用的编号是根据Kabat等人(1991,NIH Publication 91-3242,国家技术信息服务中心(National Technical Information Service),Springfield,Va.)中的EU索引。“Fc区”可以指分离的该区域或抗体或抗体片段情形下的该区域。“Fc区”包括Fc区的天然存在的等位基因变体(例如在CH2及CH3区中),包括例如调节效应子功能的修饰。Fc区也包括不引起生物功能改变的变体。举例而言,免疫球蛋白Fc区的N端或C端缺失一或多个氨基酸而生物功能无实质性损失。举例而言,在某些实施方案中,C端赖氨酸经修饰被置换或移除。在特定实施方案中,改变或移除Fc区中的一或多个C端残基。在某些实施方案中,Fc中的一或多个C端残基(例如末端赖氨酸)缺失。在某些其他实施方案中,Fc中的一或多个C端残基被替代的氨基酸取代(例如末端赖氨酸被置换)。此类变体是根据本领域中已知的通用规则选择以使对活性的影响最小(参见例如Bowie等人,Science 247:306-1310,1990)。Fc结构域为免疫球蛋白(Ig)的一部分,其被细胞受体(诸如FcR)识别且与补体活化蛋白C1q结合。CH2外显子的5'部分中所编码的下铰链区在抗体内向与FcR受体的结合提供柔性。
“嵌合抗体”为如下抗体分子,其中(a)恒定区或其部分经改变、置换或交换,使得抗原结合位点(可变区)连接至不同或改变的类别、效应子功能和/或物种的恒定区,或赋予嵌合抗体新特性的完全不同分子,例如酶、毒素、激素、生长因子及药物;或(b)可变区或其部分被具有不同或改变的抗原特异性的可变区改变、置换或交换。
“人源化”抗体为保留非人类抗体的反应性(例如结合特异性、活性)、同时在人体中免疫原性较弱的抗体。此可例如通过保留非人类CDR区且用人类对应物置换抗体的剩余部分来获得。参见例如Morrison等人,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984);Morrison及Oi,Adv.Immunol.,44:65-92(1988);Verhoeyen等人,Science,239:1534-1536(1988);Padlan,Molec.Immun.,28:489-498(1991);Padlan,Molec.Immun.,31(3):169-217(1994)。
“人类抗体”包括具有可变区的抗体,其中框架区与CDR区均衍生自人类来源的序列。此外,若抗体含有恒定区,则恒定区也衍生自此类人类序列,例如人类种系序列,或人类种系序列的突变版,或含有衍生自人类框架序列分析的共同框架序列的抗体,例如如Knappik等人,J.Mol.Biol.296:57-86,2000中所述。人类抗体可包括不由人类序列编码的氨基酸残基(例如通过体外随机或位点特异性诱变或通过体内体细胞突变引入的突变,或促进稳定性或制造的保守性取代)。
术语“分离”在用于核酸或蛋白质时表示核酸或蛋白质基本上不含在天然状态下其所缔合的其他细胞组分。其优选呈均质状态。其可呈干燥或水溶液。纯度及均质性通常使用诸如聚丙烯酰氨凝胶电泳或高效液相层析的分析化学技术来确定。作为主导物质存在于制备物中的蛋白质基本上是纯化的。具体而言,经分离的基因与侧接该基因且编码除感兴趣的基因外的蛋白质的开放阅读框分开。术语“纯化”表示核酸或蛋白质基本上在电泳凝胶中产生一个条带。具体而言,其意味核酸或蛋白质至少85%纯、更优选至少95%纯,且最优选至少99%纯。
术语“核酸”或“多核苷酸”指脱氧核糖核酸(DNA)或核糖核酸(RNA)及其呈单链或双链形式的聚合物。除非明确限制,否则该术语涵盖含有天然核苷酸的已知类似物的核酸,所述已知类似物具有与参考核酸类似的结合特性且以与天然存在的核苷酸类似的方式代谢。除非另外指明,否则特定核酸序列也隐含地涵盖其经保守修饰的变体(例如简并密码子取代)、等位基因、直系同源物、SNP及互补序列以及明确指示的序列。具体而言,简并密码子取代可通过产生其中一或多个所选(或所有)密码子的第三位置经混合碱基和/或脱氧肌苷残基取代的序列来获得(Batzer等人,Nucleic Acid Res.19:5081(1991);Ohtsuka等人,J.Biol.Chem.260:2605-2608(1985);及Rossolini等人,Mol.Cell.Probes8:91-98(1994))。
术语“多肽”、“肽”及“蛋白质”在本文中可互换使用,是指氨基酸残基的聚合物。所述术语适用于氨基酸聚合物,其中一或多个氨基酸残基为相应天然存在的氨基酸的人工化学模拟物,以及适用于天然存在的氨基酸聚合物及非天然存在的氨基酸聚合物。如本文所用,术语“包含EDB结合结构域的肽或蛋白质”涉及整体或借助于其部分/片段与EDB结合的肽或蛋白质,即,含有外结构域B的纤连蛋白。
通常,肽可以例如是具有≥3个氨基酸残基且≤50个氨基酸残基的长度的单体分子(因此,是寡肽或多肽),而蛋白质可以例如是具有一个或多个蛋白质的单体或双或多聚体分子,其每条链均具有≥50个氨基酸残基的长度。
术语“氨基酸”是指天然存在及合成的氨基酸,以及以类似于天然存在的氨基酸的方式起功能的氨基酸类似物及氨基酸模拟物。天然存在的氨基酸为由遗传密码编码的氨基酸,以及后来经修饰的那些氨基酸,例如羟基脯氨酸、γ-羧基谷氨酸及O-磷酸丝氨酸。氨基酸类似物是指基本化学结构与天然存在的氨基酸相同(即α碳与氢、羧基、氨基及R基团结合)的化合物,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。这些类似物具有经修饰的R基团(例如正亮氨酸)或经修饰的肽主链,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构,但以与天然存在的氨基酸类似的方式起作用的化合物。
“保守修饰的变体”适用于氨基酸与核酸序列。相对于特定核酸序列,保守修饰的变体是指编码相同或基本上相同的氨基酸序列的那些核酸,或在核酸不编码氨基酸序列时,是指基本上相同的序列。由于遗传密码的简并性,大量功能上相同的核酸编码任何给定蛋白质。举例而言,密码子GCA、GCC、GCG及GCU均编码氨基酸丙氨酸。因此,在丙氨酸通过密码子说明的每个位置上,密码子可在不改变所编码的多肽的情况下改变成任一个所述对应密码子。此类核酸变异为“沉默变异”,其为一种保守修饰的变异。本文中编码多肽的每个核酸序列也描述核酸的每个可能的沉默变异。本领域技术人员应认识到核酸中的各密码子(除通常为甲硫氨酸的唯一密码子的AUG及通常为色氨酸的唯一密码子的TGG之外)可经修饰以产生功能上相同的分子。因此,编码多肽的核酸的各沉默变异隐含于各所述序列中。
关于氨基酸序列,本领域技术人员应认识到,当变化导致氨基酸被化学上类似的氨基酸取代时,改变、添加或缺失编码序列中的单个氨基酸或小百分比的氨基酸的核酸、肽、多肽或蛋白质序列的个别取代、缺失或添加为“保守修饰的变体”。提供功能上类似的氨基酸的保守取代表在本领域中已熟知。这些保守修饰的变体另外为且不排除多形变体、种间同源物及等位基因。以下八组各含有彼此为保守取代的氨基酸:1)丙氨酸(A)、甘氨酸(G);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰氨(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W);7)丝氨酸(S)、苏氨酸(T);及8)半胱氨酸(C)、甲硫氨酸(M)(参见例如Creighton,Proteins(1984))。
在本文中,与非保守取代相比,本文所用的“保守氨基酸取代”对抗体功能的影响较小。尽管有许多方法对氨基酸进行分类,但通常根据其结构和它们的R基团的一般化学特征将其分为六个主要组。
在一些实施方案中,“保守氨基酸取代”是其中氨基酸残基被具有相似侧链的氨基酸残基置换的取代。例如,在本领域中已经定义了具有相似侧链的氨基酸残基家族。这些家族包括具有以下的氨基酸
·基本侧链(例如赖氨酸、精氨酸、组氨酸),
·酸性侧链(例如天冬氨酸、谷氨酸),
·不带电荷的极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸),
·非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸),
·β支化的侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和
·芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)。
其他保守氨基酸取代也可以在氨基酸侧链家族中发生,例如当用天冬酰胺代替天冬氨酸以修饰肽的电荷时。保守改变可进一步包括化学同源的非天然氨基酸的取代(即,合成的非天然的疏水性氨基酸代替亮氨酸,合成的非天然的芳香族氨基酸代替色氨酸)。
“序列相同性百分比”可通过在比较窗上比较两个经最佳比对的序列来确定,其中为了两个序列的最佳比对,多核苷酸序列在比较窗中的部分相较于不包含添加或缺失的参考序列(例如多肽)可包含添加或缺失(即,空位)。如下计算百分比:测定两个序列中存在的相同核酸碱基或氨基酸残基的位置数,得到匹配位置数,将匹配位置数除以比较窗中的总位置数且将结果乘以100,得到序列相同性百分比。
在两个或更多个核酸或多肽序列的上下文中,术语“相同”或“相同性”百分比是指两个或更多个序列或子序列为相同的序列。如使用以下序列比较算法之一或通过人工比对及目视检查所测量的,当在比较窗或指定区域上根据最大对应比较及比对时,若两个序列具有指定百分比的相同的氨基酸残基或核苷酸(即,在指定区域上至少85%、90%、95%、96%、97%、98%或99%序列相同性,或当未指定时是在参考序列的整个序列上),则该两个序列“基本上相同”。本公开提供分别与本文例示的多肽或多核苷酸基本上相同的多肽或多核苷酸。任选的,相同性存在于长度为至少约15、25或50个核苷酸的区域上,或更优选存在于长度为100至500或1000个或更多个核苷酸的区域上,或存在于参考序列的全长上。关于氨基酸序列,相同性或实质相同性可存在于长度为至少5、10、15或20个氨基酸,任选的长度为至少约25、30、35、40、50、75或100个氨基酸、任选的长度为至少约150、200或250个氨基酸的区域上或参考序列的全长上。关于较短的氨基酸序列,例如20个或更少个氨基酸的氨基酸序列,当一个或两个氨基酸残基根据本文中定义的保守取代被保守取代时,存在实质性相同。
