CN110038135B - 重新定向的免疫治疗 - Google Patents
重新定向的免疫治疗 Download PDFInfo
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- CN110038135B CN110038135B CN201811559481.4A CN201811559481A CN110038135B CN 110038135 B CN110038135 B CN 110038135B CN 201811559481 A CN201811559481 A CN 201811559481A CN 110038135 B CN110038135 B CN 110038135B
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Abstract
本发明涉及重新定向的免疫治疗,具体而言,本发明提供了一种用于预防或治疗特征在于存在不需要的细胞的病症的药剂,该药剂包含:(i)能够靶向不需要的细胞的靶向半体;和(ii)T细胞抗原,其中T细胞抗原可以通过药剂中的分裂位点的选择性分裂在不需要的细胞附近从靶向半体中释放出来。
Description
本申请是申请号为201280024084.1,申请日为2012年3月15日,发明名称为“重新定向的免疫治疗”的中国专利申请的分案申请。
技术领域
本发明涉及免疫治疗剂。特别地,涉及可以用于预防或治疗病症的药剂,所述病症的特征在于存在不需要的细胞,如引起癌症或其他疾病的细胞。
背景技术
用于靶向恶性疾病的免疫治疗策略是翻译(translational)临床研究的活跃领域,并且已经进行了数十年。目前的模型要求癌症代表可以用宿主的免疫治疗操作治疗的功能性或体质免疫缺陷。这些努力可以宽泛地分为两组。第一组通过如接种疫苗、细胞因子支持(IL-2、IFNγ)或降低免疫抑制环境(伊匹单抗(ipilimumab))这样的方法,来增强或支持内源性抗肿瘤免疫力,而第二组设法用功能性免疫应答成分来修复绝对缺陷(使用抗体的被动免疫治疗、TCR转移、干细胞移植和过继性免疫治疗)。通过高效的功能性抗肿瘤免疫应答确实是可能的论点将这些方法进行了统一。尽管在一些情况中对于有效的抗肿瘤免疫应答存在勿庸置疑的证据,但这个肿瘤免疫学的重要支柱受到目前临床现实压倒性的反对,所述临床现实为尽管进行了很多努力,但对于大部分的癌症病人没有可用的有效免疫治疗方法。几乎所有癌症疫苗接种试验都提供了否定结果,而提供肯定数据的那些最常见的是证明了小的作用。现实是,治疗抗体,除了少数例外,在肿瘤学领域中提供了非常少的临床益处。
如果可以研发出能有效地在分子上重新定向内源性细胞毒性抗病毒免疫应答到目标恶性组织的治疗策略,这将提供一种新的有力且安全的治疗恶性疾病的方法。
大部分细胞毒性治疗抗体依赖于免疫效应物机制,来传送它们的抗癌作用,如补体依赖性细胞毒性(CDC)和抗体依赖性细胞毒性(ADCC)。重要地,所有细胞(健康的和恶性的)都具有各种机制来限制免疫应答的攻击,以避免自身免疫性。这在自体免疫疾病的环境中是明显的,其中高水平的组织反应性抗体尽管常常引起器官发炎,但很少诱发完全的器官破坏。实际上,已知其中观察到完全的组织破坏的自体免疫疾病,如糖尿病,是依赖于CTL应答,而不是抗体定向的机制。
为了提高治疗抗体差的功效,已经使用了免疫偶联物(放射性核素/毒素)和工程化抗体,其能更好地保证细胞毒性效应物机制(例如,糖基化工程)。然而,这些药剂的临床试验仍然是很令人失望的,并且受到毒性的困扰。一个实例是已经研发来选择性地将抗肿瘤剂靶向肿瘤的抗体-药物偶联物(ADC)(参见US 5,773,001;US 5,767,285;US 5,739,116;US 5,693,762;US 5,585,089;US 2006/0088522;US 2011/0008840;US 7,659,241;Hughes(2010)Nat Drug Discov 9:665,Lash(2010);In vivo:The Business&MedicineReport 32-38;Mahato等(2011)Adv Drug Deliv Rev 63:659;Jeffrey等(2006)BMCL 16:358;Drugs R D 11(1):85-95)。ADC通常含有对抗存在于肿瘤细胞上的目标的单克隆抗体、细胞毒性药物以及连接抗体和药物的连接物。然而,目前只有少数ADC处于临床研发的后期,而且已经证明了这些的临床成功是难以捉摸的。
因此,仍然存在对具有更高功效和更低毒性的更有效的免疫治疗剂的需求。
发明内容
本发明的药剂是重新定向的免疫治疗的实例。这指的是将通常靶向带有外源抗原的细胞的现有免疫应答重新定向,以靶向病症(如,癌症)中不需要的细胞的概念。这个概念需要标记抗原(marker antigen)在不需要的细胞上递呈,使得它们成为免疫细胞的目标。
WO95/17212描述了由肽T细胞抗原和细胞结合配偶体组成的偶联物及其在重新定向的免疫治疗中的用途。偶联物含有对靶细胞具有选择性的结合配偶体和T细胞抗原,并且在癌症、自体免疫疾病、糖尿病或过敏疾病的治疗中诱导特异性的T细胞细胞毒性。偶联物在结合了结合配偶体到表面受体后内在化至靶细胞中,并且从偶联物加工T细胞抗原,并且以与MHC分子的复合物的形式在细胞表面上表达。由此诱导T细胞对靶细胞的细胞毒性。
然而,从WO 95/17212难以预测哪个结合配偶体能够内在化并且因此随后递呈T细胞抗原,而哪个不能。此外,WO 95/17212中所述的偶联物不能有效地靶向MHC I类抗原加工途径。与MHC II类分子不同,MHC I类途径的优势在于MHC I类分子在所有细胞类型上递呈。
Smith等(J Immunol 169:99-107,2002)描述了蓖麻毒素将细胞毒T细胞表位传递至肿瘤细胞的MHC I类途径的用途,使得肿瘤细胞随后被溶解。然而,蓖麻毒素是非常毒的,并且因为其可以结合大部分的细胞类型,其对肿瘤细胞不是选择性的。
本发明的药剂旨在避开以上所有问题,同时提高特异性,并且利用T细胞抗原可以递呈而没有首先被内在化至细胞中并参与经典抗原加工途径的事实。除了经典的MHC I类加工途径,其通过靶向的胞内蛋白体的蛋白水解连续地流入来自胞内隔间的肽,肽通过ER内的TAP和MHC I类肽装载来运输,抗原也可以递呈而没有内在化。这种不太定向的机制依赖于由于一些结合MHC的肽对MHC分子的低亲和性而引起的一些MHC I类相关肽的短半衰期。肽分解提供了空的MHC I类分子,其能够结合膜上的T细胞抗原(例如,肽)。以相同的方式,T细胞抗原可以结合MHC II类分子,并且本发明还避开了II类抗原加工途径,以在细胞膜上直接装载抗原。此外,组I CD1分子(CD1a、CD1b和CD1c)已经显示出将脂质递呈给细胞毒性αβT细胞以及细胞毒性γδT细胞(Porcelli等(1989),Nature,341,447-450)。
本发明人已经发现了,通过在T细胞抗原的近端引入切割位点,该切割位点在不需要的细胞的附近选择性地切割,可以从不需要的细胞的附近的靶向半体释放出T细胞抗原,并且可以被例如空的MHC分子或组I CD1分子结合,并引发T细胞应答。这样,不需要药剂至细胞中的内在化和抗原至经典加工途径的定向;与WO 95/17212中只有表达MHC II类的细胞相比,药剂可以靶向表达MHC I类分子的细胞;并且由于切割位点只在不需要的细胞的附近切割,特异性被提高了。例如,肿瘤细胞分泌肿瘤入侵局部组织和转移需要的蛋白酶,因此通过在药剂中包括肿瘤特异性蛋白酶切割位点,提高了药剂对肿瘤的特异性。
因而,使用切割位点来绕开为了将T细胞抗原有效递呈给T细胞而对内在化和经典加工的需求是本发明的重要优势。切割位点的存在意味着所有细胞服从重新定向的免疫治疗,而不仅仅是相对少量的表达MHC II类分子的抗原递呈细胞群体。这对于其中大部分肿瘤细胞没有表达MHC II类分子的肿瘤尤为重要。切割位点还避开了涉及确保T细胞抗原不仅成功内在化而且正确地进入合适的细胞加工途径以在细胞表面上递呈的挑战。通过绕开对内在化的需求,切割位点进一步提供了靶向相邻肿瘤细胞和基质非恶性组织(如,血管的肿瘤-成纤维细胞)的能力。其还避开了在经典抗原加工中运行的肿瘤逃逸机制。因此,总而言之,切割位点提供了针对更多的细胞类型的更简单且更有效的重新定向免疫治疗方法。
重要的是注意到本发明与交叉递呈之间的区别。在本发明中,药剂的靶向半体用来将T细胞直接带至不需要的细胞的附近。一旦与靶向半体分离,不需要的细胞然后在其表面上递呈T细胞抗原,使得不需要的细胞变成现有T细胞应答的目标。这使得现有的免疫应答直接重新定向至不需要的细胞,并且因此不需要抗原递呈细胞(APC)的共同刺激。另一方面,交叉递呈指的是如下的机制:抗原通过其转移至专业APC,其随后在MHC I类分子上递呈给天然T细胞,使得产生特异于该抗原的初级细胞毒T细胞应答。该过程在天然T细胞的激活中是重要的,其必须首先识别I类相关的肽抗原,并且还需要APC上的共同刺激剂,或由辅助T细胞提供的信号。因此,使用交叉递呈,与不需要的细胞相对,APC被靶向,使得APC可以共同刺激细胞毒T细胞,并且由此产生新的免疫应答。
提高外源性抗原的交叉递呈的效率是研发产生有效细胞免疫应答的疫苗中的关键挑战。WO 2008/019366、EP 1948802、US 2004/0001853、WO 2005/087813、EP 1664270、Kawamura等(J Immunol 168:5709,2002)和Howland等(J Immunother 31(7):607,2008)描述了通过将抗原靶向APC来提高外源性抗原的交叉递呈的方法,抗原在APC中内在化并递呈给天然T细胞。例如,WO 2008/019366讨论了将抗原连接可以被APC吞噬的颗粒,使得抗原在APC的吞噬体中可以释放,并且由此交叉递呈至MHC I类分子上。相似地,EP 1948802描述了将抗原连接抗体Fc片段,以促进抗原内在化至APC中。然而,以上文献没有一篇提及将抗原靶向不需要的细胞;而是,将抗原靶向专门的APC亚类,其随后激活细胞毒T细胞,来杀灭不需要的细胞。同样,没有一篇文献描述使用和重新定向现有的免疫应答,也没有公开可以在细胞表面上递呈T细胞抗原而不需要内在化。
本发明的第一个方面提供了一种用于预防或治疗特征在于存在不需要的细胞的病症的药剂,该药剂含有(i)能够靶向不需要的细胞的靶向半体;和(ii)T细胞抗原,其中可以在不需要的细胞的附近通过药剂中的切割位点的选择性切割从靶向半体中释放出T细胞抗原。
靶向半体
“靶向半体”包括能够靶向不需要的细胞的任何部分。优选地,靶向半体能够选择性地靶向不需要的细胞。例如,如果靶向半体以高于正常细胞的程度靶向不需要的细胞,则是优选的,并且最优选只靶向不需要的细胞。
将认识到,如果在功能上可以被其他治疗方式替代或如果对生命不是重要的,可以容忍靶向半体与正常细胞的结合。因此,不排除靶向癌细胞以及例如内分泌组织或器官的靶向半体。在这种情况中,靶向半体用来将免疫应答重新定向至不要的细胞和功能上可以被治疗方式替代的其他细胞。在挽救生命的情况中,例如,可以牺牲组织或器官,只要其功能对生命不是至关重要的,例如,在睾丸、前列腺或胰腺的情况中,或其功能可以通过激素替代治疗来提供。这样的考虑将适用于例如甲状腺、甲状旁腺、肾上腺皮质和卵巢。
认识到,靶向半体可以是能够相对于需要的细胞选择性地靶向不需要的细胞的部分,其中不需要的细胞可以包括其在宿主中的存在是不合需要的细胞,和任选其在宿主的存在是合乎需要的但其存在在功能上可以被治疗方式替代的细胞。
还认识到,由于药剂中的切割位点给予了T细胞抗原在哪释放的特异性,因此靶向半体与在其附近切割位点不会切割的正常细胞的结合也是可以忍受的。
然而,最优选地,与任何其他细胞相对,靶向半体选择性地靶向不需要的细胞。
在一个实施方案中,靶向半体是不需要的细胞表达的或与不需要的细胞相关的实体的特异性结合配偶体,通常,表达的实体是在不需要的细胞上选择性表达的。例如,不需要的细胞上表达的实体的丰度通常比待治疗躯体内的其他细胞上的高10或100或500或1000或5000或10000。然而,如上所述,切割位点提供了另外的特异性,T细胞抗原在那释放,并且因此结合配偶体可以结合相对于体内的其他细胞在不需要的细胞上相似地或甚至低表达的实体。
“结合配偶体”意思包括结合特定细胞表达的实体的分子。优选地,结合配偶体选择性地结合该实体。例如,如果结合配偶体具有比对另一种细胞(例如,正常细胞类型)表达的至少一种其他实体低至少五倍或十倍的Kd值(解离常数)(即,较高亲和性),则是优选的,并且优选地,低超过100或500倍。更优选地,该实体的结合配偶体具有比对另一种细胞(例如,正常细胞类型)表达的至少一种其他实体低超过1000或5000倍的Kd值。可以使用本领域公知的方法来容易地测定Kd值。然而,如以上所讨论的,认识到结合配偶体可以选择性地结合由不需要的细胞和由正常细胞表达的实体,只要正常细胞在功能上可以被替代或对生命不是至关重要的。例如,在淋巴瘤中,抗-CD20抗体(其靶向所有B细胞)是非常有效的,并且杀灭所有B细胞,不管是健康的还是恶性的。然而,因为B细胞对健康不是至关重要的,所以这种情况可以忍受。此外,在黑素瘤、淋巴瘤、前列腺癌、甲状腺、睾丸或卵巢癌的情况中,靶向健康的相应组织也是可以忍受的。
