CN107438624A - 人干扰素‑β变体缀合免疫细胞因子及其制备方法 - Google Patents
人干扰素‑β变体缀合免疫细胞因子及其制备方法 Download PDFInfo
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- CN107438624A CN107438624A CN201680015754.1A CN201680015754A CN107438624A CN 107438624 A CN107438624 A CN 107438624A CN 201680015754 A CN201680015754 A CN 201680015754A CN 107438624 A CN107438624 A CN 107438624A
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Abstract
本发明涉及具有人干扰素‑β变体缀合抗体或其片段的免疫细胞因子,和其制作方法。根据本发明,与天然干扰素‑β相比,人干扰素‑β变体具备更优越的活性或功能,并且此免疫细胞因子的生产率非常可观。此外,根据发明,此免疫细胞因子可以用作多发性硬化症或癌症的靶向治疗剂,因为该免疫细胞因子同时表现出了干扰素‑β的功能和绑定到特异性抗原的抗体的特征。
Description
技术领域
本发明涉及一种含有人干扰素-β变体的免疫细胞因子及其制备方法,更具体地说,涉及一种包含干扰素-β变体缀合抗体的免疫细胞因子以及其制备方法,该干扰素-β变体具有优于天然干扰素-β的活性和功能。
背景技术
本申请要求于2015年3月3日提交的韩国专利申请KR10-2015-0030037的优先权和权益,出于所有目的,该专利被引入本文作参考,即如在此充分阐述的一样。
在药物中,基于调节免疫***以达到预防以及/或治疗目的的概念,免疫疗法代表若干治疗策略。
多年来,免疫疗法被用来治疗或预防各种病理状况。自细胞融合技术被开发生产单株抗体以来,研究人员已经生产了大量的单株抗体。此后,其他技术,包括用于生产人单株抗体的B细胞杂交瘤技术和EBV杂交瘤技术,已经被用来研制单株抗体的生产。
单株抗体(mAb)可用来靶向几乎所有的抗原表位。它们对特定细胞/分子的特异性识别和缀合属性促进了mAbs作为对各种疾病状况的诊断和治疗试剂的发展。DNA重组技术已经被用于生产施用于人类的嵌合或人源化抗体。目前,数种单株抗体已经实现商用并被用来治疗癌症、传染性疾病、免疫疾病等,其中商用的例子包括利妥昔单抗、赫赛汀、阿瓦斯丁等。
单株抗体是靶向分子,并且可位于特定区域(细胞、组织等),例如病理组织。为了在特定病理组织站点靶向特定的分子,这一特征也带来了与各种物质(有效负载物)缀合的mAbs的发展。这些物质(有效负载物)可包括毒素、药物、放射性核素、药物前体等等。许多这样的缀合涉及活性部分(有效负载物)的化学缀合,以及抗体和冗余物(美国专利US4,671,958)的特定生产,这是一个易变的过程。
在这些新分子中,免疫细胞因子有着特别的意义。免疫细胞因子是指含有抗体和细胞因子的融合蛋白,这种蛋白质同时保留抗原结合能力和细胞因子活性。
细胞因子是一种信号蛋白和糖蛋白,就像激素和神经递质一样,广泛用于细胞通讯。虽然特定器官分泌激素到血液中、神经递质与神经活动相关,但就起源和用途而言,细胞因子是一种更多样化的化合物。它们是由各种造血细胞和非造血细胞类型产生,并可以对附近细胞或整个生物体产生影响,且有时高度依赖于其它化学物质的存在。细胞因子家族主要由具有原子质量为8-30kDa的较小的水溶性蛋白质和糖蛋白组成。细胞因子在自然和适应性免疫反应的功能化方面非常重要。细胞因子通常是由与病原体接触的免疫细胞分泌的,从而激活和招募更多的免疫细胞并增加对病原体的***反应。
在细胞因子中,干扰素(IFNs)是一种细胞因子且表现出抗病毒活性、抑制细胞增殖和调节天然免疫反应的功能。其中,干扰素-β(IFN-β)是一种具备五个α-螺旋的球形蛋白,其大小为22kD,当其聚糖被除去时为18kD(Arduini et al.,Protein Science 8:pp1867-1877,1999)。
对于IFN-β临床应用的研究正在积极地进行着,特别是IFN-β作为改善、缓解或治疗多发性硬化症状的药物而受到关注(Goodkin et al.,Multiple sclerosis:Treatmentoptions for patients with relapsing-remitting and secondary progressivemultiple sclerosis,1999)。
据报道,除了多发性硬化症外,IFN-β还显示出多种免疫活性,如抗病毒活性、抑制细胞生长或抗生长活性、淋巴细胞毒性-上升活性、免疫调节活性、靶细胞分化诱导或抑制活性、巨噬细胞活化活性、细胞因子产生上升活性、细胞毒性T细胞效应上升活性和自然杀伤细胞上升活性,因此,IFN-β在治疗癌症、自身免疫疾病、病毒感染、HIV相关疾病,丙型肝炎,类风湿性关节炎等等是有效的(Pilling et al.,European Journal of Immunology29:pp 1041-1050,1999;Young et al.,Neurology 51:pp 682-689,1998;and Cirelli etal.,1995 Major therapeutic uses of interferons.Clin Immunother 3:pp 27-87)。
人干扰素-β也是一种糖蛋白,与此种蛋白相连接的聚糖部分在蛋白质的活性中起重要作用。因此,当将聚糖加入糖蛋白时,糖蛋白的活性可能上升。
鉴于上述观点,韩国专利KR10-0781666公开了一种具有增强或改善活性或功能的人干扰素-β变体,其通过将聚糖引入作为糖蛋白的天然人干扰素-β中。
因此,有必要去开发免疫细胞因子,在所述细胞因子中,为了在靶向治疗中使用表现效果优于天然干扰素-β药效的人干扰素-β变体,人干扰素-β需与抗体缀合。此外,还需要一种以高产率获得这种免疫细胞因子的制备方法。
发明内容
本发明技术问题的详细描述
本发明者发明了一种免疫细胞因子,在该免疫细胞因子中,人干扰素-β变体缀合至抗体,所述人干扰素-β变体通过将聚糖引入天然人干扰素-β而使活性得以增强或改善,并发现,与天然干扰素-β缀合至抗体的免疫细胞因子相比,宿主细胞中的此种免疫细胞因子的表达水平显著增加,从而(令发明者)完成了本发明。
因此,本发明的一个方面是提供一种免疫细胞因子,其包括:(a)人干扰素-β变体;和(b)直接或间接与人干扰素-β变体共价连接的抗体或其片段,其中人干扰素-β变体是选自下面(i)、(ii)和(iii)中的一种多肽,((i)包含在SEQ ID NO:1中公开的所有氨基酸序列的多肽;(ii)包含SEQ ID NO:1中公开的氨基酸序列的实质部分的多肽;以及(iii)基本上和(a)或(b)中多肽类似的多肽),并且该多肽具有人干扰素-β活性,所述多肽包含N-连接糖链。