术语“对象(subject)”、“患者”及“个体(individual)”可互换地指哺乳动物,例如人类或非人类灵长类哺乳动物。哺乳动物也可为实验室哺乳动物,例如小鼠、大鼠、兔、仓鼠。在一些实施方案中,哺乳动物可为农用哺乳动物(例如马、绵羊、牛、猪、骆驼)或家养哺乳动物(例如犬、猫)。
如本文所用,术语“治疗”任何疾病或病症在一些实施方案中是指改善疾病或病症(即,减缓或遏制或减少疾病或其至少一个临床症状的发展)。在另一个实施方案中,“治疗”是指缓解或改善至少一种身体参数,包括患者可能辨别不出的身体参数。在又另一个实施方案中,“治疗”是指在身体上(例如可辩别症状的稳定化)、生理学上(例如身体参数的稳定化)或在两方面调节疾病或病症。在又另一个实施方案中,“治疗”或“预防”是指防止或延迟疾病或病症的发作或发展或进展。
术语“共施用”是指两种(或更多种)活性物质同时存在于个体中。共施用的活性物质可同时或依序递送。
在以下章节中详细描述本发明的各个方面。章节的使用不意欲限制本发明。各章节可适用于本发明的任何方面。本发明不限于所述组合物或所述方法的程序步骤的特定组成部分,因为此类组合物及方法可以改变。也应理解,本文所用的术语仅出于描述特定实施方案的目的,且不欲作为限制。
除非上下文另外清楚指示,否则如本说明书及随附权利要求中所用,单数形式“一(a/an)”及“该(the)”包括单数和/或复数个指示物。在本申请中,除非另有说明,否则使用“或”意味着“和/或”。另外应理解,倘若给定的参数范围是由数值定界,则认为范围包括这些限值。本文中所引用的所有技术的公开内容均以全文引用的方式并入。
如本文所使用,术语“GS接头”是指主要或排他性地由甘氨酸及丝氨酸残基组成的肽接头(也称为“Gly-Ser接头”)。在不同实施方案中,GS接头为本文在SEQ ID NO:2、6或8中的任一个中所示的接头。
如本文所用,“保守氨基酸取代”对抗体功能的影响小于非保守取代。尽管氨基酸分类方式有多种,但其通常基于其结构及其R基团的一般化学特征而分成六个主要类别。
如本文所用,术语“靶结合亲和力”是指根据本发明的结合分子对其靶的亲和力,且在数值上使用“KD”值表示。一般而言,较高KD值对应于较弱结合。在一些实施方案中,“KD”是通过放射性标记抗原结合分析(MA)或表面等离子共振(SPR)分析、使用例如BIAcoreTM-2000或BIAcoreTM-3000测量。在某些实施方案中,“结合速率(on-rate)”或“缔合的速率”或“缔合速率(association rate)”或“kon”,及“解离速率(off-rate)”或“解离的速率”或“解离速率(dissociation rate)”或“koff”也利用表面等离子共振(SPR)技术测定。在其他实施方案中,使用***来测量“KD”、“kon”及“koff”。
如本文所用,术语“竞争结合”提及由如上序列定义的抗体中的一个使用,意味着实际抗体具有与所述序列所限定的抗体结合至相同靶或靶表位或结构域或亚结构域的活性,且为后者的变体。结合效率(例如动力学或热力学)可同于或大于或小于后者的效率。举例而言,结合至底物的平衡结合常数对于两种抗体而言可不同。
如本文所用,术语“维持结合至指定靶的能力”意味着例如各个变体的靶结合亲和力为未经修饰的肽的靶结合亲和力的≥50%。
EDB纤连蛋白
纤连蛋白(UniProt:P02751)为一种细胞外基质的高分子量(约440kDa)糖蛋白,其结合至称为整联蛋白的跨膜受体蛋白。与整联蛋白类似,纤连蛋白结合细胞外基质组分,诸如胶原蛋白、纤维蛋白及类肝素硫酸蛋白聚糖类(例如多配体蛋白聚糖类(syndecans))。
纤连蛋白已涉及癌瘤发展。在肺癌中,纤连蛋白表达增加,尤其在非小细胞肺癌中。肺癌细胞与纤连蛋白的粘附增强致瘤性并赋予针对诱导细胞凋亡的化学治疗剂的抗性。纤连蛋白可促进肺肿瘤生长/存活及对治疗的抗性,且已论述为代表新抗癌药物的开发的新的靶。
纤连蛋白以蛋白质二聚体存在,该二聚体由通过一对二硫键连接的两个几乎相同的单体组成。纤连蛋白由单一基因产生,但由单一拷贝纤连蛋白基因产生的其前体mRNA的可变剪接发生于编码EDA、EDB及IIICS结构域的三个位点且引起若干同种型的产生。
包含EDA或EDB结构域的纤连蛋白同种型由于其在胚胎发育中的重要性及其有限存在于正常成人组织中而称为癌胚形式。这些同种型也识别为血管生成的重要标记物,血管生成是发育中且为肿瘤细胞在癌症进展中所需的关键生理学过程。ED-B纤连蛋白表达于肿瘤组织中,尤其表达于乳腺癌、脑瘤、淋巴瘤细胞及***癌中。ED-B纤连蛋白由于其组织特异性表达谱而是用于治疗靶向的引人注目的肿瘤抗原。
IL-12
白介素-12是对免疫***具有多重生物效应的异二聚细胞因子。其由两个亚基p35及p40构成,两者均是分泌IL-12,p70的活性形式所需的。白介素-12作用于树突状细胞(DC),引起成熟增加及抗原呈递,从而能够引发针对肿瘤特异性抗原的T细胞应答。其也驱动DC分泌IL-12,从而产生正反馈机制以扩大应答。一旦应答被引发,IL-12在将免疫***引向Th1细胞因子谱中发挥基本作用,从而诱导CD4+T细胞分泌干扰素-γ(IFN-γ)且导致CD8+细胞毒性T细胞应答。
IL-12也为引起其他细胞因子(包括肿瘤坏死因子-α(TNF-α))分泌的强促炎细胞因子,其与IFN-γ组合,成为CD4+细胞毒性T淋巴细胞(CTL)发育的前提条件。另外,IL-12可以经由其诱导IFN-γ及其他细胞因子来促进先天免疫细胞(诸如巨噬细胞及嗜酸性粒细胞)活化。此活化接着引起这些细胞分泌IL-12且使得先天应答及获得性应答进一步扩大。然而,高水平的IL-12及因此的IFN-γ也与拮抗分子(诸如IL-10)的诱导及IL-12下游信号传导分子(诸如STAT4)的耗竭有关。
先前利用IL-12作为治疗剂的尝试不成功,因为IL-12最好展示适度抗肿瘤作用,其通常伴随不可接受的毒性副作用,包括发热、疲乏、血液变化、高血糖症和/或器官功能异常。
如本文所用,“p35”意味着一种多肽,其包含与如下所示的氨基酸序列具有至少百分之八十(80%)相同性的氨基酸序列:
如本文所用,“p40”意味着一种多肽,其包含与如下所示的氨基酸序列具有至少百分之八十(80%)相同性的氨基酸序列:
如本文所用,“IL-12”意味着一种多肽,其(i)包含以下两者:
(a)p35或其片段,其中p35包含与如下所示的氨基酸序列具有至少百分之八十(80%)相同性的氨基酸序列:
及
(b)p40或其片段,其中p40包含与如下所示的氨基酸序列具有至少百分之八十(80%)相同性的氨基酸序列:
并且(ii)可以活化IL-12受体。
接头
在某些实施方案中,一或多种肽接头独立地选自(Glyn-Ser)m序列、(Glyn-Ala)m序列,或(Glyn-Ser)m/(Glyn-Ala)m序列的任何组合,其中各n独立地为1至5的整数且各m独立地为0至10的整数。在一些实施方案中,肽接头为(Gly4-Ser)m,其中m为0至10的整数。在一些实施方案中,肽接头为(Gly4-Ala)m,其中m为0至10的整数。接头的实例包括(但不限于)某些实施方案,一或多种接头包括G4S重复,例如Gly-Ser接头GGGGS(SEQ ID NO:34)或(GGGGS)m,其中m为等于或大于1的正整数。举例而言,m=1,m=2,m=3,m=4,m=5及m=6,m=7,m=8,m=9及m=10。在一些实施方案中,接头包括GGGGS(SEQ ID NO:34)的多个重复,包括(但不限于)(GGGGS)3或(GGGGS)4。在一些实施方案中,Ser可被Ala置换,例如接头G/A,诸如(GGGGA)(SEQ ID NO:35),或(GGGGA)m,其中m为等于或大于1的正整数。在一些实施方案中,接头包括GGGGA(SEQ ID NO:35)的多个重复。在其他实施方案中,接头包括GGGGS(SEQ IDNO:34)与GGGGA(SEQ ID NO:35)的组合及倍增。
在一些实施方案中,接头包含氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:2)。在一些实施方案中,接头包含氨基酸序列GSADGGSSAGGSDAG(SEQ ID NO:4)。在一些实施方案中,接头包含氨基酸序列GSSGG(SEQ ID NO:6)。在一些实施方案中,接头包含氨基酸序列SSSSGSSSSGSSSSG(SEQ ID NO:8)。在一些实施方案中,接头包含氨基酸序列GGGAKGGGGKAGGGS(SEQ ID NO:9)。在一些实施方案中,接头包含氨基酸序列GGGGDGGGGDGGGGS(SEQ ID NO:10)。在一些实施方案中,接头包含氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:11)。在一些实施方案中,接头包含氨基酸序列GGGGSGGGGEGGGGS(SEQ ID NO:12)。在一些实施方案中,接头包含氨基酸序列AEAAAKEAAAKEAAAKA(SEQ ID NO:13)。在一些实施方案中,接头包含氨基酸序列APAPAPAPAPAP(SEQ ID NO:14)。在一些实施方案中,接头包含氨基酸序列APAPAPAPAPAPAP(SEQ ID NO:15)。
抗EDB连接的IL-12
本发明尤其提供用于治疗与EDB纤连蛋白表达相关的疾病或病症(包括癌症)的方法及组合物。本文描述新组合物及方法,其利用纤连蛋白作为靶来完成IL-12向癌症的定向递送。此方法有望完全利用IL-12的治疗潜力,同时减少全身性毒性且增加IL-12的治疗窗。
虽然先前已描述含有IL-12及EDB纤连蛋白靶向结构域的其他构建体,但本发明所公开的组合物惊人地优异。
WO2006/119897公开了IL-12与EDB纤连蛋白靶向抗体(命名“L19”)组合的三种不同分子形式,该文献的内容以引用的方式并入本文中。
如图7A中所说明,一种形式为sc(IL-12)-scFv(L19)。该形式由IL-12异二聚体组成,其中两个亚基经由肽接头连接(因此,为“单链”IL-12,或sc(IL-12)),且所述IL-12接着经由第二肽接头连接至也呈单链Fv形式的L19抗体(因此,为scFv(L19))。该形式展示适度的肿瘤靶向能力,与现有技术的发现相同。
另一种形式为sc(IL-12)-SIP(L19)的同二聚体,如图7B中所说明。WO2003/076469的申请人已开发出SIP形式(“小免疫蛋白质”)且也命名为“小型抗体(miniantibody)”。SIP为由两个亚基组成的同二聚体,所述两个亚基包含与CH4结构域连接的scFv。两个CH4结构域通过二硫桥彼此连接。尽管现有技术指示可使用SIP形式改良L19的肿瘤靶向特性,但未观测到此缀合物的肿瘤吸收增加。