通常,结合配偶体是以显著高于宿主任何正常细胞中的浓度结合不需要的细胞之内或之上存在的实体或易接近结合配偶体的实体的结合配偶体。因此,结合配偶体可以结合以显著高于正常细胞的含量表达的不需要的细胞上的表面分子或抗原。相似地,结合配偶体可以结合已经由不需要的细胞以高于正常细胞的程度分泌至胞外流体中的实体。例如,结合配偶体可以结合在细胞膜上表达的或已经分泌至肿瘤胞外流体中的肿瘤相关抗原。
靶向半体可以是任意的多肽、肽、小分子或拟肽(peptidomimetic)。
在优选的实施方案中,靶向半体是结合不需要的细胞表达的抗原的抗体。优选的抗体目标(括号中为不需要的细胞类型的实例)包括:Her2/Neu(上皮恶性肿瘤);CD22(B细胞,自体免疫或恶性的);EpCAM(CD326)(上皮恶性肿瘤);EGFR(上皮恶性肿瘤);PMSA(前列腺癌);CD30(B细胞恶性肿瘤);CD20(B细胞,自体免疫、过敏或恶性的);CD33(骨髓恶性肿瘤);膜IgE(过敏性B细胞);IgE受体(CD23)(过敏性疾病中的肥大细胞或B细胞),CD80(B细胞,自体免疫、过敏或恶性的);CD86(B细胞,自体免疫、过敏或恶性的);CD2(T细胞或NK细胞淋巴瘤);CA125(多种癌症,包括卵巢癌);碳酸酐酶IX(多种癌症,包括肾细胞癌);CD70(B细胞,自体免疫、过敏或恶性);CD74(B细胞、自体免疫、过敏或恶性);CD56(T细胞或NK细胞淋巴瘤);CD40(B细胞,自体免疫、过敏或恶性);CD19(B细胞,自体免疫、过敏或恶性);c-met/HGFR(胃肠道和肝恶性肿瘤);TRAIL-R1(多种恶性肿瘤,包括卵巢和结直肠癌);DR5(多种恶性肿瘤,包括卵巢和结直肠癌);PD-1(B细胞,自体免疫、过敏或恶性的);PD1L(多种恶性肿瘤,包括上皮腺癌);IGF-1R(大部分恶性肿瘤,包括上皮腺癌);VEGF-R2(与大部分恶性肿瘤相关的脉管系统,包括上皮腺癌);前列腺干细胞抗原(PSCA)(前列腺腺癌);MUC1(上皮恶性肿瘤);CanAg(肿瘤,如结肠和胰腺的癌症);间皮素(许多肿瘤,包括间皮瘤以及卵巢和胰腺腺癌);P-钙粘蛋白(上皮恶性肿瘤,包括乳腺癌);肌肉生长抑制素(GDF8)(许多肿瘤,包括肉瘤以及卵巢和胰腺腺癌);Cripto(TDGF1)(上皮恶性肿瘤,包括结肠、乳房、肺、卵巢和胰腺癌);ACVRL1/ALK1(多种恶性肿瘤,包括白血病和淋巴瘤);MUC5AC(上皮恶性肿瘤,包括乳腺癌);CEACAM(上皮恶性肿瘤,包括乳腺癌);CD137(B细胞或T细胞,自体免疫、过敏或恶性的);CXCR4(B细胞或T细胞,自体免疫、过敏或恶性的);神经菌毛素1(上皮恶性肿瘤,包括肺癌);磷脂酰肌醇聚糖(Glypicans)(多种癌症,包括肝、脑和乳腺癌);HER3/EGFR(上皮恶性肿瘤);PDGFRa(上皮恶性肿瘤);EphA2(多种癌症,包括神经母细胞瘤、黑素瘤、乳腺癌和小细胞肺癌)和CD138(骨髓瘤)。
特别优选的抗体包括抗表皮生长因子受体抗体(如,西妥昔单抗(Cetuximab))、抗-Her2抗体、抗-CD20抗体(如,利妥昔单抗(Rituximab))、抗-CD22抗体(如,奥英妥珠单抗(Inotuzumab))、抗-CD70抗体、抗-CD33抗体(如hp67.6或吉妥珠单抗(Gemtuzumab))、抗-MUC1抗体(如,GP1.4和SM3)、抗-CD40抗体、抗-CD74抗体、抗P-钙粘蛋白抗体、抗-EpCAM抗体、抗-CD138抗体、抗E-钙粘蛋白抗体、抗-CEA抗体和抗-FGFR3抗体。
表1中给出了可以被靶向半体靶向的肿瘤相关、免疫细胞相关和传染剂相关的抗原的实例。
表1:用于靶向的细胞表面抗原
a)肿瘤相关抗原
2Clarke等(1985)Proc.Natl.Acad.Sci.USA 82,1766-1770
其他抗原包括α甲胎蛋白、Ca-125和前列腺特异性抗原。
b)免疫细胞抗原
c)传染剂相关抗原
或者,靶向半体可以是以非免疫的方式特异性地结合由不需要的细胞表达的或另外与不需要的细胞相关的实体的任何化合物或其部分。因此,特异性的结合配偶体可以是激素、生长因子、细胞因子或受体配体(例如,激动剂或拮抗剂)中的任何一种。
例如,细胞因子之前已经用于将毒素靶向入侵中的细菌。通过使用遗传工程化,已经产生重组蛋白,其含有例如IL-2和结合结构域删除的假单胞菌外毒素蛋白(Lorderboum-Galski等,1988(62))。这种免疫毒素在实验动物模型中是有效的(Kozak等,1990(63))。与IL-4、IL-6、α-MSH、EGF和TNF-α的融合蛋白也已经产生(综述于Waldmann 1992(35)),所有都适宜用作本发明中的靶向半体。
特别有用的靶向半体包括细胞因子,如IL-2、EGF、VEGF、Flt3L、HGF、IGF、IL-6或IL-4。IL-2和IL-4可以靶向成人T细胞白血病/淋巴瘤细胞,其表达高亲和性IL-2受体,而正常静息T-细胞不表达,或靶向表达IL-4受体的T细胞。之前已经表明,结合人IL-4受体的单克隆抗体MR6可以抑制IL-4诱导的克隆辅助T细胞的增殖和多克隆B细胞的IgE产生(Larche等,1988(36))。这样的靶向半体可以用于消除自体免疫疾病或过敏中的淋巴样细胞亚群。
胰岛素样生长因子(IGF-1和IGF-11)偏向性地被恶性细胞吸收,并且因此可以用于靶向肿瘤细胞。相似地,EGF可以用于靶向上调EGF受体的恶性细胞。此外,肿瘤相关的血管过表达VEGF受体,因此可以被VEGF生长因子家族靶向。
Flt3受体在白血病中过表达,并且可以是用于急性和慢性白血病以及骨髓增生性疾病的治疗目标。
骨髓瘤细胞表达IL-6受体,并且也分泌IL-6,其以自分泌方式起作用,来刺激细胞增殖。因此,IL-6可以用作骨髓瘤的靶向半体。
在另一个实例中,靶向半体是黑素瘤刺激激素(MSH),其结合在黑素瘤细胞中大量表达的MSH受体。
认识到,本领域技术人员可以容易地选择用于任何给定的不需要的细胞的合适结合配偶体,例如,通过鉴定不需要的细胞特异性的表面抗原或分子并且发现用于该抗原或分子的结合配偶体。如上所述,对肿瘤相关抗原、免疫细胞抗原和传染剂的抗体及其片段已经进行了相当多的研究。因此,便利地,选择用于给定的细胞类型的合适靶向半体通常涉及搜寻文献。或者,从病人获取不需要的细胞(例如,通过活检),并且制备针对细胞的抗体。这样的“定制”抗体是已知的。已经证明了抗体给予与肿瘤细胞的结合,所述肿瘤细胞不仅来自已经获得它们的病人而且也来自大量其他病人。因此,多种这样的抗体已经变成商业上可获得的。鉴定用于给定的不需要的细胞的合适结合配偶体的其他方法包括遗传方法(例如,芯片)、蛋白质组学方法(例如,差异质谱学)、免疫方法(例如,用肿瘤细胞免疫动物并且鉴定分泌抗体的克隆,其特异性地靶向恶性细胞)和在硅中(in silico)的方法,其中使用系统生物学方法鉴定目标。
更多的选择性目标和合适的结合配偶体显示于表2中。
表2:用于肿瘤选择性目标和肿瘤相关抗原的结合配偶体
以下提供了预防或治疗各种癌症中的更多目标。
以下提供了用于预防或治疗特征在于存在不需要的细胞的各种病症的更多选择性目标。对于以下的所有实例,治疗抗体已经是可用的或可以被本领域技术人员容易地制备。
如本文中所用的,术语“抗体”包括但不限于多克隆、单克隆、嵌合、单链、Fab片段、Fab表达文库产生的片段和双特异性抗体。这样的片段包括完整抗体的保留对目标物质的结合活性的片段、Fv、F(ab’)和F(ab’)2片段,以及单链抗体(scFv)、融合蛋白和包含抗体的抗原结合位点的其他合成蛋白。只包含抗体一部分的靶向半体由于优化了从血液的清除速率,可能是有利的,并且由于Fc部分不太可能经历非特异性结合。还包括结构域抗体(dAb)、双特异抗体、骆驼抗体和工程化的骆驼抗体。此外,为了给药于人,抗体及其片段可以是人源化抗体,其现在是本领域公知的(Janeway等(2001)Immunobiology.,第5版,GarlandPublishing);An等(2009)Therapeutic Monoclonal Antibodies(治疗性单克隆抗体):From Bench to Clinic,ISBN:978-0-470-11791-0)。
还包括不对称IgG-样抗体(例如,triomab/quadroma,Trion Pharma/FreseniusBiotech;结嵌入穴(knobs-into-holes);Genentech;Cross MAb,Roche;静电相配抗体,AMGEN;LUZ-Y,Genentech;链交换工程化结构域(SEDD)体,EMD Serono;biolonic,Merus和Fab-交换抗体,Genmab),对称IgG-样抗体(例如,双重靶向(DT)-Ig,GSK/Domantis;二重特异性(two-in-one)抗体,Genentech;交联MAb,karmanos癌中心;mAb2,F-star;和Cov X-体,Cov X/Pfizer),IgG融合体(例如,双重可变结构域(DVD)-Ig,Abbott;IgG-样双特异性抗体,Eli Lilly;Ts2Ab,Medimmune/AZ;BsAb,ZymoGenetics;HERCULES,Biogen Idec;TvAb,Roche)Fc融合体(例如,ScFv/Fc融合体,Academic Institution;SCORPION,EmergentBioSolutions/Trubion,ZymoGenetics/BMS;双重亲和性重新靶向技术(Fc-DART),MacroGenics;双重(ScFv)2-Fab,National Research Center for Antibody Medicine)Fab融合体(例如,F(ab)2,Medarex/AMGEN;双重作用或Bis-Fab,Genentech;Dock-and-Lock(DNL),ImmunoMedics;二价双特异性,Biotechnol;和Fab-Fv,UCB-Celltech),基于ScFv-和双特异性抗体的抗体(例如,双特异性T细胞啮合物(BiTE),Micromet;串联双特异性抗体(Tandab),Affimed;DARTs,MacroGenics;单链双特异性抗体,Academic;TCR-样抗体,AIT,Receptor Logics;人血清白蛋白ScFv融合体,Merrimack;和COMBODIES,Epigen Biotech),IgG/非-IgG融合体(例如,免疫细胞因子,EMDSerono,Philogen,ImmunGene,ImmunoMedics;超抗原融合蛋白,Active Biotech;和对抗癌症的免疫代谢mTCR,ImmTAC)和寡克隆抗体(例如,Symphogen和Merus)。
抗体可以具有Carter(2006)“Potent antibody therapeutics by design”(通过设计的有效抗体治疗),Nat Rev Immunol.6(5):343-57和Carter(2011)“Introduction tocurrent and future protein therapeutics:a protein engineering perspective”(目前和将来的蛋白治疗的介绍:蛋白工程化远景),Exp Cell Res.317(9):1261-9所述的任一种抗体样支架和本文中所述的特异性决定区,将上述文献按引用并入本文中作为参考。因此,术语“抗体”还包括亲和体(affibody)和非基于免疫球蛋白的框架。实例包括adnectins、抗钙素(anticalins)、亲和素(affilins)、反体(trans-bodies)、预设计锚蛋白重复蛋白(darpins)、三体X(trimer)、微蛋白、fynomers、高亲和性多聚体(avimers)、centgrins和kalbitor(艾卡拉肽(ecallantide))。
使用抗体片段而不是整个抗体的优点有很多。较小大小的片段可以提高药物特性,如更好的实体组织的渗透。此外,抗原结合片段,如Fab、Fv、ScF和dAb抗体片段可以在大肠杆菌或酵母中表达并从其分泌出来,因此可以方便地在实验室中生产并以商业规模经济地生产。
抗体可以是IgG、IgE、IgA、IgM和IgD类别中的任何一种,并且可以源自任何物种。如果抗体是IgG,可以是IgG1、IgG2、IgG3或IgG4中的任何一种。然而,优选将药剂给予特定宿主时,抗体或至少其恒定区,源自该宿主。例如,药剂待给药于人时,抗体优选是人抗体或人源化抗体等。