本发明的另一方面是提供一种编码免疫细胞因子的多核苷酸。
本发明的另一方面是提供一种提高靶特异性人干扰素-β产率的方法,该方法包括:
(a)将多核苷酸克隆到表达载体中,所述多核苷酸编码一种包括人干扰素-β变体,(b)肽接头,以及(c)抗体或其片段的融合多肽;
(b)将表达载体克隆到宿主细胞中;
(c)培养宿主细胞;以及
(d)从细胞或培养基中收集融合多肽,
其中所述人干扰素-β变体包含选自SEQ ID NO:2至SEQ ID NO:4的肽序列。
本发明的另一方面是提供一种包含多核苷酸的载体。
本发明的另一方面是提供一种载体转染的宿主细胞。
本发明的另一方面还提供一种制备免疫细胞因子的方法,该方法包括:(a)提供宿主细胞;(b)培养提供的细胞;以及(c)通过从细胞或培养基中收集免疫细胞因子来制备此种免疫细胞因子。
技术方案
根据本发明的一个方面,提供一种免疫细胞因子,其包括:(a)人干扰素-β变体;以及(b)直接或间接与人干扰素-β变体共价连接的抗体或其片段,其中人干扰素-β变体是选自下面(i)、(ii)和(iii)中的一种多肽,(i)包含SEQ ID NO:1中公开的所有氨基酸序列的多肽;(ii)包含SEQ ID NO:1中公开的氨基酸序列的实质部分的多肽;以及(iii)包含基本上与(a)或(b)中的多肽相似的多肽,并且该多肽具有人干扰素-β活性,所述多肽包含N-连接糖链。
根据本发明的另一方面,还提供一种提高靶特异性人干扰素-β产率的方法,该方法包括:
(a)将多核苷酸克隆到表达载体中,所述多核苷酸编码一种包括人干扰素-β变体,连接肽,抗体或其片段的融合多肽;
(b)将表达载体克隆到宿主细胞中;
(c)培养宿主细胞;以及
(d)从细胞或培养基中收集融合多肽,
其中所述人干扰素-β变体包含选自SEQ ID NO:2至SEQ ID NO:4中的肽序列。
根据本发明的另一方面,还提供一种编码免疫细胞因子的多核苷酸。
根据本发明的另一方面,还提供一种包含多核苷酸的载体。
根据本发明的另一方面,还提供一种由载体转染的宿主细胞。
根据本发明的其他方面,还提供一种制备免疫细胞因子的方法,该方法包括:(a)提供宿主细胞;(b)培养提供的细胞;以及(c)通过从细胞或培养基中收集免疫细胞因子来制备该种免疫细胞因子。
下文将对本发明进行详细描述。
细胞因子的治疗潜力经常受其严重副反应的限制,这种副反应甚至在其浓度低的情况下也会发生,因此,靶向组织中不存在足够浓度的细胞因子。所以,为了提高细胞因子的治疗潜力并保护正常组织免受其毒性影响,通过免疫细胞因子可以实现使用抗体的细胞因子的靶向及靶向细胞因子至疾病部位的传递。
根据本发明,免疫细胞因子是一种具有增强或改善活性或功能的人干扰素-β变体的细胞因子,所述人干扰素-β变体通过将聚糖引入天然干扰素-β而获得。本发明者基于以下事实完成了本发明:当免疫细胞因子以人干扰素-β与抗体缀合的形式被用以多发性硬化症、病毒性疾病等的靶向治疗时,与天然干扰素-β与抗体缀合的免疫细胞因子相比,此种免疫细胞因子可能会显示出优良的治疗效果。
因而,本发明提供的免疫细胞因子包括:(a)人干扰素-β变体;和(b)直接或间接与人干扰素-β变体共价连接的抗体或其片段,其中人干扰素-β变体是选自下面(i)、(ii)和(iii)中的一种多肽,(i)包含SEQ ID NO:1中公开的所有氨基酸序列的多肽;(ii)包含SEQID NO:1中公开的氨基酸序列的实质部分的多肽;以及(iii)包含基本上与(a)或(b)中的多肽类似的多肽,并且该多肽具有人干扰素-β活性,所述多肽包含N-连接糖链。
与天然人干扰素-β相比,拥有增强或改进的活性或功能的人干扰素-β变体的特征在于,天然人干扰素-β或天然人干扰素-β变体在其氨基酸序列C端含有甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸序列,并在所添加的序列的天冬酰胺残基处含有N-链接糖链。
如在此所使用的,术语“天然人干扰素-β变体”意指包括保留人干扰素-β活性同时具有所有或部分源于天然人干扰素-β的氨基酸序列的所有多肽。
在本文中,术语“人干扰素-β活性”的定义是,在已知保留的人干扰素-β活性中,足以使任何多肽被鉴定为人干扰素-β的一种或多种活性。如上文所述,此种活性的例子可包括缓解、改善或治疗多发性硬化症活性、抗病毒活性、抑制细胞增殖活性、抗生长活性、抗增殖活性、淋巴细胞病毒性-上升活性、免疫调节活性、靶细胞分化诱导或抑制活性、细胞因子产生上升活性、细胞毒性T细胞效果增强活性、巨噬细胞效果增强活性、自然杀伤细胞上升活性、癌症预防或治疗活性、自身免疫疾病预防或治疗活性、病毒感染预防或治疗活性、与HIV相关的疾病预防或治疗活性,丙型肝炎预防或治疗活性,类风湿性关节炎预防或治疗活性等。
在本文中,术语“包含所有或部分来源于天然人干扰素-β氨基酸序列的多肽”的定义是,包括由SEQ ID NO:1中所有或实质部分的氨基酸序列组成的多肽,其为一种天然人干扰素-β的氨基酸序列,或与该多肽基本相似的多肽。
这里,术语“包括SEQ ID NO:1中所有氨基酸序列的实质部分的多肽”意指由SEQID NO:1中部分氨基酸序列组成的多肽,该多肽活性等同于或高于具有SEQ ID NO:1氨基酸序列的天然人干扰素-β的活性,或仍然保留了人干扰素-β活性,尽管其活性很低。此外,术语“与SEQ ID NO:1氨基酸序列中所有或实质部分基本相似的多肽”定义为由SEQ ID NO:1氨基酸序列所有或实质部分组成的多肽,该多肽活性等同于或高于具有SEQ ID NO:1氨基酸序列的天然人干扰素-β的活性,或仍然保留了人干扰素-β活性,尽管其活性很低。
由SEQ ID NO:1所有氨基酸序列的实质部分组成的多肽可能是一种缺失N端区域以及/或C端区域、包含SEQ ID NO:1氨基酸序列的多肽。与SEQ ID NO:1氨基酸序列所有或实质部分基本类似的多肽可能是一种氨基酸在被取代之前在化学上等同于被取代的氨基酸的多肽,即使至少一种氨基酸被取代,例如,作为疏水性氨基酸的丙氨酸被另外的疏水性氨基酸取代,特别是更疏水的氨基酸,例如缬氨酸,亮氨酸或异亮氨酸。
在一些情况下,N端区域和C端区域缺失、包含被取代的氨基酸的多肽可能无法显示出人干扰素-β的活性,因N端区域、C端区域或被取代的氨基酸涉及人干扰素-β活性中的必需基序。然而,通过验证上述源于SEQ ID NO:1的多肽是否具有一种或多种如上所述的活性,以及/或通过与在本发明申请时本领域内已知的人干扰素-β的鉴定相关的方法,从活性肽中区分和检测此类非活性肽属于本领域中普通技术人员的理解范围内。
因此,根据本发明,人干扰素-β变体可以定义为以下保留人干扰素-β活性同时在C端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸和在此位置处包含N-连接糖链的肽类之一,或定义为一种在野生型干扰素-β氨基酸残基的第27位中,精氨酸(R27)被苏氨酸(R27T)或丝氨酸(R27S)转变的多肽之一:
(a)一种包含在SEQ ID NO:1公开的所有氨基酸序列的多肽;
(b)一种包含在SEQ ID NO:1公开的氨基酸序列的实质部分的多肽;
(c)一种基本上与(a)或(b)中的多肽相似的多肽。更优选地,人干扰素-β变体指包括SEQ ID NO:2至SEQ ID NO:4中的任一氨基酸序列的多肽。
因此,根据本发明,我们应该认识到,人干扰素-β变体包括所有保留人干扰素-β活性同时在C端含有甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸序列以及N-连接糖链的多肽。
如上所述,根据本发明,人干扰素-β变体包括所有保留人干扰素-β活性同时在C端含有甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸序列以及含有N连接糖链的多肽。
更优选地,本发明的“人干扰素-β变体”可能是具有SEQ ID NO:2至SEQ ID NO:4中的任一氨基酸序列的干扰素-β突变蛋白,并且已被本发明者命名为“Carbiferon”。本发明中的“Carbiferon”是将一种或两种聚糖添加到天然干扰素-β中的类型。更优选地,根据本发明,“Carbiferon”是一种在具有SEQ ID NO:1氨基酸序列的人干扰素-β中,第27位氨基酸精氨酸(R)被取代为苏氨酸(T)或丝氨酸(S)的多肽,或一种在天然人干扰素-β的C端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列并在该位置含有N-连接糖链的多肽。
与天然人干扰素-β相比,人干扰素-β变体显示出改进或增强的抗病毒活性、抑制细胞生长活性、免疫调节功能和体内半衰期。
SEQ ID NO:2是干扰素-β变体R27T的氨基酸序列,SEQ ID NO:3是干扰素-β变体R27S的氨基酸序列--在SEQ ID NO:1中第27位氨基酸被取代为S。另外,SEQ ID NO:4是干扰素-β变体GNITV的氨基酸序列,其中继终止密码子之后含有GNITV氨基酸。SEQ ID NO:1至4在N端包含起始密码子,并且当SEQ ID NO:1至4的蛋白质被连接至其他接头(接头C端被连接至Carbiferon的N端)时,起始密码子可省略。也就是说,SEQ ID NO:1至4蛋白质的起始密码子的核苷酸序列ATG或氨基酸序列甲硫氨酸可以省略。
同时,韩国专利KR 10-0781666详细描述了“人干扰素-β变体”。
如本文所用,抗体可能会不尽相同,且包括单株抗体、多株抗体、多特性抗体(如双特异性抗体)以及抗体片段(只要它们表现出所需的抗原结合活性),同时包括各种抗体结构,但不限于此。天然抗体是具有各种结构的分子。例如,天然IgG抗体是约150,000道尔顿的异四聚体糖蛋白,由二硫键连接的两条相同的轻链(L)和两条相同的重链(H)组成。从N端至C端,每条重链具有可变区(VH),也可称为可变重链结构域或重链可变域,随后是铰链区(HR)和三个恒定结构域(CH1,CH2和CH3,可选的CH4)。类似地,从N端到C端,每条轻链具有可变区(VL),也称为可变轻链结构域或轻链可变域,随后是恒定轻链(CL)结构域。基于其恒定结构域的氨基酸序列,抗体的轻链可以分配至称为k和λ的两种类型之一。
本发明的抗体可能是人抗体、嵌合抗体和/或人源化抗体,但不限于此。
嵌合抗体包括由鼠免疫球蛋白的可变区和人免疫球蛋白的恒定区构成的抗体。简单配置此类变化可使鼠抗体的恒定区为人抗体的恒定区所替代,从而产生具有足够低的免疫原性的人/鼠嵌合体以实现其药物用途。
术语“人源化抗体”是指,通过修改具有非人互补决定区(CDR)抗体的序列,(全部或部分)由源自人抗体种系的氨基酸序列组成的抗体。抗体可变区和CDR的人源化可通过本领域已知的技术进行操作。Fc依赖性效应子功能效应需要此类抗体,但保留了人恒定区,这明显不太可能诱导对抗体的免疫应答。例如,可变区的框架区域被相应的、令非人CDR基本上保持完整的人框架区域所取代,或甚至用源自人类基因组(可参考美国专利申请US2006/25885)的序列取代CDR。完全人源性抗体在转基因小鼠中产生,转基因小鼠的免疫***已经被改变以对应于人免疫***。人源化抗体也指包含人框架、至少来自非人抗体的一种CDR的抗体,其中存在的任何恒定区基本上与人免疫球蛋白恒定区完全相同,如至少约85%或90%甚至95%相同。因此,所有人源化抗体(可能的CDR除外)基本上与至少一种天然人免疫球蛋白的相应部分相同。
本文所用的术语“抗体片段”是指能够对同一抗原做出反应作为其抗体对应物的抗体片段。此类抗体片段可以被领域内的专业人士简单鉴定出来,并且,例如,其可能包括Fab片段(如通过木瓜蛋白霉消化得到)、Fab'片段(如通过胃蛋白酶消化和部分还原得到)、F(ab')2片段(如通过胃蛋白酶消化得到)、Facb片段(如通过纤溶酶消化得到)、Fd(如通过胃蛋白酶消化,部分还原和重聚集得到)、scFv(单链Fv;如通过分子生物学技术得到)片段。通过本领域中已知和/或本文描述的酶裂解、合成或重组技术可制备这些片段。
本发明证实,通过诱导细胞毒性和pSTAT酸化,具有人干扰素-β变体的免疫细胞因子显示出干扰素-β活性,这在抗体自身内无法显示出来(参见例3和例4)。
本发明提供一种免疫细胞因子,其特点在于它的抗体或其片段是一种针对选自肿瘤抗原和多发性硬化特异性抗原的抗体或片段。
肿瘤生长到预定尺寸或更大时需要形成新的血管,以进一步生长或转移到其他部位。因此,参与新血管形成的分子和信号***可能在抗癌治疗中是重要的治疗靶标。同时,据说干扰素-β已经通过抑制肿瘤细胞的生成抑制了肿瘤细胞的生长。另外,干扰素-β可能会通过在肿瘤部位周围环境诱导先天或获得性免疫应答而诱导肿瘤细胞死亡来表现出抗癌作用。
因此,依照本发明,与天然干扰素-β相比,人干扰素-β变体的活性和功能有所改善,所以当用于癌症病人的靶向治疗时,较天然干扰素-β与抗体缀合的免疫细胞因子相比,以人干扰素-β变体与专门识别肿瘤抗原的抗体缀合形式的免疫细胞因子将显示出更优异的治疗效果。
肿瘤抗原是由诱导免疫应答尤其是T细胞介导免疫应答的肿瘤细胞产生的蛋白质。肿瘤抗原在本领域中为人熟知,它的例子包括神经胶质瘤相关抗原、癌胚抗原(CEA)、β-人绒毛膜***、甲胎蛋白(AFP)、凝集素反应性AFP、甲状腺球蛋白、RAGE-1、MN-CAIX、人端粒酶逆转录酶、RU1、RU2(AS)、肠羧酸酯酶、mut hsp 70-2、MCSF、***素、***特异性抗原(PSA)、PAP、NY-ESO-1、LAGE-1α、p53、prostein、PSMA、Her2/neu、survivin和端粒酶、***癌肿瘤抗原-1(PCTA-1)、MAGE、ELF2M、嗜中性粒细胞弹性蛋白酶、ephrin-B2、CD22、胰岛素生长因子(IGF)-I、IGF-II,IGF-1受体或间皮素。