另一形式为IL-12p40与p35亚基的异二聚体,所述亚基彼此通过二硫桥连接,且各亚基与scFv(L19)融合,从而形成scFv(L19)-p35/p40-scFv(L19)异二聚体,如图7C中所说明。通过此异二聚形式,使肿瘤对组合物的吸收获得显著改良。
在WO2013/014149中,申请人已公开与抗EDA纤连蛋白肿瘤靶向抗体(命名为“F8”)连接的IL-12的两种新替代分子形式,该文献的内容以引用的方式并入本文中。
其中,另一种形式的IL-12免疫缀合物包含“单链双抗体”。其基本上由两个scFv抗体与一个五氨基酸短接头组成(因此形成“双抗体”),其彼此通过更长的十五氨基酸肽接头连接。
已表明以IL-12与单特异性F8单链双抗体融合为特征的分子形式(参见图8B)在肿瘤靶向方面经证实优于(i)scFv(F8)-p35/p40-scFv(F8)异二聚体(图8A),其L19变体经证实为WO2006/119897中所公开的最佳形式;或(ii)与双抗体连接的两个IL-12分子(图8C)。L19
如本文所用,“L19抗体”意味着结合EDB纤连蛋白或其任何部分且包含与以下氨基酸序列中的一或多个具有至少百分之七十五(75%)相同性的氨基酸序列的任何抗体:
L19 VH(SEQ ID NO:7)
L19 VL(SEQ ID NO:5)
CDR1 VH(SEQ ID NO:28)
CDR2 VH(SEQ ID NO:29)
CDR3 VH(SEQ ID NO:30)
CDR1 VL(SEQ ID NO:31)
CDR2 VL(SEQ ID NO:32)
CDR3 VL(SEQ ID NO:33)
L19双抗体(SEQ ID NO:36)
药物组合物
本发明的另一方面涉及一种药物组合物,其包含至少一种本发明的缀合物及任选包含药学上可接受的赋形剂。
本发明的药物组合物通常包含治疗有效量的根据本发明的缀合物及任选包含辅助物质,诸如(一种或多种)药学上可接受的赋形剂。所述药物组合物以医药技术中熟知的方式制备。载剂或赋形剂可为液体材料,其可充当活性成分的媒剂或介质。适合载剂或赋形剂为本领域中所熟知且包括例如稳定剂、抗氧化剂、pH调节物质、控制释放赋形剂。
本发明的药物制备物可经调适用于例如肠胃外用途,且可以溶液等的形式施用于患者。包含本发明组合物的组合物可施用于患者。施用优选以“治疗有效量”进行,此足以对患者展示益处。此类益处可至少为改善至少一种症状。实际施用量及施用速率与施用时程将视治疗的性质及严重度而定。治疗的处方(例如剂量等决定)在一般从业者及其他医疗医生的职责内。在医师判断下,治疗可每日、每周两次、每周一次或以每个月的时间间隔重复进行。
经口施用的药物组合物可以片剂、胶囊、散剂或液体形式。片剂可以包含固体载剂,诸如明胶或佐剂。液体药物组合物通常包含液体载剂,诸如水、石油、动物油或植物油、矿物油或合成油。可包括生理盐水溶液,右旋糖或其他糖溶液或二元醇类(诸如乙二醇、丙二醇或聚乙二醇)。
对于静脉内注射或在罹患位点注射而言,活性成分将呈肠胃外可接受的水溶液形式,其无热原质且具有适合的pH值、等渗性及稳定性。本领域相关技术人员能够充分使用例如等张媒剂(诸如氯化钠注射液、林格氏注射液(Ringer's Injection)、乳酸化林格氏注射液)制备适合溶液。视需要可包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂。
另外应理解,本文所公开的实施方案不意欲理解为彼此不相关的独立实施方案。用一个特定实施方案论述的特征意欲也结合本文中所示的其他实施方案公开。若在一种情况下,具体特征不用一个实施方案而用另一实施方案公开,则本领域技术人员将理解这不必意味着所述特征不意欲与所述另一实施方案组合公开。本领域技术人员将理解本申请的要旨为公开所述特征,也适用于其他实施方案,但仅出于清楚起见且使说明书保持在可管理的卷量,此尚未进行。
此外,本文所提及的参考文献的内容以引用的方式并入。这尤其指公开标准或常规方法的现有技术文献。在那种情况下,以引用的方式并入主要目的是提供充分的实施公开且避免冗长重复。
一般而言,本发明的组合物能够结合至细胞、组织、器官或患者中的特定靶结构,所述靶结构是根据包含EDB结合结构域的肽或蛋白质的特异性定义的。
到达靶后,IL-12刺激从T细胞及自然杀伤细胞产生IFNγ,且也诱导Th1辅助细胞分化。IL-12为先天免疫及细胞介导性免疫的关键介质。若构建体中包含EDB结合结构域的肽或蛋白质对表征赘生性(例如肿瘤、血液学疾病、或处于转化成癌症的过程中的细胞)的靶结构(例如受体或细胞外基质蛋白)具有特异性,则组合物的结合引发IL-12介导的强抗癌及抗转移活性。
申请人已惊人地发现,当使用包含含有GSADGGSSAGGSDAG的氨基酸基序的接头使IL-12连接至包含EDB结合结构域的肽或蛋白质(即,如WO2013/014149所公开的双抗体)时,可以获得更佳的肿瘤靶向表现以及优异的生产产量。同时,此变体的结合行为优于较短GSADGG接头的结合行为,在本文中命名为“Old”且公开于WO2013/014149中。
申请人首先已评估且表征单链双抗体形式的与L19抗体连接的人类IL-12的八种克隆(huIL-12L19L19),其中细胞因子与L19单链双抗体之间存在不同的多肽接头。
五种克隆(命名为:(i)“AKKAS”,(ii)“DDS”,(iii)“(G4S)3”,(iv)“SAD”及(v)“SES”)含有用于免疫细胞因子与重组抗体缀合的接头,且由于其不同电荷特征(中性、带正电、带负电)而选择。
开发出三种其他克隆,命名为(vi)α3、(vii)AP6及(viii)AP7。就这些三种克隆而言,考虑且实施Chen等人(2013)中所报导的原理。此综述表明刚性接头可以具有更佳的稳定性且可以维持细胞因子与抗体之间的正确距离,从而增加治疗功效。
接头(i)-(viii)中无一者先前在此特异性免疫细胞因子中测试。
令人惊讶地发现,“SAD”接头大大增强(i)肿瘤靶向表现及(ii)与包含EDB结合结构域的肽或蛋白质连接的IL-12的生产产量,而不(iii)损害与ED-B的结合行为(相较于其他克隆)。此非常惊人,即使考虑Chen报导的原理,仅SAD接头即导致相较于“Old”克隆(下文更详细地描述)与本文所述的其他新变体具有多种优异特性的组合物。
最后,对包含WO2013/014149中所公开的接头的第九种克隆(命名为“Old”)与“SAD”接头进行比较。惊人地发现,“SAD”接头尽管与“Old”接头共享序列的第一部分,也具有优异的针对ED-B的结合亲和力。
另外,尺寸排阻层析之后,相较于“Old”接头,“SAD”接头展示更高单体部分,意味着整个缀合物的组装更高效。预期由“SAD”接头得到的较高单体部分使总体制造产量增加。
如本文所用,术语“单链双抗体”是指使用短接头(优选3-10个氨基酸长,更优选5个氨基酸长)的两种单链Fv(scFv)抗体的构建体(也称为“双抗体”),该构建体彼此间通过更长接头(优选5-20个氨基酸长,更优选15个氨基酸长)、根据以下方案(N→C方向)连接:L19VH-接头3-L19VL-接头4-L19VH-接头3-L19VL。
根据本发明的一些实施方案,异二聚IL-12蛋白中的第一亚基为p40且第二亚基为p35。
如上文所讨论的,包含EDA或EDB结构域的纤连蛋白同种型由于其对发育的重要性及其在肿瘤中的再表达(与有限存在于正常成人组织中对比)而称为癌胚形式。
这些同种型也识别为血管生成的重要标记物,血管生成为发育中且为肿瘤细胞在癌症进展中所需的关键生理学过程。
因此,纤连蛋白的外结构域B(ED-B)为抗癌治疗的引人注目的靶,包括使用如本文中所讨论的免疫细胞因子。
根据本发明的一些实施方案,单链双抗体可以包含具有能够特异性结合至感兴趣的抗原的抗体的互补决定区(CDR)或VH和/或VL结构域的抗原结合位点,例如能够特异性结合至纤连蛋白的外结构域B的抗原的抗体的一或多个CDR或VH和/或VL结构域。
可借助于互补决定区(CDR)的排列提供抗原结合位点。用于携带CDR或CDR集合的结构通常为抗体重链或轻链序列或其实质性部分,其中CDR或CDR集合定位的位置对应于由重排免疫球蛋白基因编码的天然存在的VH及VL抗体可变结构域的CDR或CDR集合。免疫球蛋白可变结构域的结构及位置可通过参考以下文献来确定:Kabat等人(1987)(Sequences ofProteins of Immunological Interest第4版,美国健康及人类服务部(US Department ofHealth and Human Services))及其更新版,现可在互联网上获得(在immuno.bme.nwu.edu或使用任何搜索引擎找到“Kabat”)。
CDR区或CDR意指如以下文献中所定义的免疫球蛋白重链及轻链的高变区:Kabat等人(1987)Sequences of Proteins of Immunological Interest,第4版,美国健康及人类服务部(Kabat等人,(1991a),Sequences of Proteins of Immunological Interest,第5版,美国健康及人类服务部,公众服务署(Public Service),NIH,Washington,及后续版本)。抗体通常含有3个重链CDR及3个轻链CDR。术语CDR或CDRs在本文中用于指(根据个案)这些区域之一或这些区域中的若干者或甚至全部,其含有负责通过抗体对其所识别的抗原或表位的亲和力结合的氨基酸残基中的大部分。
因此,单链双抗体可包含具有抗体L19的一个、两个、三个、四个、五个或六个CDR,或VH和/或VL结构域的抗原结合位点。
根据本发明的一些实施方案,单链双抗体可以包含具有SEQ ID NO 28-33中所示的抗体L19的互补决定区(CDR)的抗原结合位点。抗原结合位点可包含分别阐述于SEQ IDNO 7及5中的抗体L19的VH和/或VL结构域。
抗原结合位点可包含抗体L19的一个、两个、三个、四个、五个或六个CDR。L19的CDR的氨基酸序列为:
SEQ ID NO:28(VH CDR1);
SEQ ID NO:29(VH CDR2);
SEQ ID NO:30(VH CDR3);
SEQ ID NO:31(VL CDR1);
SEQ ID NO:32(VL CDR2),和/或
SEQ ID NO:33(VL CDR3)。
SEQ ID NO 28-30为人类单克隆抗体L19的VH CDR区(分别为1-3)的氨基酸序列。SEQ ID NO 31-33为人类单克隆抗体L19的VL CDR区(分别为1-3)的氨基酸。抗体L19的VH及VL结构域的氨基酸序列分别对应于SEQ ID NO 7及5。
根据本发明的一些实施方案,单链双抗体包含以下中的至少一个:
a)包含本文中定义为SEQ ID NO 28-30的3个重链CDR及本文中定义为SEQ ID NO31-33的3个轻链CDR的集合
b)在本文中定义为SEQ ID NO 7的VH中的3个重链CDR的集合及在本文中定义为SEQ ID NO 5的VL中的3个轻链CDR的集合
c)a)或b)的重链CDR/轻链CDR组合,其条件为至少一个CDR相对于如a)或b)中所指定的各个CDR具有最多3个氨基酸取代,同时维持其结合至纤连蛋白的外结构域B(ED-B)的能力,
d)a)或b)的重链CDR/轻链CDR组合,其条件为至少一个CDR相对于如a)或b)中所指定的各个CDR具有≥66%的序列相同性,同时维持其结合至纤连蛋白的外结构域B(ED-B)的能力,
其中CDR嵌入适合的蛋白质框架中以便能够结合纤连蛋白的外结构域B(ED-B)。
在一些实施方案中,至少一个CDR相对于各个CDR具有≥67%、优选≥68%的序列相同性,更优选≥69%、≥70%、≥71%、≥72%、≥73%、≥74%、≥75%、≥76%、≥77%、≥78%、≥79%、≥80%、≥81%、≥82%、≥83%、≥84%、≥85%、≥86%、≥87%、≥88%、≥89%、≥90%、≥91%、≥92%、≥93%、≥94%、≥95%、≥96%、≥97%、≥98%中的任一个,或最优选≥99%的序列相同性。
在另一实施方案中,至少一个CDR已通过亲和力成熟或其他修饰加以修饰,相较于上文所公开的序列,产生序列修饰。
在一些实施方案中,至少一个CDR相对于如a)或b)中所指定的各个CDR具有最多2个且优选1个氨基酸取代。
根据本发明的一些实施方案,单链双抗体包含以下中的至少一个:
a)SEQ ID NO 7及5中所示的抗体L19的VH及VL结构域
b)a)的重链/轻链可变结构域序列对,其条件为所述结构域中的至少一个分别相对于SEQ ID NO 7或SEQ ID NO 5具有≥80%的序列相同性,和/或
c)a)的重链/轻链可变结构域序列对,其条件为所述结构域中的至少一个分别相对于SEQ ID NO 7或SEQ ID NO 5具有最多10个氨基酸取代,
同时维持其结合至纤连蛋白的外结构域B(ED-B)的能力。
在一些实施方案中,至少一个结构域分别相对于SEQ ID NO 7或SEQ ID NO 5具有≥81%、优选≥82%、更优选≥83%、≥84%、≥85%、≥86%、≥87%、≥88%、≥89%、≥90%、≥91%、≥92%、≥93%、≥94%、≥95%、≥96%、≥97%、≥98%或最优选≥99%的序列相同性。
在一些实施方案中,至少一个结构域分别相对于SEQ ID NO 7或SEQ ID NO 5具有最多9个、优选最多8个、更优选最多7个、6个、5个、4个、3个或2个且最优选最多1个氨基酸取代。
根据本发明的一些实施方案,单链双抗体中的至少一个氨基酸取代是保守氨基酸取代。
根据另一个实施方案,组合物具有全长结构“[p40]-[接头1]-[p35]-[SAD接头]-[L19VH]-[接头3]-[L19VL]-[接头4]-[L19VH]-[接头3]-[L19VL]”。
根据另一个实施方案,组合物具有根据SEQ ID NO 16的全长序列。
病症
根据本发明的另一方面,提供了根据前述说明的组合物在(制备)治疗人类或动物对象(的药物)中的用途,所述人类或动物对象
·诊断有发展赘生性疾病,
·患有发展赘生性疾病,或
·面临发展赘生性疾病风险,
或在(制备)预防这种状况(的药物)中的用途。
根据本发明的另一方面,根据前述权利要求中任一项的组合物在(制备)抑制人类或动物对象中血管生成(的药物)中的用途。
因此,如本文所述的缀合物可用于治疗赘生性疾病或通过体内使IL-12靶向新生血管来抑制血管生成的方法中。
术语“赘生性疾病”涵盖恶性转化及癌症,包括肿瘤及血液疾病。
也涵盖一种通过使物质(具体而言,治疗剂,例如IL-12)靶向患者中的新生血管来治疗癌症或抑制血管生成的方法,该方法包含向患者施用治疗有效量的如本文所述的缀合物。可使用如本文所述的组合物治疗的状况包括癌症、其他肿瘤及赘生性状况。组合物可用于抑制血管生成,从而治疗类风湿性关节炎、糖尿病性视网膜病变、年龄相关的肌肉退化、血管瘤、肿瘤及癌症。治疗可包括预防性治疗。组合物也可在诊断方法中施用,例如靶向及诊断可能与上述状况中的任一者相关的血管生成。也可根据组合物中所含的蛋白质治疗剂或诊断剂的性质及靶向部分的特异性来诊断及治疗其他疾病及状况。
适于如本文所述治疗的癌症包括任何类型的实体或非实体癌症或恶性淋巴瘤,特别是肝癌、淋巴瘤、白血病(例如急性髓性白血病)、肉瘤、皮肤癌、膀胱癌、乳腺癌、子宫癌、卵巢癌、***癌、肺癌、结直肠癌、子***、头颈癌、食道癌、胰腺癌、肾癌、胃癌及脑癌。癌症可为家族性或偶发性。癌症可为转移性或非转移性。
优选地,癌症为选自以下的癌症:肾癌、乳腺癌、肝癌、肺癌、淋巴瘤、肉瘤(例如肠胃基质肿瘤)、皮肤癌(例如黑素瘤)、结直肠癌及神经内分泌肿瘤。
在一些实施方案中,赘生性疾病的特征为ED-B纤连蛋白的表达或过表达。
本发明的组合物可经由任何适合的途径施用于需要治疗的患者,通常通过注射至血流中和/或直接注射至待治疗的位点,例如肿瘤或肿瘤血管。精确剂量及其施用频率将取决于多种因素、治疗途径、待治疗区域(例如肿瘤)的尺寸及位置。
就反应性而言,若对象的癌症(例如血液癌症,例如癌细胞生长、增殖和/或存活)的参数迟延或降低可检测的量,例如约5%、10%、20%、30%、40%、50%、60%、70%、80%、90%或更多,如通过任何适当测量方式所测定,例如根据肿块、细胞计数或体积所测定,则对象对治疗有反应。在一个实例中,若对象经历的预期寿命延长超过未施用治疗的情况下所预测的预期寿命约5%、10%、20%、30%、40%、50%或更多,则对象对治疗有反应。在另一实例中,若对象具有增加的无疾病存活、总存活或增加的进展时间,则对象对治疗有反应。若干方法可用于确定患者是否对治疗有反应,包括例如NCCN肿瘤学临床实务指南(Clinical Practice Guidelines in Oncology)(NCCN)提供的标准。
组合治疗
视所治疗的状况而定,组合物可单独施用或与其他治疗同时或依序组合施用。其他治疗可包括施用适合剂量的疼痛缓解药物,诸如非类固醇抗炎药(例如阿司匹林(aspirin)、布洛芬(ibuprofen)或酮基布洛芬)或阿片类,诸如***(morphine)或止吐药。
根据本发明的另一方面,提供根据以上描述的组合物或药物组合物与一或多种治疗活性化合物的组合。
根据本发明的另一方面,提供一种治疗或预防与ED-B纤连蛋白表达或过表达相关的病症或状况的方法,其包含向有需要的对象施用有效量的根据以上描述的组合物、药物组合物或组合。
试剂盒
根据本发明的另一方面,提供试剂盒,其包含:
a)根据以上描述的组合物、药物组合物或组合,
b)用于施用该组合物、组合物或组合的装置,及
c)使用说明书。
在一些实施方案中,此类试剂盒包含具有适合的患者说明书的预装药注射器。在另一个实施方案中,此类试剂盒包含具有适合的使用者说明书的输注瓶。
试剂盒的组分优选为无菌的且存在于密封小瓶或其他容器中。
试剂盒可进一步包含在本文所述的方法中使用组分的说明书。试剂盒的组分可包含或封装于容器中,例如袋、盒、缸、罐或塑料定型包装。
实施例
虽然已在附图及前述描述中详细地说明及描述了本发明,但此类说明及描述应被视为说明性或例示性的,而非限制性的;本发明不限于所公开实施方案。本领域技术人员在实施所要求保护的发明时从研究附图、公开内容和所附权利要求可以理解且实现所公开实施方案的其他变化形式。在权利要求中,词语“包含”不排除其他元素或步骤,且不定冠词“一(a或an)”不排除复数个。在互不相同的从属权利要求中引述某些措施的事实并不意味着不能有利地使用这些措施的组合。权利要求中的任何参考符号均不应视为限制范畴。
本文所公开的全部氨基酸序列均以N端至C端展示;本文所公开的全部核酸序列均以5'→3'展示。
实施例1
申请人已惊人地发现,当某些接头用于将IL-12与单链双抗体(即,WO2013/014149中所公开的优异形式)连接时,可获得更佳的肿瘤靶向表现以及优异的生产产量。
申请人已评估且表征与L19抗体连接的人类IL-12的八种克隆的单链双抗体形式(huIL-12L19L19),其中细胞因子与L19单链双抗体之间具有不同的多肽接头。
五种克隆(命名为:(i)“AKKAS”,(ii)“DDS”,(iii)“(G4S)3”,(iv)“SAD”及(v)“SES”)含有用于将免疫细胞因子与重组抗体缀合的接头,且由于其不同电荷特征(中性、带正电、带负电)而选择。
开发出三种其他克隆,命名为(vi)α3、(vii)AP6及(viii)AP7。就这三种克隆而言,考虑且实施Chen等人(2013)中所报导的教导。此综述表明刚性接头可以具有更佳的稳定性且可以维持细胞因子与抗体之间的正确距离,从而增加治疗功效。
接头(i)-(viii)中无一者先前在此特异性免疫细胞因子中测试。
惊人地发现,相较于其他克隆,“SAD”接头大大增强肿瘤靶向表现及与单链双抗体连接的IL-12的生产产量,同时能够同等地结合至ED-B。
材料及方法
实施例中所测试的变体具有以下共同结构:
如表2中所详述,不同变体(本文中也称为“克隆”)就接头2的序列而言彼此不同:
克隆具有不同接头八种融合蛋白
huIL-12L19L19编码序列已通过组装不同PCR片段:L19抗体及IL12有效负载(payload)来产生。使用适合的引物,自先前产生的融合蛋白L19-IL2模板对L19基因进行PCR扩增。用适合引物对第二L19基因进行PCR扩增。
同时,使用适合的引物,自先前产生的基于IL12的免疫细胞因子对IL-12的p35结构域的一部分基因进行PCR扩增。对两个中间片段进行PCR组装(以产生P35-L19片段),用BamHI/BspEI进行双重消化且克隆入含有p35的经双重消化的载体中。新产生的p35-L19载体随后用BspEI/NotI-HF进行双重消化且与第二L19双抗体片段基因连接。片段p35-L19L19通过BamHI/NotI-HF消化且克隆入携带p40亚基基因的先前经双重消化的哺乳动物细胞表达载体pcDNA3.1(+)中,从而产生全长IL12-L19L19。
IL12与单链双抗体L19片段之间的不同接头是借助于PCR组装片段“A”(编码p35的一部分与接头)及片段“B”(编码接头及抗体的一部分)来***。使用适合引物,自作为模板的IL12-L19L19扩增不同片段“A”及片段“B”。
针对克隆AP7设计的克隆策略引起突变体克隆(命名为AP6)产生。所有PCR产物用BamHI-HF及BspEI限制酶进行双重消化且与P35-L19L19pcDNA3.1质粒连接。扩增所得质粒,用NotI-HF及BamHI-HF限制酶进行双重消化且将***物亚克隆至含有IL12的pcDNA3.1质粒中。扩增所得DNA质粒且用于细胞转染。