本领域技术人员可以通过使用本领域长期确立的技术来制备结合由不需要的细胞表达的特定抗原的合适抗体。制备单克隆抗体和抗体片段的方法是本领域公知的,并且包括杂交瘤技术(Kohler&Milstein(1975)“Continuous cultures of fused cellssecreting antibody of predefined specificity(分泌预定特异性抗体的融合细胞的连续培养物),Nature 256:495-497);抗体噬菌体展示(Winter等(1994)“Making antibodiesby phage display technology.”(通过噬菌体展示技术制备抗体),Annu.Rev.Immunol.12:433-455);核糖体展示(Schaffitzel等(1999)“Ribosome display:an in vitro method for selection and evolution of antibodies from libraries.”(核糖体展示:用于从文库选择和评价抗体),J.Immunol.Methods 231:119-135);和反复菌落过滤筛选(Giovannoni等(2001)“Isolation of anti-angiogenesis antibodies froma large combinatorial repertoire by colony filter screening.”(通过菌落过滤筛选从大的组合库分离抗血管生成抗体),Nucleic Acids Res.29:E27)。此外,描述了适用于本发明的抗体和抗体片段,例如,在以下出版物中:“Monoclonal Hybridoma Antibodies:Techniques and Application”(单克隆杂交瘤抗体:技术和应用,Hurrell(CRC Press,1982);“Monoclonal Antibodies:A Manual of Techniques”(单克隆抗体:技术手册),H.Zola,CRC Press,1987,ISBN:0-84936-476-0;“Antibodies:A Laboratory Manual”(抗体:实验室手册),第1版,Harlow&Lane编辑,Cold Spring Harbor Laboratory Press,NewYork,1988.ISBN 0-87969-314-2;“Using Antibodies:A Laboratory Manual”(使用抗体:实验室手册),第2版,Harlow&Lane编辑,Cold Spring Harbor Laboratory Press,NewYork,1999.ISBN 0-87969-543-9和“Handbook of Therapeutic Antibodies”(治疗抗体手册),Stefan Dübel编辑,第1版-Wiley-VCH,Weinheim,2007.ISBN:3-527-31453-9。
作为靶向半体是特异性结合配偶体的替换方案,靶向半体可以是给药于患者后能够在不需要的细胞附近累积的非特异性分子。例如,已知大分子在肿瘤中非特异性地累积。已知在肿瘤中非特异性地累积的大分子包括白蛋白、免疫球蛋白、转铁蛋白、脂质体、纳米颗粒(例如,胶体纳米颗粒)和生物可降解聚合物,包括葡聚糖、聚乙二醇、聚赖氨酸和羟丙基甲基丙烯酰胺。大分子在裸鼠中的人异种移植的肿瘤中累积高达约2.0%给药剂量/克肿瘤。已经发现大分子(如,聚乙二醇和葡聚糖)改变它们连接的物质的清除速率,并且改变它们在肿瘤中的浓度(Melton等,1987;Eno-Ammoquaye等,1996)。在特殊的肿瘤中,非特异性大分子可以以高于针对分泌的抗原的抗体的浓度累积(Searle等,1981)。
将这种大分子在肿瘤中累积的发现称为增强的渗透性和停留(EPR)作用,并且归因于肿瘤毛细血管的泄漏和不足的淋巴排泄(Matsumura&Macda,1986)。
因此,当不需要的细胞是肿瘤细胞时,靶向半体可以是这些在肿瘤中累积的大分子中的任何一种。优选地,本发明中所用的大分子是亲水性的,并且特征在于可溶于体液和常规流体中,用于非肠道给药。合适地,大分子是生物可降解的,使得避免在重复给药过程中的全身累积。然而,显然地,必须不能非常快地降解,以致不能在不需要的细胞的位点(例如,肿瘤)累积。优选地,包含这样的大分子靶向半体的药剂的分子量和大小超过尿液排泄的肾脏门槛(MW 60 000),因为这有助于使血液浓度足以提供有效的血液:肿瘤浓度梯度。高达至少800 000的分子量通常是合适的,例如高达160 000。大分子优选是不容易被网状内皮系统捕获的大分子。给定的分子量排除任何水合的水。
可以以亚基形式获得并且不是生物可降解的大分子可以通过生物可降解连接单体来连接,使得非生物可降解组分通过肾脏过滤并在尿液中排泄。
或者,如果用于制备大分子的聚合物不是生物可降解的,使得偶联物的任何非生物可降解部分的分子量应当低于肾门槛(大约70000),使得在生物可降解部分降解后,通过肾脏排泄残余的非生物可降解部分,则这是优选的。
方便地,大分子可以是葡聚糖;聚氨基酸;纳米颗粒(例如,胶体纳米颗粒),或非肿瘤特异性蛋白(如,免疫球蛋白、白蛋白或转铁蛋白)中的任何一种。合适地,可以是苯乙烯和马来酐的共聚物,或可以是聚天冬氨酸、聚-L-赖氨酸、聚乙烯亚胺或聚乙二醇。
认识到,这样的大分子能用于黑素细胞针对的酶前药治疗(MDEPT)中,如WO 1998/024478中所述的。
不需要的细胞
不需要的细胞可以是其在宿主中的存在是不希望有的任何细胞。因此,细胞可以是肿瘤细胞(良性或恶性)、来自肿瘤微环境的细胞,如肿瘤成纤维细胞或肿瘤血管、病毒感染的细胞、作为基因治疗的一部分引入的细胞或出于特定原因希望破坏的正常细胞。例如,可能希望消除免疫细胞的亚群,如自体免疫疾病中的T淋巴细胞或如过敏疾病中的B淋巴细胞。
“特征在于存在不需要的细胞的病症”包括其中至少一部分病状是由不需要的细胞的存在介导的任何生物或医学病症或失调。病症可以是由不需要的细胞的存在引起的,或不需要的细胞的存在是病症的作用。特定病症的实例包括肿瘤(良性或恶性)、自体免疫病症、心血管病、变性疾病、糖尿病、过敏性疾病(例如,哮喘)、神经变性疾病(如,阿尔茨海默氏病)、移植病人和传染病。将理解,所述药剂在再生医学(例如,实验室生长的器官或组织)中也具有实用性。如果病症是肿瘤(例如,恶性疾病)并且不需要的细胞是肿瘤细胞或肿瘤相关组织,则特别优选。
对于自体免疫疾病,不需要的细胞可以表示适应性或先天性免疫应答的细胞,优选T细胞,但更优选B细胞。对于心血管病,不需要的细胞可以表示动脉粥样损伤内的细胞,如巨噬细胞。对于变性疾病,不需要的细胞可以表示诱导神经变性变化的细胞,例如,在阿尔茨海默氏病中,它们可以是小胶质细胞或星形细胞。对于其他变性疾病,促进变性或凋亡过程的任何细胞可以认为是目标。对于如老化这样的过程,其中不需要的组织例如在良性前列腺增生中构建,那么非恶性前列腺组织将是优选的目标。对于过敏性疾病,参与过敏反应的细胞,如组织肥大细胞,可以认为是理想的目标,但还包括IgE分泌细胞,如浆细胞或B细胞。在移植中,同种异体反应性淋巴细胞将表示优选的靶细胞。在传染病的内容中,带有病毒、细菌或真菌病原体的任何细胞可以认为是优选的靶细胞,例如HIV感染的细胞。
在一个实施方案中,不需要的细胞不是抗原递呈细胞,如具有交叉递呈能力的专业抗原递呈细胞。
T细胞抗原
“T细胞抗原”包括可以递呈给T细胞使得引发T细胞应答的任何抗原。例如,T细胞抗原可以通过MHC分子或通过I组CD1分子递呈给T细胞。一旦在细胞表面上递呈了抗原,则细胞将被识别为外源的,并且变成T细胞的目标,其中一些具有消除被外源生物体(如,病毒、真菌、细菌、分枝杆菌或原生动物)感染的或已经变成癌性的(例如,恶性的)外源细胞的天然功能。因此,将认识到,T细胞抗原可以是能够被不需要的细胞上的分子递呈的抗原。然而,T细胞抗原可能在不需要的细胞以外的细胞上递呈,但仍然在不需要的细胞的附近,并且借助随后的T细胞激活,将不需要的细胞杀灭,例如,通过激活的T细胞局部产生的细胞因子杀灭。例如,对于靶向支持肿瘤生长的肿瘤血管和/或基质细胞,这样的间接杀灭可能是需要的。
将认识到,T细胞抗原是可以引发给予本发明药剂的患者体内的现有T细胞应答的抗原。通常,T细胞抗原不是通过APC中的交叉递呈产生对抗原的新初级T细胞应答的抗原。为了进入另一条途径,T细胞抗原是患者体内的许多T细胞已经对其敏化的抗原。可以通过将从患者分离的外周单核血细胞接触抗原并且使用用于细胞增殖的标准试验来测定患者的细胞是否已经对给定的抗原敏化,如以下和实施例中进一步描述的。
在一个实施方案中,本发明的药剂不是对其中含有的T细胞抗原产生新的特异性T细胞应答的药剂。因此,本发明包括用于预防或治疗特征在于存在不需要的细胞的药剂,所述药剂含有(i)能够靶向不需要的细胞的靶向半体;和(ii)T细胞抗原,其中T细胞抗原可以通过药剂中的切割位点的选择性切割在不需要的细胞附近从靶向半体中释放出来,并且其中T细胞抗原能够引发患者体内现有的T细胞应答。
“T细胞”包括所有类型T细胞,包括CD4+、CD8+、γδT细胞和NK-T细胞。优选地,T细胞是细胞毒性的T细胞,使得引发细胞毒性的T细胞应答。
如本领域已知的,抗原递呈机制将取决于T细胞的类型。通常,CD4+T细胞识别结合II类MHC分子的肽抗原,CD8+T细胞识别结合I类MHC分子的肽抗原,γδT细胞识别结合I组CD1分子的小的磷酸化分子、烷基胺或脂质,以及NK-T细胞识别结合I组CD1分子的脂质抗原。将理解,可以使用任何递呈途径,只要抗原引发T细胞应答。因此,T细胞抗原可以是能够结合I类MHC分子或II类MHC分子的抗原,或能够结合I组CD1分子的抗原。
优选地,T细胞抗原是免疫显性抗原(例如,引发现有免疫显性应答的抗原)。“免疫显性”包括以高量级、灵敏度、组织归巢特征和杀灭携带抗原的细胞的效率引发T细胞应答的抗原。通常,免疫显性应答包括超过0.1%的患者的CD8+或CD4+T细胞。例如,可以通过将从患者分离的外周单核血细胞接触抗原并使用本领域已知的用于细胞增殖的标准试验来进行对给定抗原的T细胞应答程度的测定。用于测定免疫应答程度的合适试验包括ELISpot、胞内细胞因子染色、HLA-肽四聚体染色、增殖试验、激活试验(例如,CD69)、CD107动员试验或代谢试验(例如,MTT)。
合适的T细胞抗原的实例包括肽、多肽、磷酸肽或脂质中的任何一种,如磷脂或鞘脂,并且以下提供了这些中每一种的更多实例。
当T细胞抗原是肽或多肽时,它通常是结合MHC分子时能够被T细胞受体识别的肽或多肽。T细胞抗原可以是I类MHC限制抗原,其只结合I类MHC分子,或可以是II类MHC限制抗原,其只结合II类MHC分子。认识到,抗原可以只结合特定的变体I类MHC和/或II类MHC分子(例如,特定患者中发现的自然变体),或抗原能够结合任何I类MHC和/或II类MHC分子(即,抗原是混杂的)。
在一个实施方案中,T细胞抗原能够结合I类MHC分子,如HLA-A、HLA-B和HLA-C中的任何一种。因为I类MHC分子在所有细胞类型上表达,这使得本发明的药剂将免疫应答重新定向至任何不需要的细胞。最优选地,肽能够结合A1、A2.1、A3.2、A11、A24、B7、B8、B35、B44、Cw1、Cw2、Cw3、Cw4和Cw6型HLA或其混合物,认为其覆盖超过90%的高加索和亚洲人群。
在另一个实施方案中,T细胞抗原能够结合II类MHC分子,如HLA-DP、HLA-DQ或HLA-DR的任意一种。常见的II类MHC类型包括DR1、DR3、DR4、DR7、DR52、DQ1、DQ2、DQ4、DQ8和DP1。II类MHC分子在免疫细胞上表达,包括抗原递呈细胞,如树突细胞、B细胞和巨噬细胞。因此,当T细胞抗原是II类MHC限制时,本发明的药剂可以用于治疗如淋巴瘤或自体免疫疾病这样的病症。
可以使用的混杂肽的实例是Alexander等(2000)The Journal of Immunology164:1625-1633中限定的PADRE MHC II类表位;aKXVAAWTLKAAaZC(a=d-丙氨酸,X=L-环己基丙氨酸,Z=氨基己酸))(SEQ ID No:1)。由于这个表位是人造的,首先需要在给予本发明的药剂前,在病人中引入疫苗,以产生免疫应答。可以使用的另一种混杂肽是破伤风片段C肽。
便利地,T细胞抗原是由MHC分子识别的免疫原性肽。这样的肽通常长9至22个氨基酸(对于在II类MHC复合物中的识别)或长8至13个氨基酸(对于在I类MHC复合物中的识别)。优选地,肽是免疫显性肽。
免疫显性肽的实例包括病毒衍生的引发内源性抗病毒应答的肽。因此,肽可以源自内源性病毒,如水痘-带状疱疹病毒、单纯疱疹病毒、细胞巨化病毒、EB病毒或流感病毒。特别优选的实例包括源自人细胞巨化病毒(CMV或人疱疹病毒5/HHV5)或EB病毒(EBV或HHV4);疱疹病毒,如HHV1、HHV2和HHV3;A型流感病毒;B型流感病毒;鼻病毒;腺病毒;和肝病毒科(Hepadnaviridae)的肽。
对于人细胞巨化病毒(HHV5),免疫显性抗原得到了充分表征(参见SylwesterAW等,J Exp Med.2005 Sep 5;202(5):673-85,按引用并入本文中作为参考),并且Sylwester等描述的任何这样的抗原可以用于本发明中。特别地,Sylester等合成了连续的15mer肽,对于213个预测的人CMV蛋白,有10个氨基酸重叠。这产生13,687个排列在ORF或亚-ORF特异性混合物中的肽。发现源自ORF UL55(gB)、UL 83(pp65)、UL 86、UL 99(pp28)、UL 122(IE2)、UL 36、UL 48、UL32(pp150)、UL 113、IRS-1、UL 123(IE1)、UL25、UL 141、UL 52和UL82(pp71)的肽引发最多的CD4+T细胞应答,并且因此如果肽源自这些ORF中的一个,将特别优选。或者,发现源自ORF UL48、UL83(pp66)、UL 123(IE1)、UL 123(IE2)、US 32、UL 28、US29、US3、UL 32(pp150)、UL 55(gB)、UL 94、UL 69、UL 105、UL 82(pp71)和UL 99(pp28)的肽引发最多的CD8+T细胞应答,因此如果肽源自这些ORF中的一个,将特别优选。