本文特指的肿瘤抗原类型可能是肿瘤特异性抗原(TSA)或肿瘤相关抗原(TAA)。TSA是肿瘤细胞独有,不存在体内其他细胞内。TAA则非肿瘤细胞独有,在正常细胞不能诱导对抗原的免疫耐受性的情况下,它也表达在正常细胞中。在免疫***对抗原做出反应的条件下,抗原对肿瘤可能发生表达。当免疫***不成熟且无法应答时,TAA可能是在胎儿发育期间在正常细胞上表达的抗原,或可能是在正常细胞上通常以极低的水平存在的抗原,但以更高的水平表达在肿瘤细胞上。
TSA或TAA的非限制性例子包括:分化抗原,如MART-1/MelanA(MART-1),gp1OO(Pmel 17),酪氨酸酶,TRP-1,和TRP-2;肿瘤特异性多谱系抗原,如MAGE-1,MAGE-3,BAGE,GAGE-1,GAGE-2和p15;过度表达的胚胎抗原,如CEA;过度表达的致癌基因和突变的肿瘤抑制基因,如p53,Ras,HER-2/neu;染色体易位产生的特有肿瘤抗原,诸如BCR-ABL,E2A-PRL,H4-RET,IGH-IGK,MYL-RAR;和病毒抗原,诸如爱泼斯坦巴尔病毒抗原EBVA和人***瘤病毒(HPV)抗原E6和E7。其他大的、基于蛋白的抗原包括TSP-180、MAGE-4、MAGE-5、MAGE-6、RAGE、NY-ESO、p185erbB2、p180erbB-3、c-met、nm-23H1、PSA、TAG-72、CA 19-9、CA 72-4、CAM17.1、NuMa、K-ras、β-联蛋白、CDK4、Mum-1、p 15、p 16、43-9F、5T4、791Tgp72、α-胎蛋白、β-HCG、BCA225、BTAA、CA 125、CA 15-3/CA 27.29/BCAA、CA 195、CA 242、CA-50、CAM43、CD68/P1、CO-029、FGF-5、G250、Ga733/EpCAM、HTgp-175、M344、MA-50、MG7-Ag、MOV 18、NB/70K、NY-CO-1、RCAS1、SDCCAG16、TA-90/Mac-2结合蛋白/亲环蛋白C相关蛋白、TAAL6、TAG72、TLP和TPS。
专门识别肿瘤抗原的抗体包括,例如HuM195(参见例如Kossman et.al,(1999)Clin.Cancer Res.5:2748-2755),CMA-676(Sievers et.al,(1999)Blood 93:3678-3684),AT13/5(参见例如Ellis et.al,(1995)J.Immunol.155:925-937),HB7,曲妥珠单抗(参见例如赫赛汀;Fornier et.al.,(1999)Oncology(Huntingt)13:647-58),TAB-250(Rosenblumet.al.,(1999)Clin.Cancer Res.5:865-874),BACH-250(Id.),TA1(Maier et.al.,(1991)CancerRes.51:5361-5369),美国专利US5772997和US5770195(mAb 4D5;ATCC CRL10463)中公开的mAb;和美国专利US5677171中公开的mAb;Mc5(参见例如Peterson et.al.,(1997)Cancer Res.57:1103-1108;Ozzello et.al.,(1993)Breast Cancer Res.Treat.25:265-276),hCTMO1(参见例如Van YM et.al.,(1996)Cancer Res.56:5179-5185)CC49(参见例如Pavlinkova et.al.,(1999)Clin.Cancer Res.5:2613-2619),B72.3(参见例如,Divgiet.al.,(1994)Nucl.Med.Biol.21:9-15),鼠源单克隆抗HM1.24IgG2a/κ,人源化抗HM1.24IgG1/κ抗体(参见,例如Ono et.al.,(1999)Mol.Immuno.36:387-395),曲妥珠单抗(HERCEPTIN,Fornier et.al.,(1999)Oncology(Huntington)13:647-658),TAB-250(Rosenblum et.al.,(l999)Clin.Cancer Res.5:865-874),BACH-250(Id。),TA1(参见例如,Maier et.al.,(1991)Cancer Res.51:5361-5369),利妥昔单抗,伊曲霉单核菌素和托西莫单抗,AME-133v(Applied Molecular Evolution),ocrelizumab(Roche),ofatumumab(Genmab),TRU-015(Trubion),IMMU-106(Immunomedics)等,但不限于此。
本发明不一定局限于上述抗体的使用,本领域中技术人员已知的其他抗体也可能被用于本文描述的组合物和方法中。
同时,IFN-β是首次作为多发性硬化症的治疗剂以实现抗病毒效果,之后,许多研究揭露了其机制。首先,IFN-β抑制了由IFN-α诱导的HLA-II类分子的活性,从而抑制抗原表达并防止T细胞活化。此外,IFN-β通过灭活共刺激分子来抑制T细胞活化,并诱导自动应答的T细胞的细胞凋亡。关于IFN-β对脑血管屏障的影响,(领域)认为IFN-β抑制了T细胞对血管内皮细胞的粘附性并降低其进入大脑的能力。在这方面,MRI研究曾报道,在约90%接受IFN-β治疗的多发性硬化症患者中,造影增强病变有所减轻。
因此,依据本发明,与天然干扰素-β相比,人干扰素-β变体的活性和功能有所改善,所以,当用于靶向治疗时,以人干扰素-β变体与识别多发性硬化症特异性抗原的抗体缀合的这一形式的免疫细胞因子将会比单独的干扰素-β试剂显示出更优异的治疗效果。
多发性硬化症特异性抗原和抗体的例子,包括CD20和识别其的利妥昔单抗、CD52和识别其的阿伦单抗、白细胞介素-2α受体和识别其的达利珠单抗,但不限于此。
本发明还提供一种通过肽接头使人干扰素-β变体与抗体或其片段缀合的免疫细胞因子。肽接头指的是短片段氨基酸或氨基酸类似物,在此类氨基酸或氨基酸类似物中,两种或多种氨基酸或类氨基酸物质通过肽键彼此连接,并将
两种或更多种单独物质彼此连接。用氨基酸如甘氨酸、丝氨酸和丙氨酸作为主要成分,可以制备甘氨酸-丝氨酸接头、甘氨酸-丝氨酸-丙氨酸接头等诸如此类。根据本发明的优选实施方案,接头可由SEQ ID NO:5至SEQ ID NO:11氨基酸序列中的任何一种组成。
优选地,本发明的免疫细胞因子可能包括***在人干扰素-β变体与抗体或其片段的多肽之间的柔性接头序列。接头序列允许相对于人干扰素-β变体的抗体或其片段的有效定位,从而允许两者结构域的活性。
接头指的是天然衍生的或合成衍生的肽接头。它们构成线性氨基酸链,在这种线性氨基酸链中,有20种天然存在的氨基酸是单聚体构建物。所述接头可包括重复的氨基酸序列,或天然存在的多肽序列,例如具有铰链功能的多肽。所有的肽接头可以由核酸分子编码,并且因此可以重组表达。由于接头本身是肽,所以人干扰素-β变体和抗体或其片段通过肽键而连接到接头上。