具有不同接头的八种融合蛋白的表达纯化
为了产生各种人类IL-12融合体,使用悬浮液中的CHO-S细胞。利用瞬时基因表达来表达huIL-12L19L19变体。为了1ml产量,将悬浮液中的4×106个CHO-S细胞离心且重悬于1mL适于CHO-S的培养基中。接着将每百万个细胞0.625μg质粒DNA、随后2.5μg聚乙烯亚胺(PEI;1mg/mL水溶液,pH 7.0)添加至细胞中且轻轻混合。经转染的培养物在振荡培育箱中、在31℃孵育6天。
最后,通过瞬时基因表达而产生的融合蛋白通过蛋白A亲和层析而自细胞培养物培养基中纯化且接着用PBS透析。
SDS-PAGE
通过SDS-PAGE 10%及SDS-PAGE 12%,在还原及非还原条件下分析融合蛋白的正确分子量。
ELISA
为了检查各种IL-12融合体的正确结合,Elisa盘用50ug/ml纤连蛋白结构域7B89包被过夜(参见WO2001/062800A1,其内容以引用的方式并入本文中)。免疫细胞因子在10ug/ml及1ug/ml测试。使用蛋白A辣根过氧化物酶作为第二试剂。分析使用BM-Blue POD可溶性底物显影。通过添加333mM H2SO4来中止比色反应且使用微量滴定盘读取器测量波长450nm及650nm处的吸光度。
尺寸排阻层析及Biacore
在使用Superdex 200增加柱的FPLC***上进行尺寸排阻层析。通过Biacore X100仪器,使用经纯化的huIL-12L19L19克隆、在包被有纤连蛋白7B89结构域的CM5芯片上进行表面等离子共振实验亲和力测量。样品是以连续稀释(1μM至250nM浓度范围)注射。
免疫荧光
为证实各种huIL-12融合体结合癌细胞的能力,对冷冻的同基因F9畸胎癌试样冷冻切片(8um)进行免疫荧光术。肿瘤切片通过冰冷的丙酮固定(5分钟)。固定的后,洗涤盖玻片且用含20%胎牛血清的PBS封闭45分钟。5μg/ml浓度的HuIL-12L19L19克隆添加至2%BSA/PBS溶液中、在室温持续1小时。盖玻片接着用PBS洗涤两次且将二抗小鼠抗人类白介素-12添加到2%BSA/PBS溶液中(最终稀释度1:1000),在室温持续1小时。盖玻片接着用PBS再次洗涤两次且添加三抗山羊抗小鼠(最终稀释度1:500)。使用DAPI将细胞核对比染色。
放射性标记及体内肿瘤靶向
为证实各种IL-12融合体体内结合肿瘤的能力,通过生物分布分析来评估其靶向能力。100μg各IL-12L19L19克隆用125I及氯胺T水合物进行放射性碘标记且在PD10柱上纯化。将经放射性标记的蛋白质注射至皮下带有移植的F9鼠类畸胎癌的免疫活性小鼠的外侧尾静脉中。每只小鼠的注射剂量在4与9μg之间变化。注射后24小时处死小鼠。将器官称重且使用Packard Cobraγ计数器对放射性计数。代表性器官的放射活性含量是以每克组织的注射剂量百分比(%ID/g±标准误差)表示。
结果
克隆、表达及SDS-PAGE
成功地克隆huIL-12L19L19融合蛋白的八种变体,每一种在细胞因子与L19单链双抗体之间具有不同多肽接头。SDS-PAGE表征显示所有变体的分子量为约120kDa,证实预期的蛋白质尺寸(约109kDa,未糖基化)。所有变体的表达产量(通过在CHO-S细胞中的瞬时基因表达)在3.5与5mg/L之间的范围。惊人地,命名为“SAD”的克隆展示9mg/L的产量,这显著高于其他7种克隆的产量。结果展示于图1中。
ELISA
在ELISA中,八种克隆α3、AP6、AP7、DDS、SES、AKKAS、(G4S)3及SAD皆证实对人类纤连蛋白的结构域7B89的结合(均在10μg/ml及1μg/ml浓度)。结果展示于图2中。
BiaCore
通过Biacore分析,在人类纤连蛋白包被的芯片上对结构域7B89进行更精确的亲和力常数测定(图3)。样品是以浓度等于1000nM、750nM、500nM及250nM的连续稀释液注射(图3)。通过Biacore X100评估软件估算表面(apparent)KD。
尺寸排阻层析
经由尺寸排阻层析(SEC-200增加)来表征八种克隆α3、AP6、AP7、DDS、SES、AKKAS、(G4S)3及SAD,其中所有克隆均展示相当的谱,其中主峰对应于单体免疫细胞因子(图4)。
免疫荧光
使用克隆α3、AP6、AP7、DDS、SES、AKKAS、(G4S)3及SAD,对冷冻的同基因F9畸胎癌试样冷冻切片(8um)进行免疫荧光实验。相较于阴性对照,所有克隆均展示针对血管的特异性结合(图5)。
体内肿瘤靶向
通过生物分布分析来评估体内靶向。八种克隆α3、AP6、AP7、DDS、SES、AKKAS、(G4S)3及SAD以及阳性对照(与鼠类IL-12连接的L19单链双抗体)用125I进行放射性碘标记且注射(4-9μg蛋白质/动物)至皮下带有移植的F9鼠类畸胎癌的免疫活性小鼠中。注射后24小时计数的放射性展示所有克隆均在肿瘤中聚积,然而,相较于其他七种克隆,“SAD”克隆显示优异聚积于肿瘤中。(图6)。
实施例2
在另一组比较实验中惊人地发现,就结合能力、单体谱及肿瘤靶向能力而言,“SAD”接头也优于WO2013/014149中所公开的旧(且较短)的GSADGG接头(SEQ ID NO 26)。
材料及方法
此实施例中所测试的变体具有以下共同结构:
不同变体(本文中也称为“克隆”)就接头2的序列而言彼此不同:
接头2 | SEQ ID NO | 序列 |
SAD | 4 | GSADGGSSAGGSDAG |
Old | 26 | GSADGG |
融合蛋白的克隆
沿着上述的线克隆融合蛋白,所述融合蛋白包含经由6或15个氨基酸接头与L19抗体融合的huIL-12,呈单链双抗体形式(分别即,huIL-12L19L19“Old”及huIL-12L19L19“SAD”变体)。
融合蛋白的表达
在悬浮液调适的CHO细胞培养物中,通过瞬时基因表达来产生融合蛋白,所述融合蛋白包含经由6或15个氨基酸接头与L19抗体融合的huIL-12,呈单链双抗体形式(分别即,huIL-12L19L19“Old”及huIL-12L19L19“SAD”变体)。转染后,使细胞在31℃、在振荡条件下、在ProCHO-4培养基(补充有4mM超谷氨酰胺)中维持6天,随后通过离心收获培养物上清液且进一步处理以纯化融合蛋白。
使用蛋白A树脂纯化融合蛋白
使转染的CHO细胞悬浮液培养物在4℃以5000rpm离心30分钟。通过使用0.45um过滤器过滤来进一步澄清上清液。将蛋白A树脂添加至经过滤的上清液中且在振荡条件下孵育混合物约1小时。接着在液相层析柱中收集树脂,且用“缓冲剂A”(100mM NaCl、0.5mMEDTA、含0.1%Tween 20的PBS pH 7.4)洗涤,随后用“缓冲剂B”(500mM NaCl、含0.5mM EDTA的PBS pH 7.4)进行第二次洗涤。包含huIL-12的融合蛋白通过重力流、使用100mM TEA洗脱。收集等分试样且合并含有融合蛋白的级份(如通过UV光谱法所证实)且用PBS透析过夜。
融合蛋白的尺寸排阻层析
在***上,使用Superdex 200增加10/300GL柱,以PBS作为运行缓冲剂,对融合蛋白进行尺寸排阻层析。将100μl蛋白质溶液注射至回路中且自动注射至柱上。评估随时间变化的280nm处UV吸光度。利用UNICORN软件的峰积分函数来分析融合蛋白的SEC谱,以定量单体级分相对于总面积%或相对于峰面积%的百分比。为排除由于样品装载或样品缓冲剂中存在的盐所致的峰值伪迹,仅考虑保留体积5-17.5mL之间的间隔进行定量。
BIACore
通过BiacoreX100仪器、使用经纯化的“Old”及“SAD”克隆、在纤连蛋白7B89结构域新鲜包被的CM5芯片上进行表面等离子共振实验亲和力测量。样品以浓度等于250nM、125nM及62.5mM的连续稀释注射(图10)。通过Biacore X100评估软件估算表面KD。
放射性标记及体内肿瘤靶向
纯化的蛋白质样品huIL-12L19L19“SAD”(具有接头GSADGGSSAGGSDAG,SEQ ID NO4)及huIL-12L19L19“Old”(具有接头GSADGG,SEQ ID NO 26)(100μg)用125I及氯胺T水合物进行放射性碘标记且在PD10柱上纯化。蛋白A亲和层析后,对蛋白质进行放射性碘标记。将蛋白质注射至皮下带有移植的F9鼠类畸胎癌的免疫活性(129/Sv)小鼠的外侧尾静脉中。每只小鼠的注射剂量在10与11μg之间变化。注射后24小时处死小鼠。将器官样品称重且使用Packard Cobraγ计数器对放射性计数。计算不同器官中的蛋白质吸收且以每克组织的注射剂量百分比(%ID/g±标准误差)表示。根据Tarli等人(1999),依据肿瘤生长来调整肿瘤中的蛋白质吸收。
结果
融合蛋白的表达和纯化及尺寸排阻层析
通过在CHO细胞中瞬时基因表达来产生两种huIL-12L19L19“SAD”及huIL-12L19L19“Old”变体。双重复进行实验,其中在不同日进行两组产生实验,分别产生批次A及B。通过蛋白A亲和层析进行单步纯化且用PBS透析后,通过尺寸排阻层析来评估蛋白质样品的均质性(图9)。两种蛋白质变体均展示一定程度的蛋白质聚集,如以早期保留体积洗脱的高分子量变体的存在所突出显示。huIL-12L19L19“SAD”在两种情况下均展示更佳的谱,如通过使用UNICORN软件的峰积分函数对蛋白质的单体部分定量所证实。的确,当与huIL-12L19L19“Old”比较时,huIL-12L19L19“SAD”变体展示较低聚集倾向,此考虑单体峰面积相对于基线上的曲线下总面积的百分比(平均值分别为:54.57%相对于46.69%),或单体峰面积相对于所有积分峰值的总和的百分比(平均值分别为:58.83%相对于52.74%)(表1)。
表1:通过UNICORN软件的峰积分函数所评估的不同融合蛋白的单体级分的定量。(*)峰面积相对于基线上的曲线下总面积的百分比。(°)峰面积相对于所有积分峰值的总和的百分比。
Biacore
通过Biacore X100评估软件估算“Old”克隆(具有接头GSADGG的huIL-12L19L19“Old”)的表面KD为6.7nM,且“SAD”克隆(具有接头GSADGGSSAGGSDAG的huIL-12L19L19“SAD”)的表面KD为3.8nM(图10)。
体内肿瘤靶向
注射后24小时计数的放射性表明,“SAD”克隆相较于“Old”克隆具有出乎意料的优异肿瘤吸收(图11)。
实施例3