特别地,以下列出了细胞巨化病毒T细胞抗原。
细胞巨化病毒抗原的CD8+T细胞表位,如IE1,包括YILEETSVM(SEQ ID No:2),YVLEETSVM(SEQ ID No:3),VLEETSVML(SEQ ID No:4),VLAELVKQI(SEQ ID No:5),ATTFLQTMLR(SEQ ID No:6),EVISVMKRR(SEQ ID No:7),CRVLCCYVL(SEQ ID No:8),ELRRKMMYM(SEQ ID No:9),ELKRKMIYM(SEQ ID No:10),QIKVRVDMV(SEQ ID No:11),CVETMCNEY(SEQ ID No:12),RRKMMYMCY(SEQ ID No:13),KRKMIYMCY(SEQ ID No:14),RRIEEICMK(SEQ ID No:15),DELRRKMMY(SEQ ID No:16),KEVNSQLSL(SEQ ID No:17),EEAIVAYTL(SEQ ID No:18)和FPKTTNGCSQA(SEQ ID No:19):对于pp65,包括YSEHPTFTSQY(SEQ ID No:20),NLVPMVATV(SEQ ID No:21),MLNIPSINV(SEQ ID No:22),RIFAELEGV(SEQID No:23),QYDVPAALF(SEQ ID No:24),FTSQYRIQGKL(SEQ ID No:25),VYALPLKML(SEQ IDNo:26),QYVKVYLESF(SEQ ID No:27),FVFPTKDVALR(SEQ ID No:28),YTPDSTPCHR(SEQ IDNo:29),DTPVLPHETR(SEQ ID No:30),TPRVTGGGAM(SEQ ID No:31),RPHERNGFTVL(SEQ IDNo:32),IPSINVHHY(SEQ ID No:33),FPTKDVAL(SEQ ID No:34),CPSQEPMSIYVY(SEQ ID No:35),QPSLILVSQY(SEQ ID No:36),SEHPTFTSQY(SEQ ID No:37),EFFDANDIY(SEQ ID No:38);对于pp150,包括TTVYPPSSTAK(SEQ ID No:39),QTVTSTPVQGR(SEQ ID No:40),NVRRSWEEL(SEQ ID No:41),KARDHLAVL(SEQ ID No:42);对于gB,包括RIWCLVVCV(SEQ IDNo:43);并且对于pp50,包括VTEHDTLLY(SEQ ID No:44),RGDPFDKNY(SEQ ID No:45),TVRSHCVSK(SEQ ID No:46)。
对于细胞巨化病毒抗原的CD4+T细胞表位,如pp65,包括PQYSEHPTFTSQYRIQ(SEQID No:47),FTSQYRIQGKLEYRHT(SEQ ID No:48),LLQTGIHVRVSQPSL(SEQ ID No:49),NPQPFMRPHERNGFT(SEQ ID No:50),EPDVYYTSAFVFPTK(SEQ ID No:51),IIKPGKISHIMLDVA(SEQ ID No:52),AGILARNLVPMVATV(SEQ ID No:53),KYQEFFWDANDIYRI(SEQ ID No:54);对于gB,包括DYSNTHSTRYV(SEQ ID No:55),CMLTITTARSKYPYH(SEQ ID No:56)和VFETSGGLVVFWQGI(SEQ ID No:57);对于IE1,包括VRVDMVRHRIKEHMLKKYTQ(SEQ ID No:58)和NYIVPEDKREMWMACIKELH(SEQ ID No:59)。
对于EB病毒(EBV或HHV4),免疫显性蛋白也得到了充分表征,并且Hislop AD等,Annu Rev Immunol.2007;25:587-617中有提供(按引用并入本文中作为参考)。以下提供了改编自Hislop等的T细胞表位的列表。
表3:EBV裂解的和潜伏的循环蛋白中鉴定的CD8+和CD4+T细胞表位(改编自Hislop等)
CD8+T细胞表位
CD4+T细胞表位
免疫显性肽的更多实例包括HLA-A*0201-限制表位(HCNV pp65 495-504-NLVNLVPMVATV(SEQ ID No:21),HCMV IE1 VLEETSVML(SEQ ID No:4),EBV LMP-2 356-364FLYALALLL(SEQ ID No:127),EBV BMLF-1 259-267 GLCTLVAML(SEQ ID No:155));HLA-A*0101-限制表位(HCMV pp50 245-253-VTEHDTLLY(SEQ ID No:44);HCMV pp65 363-373-YSEHPTFTSQY)(SEQ ID No:20);HLA-A*0301-限制表位(HCMV pp50-TVRSHCVSK(SEQ ID No:46),);HLA-B*0702-限制表位(HCMV pp65 417-426 TPRVTGGGAM(SEQ ID No:31),pp65265-275 RPHERNGFTVL(SEQ ID No:32));和HLA-B*0801-限制表位(HCMV IE1 88-96-ELKRKMMYM(SEQ ID N:o 253),IE1 88-96 QIKVRVDMV(SEQ ID No:11),EBV BZLF-1 190-197 RAKFKQLL(SEQ ID No:152),其中任何一个都可以用于本发明的内容中。
认识到T细胞抗原(例如,肽)可以是源自活疫苗的抗原,所述活疫苗如麻疹、流行性腮腺炎、风疹(MMR)或HHV3;或是源自胞内细菌的抗原,所述细菌如分枝杆菌,特别是通过用BCG免疫引起的那些。这样的肽是本领域公知的。相似地,T细胞抗原(例如,肽)可以源自破伤风类毒素,如P2、P4或P30。因此,将理解T细胞抗原(例如,肽)可以是引发患者体内现有的免疫应答的抗原,所述现有的免疫应答是通过之前对抗感染剂的疫苗接种产生的。因此,为了增加对T细胞抗原敏化的T细胞数量,用含有T细胞抗原的疫苗接种或加强患者是合乎需要的。例如,患者可以接种破伤风毒素,接着给药本发明的包含相关T细胞抗原的药剂。
将认识到,因为许多人在孩童时期接种了这些疫苗,他们很可能含有对这些T细胞抗原敏化的T细胞。因此,在一个实施方案中,T细胞抗原是在孩童时期疫苗中发现的抗原。
尽管不是优选地,T细胞抗原(例如,肽)还可以是引发患者体内现有免疫应答的抗原,所述现有免疫应答是通过将患者的T细胞在体外暴露于抗原产生的。
可以通过公知的化学程序来产生肽,所述化学程序如溶液或固相合成,或溶液中的半合成,所述半合成用通过本领域已知的常规溶液方法偶联的蛋白片段开始。或者,可以通过确定的方法,包括重组方法,来合成肽。
尽管优选T细胞抗原是多肽或肽,已知其他抗原也能够引发免疫应答,并且因此在本发明中具有实用性。例如,γδT细胞不识别MHC-相关的肽抗原,并且不是MHC限制的。一些γδT细胞克隆识别小的磷酸化分子、焦磷酸化化合物(例如,HMBPP(E-4-羟基-3-甲基-丁-2-烯基-焦磷酸酯)和IPP(异戊烯基焦磷酸酯))、烷基胺或脂质(例如,磷酸化脂质),这些物质可以通过称为CD1分子的“非经典”I类MHC-样分子递呈。相似地,NK-T细胞(例如,Vα24Vβ11细胞)识别结合CD1分子的脂质(例如,神经酰胺,如α-gal-神经酰胺)。因此,T细胞抗原可以是已知引发T细胞应答的这些分子中的任何一种。
当药剂是用于治疗自体免疫或过敏性疾病时,将认识到T细胞抗原可以分别是自身抗原或过敏原。这样,有助于失调的免疫应答被重新定向至不需要的细胞,以抵抗失调。
认识到T细胞抗原可以是化学修饰的,只要其仍然能够引发T细胞应答。这样的化学修饰可以包括,例如,添加金属,如镍,因为已经显示出在特定的过敏病人中,存在识别具有结合的镍原子的肽的T细胞(Romagnoli等1991,EMBO J 10:1303-1306)。T细胞抗原也可以通过有机分子来修饰,其增强了免疫原性(Romero等,1993,J Immunol 150:3825-3831)。其他修饰包括磷酸化、乙酰化、烷基化、酰化、瓜氨酸化(citrulination)、硝化、硫酸化和羟基化、与酸或碱形成盐、形成末端羧基的酯或酰胺和连接氨基酸保护基团,如N-t-丁氧基羰基(butoxycarbonal)。
当T细胞抗原是肽时,认识到可以包含由DNA编码的天然产生的氨基酸和/或一个或多个非天然氨基酸,包括“D”异构形式的氨基酸,只要它被相应的T细胞识别。因此,肽可以是肽“模拟物”,即素拟肽(peptidomimetic),其模拟上述任一种肽的结构特征。例如,T细胞抗原是逆反(retro inverso)肽。
相似地,T细胞抗原,当肽可以是模拟表位(minotope),即,由天然或非天然氨基酸组成的模拟天然表位结构的肽。模拟表位常常更有效地刺激T细胞。
优选地,T细胞抗原在T淋巴细胞不存在的情况中,基本上是无毒的。“基本上无毒的”意思是与毒素(如,假单胞菌内毒素)相比,抗原具有相当低或优选不可检测的毒性。
通过使用http://www.immuneepitope.org(Vita R,Zarebski L,Greenbaum JA,Emami H,Hoof I,Salimi N,Damle R,Sette A,Peters B.The immune epitope database2.0(免疫表位数据库2.0),Nucleic Acids Res.2010 Jan;38(数据库发表):D854-62.Epub2009年11月11日),本领域技术人员将能够鉴定更多的可以用于本发明中的T细胞抗原。
选择性切割
“通过药剂中的切割位点的选择性切割在不需要的细胞附近从靶向半体中释放出来”包括T细胞抗原通过T细胞抗原和靶向半体之间的切割位点从靶向半体中释放出来的意思,所述靶向半体在不需要的细胞附近被选择性地切割。
“不需要的细胞附近的可选择性切割的切割位点”包括只可以通过选择性地停留在不需要的细胞附近的分子来切割的位点的意思,从而从靶向半体中释放出T细胞抗原。优选地,切割切割位点的分子以高于不需要的细胞附近以外的分子浓度至少五倍或十倍的浓度停留在不需要的细胞的附近,并且更优选以高至少100或500或1000倍的浓度。最优选地,只在不需要的细胞附近发现切割切割位点的分子。例如,当不需要的细胞是特定的肿瘤细胞(例如,乳房肿瘤细胞)时,切割位点可以是通过选择性地停留在特定肿瘤(例如,乳房肿瘤)中的分子来切割的位点,但该分子没有停留在特定肿瘤(例如,乳房肿瘤)附近以外。
“细胞的附近”包括在细胞表面或接近细胞表面或两者或在就在围绕细胞的环境中(例如,血液、淋巴和其他体液)的意思。在特别优选的实施方案中,切割位点在不需要的细胞外、在其表面或接近其表面选择性地切割,使得可以通过不需要的细胞将T细胞抗原递呈给T细胞,而不需要被内在化。
切割位点在不需要的细胞附近选择性地切割,使得T细胞抗原偏向性地被不需要的细胞递呈,而不是被需要的细胞递呈。因此,优选切割位点是选择性切割的位点,以使得T细胞抗原以高于在需要的细胞附近释放的程度至少五倍或十倍的程度在不需要的细胞附近释放,并且更优选高至少100或500或1000倍。最优选地,T细胞抗原没有在需要的细胞附近释放,并且因此没有被需要的细胞递呈。
对于给定的不需要的细胞,本领域技术人员使用本领域中确定的方法将能够鉴定在不需要的细胞附近可选择性切割的合适切割位点。例如,可以通过参照肽文库和研究切割后片段化特征的MS分析来确定哪种蛋白酶可以切割哪种肽。此外,可以按照以下进一步的描述来研究蛋白酶切割基序和肽切割数据的出版文献。还可以分析基因表达和蛋白质组学数据来鉴定特定的不需要的细胞表达哪种蛋白酶。
借助在不需要的细胞附近可选择性切割的切割位点,T细胞抗原在不需要的细胞附近选择性地释放。发明人认为这允许不需要的细胞将T细胞抗原递呈给T细胞,由此将现有的免疫应答重新定向至不需要的细胞。
在优选的实施方案中,切割位点是在不需要的细胞附近和在不需要的细胞外切割的位点,例如,在细胞表面。这样,T细胞抗原可以在细胞外表面的附近释放并且直接递呈给T细胞,而不需要被内在化和进入合适的加工途径。因此,本发明包括用于预防或治疗特征在于存在不需要的细胞的病症的药剂,该药剂含有(i)能够靶向不需要的细胞的靶向半体;和(ii)T细胞抗原,其中T细胞抗原通过不需要的细胞附近和之外的药剂中的切割位点的选择性切割从靶向半体中释放出来。优选地,T细胞抗原是没有产生新的用于该抗原的初级T细胞应答而是引发了患者体内现有的T细胞应答的抗原。
然而,发明人还认为T细胞抗原可以在细胞内释放,而不需要经历传统的抗原加工,并且仍将递呈给T细胞。因此,将理解切割位点不需要在细胞表面切割,但可以在细胞内切割,例如,通过受体循环途径或在膜附近区隔中,如泡囊(例如,胞饮泡囊)。
切割位点可以是通过酶可以切割的位点,所述酶如蛋白酶、核酶、脂酶、裂解酶、磷酸酶或糖酶中的任何一种,其可以是或不是膜结合的。
通常,切割位点是蛋白酶切割位点。因此,当不需要的细胞是肿瘤细胞时,切割位点可以是通过停留在肿瘤细胞附近的蛋白酶选择性切割的切割位点。换句话说,蛋白酶切割位点可以是通过肿瘤相关蛋白酶可切割的位点。公知在肿瘤发展过程中,肿瘤异常地表达蛋白酶,该蛋白酶使得它们入侵局部组织并且最终转移。