接头是由肽键连接在一起的氨基酸组成,优选地,由肽键连接的1至20种氨基酸,这些氨基酸是选自20种天然的氨基酸。在这些氨基酸中,至少有一种是糖基化的,正如本领域中技术人员所熟知那样。优选地,1至20种氨基酸选自甘氨酸、丙氨酸、脯氨酸、天冬酰胺、谷氨酰胺和赖氨酸,但不限于此。
适当的接头包括,例如,可断裂接头和不可断裂接头。可断裂接头在细胞内的条件下通常容易受切割。适当的可断裂接头包括,例如可被细胞内蛋白酶,诸如溶酶体蛋白酶或核内体蛋白酶,切割的肽接头。
关于接头,例如,接头N端可能被连接至抗体的重链C端。优选地,抗体重链C端的接头连接以如下方式进行:编码接头序列的核苷酸序列被连接至表达本发明抗体的表达载体,同时蛋白质表达框架互相匹配,以使得核苷酸序列与由表达载体表达的抗体直接相连。此外,接头可以连接至抗体轻链C端,或可连接到抗体轻链C端和重链C端中的任何一端。另外,本发明的人干扰素-β变体的N端被连接至接头C端。
本发明的肽接头可能是本领域中已知的肽接头,但优选地,可能是甘氨酸-丝氨酸接头或含有SEQ ID NO:5至SEQ ID NO:11所示氨基酸序列的肽接头。
优选地,肽接头可能是甘氨酸接头,诸如(GlyxSery)z型(其中x是1至5的整数,y是1至2的整数,z是1至6的整数),比如(gly4ser1)3或(gly3ser2)3,更优选地,可能是GGGGS或GGGGSGGGGSGGGSG代表的氨基酸序列,但不限于此。
此外,本发明提供一种免疫细胞因子,其特点在于,人干扰素-β变体多肽的氨基酸序列位于重链C端,轻链C端,或抗体或其片段氨基酸序列的重链和轻链C端中的任何一端。
人干扰素-β变体的氨基酸序列可能位于重链C端、轻链C端,或抗体或其片段氨基酸序列的重链和轻链C端中的任何一端,且优选地,也可能位于抗体或其片段氨基酸序列的C端。
本发明还提供一种免疫细胞因子,其特点是,该免疫细胞因子包括选自由SEQ IDNO:12,13,15,17构成的氨基酸序列。
本发明还提供一种免疫细胞因子,包括:(a)以SEQ ID NO:2至SEQ ID NO:4中的任一种表示的人干扰素-β变体;(b)以SEQ ID NO:5至SEQ ID NO:11中的任一种表示的肽接头;(c)抗体或其片段。
本发明还提供一种编码免疫细胞因子的多核苷酸。
上述多肽可被使用,但不限于此,只要多肽编码本发明中的免疫细胞因子的多肽,在该免疫细胞因子中人干扰素-β变体与抗体或其片段缀合,并且其包括全部DNA、cDNA和RNA序列。优选地,多核苷酸是指具有由SEQ ID NO:3表示的氨基酸序列或与该氨基酸序列有至少70%同源性的氨基酸序列,然而它可能与自然界分离,或可能由本领域中已知的遗传工程方法所制备。
本发明还提供一种包含多核苷酸的载体。
载体指的是,用本领域中熟知的方法,通过适当的转录/翻译调节序列将多核苷酸***至载体用来表达本发明中免疫细胞因子而制备的表达载体。
根据本发明,优选地,克隆的多核苷酸可能被连接至合适的表达控制序列,然而可操作连接的基因序列和表达控制序列可能包含在同时具备选择标记和复制起点的一个表达载体中。术语“可操作连接的”是指多核苷酸以允许其基因表达的方式与表达控制序列相连。术语“表达控制序列”是指在特定宿主细胞中控制可操作连接的多核苷酸序列表达的DNA序列。此类表达控制序列可能包括至少一种选自用于进行转录的启动子、用于控制转录的操纵子、用于编码合适的mRNA核糖体结合位点序列,和用于控制转录和翻译终止序列。
用作表达载体的母载体的载体不受特别限制,而本发明涉及的技术领域中常用的、在微生物中作为宿主细胞用来表达的任何质粒、病毒或其它培养基都可以使用。质粒的实例可能包括来自大肠杆菌的质粒(pBR322,pBR325,pUC118,pUC119和pET-22b(+))、来自枯草芽孢杆菌的质粒(pUB110和pTP5)和酵母衍生的质粒(YEp13,YEp24和YCp50),但不限于此。病毒的实例可能包括动物病毒(如逆转录病毒,腺病毒和痘苗病毒),昆虫病毒(例如杆状病毒)等,但不限于此。
本发明还提供通过载体传染的宿主细胞。
宿主细胞可能选自控制***序列表达或允许基因产物以优选特定的方式进行的细胞。在蛋白质翻译、翻译后处理和修饰方面,不同的宿主细胞有它们各自的特点和特有机制。合适的细胞系或宿主***可能选自于提供被表达的外源蛋白的更好的修饰和处理的细胞系或宿主***。酵母中的表达可以产生生物活性产物。真核细胞中的表达会增加“自然”倍数的可能性。
根据本发明,本领域中已知的任何宿主细胞可能被用作能够进行持续克隆和表达且同时稳定载体的宿主细胞。宿主细胞的例子可能包括大肠杆菌JM109,大肠杆菌BL21DE,大肠杆菌DH5,大肠杆菌RR1,大肠杆菌LE392,大肠杆菌B,大肠杆菌X1776和大肠杆菌W3110。此外,还包括土壤杆菌属菌株,如Agrobacterium A4,杆菌属菌株,如枯草芽孢杆菌,其他肠道细菌如鼠伤寒沙门氏菌或粘质沙雷氏菌,以及各种假单胞菌属菌株都可能用作宿主细胞。
另外,依据本发明,在载体转染真核细胞的情况下,酵母(酿酒酵母)、昆虫细胞和人细胞(如CHO细胞系(中华仓鼠卵巢细胞系),W138,BHK,COS-7,293,HepG2,3T3,RIN和MDCK细胞系)可能被用作宿主细胞。
优选地,本文提到的宿主细胞可能属于CHO细胞系。载体被传递至宿主细胞进行的载体转染宿主细胞的任何已知方法可被使用,但没有特别的限制。例如,当宿主细胞可能通过磷酸钙沉淀、DEAE葡聚糖法、电穿孔、直接显微注射、负载DNA的脂质体法、脂质体-DNA复合物法、细胞超声处理、使用高速微粒子的基因枪法、聚阳离子法和受体介导而转染。这类技术可被改进以用于体内或离体。。
本发明还提供一种制备免疫细胞因子的方法,该方法包括:(a)提供宿主细胞;(b)培养所提供的细胞;(c)通过从细胞或培养基中收集免疫细胞因子来制备免疫细胞因子。
在合适的条件下,可培养转基因生物,该条件允许免疫细胞因子作为靶蛋白的表达,在该免疫细胞因子中人干扰素-β变体与抗体或其片段缀合,并且这些条件可通过本领域技术人员熟知的方法而确立。常规培养方法可以大量培养转基因微生物。可以使用包含碳源、氮源、维生素和矿物质的基液作为培养基,例如,Luria-Bertani(LB培养基)液体培养基。在常规微生物培养条件下可培养微生物,例如在15℃-45℃范围内培养10-40小时。离心或过滤可以除去培养液中的培养基,并仅回收浓缩的细胞,并且这些步骤可以根据本领域内技术人员的需要而进行。将浓缩的细胞用常规方法冷冻或冻干可以保存细胞以使其不失去活性。