评估huIL-12L19L19“SAD变体”在人类患者中的效力,所述人类患者患有恶性黑素瘤、非小细胞肺癌(NSCLC)、肾细胞癌、尿路上皮癌、头颈部鳞状细胞癌(HNSCC)、微卫星高不稳定性(MSI-H)或错配修复缺陷(dMMR)转移性结直肠癌、肝细胞癌、胃癌、皮肤鳞状细胞癌、子***及弥漫性大B细胞淋巴瘤(DLBCL)。至少一队患者展现作为先前最近治疗施用的基于免疫检查点阻断治疗的方案的疾病进展。
患者通过静脉内施用8周、每周一次来接受huIL-12L19L19“SAD”变体。患者接受的剂量为4μg/kg;8μg/kg;12μg/kg;16μg/kg;或20μg/kg。
患者自治疗开始随访6个月,或直至撤回同意书或直至进行性疾病。
利用融合分子及IL12部分的夹心捕捉,评估IL12-L19L19L19-L12的药物动力学分析。通过表面等离子共振分析及夹心捕捉术来测试人类抗融合蛋白抗体(HAFA)。使用RECIST(1.1版)针对实体肿瘤或以LUGANO标准作为恶性淋巴瘤评估标准来评估第8周、第16周及第24周的抗肿瘤活性,例如功效。
其他实施方案
根据第一组实施方案,提供以下:
1.一种缀合物,包含
a)具有第一及第二亚基的异二聚IL-12蛋白,
b)单链双抗体,及
c)介于所述IL-12蛋白与所述单链双抗体之间的接头,该接头包含含有SAD的氨基酸基序。
2.根据第1点的缀合物,其中所述SAD接头包含氨基酸基序GSADGGSSAGGSDAG(SEQID NO:4)。
3.根据第1点至第2点中任一点的缀合物,其中所述异二聚IL-12蛋白的第一亚基为p40且第二亚基为p35。
4.根据第1点至第3点中任一点的缀合物,其中所述单链双抗体是单特异性的或双特异性的。
5.根据第1点至第4点中任一点的缀合物,其中所述单链双抗体结合纤连蛋白的外结构域B(ED-B)。
6.根据第1点至第5点中任一点的缀合物,其中所述单链双抗体包含两个L19VH结构域及两个L19VL结构域。
7.根据第1点至第6点中任一点的缀合物,其具有全长结构[p40]-[接头1]-[p35]-[SAD接头]-[L19VH]-[接头3]-[L19VL]-[接头4]-[L19VH]-[接头3]-[L19VL]。
8.根据第1点至第7点中任一点的缀合物,其具有根据SEQ ID NO:16的全长序列。
9.根据前述点中任一点的缀合物在(制备)治疗人类或动物对象(的药物)中的用途,所述人类或动物对象
·诊断有发展赘生性疾病,
·患有发展赘生性疾病,或
·面临发展赘生性疾病风险,
或在(制备)预防这种状况(的药物)中的用途。
10.根据前述点中任一点的缀合物在(制备)抑制人类或动物对象中血管生成(的药物)中的用途。
11.一种药物组合物,其至少包含根据第1点至第8点中任一点的缀合物,及任选包含一或多种药学上可接受的赋形剂。
12.一种组合,其包含(i)根据第1点至第8点中任一点的缀合物或根据第11点的药物组合物,及(ii)一或多种治疗活性化合物。
13.一种用于治疗或预防与ED-B纤连蛋白表达或过表达相关的病症或状况的方法,其包含向有需要的对象施用有效量的根据第1点至第8点中任一点的缀合物、根据第11点的药物组合物或根据第12点的组合。
14.一种治疗试剂盒,其包含:
a)根据第1点至第8点中任一点的缀合物、根据第11点的药物组合物或根据第12点的组合,
b)用于施用所述缀合物、组合物或组合的装置,及
c)使用说明书。
根据第二组实施方案,提供以下:
1.一种缀合物,其包含
a)具有第一及第二亚基的异二聚IL-12蛋白,
b)单链双抗体,及
c)介于所述IL-12蛋白与所述单链双抗体之间的接头,所述接头包含含有GSADGGSSAGGSDAG(SEQ ID NO:4)的氨基酸基序。
2.根据第1点中任一点的缀合物,其中所述异二聚IL-12蛋白的第一亚基为p40且第二亚基为p35。
3.根据第1点至第2点中任一点的缀合物,其中所述单链双抗体是单特异性的或双特异性的。
4.根据第1点至第3点中任一点的缀合物,其中所述单链双抗体结合纤连蛋白的外结构域B(ED-B)。
5.根据第1点至第4点中任一点的缀合物,其中所述单链双抗体包含两个L19VH结构域及两个L19VL结构域。
6.根据第1点至第5点中任一点的缀合物,其具有全长结构[p40]-[接头1]-[p35]-[SAD接头]-[L19VH]-[接头3]-[L19VL]-[接头4]-[L19VH]-[接头3]-[L19VL]。
7.根据第1点至第6点中任一点的缀合物,其具有根据SEQ ID NO:16的全长序列。
8.根据前述点中任一点的缀合物在(制备)治疗人类或动物对象(的药物)中的用途,所述人类或动物对象
·诊断有发展赘生性疾病,
·患有发展赘生性疾病,或
·面临发展赘生性疾病风险,
或在(制备)预防这种状况(的药物)中的用途。
9.根据前述点中任一点的缀合物在(制备)抑制人类或动物对象中血管生成(的药物)中的用途。
10.一种药物组合物,其至少包含根据第1点至第7点中任一点的缀合物,及任选包含一或多种药学上可接受的赋形剂。
11.一种组合,其包含(i)根据第1点至第7点中任一点的缀合物或根据第10点的药物组合物,及(ii)一或多种治疗活性化合物。
12.一种用于治疗或预防与ED-B纤连蛋白表达或过表达相关的病症或状况的方法,其包含向有需要的对象施用有效量的根据第1点至第7点中任一点的缀合物、根据第10点的药物组合物或根据第11点的组合。
13.一种治疗试剂盒,其包含:
a)根据第1点至第7点中任一点的缀合物、根据第10点的药物组合物或根据第11点的组合,
b)用于施用所述缀合物、组合物或组合的装置,及
c)使用说明书。
根据第三组实施方案,提供以下:
1.一种缀合物,包含
a)具有第一及第二亚基的异二聚IL-12蛋白,
b)单链双抗体,及
c)介于所述IL-12蛋白与所述单链双抗体之间的接头,所述接头包含含有GSADGGSSAGGSDAG(SEQ ID NO:4)的氨基酸基序。
2.根据第1点的缀合物,其中所述异二聚IL-12蛋白的第一亚基为p40且第二亚基为p35。
3.根据第1点至第2点中任一点的缀合物,其中所述单链双抗体是单特异性的或双特异性的。
4.根据第1点至第3点中任一点的缀合物,其中所述单链双抗体结合纤连蛋白的外结构域B(ED-B)。
5.根据第1点至第4点中任一点的缀合物,其中所述单链双抗体包含具有SEQ IDNO 28至33中所示的抗体L19的互补决定区(CDR)的抗原结合位点。
6.根据第1点至第5点的缀合物,其中所述单链双抗体包含SEQ ID NO 7及5中所示的抗体L19的VH及VL结构域。
7.根据第1点至第6点中任一点的缀合物,其中所述单链双抗体包含以下中的至少一个:
a)第6点的重链/轻链可变结构域序列对,其条件为所述结构域中的至少一个分别相对于SEQ ID NO 7或SEQ ID NO 5具有≥80%的序列相同性,和/或
b)第6点的重链/轻链可变结构域序列对,其条件为所述结构域中的至少一个分别相对于SEQ ID NO 7或SEQ ID NO 5具有最多10个氨基酸取代,
同时维持其结合至纤连蛋白的外结构域B(ED-B)的能力。
8.根据第1点至第7点中任一点的缀合物,其中所述单链双抗体中的至少一个氨基酸取代为保守氨基酸取代。
9.根据第1点至第8点中任一点的缀合物,其中所述单链双抗体
·相较于第5点或第6点的抗体之一,对纤连蛋白的外结构域B(ED-B)具有≥50%的靶结合亲和力,和/或
·与第5点或第6点的抗体之一竞争结合以结合至纤连蛋白的外结构域B(ED-B)。
10.根据第1点至第9点中任一点的缀合物,其中所述单链双抗体包含两个L19VH结构域及两个L19VL结构域。
11.根据第1点至第10点中任一点的缀合物,其具有全长结构[p40]-[接头1]-[p35]-[SAD接头]-[L19VH]-[接头3]-[L19VL]-[接头4]-[L19VH]-[接头3]-[L19VL]。
12.根据第1点至第11点中任一点的缀合物,其具有根据SEQ ID NO:16的全长序列。
13.根据前述点中任一点的缀合物在(制备)治疗人类或动物对象(的药物)中的用途,所述人类或动物对象
·诊断有发展赘生性疾病,
·患有发展赘生性疾病,或
·面临发展赘生性疾病风险,
或在(制备)预防这种状况(的药物)中的用途。
14.根据前述点中任一点的缀合物在(制备)用于抑制人类或动物对象中血管生成(的药物)中的用途。
15.一种药物组合物,其至少包含根据第1点至第12点中任一点的缀合物,及任选包含一或多种药学上可接受的赋形剂。
16.一种组合,其包含(i)根据第1点至第12点中任一点的缀合物或根据第15点的药物组合物,及(ii)一或多种治疗活性化合物。
17.一种用于治疗或预防与ED-B纤连蛋白表达或过表达相关的病症或状况的方法,其包含向有需要的对象施用有效量的根据第1点至第12点中任一点的缀合物、根据第15点的药物组合物或根据第16点的组合。
18.一种治疗试剂盒,其包含:
a)根据第1点至第12点中任一点的缀合物、根据第15点的药物组合物或根据第16点的组合,
b)用于施用所述缀合物、组合物或组合的装置,及
c)使用说明书。
根据本发明的另一实施方案,SAD接头包含氨基酸基序GSADGGSSAGGSDAG(SEQ IDNO:4)。如本文所用,术语“单链双抗体”是指具有短接头(优选5个氨基酸长)的两种单链Fv(scFv)抗体的构建体,所述构建体彼此通过更长接头(优选15个氨基酸长)根据以下方案(N→C方向)缀合:L19VH-接头3-L19VL-接头4-L19VH-接头3-L19VL。
根据本发明的一个实施方案,接头3为GSSGG(SEQ ID NO:6)且接头4为SSSSGSSSSGSSSSG(SEQ ID NO:8)。根据本发明的一个实施方案,异二聚IL-12蛋白中的第一亚基为p40且第二亚基为p35。优选地,所述两个亚基是通过指定接头、根据以下方案(N→C方向)彼此缀合:p40-接头1-p35。
优选地,IL-12为人类IL-12。在一个优选实施方案中,接头1为GGGGSGGGGSGGGGS(SEQ ID NO:2)。根据本发明的一个实施方案,所述单链双抗体是单特异性的或双特异性的。根据本发明的一个实施方案,所述单链双抗体结合纤连蛋白的剪接同种型。根据本发明的一个实施方案,所述单链双抗体结合纤连蛋白的外结构域B(ED-B)。
参考文献
Car et al.,Toxicologic Pathology(1999),27(1),58-63
Chen et al.,Adv Drug Deliv Rev.(2013),65(10),1357-1369
WO2013/014149
WO2006/119897
Tarli et al.,Blood(1999),94(1),192-198.