蛋白酶可以包括半胱氨酸蛋白酶(包括组织蛋白酶家族B、L、S等)、天冬氨酰蛋白酶(包括组织蛋白酶D和E)和丝氨酸蛋白酶(包括组织蛋白酶A和G、凝血酶、纤溶酶、尿激酶、组织纤溶酶原激活剂)中的任何一种。蛋白酶可以是金属蛋白酶(MMP1-28),包括膜结合(MMP14-17和MMP24-25)和分泌形式(MMP1-13、MMP18-23和MMP26-28)。蛋白酶可以属于解聚素A(A Disintegrin)和金属蛋白酶(ADAM)和具有蛋白酶凝血栓蛋白基序(ADAMTA)家族的解聚素A或金属蛋白酶。其他实例包括CD10(CALLA)和前列腺特异性抗原(PSA)。认识到蛋白酶可以是或不是膜结合的。
蛋白酶切割位点是科学文献中公知的,并且可以使用确定的遗传工程技术或通过本领域已知的合成的合成技术,来容易地构建包含这样的切割位点的连接物序列。
蛋白酶切割位点可以是通过以下表4中所列的任一种蛋白酶可切割的位点,这表明了选定的蛋白酶在各种肿瘤类型中的表达。提供了蛋白酶的候选底物。因此,为了治疗特定的肿瘤类型,本领域技术人员通常将选择通过已知在该肿瘤类型中高表达的蛋白酶选择性切割的蛋白酶切割位点,如从表格中可以看到。例如,为了治疗乳腺癌,优选使用通过uPA、tPA、间质蛋白酶(matriptase)、间质蛋白酶2、组织蛋白酶K、组织蛋白酶O、MMP1、MMP2、MMP3、MMP11、MMP12、MMP17、ADAM9、ADAM12、ADAM15、ADAM17、ADAM28或ADAMTS15等中的任何一种可切割的蛋白酶切割位点。
相似地,表5列出了其中已经报道了ADAM蛋白酶过表达的肿瘤位点,并且因此在一个实施方案中,切割位点是通过表5中所列的ADAM蛋白酶中的任何一种选择性切割的切割位点。因此,药剂可以用于预防或治疗相应的肿瘤类型。
切割位点可以通过以下的人蛋白酶中的任何一种选择性地切割(括号内提供了MEROPS肽酶数据库编号;Rawlings N.D.,Morton F.R.,Kok,C.Y.,Kong,J.&Barrett A.J.(2008)MEROPS:the peptidase database(肽酶数据库).Nucleic Acids Res.36 databaseissue(数据库发表),D320-325):胃蛋白酶A(MER000885),胃亚蛋白酶(MER000894),膜天冬 氨酸蛋白酶2(memapsin-2)(MER005870),肾素(MER000917),组织蛋白酶D(MER000911),组织蛋白酶E(MER000944),膜天冬氨酸蛋白酶-1(MER005534),天冬氨酸蛋白酶(napsin)A(MER004981),Mername-AA034肽酶(MER014038),胃蛋白酶A4(MER037290),胃蛋白酶A5(智人(Homo sapiens))(MER037291),hCG1733572(智人(Homo sapiens))-型推定肽酶(MER107386),天冬氨酸蛋白酶B假基因(MER004982),CYMP g.p.((智人(Homo sapiens))(MER002929),亚家族A1A未分配肽酶(MER181559),小鼠乳房肿瘤病毒逆胃蛋白酶(MER048030),兔内源性逆转录病毒内肽酶(MER043650),S71-相关的人内源性逆胃蛋白酶(MER001812),RTVL-H-型推定肽酶(MER047117),RTVL-H-型推定肽酶(MER047133),RTVL-H-型推定肽酶(MER047160),RTVL-H-型推定肽酶(MER047206),RTVL-H-型推定肽酶(MER047253),RTVL-H-型推定肽酶(MER047260),RTVL-H-型推定肽酶(MER047291),RTVL-H-型推定肽酶(MER047418),RTVL-H-型推定肽酶(MER047440),RTVL-H-型推定肽酶(MER047479),RTVL-H-型推定肽酶(MER047559),RTVL-H-型推定肽酶(MER047583),RTVL-H-型推定肽酶(MER015446),人内源性逆转录病毒逆蛋白酶同源物1(MER015479),人内源性逆转录病毒逆胃蛋白酶同源物2(MER015481),内源性逆转录病毒逆胃蛋白酶假基因1(智人(Homo sapiens)染色体14)(MER029977),内源性逆转录病毒逆胃蛋白酶假基因2(智人(Homo sapiens)染色体8)(MER029665),内源性逆转录病毒逆胃蛋白酶假基因3(智人(Homosapiens)染色体17)(MER002660),内源性逆转录病毒逆胃蛋白酶假基因3(智人(Homosapiens)染色体17)(MER030286),内源性逆转录病毒逆胃蛋白酶假基3(智人(Homosapiens)染色体17)(MER047144),内源性逆转录病毒逆胃蛋白酶假基因5(智人(Homosapiens)染色体12)(MER029664),内源性逆转录病毒逆胃蛋白酶假基因6(智人(Homosapiens)染色体7)(MER002094),内源性逆转录病毒逆胃蛋白酶假基因7(智人(Homosapiens)染色体6)(MER029776),内源性逆转录病毒逆胃蛋白酶假基因8(智人(Homosapiens)染色体Y)(MER030291),内源性逆转录病毒逆胃蛋白酶假基因9(Homo智人(Homosapiens)染色体19)(MER029680),内源性逆转录病毒逆胃蛋白酶假基因10(智人(Homosapiens)染色体12)(MER002848),内源性逆转录病毒逆胃蛋白酶假基因11(智人(Homosapiens)染色体17)(MER004378),内源性逆转录病毒逆胃蛋白酶假基因12(智人(Homosapiens)染色体11)(MER003344),内源性逆转录病毒逆胃蛋白酶假基因13(智人(Homosapiens)染色体2和相似的)(MER029779),内源性逆转录病毒逆胃蛋白酶假基因14(智人(Homo sapiens)染色体2)(MER029778),内源性逆转录病毒逆胃蛋白酶假基因15(智人(Homo sapiens)染色体4)(MER047158),内源性逆转录病毒逆胃蛋白酶假基因15(智人(Homo sapiens)染色体4)(MER047332),内源性逆转录病毒逆胃蛋白酶假基因15(智人(Homo sapiens)染色体4)(MER003182),内源性逆转录病毒逆胃蛋白酶假基因16(MER047165),内源性逆转录病毒逆胃蛋白酶假基因16(MER047178),内源性逆转录病毒逆胃蛋白酶假基因16(MER047200),内源性逆转录病毒逆胃蛋白酶假基因16(MER047315),内源性逆转录病毒逆胃蛋白酶假基因16(MER047405),内源性逆转录病毒逆胃蛋白酶假基因16(MER030292),内源性逆转录病毒逆胃蛋白酶假基因17(智人(Homo sapiens)染色体8)(MER005305),内源性逆转录病毒逆胃蛋白酶假基因18(智人(Homo sapiens)染色体4)(MER030288),内源性逆转录病毒逆胃蛋白酶假基因19(智人(Homo sapiens)染色体16)(MER001740),内源性逆转录病毒逆胃蛋白酶假基因21(智人(Homo sapiens))(MER047222),内源性逆转录病毒逆胃蛋白酶假基因21(智人(Homo sapiens))(MER047454),内源性逆转录病毒逆胃蛋白酶假基因21(智人(Homo sapiens))(MER047477),内源性逆转录病毒逆胃蛋白酶假基因21(智人(Homo sapiens))(MER004403),内源性逆转录病毒逆胃蛋白酶假基因22(智人(Homo sapiens)染色体X)(MER030287),亚家族A2A非-肽酶同系物(MER047046),亚家族A2A非-肽酶同系物(MER047052),亚家族A2A非-肽酶同系物(MER047076),亚家族A2A非-肽酶同系物(MER047080),亚家族A2A非-肽酶同系物(MER047088),亚家族A2A非-肽酶同系物(MER047089),亚家族A2A非-肽酶同系物(MER047091),亚家族A2A非-肽酶同系物(MER047092),亚家族A2A非-肽酶同系物(MER047093),亚家族A2A非-肽酶同系物(MER047094),亚家族A2A非-肽酶同系物(MER047097),亚家族A2A非-肽酶同系物(MER047099),亚家族A2A非-肽酶同系物(MER047101),亚家族A2A非-肽酶同系物(MER047102),亚家族A2A非-肽酶同系物(MER047107),亚家族A2A非-肽酶同系物(MER047108),亚家族A2A非-肽酶同系物(MER047109),亚家族A2A非-肽酶同系物(MER047110),亚家族A2A非-肽酶同系物(MER047111),亚家族A2A非-肽酶同系物(MER047114),亚家族A2A非-肽酶同系物(MER047118),亚家族A2A非-肽酶同系物(MER047121),亚家族A2A非-肽酶同系物(MER047122),亚家族A2A非-肽酶同系物(MER047126),亚家族A2A非-肽酶同系物(MER047129),亚家族A2A非-肽酶同系物(MER047130),亚家族A2A非-肽酶同系物(MER047134),亚家族A2A非-肽酶同系物(MER047135),亚家族A2A非-肽酶同系物(MER047137),亚家族A2A非-肽酶同系物(MER047140),亚家族A2A非-肽酶同系物(MER047141),亚家族A2A非-肽酶同系物(MER047142),亚家族A2A非-肽酶同系物(MER047148),亚家族A2A非-肽酶同系物(MER047149),亚家族A2A非-肽酶同系物(MER047151),亚家族A2A非-肽酶同系物(MER047154),亚家族A2A非-肽酶同系物(MER047155),亚家族A2A非-肽酶同系物(MER047156),亚家族A2A非-肽酶同系物(MER047157),亚家族A2A非-肽酶同系物(MER047159),亚家族A2A非-肽酶同系物(MER047161),亚家族A2A非-肽酶同系物(MER047163),亚家族A2A非-肽酶同系物(MER047166),亚家族A2A非-肽酶同系物(MER047171),亚家族A2A非-肽酶同系物(MER047173),亚家族A2A非-肽酶同系物(MER047174),亚家族A2A非-肽酶同系物(MER047179),亚家族A2A非-肽酶同系物(MER047183),亚家族A2A非-肽酶同系物(MER047186),亚家族A2A非-肽酶同系物(MER047190),亚家族A2A非-肽酶同系物(MER047191),亚家族A2A非-肽酶同系物(MER047196),亚家族A2A非-肽酶同系物(MER047198),亚家族A2A非-肽酶同系物(MER047199),亚家族A2A非-肽酶同系物(MER047201),亚家族A2A非-肽酶同系物(MER047202),亚家族A2A非-肽酶同系物(MER047203),亚家族A2A非-肽酶同系物(MER047204),亚家族A2A非-肽酶同系物(MER047205),亚家族A2A非-肽酶同系物(MER047207),亚家族A2A非-肽酶同系物(MER047208),亚家族A2A非-肽酶同系物(MER047210),亚家族A2A非-肽酶同系物(MER047211),亚家族A2A非-肽酶同系物(MER047212),亚家族A2A非-肽酶同系物(MER047213),亚家族A2A非-肽酶同系物(MER047215),亚家族A2A非-肽酶同系物(MER047216),亚家族A2A非-肽酶同系物(MER047218),亚家族A2A非-肽酶同系物(MER047219),亚家族A2A非-肽酶同系物(MER047221),亚家族A2A非-肽酶同系物(MER047224),亚家族A2A非-肽酶同系物(MER047225),亚家族A2A非-肽酶同系物(MER047226),亚家族A2A非-肽酶同系物(MER047227),亚家族A2A非-肽酶同系物(MER047230),亚家族A2A非-肽酶同系物(MER047232),亚家族A2A非-肽酶同系物(MER047233),亚家族A2A非-肽酶同系物(MER047234),亚家族A2A非-肽酶同系物(MER047236),亚家族A2A非-肽酶同系物(MER047238),亚家族A2A非-肽酶同系物(MER047239),亚家族A2A非-肽酶同系物(MER047240),亚家族A2A非-肽酶同系物(MER047242),亚家族A2A非-肽酶同系物(MER047243),亚家族A2A非-肽酶同系物(MER047249),亚家族A2A非-肽酶同系物(MER047251),亚家族A2A非-肽酶同系物(MER047252),亚家族A2A非-肽酶同系物(MER047254),亚家族A2A非-肽酶同系物(MER047255),亚家族A2A非-肽酶同系物(MER047263),亚家族A2A非-肽酶同系物(MER047265),亚家族A2A非-肽酶同系物(MER047266),亚家族A2A非-肽酶同系物(MER047267),亚家族A2A非-肽酶同系物(MER047268),