可采用常规方法纯化转基因微生物(或转化体)中表达的蛋白质。例如,依据本发明,免疫细胞因子可以单独利用或组合利用下述方法进行纯化:盐析(如硫酸铵沉淀或磷酸钠沉淀),溶剂沉淀(如使用丙酮、乙醇等的分级沉淀蛋白质),透析,凝胶过滤,离子交换,柱层析法,如反相柱层析法、超滤(Maniatis et al,Molecular Cloning:A LaboratoryManual,Cold Spring Harbor Laboratory,Cold Spring Harbor,N.Y.(1982);Sambrooket al,Molecular Cloning:A Laboratory Manual,2d Ed.,Cold Spring HarborLaboratory Press(1989);Deutscher,M.,Guide to Protein Purification MethodsEnzymology,vol.182.Academic Press.Inc.,San Diego,CA(1990))。
根据本发明,与具有人干扰素-β(参见例2)的免疫细胞因子相比,具有人干扰素-β变体的免疫细胞因子可以显著地极高的效率进行制备。
同时,本发明提供了一种提高靶特异性人干扰素-β产率的方法,该方法包括:
(a)将多核苷酸克隆到表达载体中,所述多核苷酸编码包括人干扰素-β变体、肽接头、抗体或其片段组成的融合多肽;
(b)将表达载体克隆到宿主细胞中;
(c)培养宿主细胞,以及
(d)从细胞或培养基中收集融合多肽,
其中所述的人干扰素-β变体由选自由SEQ ID NO:1至SEQ ID NO:4的肽序列组成的群组。
用于本发明产率提高的方法的每一个元素如上所述,此时,靶特异性人干扰素-β可为本发明所述的免疫细胞因子。
有利效果
依据本发明,含有人干扰素-β变体和抗体或其片段的免疫细胞因子同时表现出干扰素-β活性和抗体的特点,因此可被用于多发性硬化症或癌症的靶向治疗上。根据本发明,与含有天然干扰素-β的免疫细胞因子相比,该免疫细胞因子以较高的效率被制备。
附图说明
图1显示了本发明中的在宿主细胞中产生的免疫细胞因子表达水平的蛋白质印迹分析结果(1:培养基,2:B12重链天然干扰素,3:B12重链干扰素变体,4:B12轻链天然干扰素,5:B12轻链干扰素变体)。
图2是本发明中含有人干扰素-β变体免疫细胞因子的示意图。
图3是通过将重链接头干扰素的基因核苷酸序列***pRBLX2载体(左)构建pRBLX2-IFN的过程以及通过将重链接头干扰素-β变体的基因核苷酸序列***pRBLX2载体(右)构建pRBLX2-INF的过程的示意图。
图4显示了本发明中具有人干扰素-β变体的免疫细胞因子(右)和具有人干扰素-β的免疫细胞因子(左)的表达的SDS-PAGE结果。在这里,每个情况的重链和轻链都用表示(泳道1是一个标记)。
图5显示了本发明中具有人干扰素-β变体的免疫细胞因子(泳道2)和具有控制人干扰素-β的免疫细胞因子(道1)的蛋白质表达的蛋白质印迹分析结果,两者分别使用抗人IgG抗体(左)和抗干扰素抗体(右)。
图6显示了宿主细胞中免疫细胞因子表达水平的BCA测定结果(ACC#1:B12重链天然干扰素,ACC#2:B12重链干扰素变体,ACC#6:B12轻链天然干扰素,ACC#7:B12轻链干扰素变体)。
图7显示了STAT-1磷酸化的效果,表明了免疫细胞因子的干扰素活性,根据本发明,该免疫细胞因子中的人干扰素-β变体与B12抗体缀合。
图8显示了用免疫细胞因子治疗细胞的结果,根据发明,该免疫细胞因子中的人干扰素-β变体与B12抗体缀合24小时,然后通过细胞毒性研究免疫细胞因子的干扰素-β的活性(Carbiferon:人类干扰素-β变体,B12:B12抗体,ACC#2:免疫细胞因子中的人干扰素-β变体与B12抗体缀合)。
图9显示了用免疫细胞因子治疗细胞的结果,根据发明,该免疫细胞因子中的人干扰素-β变体与B12抗体缀合48小时,然后通过细胞毒性研究免疫细胞因子的干扰素-β的活性(Carbiferon:人类干扰素-β变体,B12:B12抗体,ACC#2:免疫细胞因子中的人干扰素-β变体与B12抗体缀合)。
图10是将刚性螺旋接头连接至ERBB2(赫赛汀)抗体(A)和c-MET抗体(B)、然后分别缀合人干扰素-β变体进而产生免疫细胞因子的示意图。
具体实施方式
下面将对本发明进行详细描述。
然而,以下例子仅用于解说本发明,并非试图限制本发明的范围。
实施例1
载体克隆和宿主细胞转染
为了克隆干扰素-β变体与抗体重链(ACC#2)缀合的免疫细胞因子和干扰素-β变体与抗体轻链(ACC#7)缀合的免疫细胞因子,利用了B12序列。用接头把人干扰素-β变体序列分别***B12序列的重链和轻链中,然后通过载体合成。合成基因被各自适当的限制酶消化,并与IgG表达载体连接,随后进行测序,最后构建表达ACC#2和ACC#7的载体。克隆完成后,ACC#2和ACC#7的载体通过转化分别被大量提取,然后用于转染。
将CHO-S细胞以3×105个细胞/ml的密度进行继代培养-至少5代,以为转染做准备。当继代培养后细胞的存活率保持在90%以上或更高时,将细胞以5×105个细胞/ml的密度进行接种,以为转染做准备。接种后24小时检测存活率(>95%)和细胞密度(1×105个细胞/ml),将50μgDNA转染至CHO-S细胞中,该细胞用转染溶剂在30ml的培养基中培养。
实施例2
宿主细胞中免疫细胞因子表达的确认
细胞转染48小时后,ACC#2和ACC#7的表达水平通过浓度测定法(BCA测定)和蛋白质印迹法测定。
至于BCA测定,以50:1的比例制作试剂A(含有碳酸钠、二喹啉甲酸)和试剂B(含有4%的硫酸铜),并与标准溶液(BSA溶液,0-2000ug/ml)和样品(10μL样品和200μL试剂)混合。将合成的溶液在37℃下培育30分钟,然后在562nm处测定吸光度,用以浓度计算。基于标准溶液获得的曲线被用于浓度计算。
下文将详细描述蛋白免疫印迹测试的操作。首先,收集两种培养基,并负载至10%SDS PAGE凝胶上。将负载凝胶转移至PVDF膜上,然后用5%的BSA溶液封闭,之后用一抗和二抗探测。在TBST溶液洗涤完成后,将PVDF进行显影。显影可通过显影剂和固定剂进行发展。
结果表明,与天然人干扰素-β缀合至B12重链和轻链(图1)的免疫细胞因子的表达水平相比,人干扰素-β变体缀合B12重链和轻链的免疫细胞因子的表达水平较高(图1)。
实施例3
免疫细胞因子的制备
将以SEQ ID NO:5表示的接头***抗体的重链区中,并将干扰素-β或干扰素-β变体也缀合至此。图2是具有人干扰素-β变体的免疫细胞因子结构的示意图。
以SEQ ID NO:5表示的接头和干扰素-β或干扰素-β变体被克隆至抗体重链。之后,将限制酶Avrll(CCTAGG)切割位点和Bstz171(GTATAC)切割位点分别***整个基因的3’端和5’端,从而确保重链的最终基因。此外,将限制酶EcoRV(GTATAC)切割位点和Pacl(TTAATTAA)切割位点分别***到抗体轻链的3’端和5’端,从而确保轻链的最终基因。图3是生产流程的示意图。
实施例4
免疫细胞因子表达的确认
为了确认具有人干扰素-β的细胞因子和具有人干扰素-β变体的细胞因子的表达,将50μg的pRBLX2-INF或pRBLX2-CAF载体转染至CHO-S细胞,当细胞培养7天后进行诱导表达。7天后,收集培养液,并作离心(8000rpm,10分钟)处理以去除细胞。取少量去除细胞的培养液,与5x样品缓冲液混合,并在100℃煮沸10分钟,从而诱导足够的蛋白质变性。将制作好的样品与标记物一并负载到Tricine SDS-PAGE凝胶上,并在130V电压下电泳1小时30分钟。之后,小心分离凝胶,并浸入考马斯亮蓝染色剂中,然后摇动溶液30分钟以进行染色。染色后,将凝胶转移至脱色缓冲液中,然后摇动30分钟以进行脱色。脱色过程需重复3次。