序列
以下序列形成本申请的公开内容的一部分。WIPO ST 25兼容性电子序列表也随本申请一起提供。为避免疑问,若下表中的序列与电子序列表之间存在差异,则此表中的序列应视为正确序列。
序列表
<110> 菲洛根股份公司
<120> 靶向EDB的IL-12组合物
<130> PD43169
<160> 36
<170> PatentIn version 3.5
<210> 1
<211> 306
<212> PRT
<213> Homo sapiens
<400> 1
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser
305
<210> 2
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 2
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 3
<211> 197
<212> PRT
<213> Homo sapiens
<400> 3
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser
180 185 190
Tyr Leu Asn Ala Ser
195
<210> 4
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 4
Gly Ser Ala Asp Gly Gly Ser Ser Ala Gly Gly Ser Asp Ala Gly
1 5 10 15
<210> 5
<211> 108
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (variable domain)
<400> 5
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 6
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 6
Gly Ser Ser Gly Gly
1 5
<210> 7
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (variable domain)
<400> 7
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 Phe
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr 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 Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 8
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 8
Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
1 5 10 15
<210> 9
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 9
Gly Gly Gly Ala Lys Gly Gly Gly Gly Lys Ala Gly Gly Gly Ser
1 5 10 15
<210> 10
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 10
Gly Gly Gly Gly Asp Gly Gly Gly Gly Asp Gly Gly Gly Gly Ser
1 5 10 15
<210> 11
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 11
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 12
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 12
Gly Gly Gly Gly Ser Gly Gly Gly Gly Glu Gly Gly Gly Gly Ser
1 5 10 15
<210> 13
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 13
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Ala
<210> 14
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 14
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10
<210> 15
<211> 14
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 15
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10
<210> 16
<211> 1006
<212> PRT
<213> artificial sequence
<220>
<223> Immunoconjugate sequence
<400> 16
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Ser Ala Asp Gly Gly Ser Ser Ala Gly
515 520 525
Gly Ser Asp Ala Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
545 550 555 560
Thr Phe Ser Ser Phe Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly
625 630 635 640
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ser Gly Gly Glu Ile
645 650 655
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
660 665 670
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu
675 680 685
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
690 695 700
Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
705 710 715 720
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
725 730 735
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr
740 745 750
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Ser Gly Ser
755 760 765
Ser Ser Ser Gly Ser Ser Ser Ser Gly Glu Val Gln Leu Leu Glu Ser
770 775 780
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
785 790 795 800
Ala Ser Gly Phe Thr Phe Ser Ser Phe Ser Met Ser Trp Val Arg Gln
805 810 815
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Ser
820 825 830
Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
835 840 845
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
850 855 860
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Phe Pro Tyr Phe
865 870 875 880
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ser
885 890 895
Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
900 905 910
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
915 920 925
Ser Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
930 935 940
Leu Leu Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg
945 950 955 960
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
965 970 975
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg
980 985 990
Ile Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
995 1000 1005
<210> 17
<211> 999
<212> PRT
<213> artificial sequence
<220>
<223> Immunoconjugate sequence
<400> 17
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Arg Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Arg Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Ser Ala Asp Gly Glu Val
515 520 525
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
530 535 540
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Ser Met
545 550 555 560
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
565 570 575
Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
580 585 590
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
595 600 605
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
610 615 620
Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
625 630 635 640
Ser Ser Gly Ser Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
645 650 655
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
660 665 670
Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro
675 680 685
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser Arg Ala Thr
690 695 700
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
705 710 715 720
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
725 730 735
Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
740 745 750
Glu Ile Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser
755 760 765
Ser Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
770 775 780
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
785 790 795 800
Ser Phe Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
805 810 815
Trp Val Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp
820 825 830
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
835 840 845
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
850 855 860
Tyr Cys Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
865 870 875 880
Leu Val Thr Val Ser Ser Gly Ser Ser Gly Gly Glu Ile Val Leu Thr
885 890 895
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
900 905 910
Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr
915 920 925
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser
930 935 940
Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
945 950 955 960
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
965 970 975
Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln
980 985 990
Gly Thr Lys Val Glu Ile Lys
995
<210> 18
<211> 45
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 18
Gly Gly Ala Gly Gly Gly Gly Gly Ala Gly Cys Thr Ala Ala Ala Gly
1 5 10 15
Gly Thr Gly Gly Cys Gly Gly Thr Gly Gly Cys Ala Ala Gly Gly Cys
20 25 30
Ala Gly Gly Gly Gly Gly Ala Gly Gly Gly Ala Gly Thr
35 40 45
<210> 19
<211> 42
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 19
gcaccagcac cagcaccagc accagcacca gcaccagcac ca 42
<210> 20
<211> 45
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 20
ggaggtgggg gtgatggtgg gggaggtgac ggcggaggtg ggtct 45
<210> 21
<211> 36
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 21
gcaccagcac cagcaccagc accagcacca gcacca 36
<210> 22
<211> 45
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 22
ggtggaggcg ggtcaggcgg agggggttct ggcggtggcg gatcg 45
<210> 23
<211> 45
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 23
ggtgggggtg ggtccggagg cggaggcgaa ggcggaggtg ggtcg 45
<210> 24
<211> 51
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 24
gcagaagcag cagcaaaaga agcagcagca aaagaagcag cagcaaaagc a 51
<210> 25
<211> 45
<212> DNA
<213> artificial sequence
<220>
<223> linker
<400> 25
gggtctgcag acggcggatc atcagctggg ggaagtgacg cagga 45
<210> 26
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> linker
<400> 26
Gly Ser Ala Asp Gly Gly
1 5
<210> 27
<211> 997
<212> PRT
<213> artificial sequence
<220>
<223> Immunoconjugate sequence
<400> 27
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Ser Ala Asp Gly Gly Glu Val Gln Leu
515 520 525
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
530 535 540
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Ser Met Ser Trp
545 550 555 560
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
565 570 575
Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
580 585 590
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
595 600 605
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Phe
610 615 620
Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
625 630 635 640
Gly Ser Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
645 650 655
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
660 665 670
Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
675 680 685
Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile
690 695 700
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
705 710 715 720
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
725 730 735
Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
740 745 750
Lys Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly
755 760 765
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
770 775 780
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