亚家族A2A非-肽酶同系物(MER047269),亚家族A2A非-肽酶同系物(MER047272),亚家族A2A非-肽酶同系物(MER047273),亚家族A2A非-肽酶同系物(MER047274),亚家族A2A非-肽酶同系物(MER047275),亚家族A2A非-肽酶同系物(MER047276),亚家族A2A非-肽酶同系物(MER047279),亚家族A2A非-肽酶同系物(MER047280),亚家族A2A非-肽酶同系物(MER047281),亚家族A2A非-肽酶同系物(MER047282),亚家族A2A非-肽酶同系物(MER047284),亚家族A2A非-肽酶同系物(MER047285),亚家族A2A非-肽酶同系物(MER047289),亚家族A2A非-肽酶同系物(MER047290),亚家族A2A非-肽酶同系物(MER047294),亚家族A2A非-肽酶同系物(MER047295),亚家族A2A非-肽酶同系物(MER047298),亚家族A2A非-肽酶同系物(MER047300),亚家族A2A非-肽酶同系物(MER047302),亚家族A2A非-肽酶同系物(MER047304),亚家族A2A非-肽酶同系物(MER047305),亚家族A2A非-肽酶同系物(MER047306),亚家族A2A非-肽酶同系物(MER047307),亚家族A2A非-肽酶同系物(MER047310),亚家族A2A非-肽酶同系物(MER047311),亚家族A2A非-肽酶同系物(MER047314),亚家族A2A非-肽酶同系物(MER047318),亚家族A2A非-肽酶同系物(MER047320),亚家族A2A非-肽酶同系物(MER047321),亚家族A2A非-肽酶同系物(MER047322),亚家族A2A非-肽酶同系物(MER047326),亚家族A2A非-肽酶同系物(MER047327),亚家族A2A非-肽酶同系物(MER047330),亚家族A2A非-肽酶同系物(MER047333),亚家族A2A非-肽酶同系物(MER047362),亚家族A2A非-肽酶同系物(MER047366),亚家族A2A非-肽酶同系物(MER047369),亚家族A2A非-肽酶同系物(MER047370),亚家族A2A非-肽酶同系物(MER047371),亚家族A2A非-肽酶同系物(MER047375),亚家族A2A非-肽酶同系物(MER047376),亚家族A2A非-肽酶同系物(MER047381),亚家族A2A非-肽酶同系物(MER047383),亚家族A2A非-肽酶同系物(MER047384),亚家族A2A非-肽酶同系物(MER047385),亚家族A2A非-肽酶同系物(MER047388),亚家族A2A非-肽酶同系物(MER047389),亚家族A2A非-肽酶同系物(MER047391),亚家族A2A非-肽酶同系物(MER047394),亚家族A2A非-肽酶同系物(MER047396),亚家族A2A非-肽酶同系物(MER047400),亚家族A2A非-肽酶同系物(MER047401),亚家族A2A非-肽酶同系物(MER047403),亚家族A2A非-肽酶同系物(MER047406),亚家族A2A非-肽酶同系物(MER047407),亚家族A2A非-肽酶同系物(MER047410),亚家族A2A非-肽酶同系物(MER047411),亚家族A2A非-肽酶同系物(MER047413),亚家族A2A非-肽酶同系物(MER047414),亚家族A2A非-肽酶同系物(MER047416),亚家族A2A非-肽酶同系物(MER047417),亚家族A2A非-肽酶同系物(MER047420),亚家族A2A非-肽酶同系物(MER047423),亚家族A2A非-肽酶同系物(MER047424),亚家族A2A非-肽酶同系物(MER047428),亚家族A2A非-肽酶同系物(MER047429),亚家族A2A非-肽酶同系物(MER047431),亚家族A2A非-肽酶同系物(MER047434),亚家族A2A非-肽酶同系物(MER047439),亚家族A2A非-肽酶同系物(MER047442),亚家族A2A非-肽酶同系物(MER047445),亚家族A2A非-肽酶同系物(MER047449),亚家族A2A非-肽酶同系物(MER047450),亚家族A2A非-肽酶同系物(MER047452),亚家族A2A非-肽酶同系物(MER047455),亚家族A2A非-肽酶同系物(MER047457),亚家族A2A非-肽酶同系物(MER047458),亚家族A2A非-肽酶同系物(MER047459),亚家族A2A非-肽酶同系物(MER047463),亚家族A2A非-肽酶同系物(MER047468),亚家族A2A非-肽酶同系物(MER047469),亚家族A2A非-肽酶同系物(MER047470),亚家族A2A非-肽酶同系物(MER047476),亚家族A2A非-肽酶同系物(MER047478),亚家族A2A非-肽酶同系物(MER047483),亚家族A2A非-肽酶同系物(MER047488),亚家族A2A非-肽酶同系物(MER047489),亚家族A2A非-肽酶同系物(MER047490),亚家族A2A非-肽酶同系物(MER047493),亚家族A2A非-肽酶同系物(MER047494),亚家族A2A非-肽酶同系物(MER047495),亚家族A2A非-肽酶同系物(MER047496),亚家族A2A非-肽酶同系物(MER047497),亚家族A2A非-肽酶同系物(MER047499),亚家族A2A非-肽酶同系物(MER047502),亚家族A2A非-肽酶同系物(MER047504),亚家族A2A非-肽酶同系物(MER047511),亚家族A2A非-肽酶同系物(MER047513),亚家族A2A非-肽酶同系物(MER047514),亚家族A2A非-肽酶同系物(MER047515),亚家族A2A非-肽酶同系物(MER047516),亚家族A2A非-肽酶同系物(MER047520),亚家族A2A非-肽酶同系物(MER047533),亚家族A2A非-肽酶同系物(MER047537),亚家族A2A非-肽酶同系物(MER047569),亚家族A2A非-肽酶同系物(MER047570),亚家族A2A非-肽酶同系物(MER047584),亚家族A2A非-肽酶同系物(MER047603),亚家族A2A非-肽酶同系物(MER047604),亚家族A2A非-肽酶同系物(MER047606),亚家族A2A非-肽酶同系物(MER047609),亚家族A2A非-肽酶同系物(MER047616),亚家族A2A非-肽酶同系物(MER047619),亚家族A2A非-肽酶同系物(MER047648),亚家族A2A非-肽酶同系物(MER047649),亚家族A2A非-肽酶同系物(MER047662),亚家族A2A非-肽酶同系物(MER048004),亚家族A2A非-肽酶同系物(MER048018),亚家族A2A非-肽酶同系物(MER048019),亚家族A2A非-肽酶同系物(MER048023),亚家族A2A非-肽酶同系物(MER048037),亚家族A2A未分配肽酶(MER047164),亚家族A2A未肽酶(MER047231),亚家族A2A未分配肽酶(MER047386),皮肤天冬氨酸蛋白酶(MER057097),早老素(presenilin)1(MER005221),早老素2(MER005223),impas 1肽酶(MER019701),impas 1肽酶(MER184722),impas 4肽酶(MER019715),impas 2肽酶(MER019708),impas 5肽酶(MER019712),impas 3肽酶(MER019711),可能的家族A22假基因(智人(Homo sapiens)染色体18)(MER029974),可能的家族A22假基因(智人(Homosapiens)染色体11)(MER023159),组织蛋白酶V(MER004437),组织蛋白酶X(MER004508),组织蛋白酶F(MER004980),细织蛋白酶L(MER000622),组织蛋白酶S(MER000633),组织蛋白酶O(MER001690),组织蛋白酶K(MER000644),组织蛋白酶W(MER003756),组织蛋白酶H(MER000629),组织蛋白酶B(MER000686),二肽酰-肽酶I(MER001937),博来霉素水解酶(动物)(MER002481),肾小管间质性肾炎抗原(MER016137),肾小管间质性肾炎抗原相关蛋白(MER021799),细织蛋白酶L-样假基因1(智人(Homo sapiens))(MER002789),组织蛋白酶B-样假基因(染色体4,智人(Homo sapiens))(MER029469),组织蛋白酶B-样假基因(染色体1,智人(Homo sapiens))(MER029457),CTSLL2 g.p.(智人(Homo sapiens))(MER005210),CTSLL3 g.p.(智人(Homo sapiens))(MER005209),钙蛋白酶(calpain)-1(MER000770),钙蛋白酶-2(MER000964),钙蛋白酶-3(MER001446),钙蛋白酶-9(MER004042),钙蛋白酶-8(MER021474),钙蛋白酶-15(MER004745),钙蛋白酶-5(MER002939),钙蛋白酶-11(MER005844),钙蛋白酶-12(MER029889),钙蛋白酶-10(MER013510),钙蛋白酶-13(MER020139),钙蛋白酶-14(MER029744),Mername-AA253肽酶(MER005537),钙蛋白酶 (calpamodulin)(MER000718),假设蛋白flj40251(MER003201),泛素水解酶-L1(MER000832),泛素水解酶-L3(MER000836),泛素水解酶-BAP1(MER003989),泛素水解酶-UCH37(MER005539),泛素特异性肽酶5(MER002066),泛素特异性肽酶6(MER000863),泛素特异性肽酶4(MER001795),泛素特异性肽酶8(MER001884),泛素特异性肽酶13(MER002627),泛素特异性肽酶2(MER004834),泛素特异性肽酶11(MER002693),泛素特异性肽酶14(MER002667),泛素特异性肽酶7(MER002896),泛素特异性肽酶9X(MER005877),泛素特异性肽酶10(MER004439),泛素特异性肽酶1(MER004978),泛素特异性肽酶12(MER005454),泛素特异性肽酶16(MER005493),泛素特异性肽酶15(MER005427),泛素特异性肽酶17(MER002900),泛素特异性肽酶19(MER005428),泛素特异性肽酶20(MER005494),泛素特异性肽酶3(MER005513),泛素特异性肽酶9Y(MER004314),泛素特异性肽酶18(MER005641),泛素特异性肽酶21(MER006258),泛素特异性肽酶22(MER012130),泛素特异性肽酶33(MER014335),泛素特异性肽酶29(MER012093),泛素特异性肽酶25(MER011115),泛素特异性肽酶36(MER014033),泛素特异性肽酶32(MER014290),泛素特异性肽酶26(Homosapiens-型)(MER014292),泛素特异性肽酶24(MER005706),泛素特异性肽酶42(MER011852),泛素特异性肽酶46(MER014629),泛素特异性肽酶37(MER014633),泛素特异性肽酶28(MER014634),泛素特异性肽酶47(MER014636),泛素特异性肽酶38(MER014637),泛素特异性肽酶44(MER014638),泛素特异性肽酶50(MER030315),泛素特异性肽酶35(MER014646),泛素特异性肽酶30(MER014649),Mername-AA091肽酶(MER014743),泛素特异性肽酶45(MER030314),泛素特异性肽酶51(MER014769),泛素特异性肽酶34(MER014780),泛素特异性肽酶48(MER064620),泛素特异性肽酶40(MER015483),泛素特异性肽酶41(MER045268),泛素特异性肽酶31(MER015493),Mername-AA129肽酶(MER016485),泛素特异性肽酶49(MER016486),Mername-AA187肽酶(MER052579),USP17-样肽酶(MER030192),泛素特异性肽酶54(MER028714),泛素特异性肽酶53(MER027329),泛素特异性内肽酶39[易误解的](MER064621),Mername-AA090非-肽酶同系物(MER014739),泛素特异性肽酶43[易误解的](MER030140),泛素特异性肽酶52[易误解的](MER030317),NEK2假基因(MER014736),C19假基因(智人(Homo sapiens):染色体5)(MER029972),Mername-AA088肽酶(MER014750),自噬素(autophagin)-2(MER013564),自噬素-1(MER013561),自噬素-3(MER014316),自噬素-4(MER064622),Cezanne去泛素化肽酶(MER029042),Cezanne-2肽酶(MER029044),肿瘤坏死因子α-诱导的蛋白3(MER029050),trabid肽酶(MER029052),VCIP135去泛素化肽酶(MER152304),otubain-1(MER029056),otubain-2(MER029061),CylD蛋白(MER030104),UfSP1肽酶(MER042724),UfSP2肽酶(MER060306),DUBA去泛素化酶(MER086098),KIAA0459(智人(Homo sapiens))-样蛋白(MER122467),Otud1蛋白(MER125457),含糖基转移酶28结构域的1,同工型CRA_c(智人(Homo sapiens))-样(MER123606),hin1L g.p.