为了更清晰地对比表达水平,用抗干扰素-β变体和抗人IgG-HRP进行蛋白免疫印迹操作。用上述相同方法进行Tricine SDS-PAGE的操作后,小心分离凝胶,并放在3M纸之上,然后将聚偏二氟乙烯(PVDF)膜置于其上,并再次用3M纸覆盖。之后,将所得结构浸入1x转移缓冲液中,并在100V的电压下将蛋白质转移70分钟。加入5%的Tris缓冲盐水-吐温20(TBS-T,0.1%的吐温20)后,将该膜在室温下封闭1小时30分钟。用TBS-T将PVDF膜洗涤两次,然后浸入TBS-T中。在TBS-T中以1:1000的比例稀释得到抗干扰素-β抗体,而在TBS-T中以1:3000的比例稀释得到抗人IgG-HRP抗体。把PVDF膜浸入抗体稀释液中,然后在室温下摇动反应2小时。程序完成后,用TBS-T洗涤所得物3次共10分钟,然后加入与辣根过氧化物酶(HRP)缀合的二抗在室温下反应1小时。再次进行洗涤后,用增强型化学发光试剂鉴定条带。C-DiGit(LI-COR,USA)可测定条带的强度。
如图4所示,结果是,在25KDa的位点可观察到轻链,而在70KDa和100KDa之间观察到具有干扰素-β的免疫细胞因子或具有干扰素-β变体的免疫细胞因子复合物。
如图5所示,泳道1显示的是具有人干扰素-β的免疫细胞因子,泳道2显示的是具有人干扰素-β变体的免疫细胞因子。Tricine-SDS PAGE和蛋白质印迹结果证实具有人干扰素-β变体的免疫细胞因子的表达水平高于比具有人干扰素-β的免疫细胞因子的表达水平。此外,为了精确地比较表达水平,用Cedex Bio(Roche,USA)测量每种培养液。结果证实,具有人干扰素-β的免疫细胞因子的浓度低于测量范围(10mg/L或更低),表明更低的表达水平,而具有人干扰素-β变体的免疫细胞因子的浓度约在32mg/L,表明表达水平提高3倍。
实施例5
通过pSTAT-1磷酸化确认免疫细胞因子的干扰素活性
根据本发明,为了确认人干扰素-β变体与B12抗体缀合的免疫细胞因子的干扰素功能,基于用干扰素或抗体干扰素缀合物治疗的STAT-1磷酸化被检测。
将3×105OVCAR-3细胞分配在6孔板的每一个孔上,并在37.5℃和5%的二氧化碳中培养24小时。24小时后,除去细胞培养液,把人干扰素-β变体(Carbiferon)稀释至浓度为600ng/mL,并在培养液中将具有人干扰素-β变体与B12抗体(ACC)缀合的免疫细胞因子稀释至浓度为600ng/mL或1800ng/mL,然后处理1小时。之后,收集孔板,把每个孔用PBS清洗3次,用100μL含有蛋白酶抑制剂和磷酸酶抑制剂的RIPA缓冲液处理,并放置在冰上30分钟以溶解细胞。将溶解的细胞置于1.5mL的试管中,在4℃条件下13000rpm离心,然后仅取出上层清液(裂解物),并收集在新试管中。BCA测定法可量化裂解物的蛋白质浓度,然后取出30μg裂解物并与5×样品缓冲液混合,并在100℃煮沸10分钟来诱导足够的蛋白质变性。将制作好的样品用标记物负载到10%的SDS-PAGE凝胶上,并在70V下放置30分钟、在120V下放置1小时。之后,小心分离凝胶并置于3M纸上,再把偏聚二氟乙烯(PVDF)膜置于其上,再用3M纸覆盖。之后,将所得物结构浸入转移缓冲液中,然后在100V下进行蛋白质转移90分钟。把PVDF膜在含有5%的Tris缓冲盐水-吐温20(TBS-T,0.1%的吐温20)中封闭1小时30分钟,在TBS-T中以1:1000的比例稀释得到抗p-STAT1抗体,而在TBS-T中以1:3000的比例稀释得到抗GAPDH抗体。把PVDF膜浸入抗体稀释液中,然后在室温下摇动反应2小时。程序完成后,用TBS-T洗涤所得物3次共10分钟,然后加入与辣根过氧化物酶(HRP)缀合的二抗并在室温下反应1小时。再次进行洗涤后,用增强型化学发光(ECL,Intron)试剂鉴定条带,然后再进行显影。
结果证实,人干扰素-β(Carbiferon)和免疫细胞因子治疗组均显示出p STAT-1磷酸化,表明人干扰素-β变体(Carbiferon)与B12抗体缀合的免疫细胞因子的干扰素-β活性并未受损(参见图7)。
实施例6
通过细胞毒性测试确认免疫细胞因子的干扰素活性
根据发明,为了确认人干扰素-β变体缀合B12抗体的免疫细胞因子的干扰素功能,基于用干扰素或抗体-干扰素缀合物治疗的细胞毒性被检测。
为了检测细胞毒性,把1×104个OVCAR-3细胞分配在96孔板的每个孔上,并在37.5℃和5%的二氧化碳中培养24小时。24小时后,除去细胞培养液,分别用人干扰素-β变体(Carbiferon),B12抗体和10-10000ng/mL免疫细胞因子处理细胞,然后培养24小时或48小时。培养24或48小时后,除去培养液,用PBS洗涤两次。把WST试剂与培养液以1:10的比例混合,每个孔用10μL混合物处理,再在37.5℃和5%的二氧化碳中放置2小时,然后在波长为430nm处可测定吸光度。
结果证实,只用B12抗体治疗的细胞组显示没有细胞毒性,然而用人干扰素-β变体或免疫细胞因子治疗的细胞组以浓度依赖性的方式显示出有细胞毒性,表明,即便是以免疫细胞因子的形式,人干扰素-β变体依然表现出干扰素活性(图8和图9)。
实施例7
抗体重链缀合干扰素-β变体的免疫细胞因子的制备
除了B12抗体,在免疫细胞因子中,ERBB2(赫赛汀)和c-MET抗体分别缀合干扰素-β变体的制备方法如下。
正如图10所示,将刚性螺旋接头分别连接至ERBB2(赫赛汀)抗体和c-MET抗体的重链区。之后,将人干扰素-β变体缀合至此,从而分别产生表达抗c-MET免疫细胞因子(A)和抗ERBB2免疫细胞因子(B)的表达盒。
把这两个免疫细胞因子分别克隆至pRBLX2载体,然后将每个载体转染至CHO-S细胞中,之后再培养7天,从而诱导表达。如实施例4中所述,进行表达产物的转染、培养和收集。
使用用CHO-S细胞,当比较人干扰素-β和人干扰素-β变体分别缀合c-MET抗体或ERBB2抗体中的同一种的两种免疫细胞因子的表达水平时,已证明含有人干扰素-β变体的免疫细胞因子的表达水平要比含有人干扰素-β的免疫细胞因子的表达水平要高,这表明,相对于含有人干扰素-β的免疫细胞因子,含有人干扰素-β变体的免疫细胞因子拥有优良的干扰素活性。
如上所述,根据本发明,与野生型干扰素-β相比,人干扰素-β变体非常有利于表达。
工业实用性
根据本发明,具有人干扰素-β变体的免疫细胞因子可以用作疾病(例如多发性硬化症或癌症)的靶向治疗剂,因为与具有天然干扰素-β的免疫细胞因子相比,该免疫细胞因子在干扰素活性和识别特异性抗原的抗体特征方面都很优秀,且其产率也明显上升,使它们具有高度工业实用性。
<110> ABION Inc.