785 790 795 800
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
805 810 815
Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val
820 825 830
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
835 840 845
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
850 855 860
Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
865 870 875 880
Thr Val Ser Ser Gly Ser Ser Gly Gly Glu Ile Val Leu Thr Gln Ser
885 890 895
Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
900 905 910
Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln
915 920 925
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser Arg
930 935 940
Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
945 950 955 960
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
965 970 975
Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly Thr
980 985 990
Lys Val Glu Ile Lys
995
<210> 28
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (CDR)
<400> 28
Ser Phe Ser Met Ser
1 5
<210> 29
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (CDR)
<400> 29
Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 30
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (CDR)
<400> 30
Pro Phe Pro Tyr Phe Asp Tyr
1 5
<210> 31
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (CDR)
<400> 31
Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala
1 5 10
<210> 32
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (CDR)
<400> 32
Tyr Ala Ser Ser Arg Ala Thr
1 5
<210> 33
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> antibody sequence (CDR)
<400> 33
Gln Gln Thr Gly Arg Ile Pro Pro Thr
1 5
<210> 34
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> GGGGS linker
<400> 34
Gly Gly Gly Gly Ser
1 5
<210> 35
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> GGGGA linker
<400> 35
Gly Gly Gly Gly Ala
1 5
<210> 36
<211> 229
<212> PRT
<213> artificial sequence
<220>
<223> L19 Diabody
<400> 36
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 Phe
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr 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 Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Ser Ser Gly Gly Glu Ile Val Leu Thr Gln Ser
115 120 125
Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
130 135 140
Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln
145 150 155 160
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Ser Arg
165 170 175
Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
180 185 190
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
195 200 205
Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr Phe Gly Gln Gly Thr
210 215 220
Lys Val Glu Ile Lys
225
Claims (46)
1.一种组合物,其包含
a.包含第一IL-12亚基及第二IL-12蛋白亚基的IL-12蛋白;
b.包含EDB结合结构域的肽或蛋白质;及
c.介于所述IL-12蛋白与所述包含EDB结合结构域的肽或蛋白质之间的接头。
2.权利要求1的组合物,其中所述介于所述IL-12蛋白与所述包含EDB结合结构域的肽或蛋白质之间的接头包含GSADGGSSAGGSDAG(SEQ ID NO:4)。
3.权利要求1或2的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含scFv。
4.权利要求1或2的组合物,其中所述包含EDB结合结构域的肽或蛋白质是双抗体。
5.权利要求1或2的组合物,其中所述包含EDB结合结构域的肽或蛋白质是单链双抗体。
6.权利要求1至5中任一项的组合物,其中所述IL-12蛋白的所述第一亚基为p40且所述第二亚基为p35。
7.权利要求1至6的组合物,其中所述IL-12蛋白的所述第一亚基为包含与SEQ ID NO:1中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列的p40或其片段,其中所述IL-12蛋白可以活化IL-12受体。
8.权利要求1至7的组合物,其中所述IL-12蛋白的所述第二亚基为包含与SEQ ID NO:3中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列的p35或其片段,其中所述IL-12蛋白可以活化IL-12受体。
9.权利要求1至8中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质是单特异性的或双特异性的。
10.权利要求1至9中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质结合纤连蛋白的外结构域B(ED-B)。
11.权利要求1至10中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含与SEQ ID NO:28至33中所示的氨基酸序列中的一或多个具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
12.权利要求1至10中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含SEQ ID NO:28至33的氨基酸序列中的每一个。
13.权利要求1至12中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含与SEQ ID NO:7及5中所示的氨基酸序列中的一或多个具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
14.权利要求1至13中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含SEQ ID NO:7及5中所示的氨基酸序列中的每一个。
15.权利要求1至14中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含以下中的至少一个:
a)权利要求14的序列对,其条件为所述结构域中的至少一个相对于SEQ ID NO:7或SEQID NO:5分别具有≥80%的序列相同性,和/或
b)权利要求14的序列对,其条件为所述结构域中的至少一个相对于SEQ ID NO:7或SEQID NO:5分别具有最多10个氨基酸取代,
同时维持其结合至所述纤连蛋白的外结构域B(ED-B)的能力。
16.权利要求15的组合物,其中至少一个氨基酸取代为保守氨基酸取代。
17.权利要求1至16中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质
·相较于权利要求11至16的所述包含EDB结合结构域的肽或蛋白质之一,对所述纤连蛋白的外结构域B(ED-B)具有≥50%的靶结合亲和力,和/或
·与权利要求11至16的所述包含EDB结合结构域的肽或蛋白质之一竞争结合至所述纤连蛋白的外结构域B(ED-B)。
18.权利要求1至17中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含两个L19 VH结构域及两个L19 VL结构域。
19.权利要求18的组合物,其中:
·所述两个L19 VH结构域具有相同的氨基酸序列;
·所述两个L19 VH结构域具有不同的氨基酸序列;
·所述两个L19 VL结构域具有相同的氨基酸序列;或
·所述两个L19 VL结构域具有不同的氨基酸序列。
20.权利要求1至17中任一项的组合物,其中所述包含EDB结合结构域的肽或蛋白质包含一个L19 VH结构域及一个L19 VL结构域。
21.权利要求1至17中任一项的组合物,其中所述组合物包含:
·p40结构域,其通过第一接头连接至p35结构域;
·第一L19 VH结构域,其通过SAD接头连接至所述p35结构域;
·第一L19 VL结构域,其通过第三接头连接至所述第一L19 VH结构域;
·第二L19 VH结构域,其通过第四接头连接至所述第一L19 VL结构域;
·第二L19 VL结构域,其通过第五接头连接至所述第二L19 VH结构域。
22.权利要求21的组合物,其中所述p40结构域包含与SEQ ID NO:1中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列或其片段。
23.权利要求21至22中任一项的组合物,其中所述p35结构域包含与SEQ ID NO:3中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列或其片段。
24.权利要求21至23中任一项的组合物,其中所述第一接头为GS接头。
25.权利要求21至24中任一项的组合物,其中所述第一接头包含与SEQ ID NO:2中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
26.权利要求21至25中任一项的组合物,其中所述第一L19 VH结构域、所述第二L19 VH结构域或两者均包含与SEQ ID NO:28至30中所示的至少一个氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
27.权利要求21至26中任一项的组合物,其中所述第一L19 VL结构域、所述第二L19 VL结构域或两者均包含与SEQ ID NO:31至33中所示的至少一个氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
28.权利要求21至27中任一项的组合物,其中所述第一L19 VH结构域、所述第二L19 VH结构域或两者均包含与SEQ ID NO:7中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
29.权利要求21至27中任一项的组合物,其中所述第一L19 VL结构域、所述第二L19 VL结构域或两者均包含与SEQ ID NO:5中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
30.权利要求21至29中任一项的组合物,其中所述SAD接头包含与SEQ ID NO:4中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
31.权利要求21至30中任一项的组合物,其中所述第三接头为GS接头。
32.权利要求21至31中任一项的组合物,其中所述第三接头包含与SEQ ID NO:6中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
33.权利要求21至32中任一项的组合物,其中所述第五接头为GS接头。
34.权利要求21至33中任一项的组合物,其中所述第三接头包含与SEQ ID NO:6中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
35.权利要求21至34中任一项的组合物,其中所述第三接头及第五接头包含相同的氨基酸序列。
36.权利要求21至35中任一项的组合物,其中所述第四接头为GS接头。
37.权利要求21至36中任一项的组合物,其中所述第四接头包含与SEQ ID NO:8中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
38.权利要求1至37中任一项的组合物,其中所述组合物包含与SEQ ID NO:16中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列。
39.权利要求1至38中任一项的组合物,其中所述组合物由与SEQ ID NO:16中所示的氨基酸序列具有至少75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性的氨基酸序列组成。
40.权利要求1至39中任一项的组合物在(制备)治疗人类或动物对象(的药物)中的用途,所述人类或动物对象
·诊断有发展赘生性疾病,
·患有发展赘生性疾病,或
·面临发展赘生性疾病风险,
或在(制备)预防这种状况(的药物)中的用途。
41.权利要求40的用途,其中所述赘生性疾病选自恶性黑素瘤、非小细胞肺癌(NSCLC)、肾细胞癌、尿路上皮癌、头颈部鳞状细胞癌(HNSCC)、微卫星高不稳定性(MSI-H)或错配修复缺陷(dMMR)转移性结直肠癌、肝细胞癌、胃癌、皮肤鳞状细胞癌、子***及弥漫性大B细胞淋巴瘤(DLBCL)。
42.权利要求1至39中任一项的组合物在(制备)用于抑制人类或动物对象中血管生成(的药物)中的用途。
43.一种药物组合物,其包含权利要求1至39中任一项的组合物,及任选包含一或多种药学上可接受的赋形剂。
44.一种组合,其包含(i)权利要求1至39中任一项的组合物或权利要求43的药物组合物,及(ii)一或多种治疗活性化合物。
45.一种用于治疗或预防与ED-B纤连蛋白表达或过表达相关的病症或状况的方法,其包含向有需要的对象施用有效量的权利要求1至39中任一项的组合物、权利要求43的药物组合物或权利要求44的组合。
46.一种治疗试剂盒,其包含:
a)权利要求1至39中任一项的组合物、权利要求43的药物组合物或权利要求44的组合,
b)用于施用所述组合物、组合物或组合的装置,及
c)使用说明书。
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PCT/EP2019/053136 WO2019154986A1 (en) | 2018-02-09 | 2019-02-08 | Edb targeting il-12 compositions |
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CN112771071A (zh) * | 2018-09-28 | 2021-05-07 | 麻省理工学院 | 胶原蛋白定位的免疫调节分子及其方法 |
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KR102524247B1 (ko) * | 2018-12-21 | 2023-04-21 | 가톨릭대학교 산학협력단 | p40-EBI3의 복합체 및 이의 용도 |
WO2021050789A1 (en) | 2019-09-10 | 2021-03-18 | Obsidian Therapeutics, Inc. | Ca2-il15 fusion proteins for tunable regulation |
JP7438396B2 (ja) * | 2020-04-14 | 2024-02-26 | フィロジェン ソチエタ ペル アツィオーニ | インターロイキン-12とフィブロネクチンのエクストラドメインbに結合する抗体とを含む組換えタンパク質を含む組成物の投与単位およびレジメン、使用、方法または製剤 |
KR102649794B1 (ko) * | 2020-10-19 | 2024-03-22 | 고려대학교 산학협력단 | 암 및/또는 뇌질환 바이오마커인 엑스트라-도메인 b 파이브로넥틴 및 이를 이용한 진단 방법 |
CA3242326A1 (en) * | 2022-01-04 | 2023-07-13 | Cipo | Combination of an immunocytokine comprising il-12 and a kinase inhibitor |
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UY38074A (es) | 2019-10-01 |
CO2020009737A2 (es) | 2020-08-21 |
CA3087488C (en) | 2021-11-02 |
AU2019219201A1 (en) | 2020-07-23 |
KR102259085B1 (ko) | 2021-06-03 |
AU2021203986A1 (en) | 2021-07-08 |
ECSP20047171A (es) | 2020-09-30 |
MX2020008231A (es) | 2020-09-25 |
JP2023113648A (ja) | 2023-08-16 |
AU2019219201B2 (en) | 2021-07-08 |
TW201934136A (zh) | 2019-09-01 |
PH12020551230A1 (en) | 2021-05-17 |
PE20210122A1 (es) | 2021-01-19 |
JP2021513536A (ja) | 2021-05-27 |
CR20200342A (es) | 2020-10-19 |
WO2019154986A1 (en) | 2019-08-15 |
CA3087488A1 (en) | 2019-08-15 |
IL275713A (en) | 2020-08-31 |
JOP20200193A1 (ar) | 2020-08-06 |
KR20200109380A (ko) | 2020-09-22 |
EP3749372A1 (en) | 2020-12-16 |
CU20200054A7 (es) | 2021-05-12 |
RU2021130306A (ru) | 2021-11-10 |
KR20210063467A (ko) | 2021-06-01 |
KR102488801B1 (ko) | 2023-01-13 |
JP7279054B2 (ja) | 2023-05-22 |
SG11202006334XA (en) | 2020-08-28 |
RU2758143C1 (ru) | 2021-10-26 |
US20200397915A1 (en) | 2020-12-24 |
BR112020012888A2 (pt) | 2020-12-08 |
CL2020002052A1 (es) | 2021-01-04 |
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