(智人Homo sapiens)(MER139816),ataxin-3(MER099998),ATXN3L推定肽酶(MER115261),含Josephin结构域1(智人(Homo sapiens))(MER125334),含Josephin结构域2(智人(Homo sapiens))(MER124068),YOD1肽酶(MER116559),豆球蛋白(植物α形式)(MER044591),豆球蛋白(MER001800),糖基化磷脂酰肌醇:蛋白转酰氨基酶(MER002479),豆球蛋白假基因(智人(Homo sapiens))(MER029741),家族C13未分配肽酶(MER175813),半胱天冬酶-1(MER000850),半胱天冬酶-3(MER000853),半胱天冬酶-7(MER002705),半胱天冬酶-6(MER002708),半胱天冬酶-2(MER001644),半胱天冬酶-4(MER001938),半胱天冬酶-5(MER002240),半胱天冬酶-8(MER002849),半胱天冬酶-9(MER002707),半胱天冬酶-10(MER002579),半胱天冬酶-14(MER012083),paracaspase(MER019325),Mername-AA143肽酶(MER021304),Mername-AA186肽酶(MER020516),推定半胱天冬酶(智人Homo sapiens)(MER021463),FLIP蛋白(MER003026),Mername-AA142蛋白(MER021316),半胱天冬酶-12假基因(智人Homo sapiens)(MER019698),Mername-AA093半胱天冬酶假基因(MER014766),亚家族C14A非-肽酶同系物(MER185329),亚家族C14A非-肽酶同系物(MER179956),分离酶(separase)(智人型Homo sapiens-type)(MER011775),分离酶-样假基因(MER014797),SENP1肽酶(MER011012),SENP3肽酶(MER011019),SENP6肽酶(MER011109),SENP2肽酶(MER012183),SENP5肽酶(MER014032),SENP7肽酶(MER014095),SENP8肽酶(MER016161),SENP4肽酶(MER005557),焦谷氨酰-肽酶I(脊索动物)(MER011032),Mername-AA073肽酶(MER029978),超声刺猬蛋白(Sonic hedgehog protein)(MER002539),印度刺猬蛋白(MER002538),沙漠刺猬蛋白(MER012170),二肽酰-肽酶III(MER004252),Mername-AA164蛋白(MER020410),LOC138971 g.p.(智人(Homo sapiens))(MER020074),Atp23肽酶(MER060642),异戊二烯基肽酶1(MER004246),氨基肽酶N(MER000997),氨基肽酶A(MER001012),白细胞三烯A4水解酶(MER001013),焦谷氨酰-肽酶II(MER012221),细胞溶质丙氨酰氨肽酶(MER002746),半胱氨酸氨肽酶(MER002060),氨基肽酶B(MER001494),氨基肽酶PILS(MER005331),丙氨酰氨基肽酶-样1(MER012271),白细胞衍生的精氨酸氨基肽酶(MER002968),氨基肽酶Q(MER052595),氨基肽酶O(MER019730),Tata结合蛋白相关因子(MER026493),血管紧张素-转化酶肽酶单体1(MER004967),血管紧张素-转化酶肽酶单体2(MER001019),血管紧张素-转化酶-2(MER011061),Mername-AA153蛋白(MER020514),thimet寡肽酶(MER001737),溶神经素(MER010991),线粒体中间体肽酶(MER003665),Mername-AA154蛋白(MER021317),利什曼溶蛋白(leishmanolysin)-2(MER014492),利什曼溶蛋白-3(MER180031),基质金属肽酶-1(MER001063),基质金属肽酶-8(MER001084),基质金属肽酶-2(MER001080),基质金属肽酶-9(MER001085),基质金属肽酶-3(MER001068),基质金属肽酶-10(Homo sapiens-型)(MER001072),基质金属肽酶-11(MER001075),基质金属肽酶-7(MER001092),基质金属肽酶-12(MER001089),基质金属肽酶-13(MER001411),膜-型基质金属肽酶-1(MER001077),膜-型基质金属肽酶-2(MER002383),膜-型基质金属肽酶-3(MER002384),膜-型基质金属肽酶-4(MER002595),基质金属肽酶-20(MER003021),基质金属肽酶-19(MER002076),基质金属肽酶-23B(MER004766),膜-型基质金属肽酶-5(MER005638),膜-型基质金属肽酶-6(MER012071),基质金属肽酶-21(MER006101),基质金属肽酶-22(MER014098),基质金属肽酶-26(MER012072),基质金属肽酶-28(MER013587),基质金属肽酶-23A(MER037217),巨噬细胞弹性蛋白酶同系物(染色体8,智人(Homo sapiens))(MER030035),Mername-AA156蛋白(MER021309),基质金属肽酶-样1(MER045280),亚家族M10A非-肽酶同系物(MER175912),亚家族M10A非-肽酶同系物(MER187997),亚家族M10A非-肽酶同系物(MER187998),亚家族M10A非-肽酶同系物(MER180000),meprinα亚基(MER001111),meprinβ亚基(MER005213),前胶原C-肽酶(MER001113),哺乳动物胶体-样1蛋白(MER005124),哺乳动物型胶体-样2蛋白(MER005866),ADAMTS9肽酶(MER012092),ADAMTS14肽酶(MER016700),ADAMTS15肽酶(MER017029),ADAMTS16肽酶(MER015689),ADAMTS17肽酶(MER016302),ADAMTS18肽酶(MER016090),ADAMTS19肽酶(MER015663),ADAM8肽酶(MER003902),ADAM9肽酶(MER001140),ADAM10肽酶(MER002382),ADAM12肽酶(MER005107),ADAM19肽酶(MER012241),ADAM15肽酶(MER002386),ADAM17肽酶(MER003094),ADAM20肽酶(MER004725),ADAMDEC1肽酶(MER000743),ADAMTS3肽酶(MER005100),ADAMTS4肽酶(MER005101),ADAMTS1肽酶(MER005546),ADAM28肽酶(智人(Homo sapiens)-型)(MER005495),ADAMTS5肽酶(MER005548),ADAMTS8肽酶(MER005545),ADAMTS6肽酶(MER005893),
ADAMTS7肽酶(MER005894),ADAM30肽酶(MER006268),ADAM21肽酶(智人(Homosapiens)-型)(MER004726),ADAMTS10肽酶(MER014331),ADAMTS12肽酶(MER014337),ADAMTS13肽酶(MER015450),ADAM33肽酶(MER015143),ovastacin(MER029996),ADAMTS20肽酶(智人(Homo sapiens)-型)(MER026906),前胶原I N-肽酶(MER004985),ADAM2蛋白(MER003090),ADAM6蛋白(MER047044),ADAM7蛋白(MER005109),ADAM18蛋白(MER012230),ADAM32蛋白(MER026938),非-肽酶同系物(智人(Homo sapiens)染色体4)(MER029973),家族M12非-肽酶同系物(智人(Homo sapiens)染色体16)(MER047654),家族M12非-肽酶同系物(智人(Homo sapiens)染色体15)(MER047250),ADAM3B蛋白(智人(Homo sapiens)-型)(MER005199),ADAM11蛋白(MER001146),ADAM22蛋白(MER005102),ADAM23蛋白(MER005103),ADAM29蛋白(MER006267),ADAM21肽酶前蛋白原相似蛋白(智人(Homosapiens))(MER026944),Mername-AA225肽酶同系物(智人(Homo sapiens))(MER047474), 推定的ADAM假基因(染色体4,智人(Homo sapiens))(MER029975),ADAM3A g.p.智人(Homosapiens)(MER005200),ADAM1 g.p.智人(Homo sapiens)(MER003912),亚家族M12B非-肽酶同系物(MER188210),亚家族M12B非-肽酶同系物(MER188211),亚家族M12B非-肽酶同系物(MER188212),亚家族M12B非-肽酶同系物(MER188220),肾胰岛素残基溶酶(MER001050),内皮素-转化酶1(MER001057),内皮素-转化酶2(MER004776),DINE肽酶(MER005197),肾胰岛素残基溶酶-2(MER013406),Kell血型蛋白(MER001054),PHEX肽酶(MER002062),i-AAA肽酶(MER001246),i-AAA肽酶(MER005755),paraplegin(MER004454),Afg3-样蛋白2(MER005496),Afg3-样蛋白1A(MER014306),冠毛素-1(MER002217),冠毛素-2(MER014521),法尼基化-蛋白转化酶1(MER002646),金属蛋白酶-相关蛋白-1(MER030873),氨基肽酶AMZ2(MER011907),氨基肽酶AMZ1(MER058242),羧基肽酶A1(MER001190),羧基肽酶A2(MER001608),羧基肽酶B(MER001194),羧基肽酶N(MER001198),羧基肽酶E(MER001199),羧基肽酶M(MER001205),羧基肽酶U(MER001193),羧基肽酶A3(MER001187),金属羧基肽酶D肽酶单位1(MER003781),金属羧基肽酶Z(MER003428),金属羧基肽酶D肽酶单位2(MER004963),羧基肽酶A4(MER013421),羧基肽酶A6(MER013456),羧基肽酶A5(MER017121),金属羧基肽酶O(MER016044),细胞溶质羧基肽酶-样蛋白5(MER033174),细胞溶质羧基肽酶3(MER033176),细胞溶质羧基肽酶6(MER033178),细胞溶质羧基肽酶1(MER033179),细胞溶质羧基肽酶2(MER037713),金属羧基肽酶D非-肽酶单位(MER004964),脂肪细胞-增强子结合蛋白1(MER003889),羧基肽酶-样蛋白X1(MER013404),羧基肽酶-样蛋白X2(MER078764),细胞溶质羧基肽酶(MER026952),家族M14非-肽酶同系物(MER199530),胰岛素溶酶(MER001214),线粒体加工肽酶β-亚基(MER004497),苯乙肼裂解酶(MER003883),eupitrilysin(MER004877),线粒体加工肽酶非-肽酶α亚基(MER001413),泛素-细胞色素c还原酶核心蛋白I(MER003543),泛素-细胞色素c还原酶核心蛋白II(MER003544),泛素-细胞色素c还原酶核心蛋白结构域2(MER043998),胰岛素溶酶单位2(MER046821),苯乙肼裂解酶单位2(MER046874),胰岛素溶酶单位3(MER078753),线粒体加工酶肽酶亚基α单位2(MER124489),苯乙肼裂解酶单位3(MER142856),LOC133083 g.p.