<120> Immunocytokine conjugated with human interferon beta-mutein and
method for preparing thereof
<130> OP17-0123/PCT/CN
<150> PCT/KR 10-2015-0030037
<151> 2015-03-03
<160> 17
<170> KopatentIn 2.0
<210> 1
<211> 166
<212> PRT
<213> Artificial Sequence
<220>
<223> Human interferon-beta
<400> 1
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
115 120 125
Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
130 135 140
Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn
165
<210> 2
<211> 166
<212> PRT
<213> Artificial Sequence
<220>
<223> Interferon beta mutein - R27T protein
<400> 2
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
115 120 125
Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
130 135 140
Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn
165
<210> 3
<211> 166
<212> PRT
<213> Artificial Sequence
<220>
<223> Interferon beta mutein - R27S protein
<400> 3
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Ser Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
115 120 125
Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
130 135 140
Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn
165
<210> 4
<211> 171
<212> PRT
<213> Artificial Sequence
<220>
<223> Interferon beta mutein - GNITV protein
<400> 4
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
115 120 125
Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
130 135 140
Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn Gly Asn Ile Thr Val
165 170
<210> 5
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 5
Gly Gly Gly Gly Ser
1 5
<210> 6
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 6
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
<210> 7
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> GGGGSGGGGSGGGGSGGGGS linker
<400> 7
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 8
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> ASGG linker
<400> 8
Gly Gly Gly Ser
1
<210> 9
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> GVGGSGGGGSGGGGS linker
<400> 9
Gly Val Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 10
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> DDDDK linker
<400> 10
Asp Asp Asp Asp Lys
1 5
<210> 11
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> AEAAAKEAAAKEAAAKA linker
<400> 11
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Ala
<210> 12
<211> 627
<212> PRT
<213> Artificial Sequence
<220>
<223> Immunocytokine 1
<400> 12
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 Gly Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser His Asp Gly Ser Ser 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 Asp Ala Arg Val Cys Thr Pro Lys Arg Cys Tyr Ser Tyr Asp
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Ser Tyr
450 455 460
Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys
465 470 475 480
Leu Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu Lys Asp Arg
485 490 495
Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln
500 505 510
Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe
515 520 525
Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile
530 535 540
Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys
545 550 555 560
Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys
565 570 575
Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His
580 585 590
Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg
595 600 605
Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr
610 615 620
Leu Arg Asn
625
<210> 13
<211> 386
<212> PRT
<213> Artificial Sequence
<220>
<223> Immunocytokine 2
<400> 13
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ala Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Asp Ser Leu
85 90 95
Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Ala Glu Cys Ser Gly Gly Gly Gly Ser Ser Tyr Asn
210 215 220
Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu
225 230 235 240
Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu Lys Asp Arg Met
245 250 255
Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys
260 265 270
Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala
275 280 285
Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile Val
290 295 300
Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys Thr
305 310 315 320
Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu
325 330 335
Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr
340 345 350
Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg Val
355 360 365
Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu
370 375 380
Arg Asn
385
<210> 14
<211> 648
<212> PRT
<213> Artificial Sequence
<220>
<223> anti c-Met interferon-beta
<400> 14
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Gly Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Ala Ile Ser His Ser Gly Gly Ser Thr Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Lys Trp Gly Pro Ala Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
465 470 475 480
Ala Lys Ala Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn
485 490 495
Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr
500 505 510
Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln
515 520 525
Leu Gln Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met
530 535 540
Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly
545 550 555 560
Trp Ala Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln
565 570 575
Ile Asn His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp
580 585 590
Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr
595 600 605
Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala
610 615 620
Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn
625 630 635 640
Arg Leu Thr Gly Tyr Leu Arg Asn
645
<210> 15
<211> 648
<212> PRT
<213> Artificial Sequence
<220>
<223> anti c-Met interferon-beta mutein
<400> 15
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Gly Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Ala Ile Ser His Ser Gly Gly Ser Thr Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Lys Trp Gly Pro Ala Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
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Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly
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Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr
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Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala
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<210> 16
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<213> Artificial Sequence
<220>
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Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly
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Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys
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Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
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Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
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Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
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Ser Leu Ser Pro Gly Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala
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Lys Glu Ala Ala Ala Lys Ala Ser Tyr Asn Leu Leu Gly Phe Leu Gln
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Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly
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Arg Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu
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Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
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Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
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Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
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Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
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Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
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Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
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Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
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Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
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Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
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Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
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Ser Leu Ser Pro Gly Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala
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Thr Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu
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Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu Leu Ala Asn
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Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn Phe
625 630 635 640
Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn
645 650
Claims (13)
1.一种免疫细胞因子,包括:(a)人干扰素-β变体;和(b)与人干扰素-β变体直接或间接共价连接的抗体或其片段;
其中,所述人干扰素-β变体是一种多肽,其选自下面(i)、(ii)、(iii)中的一种,该多肽具有人干扰素-β活性,所述多肽包括N-连接糖链:
(i)、由SEQ ID NO:1中公开的所有氨基酸序列组成的多肽;
(ii)由SEQ ID NO:1中公开的氨基酸序列的实质部分组成的多肽;和
(iii)基本上与(a)或(b)中的多肽相似的多肽。
2.根据权利要求1所述的免疫细胞因子,其特征在于,所述抗体或其片段是肿瘤抗原的抗体或其片段。
3.根据权利要求1所述的免疫细胞因子,其特征在于,所述人干扰素-β变体通过肽接头缀合抗体或其片段。
4.根据权利要求3所述的免疫细胞因子,其特征在于,所述接头包括选自SEQ ID NO:5至SEQ ID NO:11的氨基酸序列。
5.根据权利要求1至4中的任一项所述的免疫细胞因子,其特征在于,所述人干扰素-β变体多肽的氨基酸序列位于重链C端,轻链C端,或抗体或其片段的氨基酸序列的重链和轻链的C端的任何一端。
6.根据权利要求1所述的免疫细胞因子,其特征在于,所述免疫细胞因子包括选自SEQID NO:12,13,15和17中的一种氨基酸序列。
7.一种免疫细胞因子,包括:
(a)以SEQ ID NO:2至SEQ ID NO:4中的任一种表示的人干扰素-β变体;
(b)以SEQ ID NO:5至SEQ ID NO:11中的任一种表示的肽接头;和
(c)抗体或其片段。
8.一种编码如权利要求1所述的免疫细胞因子的多核苷酸。
9.一种包含如权利要求8所述的多核苷酸的载体。
10.一种由权利要求9所述的载体转染的宿主细胞。
11.一种制备免疫细胞因子的方法,该方法包括:
(a)提供如权利要求10所述的宿主细胞;
(b)培养所提供的细胞;和
(c)通过从细胞或培养基中收集免疫细胞因子来制备免疫细胞因子。
12.一种提高靶特异性人干扰素-β产率的方法,该方法包括:
(a)把多核苷酸克隆到表达载体中,所述多核苷酸编码包括人干扰素-β变体、肽接头和抗体或其片段的融合多肽;
(b)把表达载体克隆到宿主细胞中;
(c)培养宿主细胞;和
(d)从细胞或培养基中收集融合多肽;
其中,所述人干扰素-β变体包括选自SEQ ID NO:2至SEQ ID NO:4的肽序列。
13.根据权利要求12所述的方法,其特征在于,所述靶特异性人干扰素-β是一种免疫细胞因子。
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PCT/KR2016/002129 WO2016140528A1 (ko) | 2015-03-03 | 2016-03-03 | 인간 인터페론-베타 변이체가 접합된 면역사이토카인 및 이의 제조방법 |
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CN114555111A (zh) * | 2019-08-19 | 2022-05-27 | 基因制药株式会社 | 包含干扰素-β或其变体的免疫细胞因子用于治疗人表皮生长因子受体2阳性癌症的用途 |
CN115279792A (zh) * | 2020-03-13 | 2022-11-01 | 酷罗赛尔公司 | 对bcma特异的抗体及嵌合抗原受体 |
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CN112912402A (zh) * | 2018-10-17 | 2021-06-04 | 古德T细胞有限公司 | Lrig-1蛋白的特异性结合分子及其用途 |
CN116075523A (zh) * | 2020-04-29 | 2023-05-05 | 基因制药株式会社 | 具有融合的干扰素-β突变蛋白和抗体的重组蛋白以及包含其的药物组合物 |
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CN115279792A (zh) * | 2020-03-13 | 2022-11-01 | 酷罗赛尔公司 | 对bcma特异的抗体及嵌合抗原受体 |
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US20180236092A1 (en) | 2018-08-23 |
JP2018508220A (ja) | 2018-03-29 |
JP6779896B2 (ja) | 2020-11-04 |
KR20160107070A (ko) | 2016-09-13 |
US10806799B2 (en) | 2020-10-20 |
KR101838919B1 (ko) | 2018-03-15 |
ES2839404T3 (es) | 2021-07-05 |
EP3266801B1 (en) | 2020-11-11 |
EP3266801A4 (en) | 2018-09-12 |
WO2016140528A1 (ko) | 2016-09-09 |
EP3266801A1 (en) | 2018-01-10 |
CN107438624B (zh) | 2022-01-07 |
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