(智人(Homo sapiens))(MER021876),亚家族M16B非-肽酶同系物(MER188757),亮氨酰氨基肽酶(动物)(MER003100),Mername-AA040肽酶(MER003919),亮氨酰氨基肽酶-1(新杆状线虫(Caenorhabditis)-型)(MER013416),甲硫氨酰氨基肽酶1(MER001342),甲硫氨酰氨基肽酶2(MER001728),氨基肽酶P2(MER004498),Xaa-Pro二肽酶(真核细胞)(MER001248),氨基肽酶P1(MER004321),线粒体中间体切割肽酶55kDa(MER013463),线粒体甲硫氨酰氨基肽酶(MER014055),Mername-AA020肽酶同系物(MER010972),增殖相关蛋白1(MER005497),染色体-特异性转录延伸因子140kDa亚基(MER026495),增殖相关蛋白1-样(智人(Homosapiens)染色体X)(MER029983),Mername-AA226肽酶同系物(智人(Homo sapiens)(MER056262),Mername-AA227肽酶同系物(智人(Homo sapiens)(MER047299),亚家族M24A非-肽酶同系物(MER179893),天冬氨酰氨基肽酶(MER003373),Gly-Xaa羧基肽酶(MER033182),肌肽二肽酶II(MER014551),肌肽二肽酶I(MER015142),Mername-AA161蛋白(MER021873),氨基酰基转移酶(MER001271),谷氨酸酯羧基肽酶II(MER002104),NAALADASEL肽酶(MER005239),谷氨酸酯羧基肽酶III(MER005238),血浆谷氨酸酯羧基肽酶(MER005244),Mername-AA103肽酶(MER015091),Fxna肽酶(MER029965),转铁蛋白受体蛋白(MER002105),转铁蛋白受体蛋白2蛋白(MER005152),谷氨酰胺环化酶(MER015095),谷氨酸酯羧基肽酶II(智人(Homo sapiens))-型非-肽酶同系物(MER026971),nicalin(MER044627),膜二肽酶(MER001260),膜-结合的二肽酶-2(MER013499),膜-结合的二肽酶-3(MER013496),二氢-乳清酸酶(MER005767),二氢嘧啶酶(MER033266),二氢嘧啶酶相关蛋白-1(MER030143),二氢嘧啶酶相关蛋白-2(MER030155),二氢嘧啶酶相关蛋白-3(MER030151),二氢嘧啶酶相关蛋白-4(MER030149),二氢嘧啶酶相关蛋白-5(MER030136),假设蛋白样5730457F11RIK(MER033184),1300019j08rik蛋白(MER033186)),鸟嘌呤氨基水解酶(MER037714),Kae1推定肽酶(MER001577),OSGEPL1-样蛋白(MER013498),S2P肽酶(MER004458),亚家族M23B非-肽酶同系物(MER199845),亚家族M23B非-肽酶同系物(MER199846),亚家族M23B非-肽酶同系物(MER199847),亚家族M23B非-肽酶同系物(MER137320),亚家族M23B非-肽酶同系物(MER201557),亚家族M23B非-肽酶同系物(MER199417),亚家族M23B非-肽酶同系物(MER199418),亚家族M23B非-肽酶同系物(MER199419),亚家族M23B非-肽酶同系物(MER199420),亚家族M23B非-肽酶同系物(MER175932),亚家族M23B非-肽酶同系物(MER199665),Poh1肽酶(MER020382),Jab1/MPN结构域金属酶(MER022057),Mername-AA165肽酶(MER021865),Brcc36异肽酶(MER021890),组蛋白H2A去泛素酶MYSM1(MER021887),AMSH去泛素化肽酶(MER030146),推定的肽酶(智人(Homo sapiens)染色体2)(MER029970),Mername-AA168蛋白(MER021886),COP9信号小体(signalosome)亚基6(MER030137),26S蛋白酶体非-ATP酶调控亚基7(MER030134),真核翻译启动因子3亚基5(MER030133),IFP38肽酶同系物(MER030132),亚家族M67A非-肽酶同系物(MER191181),亚家族M67A未分配肽酶(MER191144),粒酶B(智人(Homo sapiens)-型)(MER000168),睾蛋白(testisin)(MER005212),类胰蛋白酶β(MER000136),血管舒缓素-相关肽酶5(MER005544),丝氨酸肽酶(corin)(MER005881),血管舒缓素-相关肽酶12(MER006038),DESC1肽酶(MER006298),类胰蛋白酶γ1(MER011036),血管舒缓素-相关肽酶14(MER011038),透明质酸-结合肽酶(MER003612),跨膜肽酶,丝氨酸4(MER011104),肠丝氨酸肽酶(啮齿动物)(MER016130),肾上腺分泌丝氨酸肽酶(MER003734),类胰蛋白酶σ1(智人(Homo sapiens))(MER005948),间质蛋白酶-3(MER029902),marapsin(MER006119),类胰蛋白酶-6(MER006118),卵质酶-1结构域1(MER099182),跨膜肽酶,丝氨酸3(MER005926),血管舒缓素肽酶15(MER000064),Mername-AA031肽酶(MER014054),TMPRSS13肽酶(MER014226),Mername-AA038肽酶(MER062848),Mername-AA204肽酶(MER029980),阳离子胰蛋白酶(智人(Homo sapiens)-型)(MER000020),弹性蛋白酶-2(MER000118),甘露聚糖-结合植物凝集素-相关丝氨酸肽酶-3(MER031968),组织蛋白酶G(MER000082),成髓细胞蛋白酶(MER000170),粒酶A(MER001379),粒酶M(MER001541),胃促胰酶(智人(Homo sapiens)-型)(MER000123),类胰蛋白酶α(MER000135),粒酶K(MER001936),粒酶H(MER000166),糜蛋白酶B(MER000001),弹性蛋白酶-1(MER003733),胰腺肽酶E(MER000149),胰腺弹性蛋白酶II(MER000146),肠肽酶(MER002068),糜蛋白酶C(MER000761),前列腺蛋白酶(MER002460),血管舒缓素1(MER000093),血管舒缓素-相关肽酶2(MER000094),血管舒缓素-相关肽酶3(MER000115),中胰蛋白酶(MER000022),补体成分C1r-样肽酶(MER016352),补体因子D(MER000130),补体成分激活的C1r(MER000238),补体成分激活的C1s(MER000239),补体成分C2a(MER000231),补体因子B(MER000229),甘露聚糖结合植物凝集素相关丝氨酸肽酶1(MER000244),补体因子I(MER000228),胰腺内肽酶E形式B(MER000150),胰腺弹性蛋白酶IIB(MER000147),凝血因子XIIa(MER000187),血浆血管舒缓素(MER000203)凝血因子Xia(MER000210),凝血因子IXa(MER000216),凝血因子VIIa(MER000215),凝血因子Xa(MER000212),凝血酶(MER000188),蛋白C(激活的)(MER000222),顶体酶(MER000078),hepsin(MER000156),肝细胞生长因子激活剂(MER000186),甘露聚糖结合植物凝集素相关丝氨酸肽酶2(MER002758),u-血纤维蛋白溶酶原激活剂(MER000195),t-血纤维蛋白溶酶原激活剂(MER000192),血纤维蛋白溶酶(MER000175),血管舒缓素-相关肽酶6(MER002580),神经胰蛋白酶(MER004171),血管舒缓素-相关肽酶8(MER005400),血管舒缓素-相关肽酶10(MER003645),epitheliasin(MER003736),神经胰蛋白酶肽酶4(MER005266),prosemin(MER004214),
chymopasin(MER001503),血管舒缓素-相关肽酶11(MER004861),血管舒缓素-相关肽酶11(MER216142),胰蛋白酶-2型A(MER000021),HtrA1肽酶(智人(Homo sapiens)-型)(MER002577),HtrA2肽酶(MER208413),HtrA2肽酶(MER004093),HtrA3肽酶(MER014795),HtrA4肽酶(MER016351),Tysnd1肽酶(MER050461),TMPRSS12肽酶(MER017085),HAT-样推定肽酶2(MER021884),胰蛋白酶C(MER021898),血管舒缓素-相关肽酶7(MER002001),间质蛋白酶(MER003735),血管舒缓素-相关肽酶13(MER005269),血管舒缓素-相关肽酶9(MER005270),间质蛋白酶-2(MER005278),脐静脉肽酶(MER005421),LCLP肽酶(MER001900),spinesin(MER014385),marapsin-2(MER021929),补体因子D-样推定肽酶(MER056164),卵质酶-2(MER022410),HAT-样4肽酶(MER044589),卵质酶1结构域1(MER022412),表皮-特异性SP-样推定肽酶(MER029900),睾丸丝氨酸肽酶5(MER029901),Mername-AA258肽酶(MER000285),聚合酶-IA单位1(MER030879),聚合酶-IA单位2(MER030880),睾丸丝氨酸肽酶2(人-型)(MER033187),假设顶体酶-样肽酶(智人(Homosapiens))(MER033253),HAT-样5肽酶(MER028215),聚合酶-3单位1(MER061763),聚合酶-3单位2(MER061748),与色氨酸/丝氨酸蛋白酶相似的肽酶(MER056263),聚合酶-2单位1(MER061777),Mername-AA123肽酶(MER021930),HAT-样2肽酶(MER099184),hCG2041452-样蛋白(MER099172),hCG22067(智人(Homo sapiens))(MER099169),脑-救助-因子-1(智人(Homo sapiens))(MER098873),hCG2041108智人(Homo sapiens))(MER099173),聚合酶-2单位2(MER061760),聚合酶-2单位3(MER065694),Mername-AA201(肽酶同系物)MER099175,分泌的胰蛋白酶-样丝氨酸肽酶同系物(MER030000),聚合酶-1A单位3(MER029880),天青素 (azurocidin)(MER000119),结合珠蛋白-1(MER000233),结合珠蛋白-相关蛋白(MER000235),巨噬细胞刺激蛋白(MER001546),肝细胞生长因子(MER000185),蛋白Z(MER000227),TESP1蛋白(MER047214),LOC136242蛋白(MER016132),血浆血管舒缓素-样蛋白4(MER016346),PRSS35蛋白(MER016350),DKFZp586H2123-样蛋白(MER066474),阿朴脂蛋白(MER000183),psi-KLK1假基因(智人(Homo sapiens))(MER033287),类胰蛋白酶假基因I(MER015077),类胰蛋白酶假基因II(MER015078),类胰蛋白酶假基因III(MER015079),亚家族S1A未分配肽酶(MER216982),亚家族S1A未分配肽酶(MER216148),酰胺基磷酸核糖转移酶前体(MER003314),谷氨酰胺-果糖-6-磷酸氨基转移酶1(MER003322),谷氨酰胺:果糖-6-磷酸氨基转移酶(MER012158),Mername-AA144蛋白(MER021319),天冬酰胺合成酶(MER033254),家族C44非-肽酶同系物(MER159286),家族C44未分配肽酶(MER185625),家族C44未分配肽酶(MER185626),分离代表(secernin)1(MER045376),分离代表2(MER064573),分离代表3(MER064582),酸性神经酰胺酶前体(MER100794),N-酰基乙醇胺酸性酰胺酶前体(MER141667),蛋白酶体催化亚基1(MER000556),蛋白酶体催化亚基2(MER002625),蛋白酶体催化亚基3(MER002149),蛋白酶体催化亚基1i(MER000552),蛋白酶体催化亚基2i(MER001515),蛋白酶体催化亚基3i(MER000555),蛋白酶体催化亚基5t(MER026203),蛋白丝氨酸激酶c17(MER026497),蛋白酶体亚基α6(MER000557),蛋白酶体亚基α2(MER000550),蛋白酶体亚基α4(MER000554),蛋白酶体亚基α7(MER033250),蛋白酶体亚基α5(MER000558),蛋白酶体亚基α1(MER000549),蛋白酶体亚基α3(MER000553),蛋白酶体亚基XAPC7(MER004372),蛋白酶体亚基β3(MER001710),蛋白酶体亚基β2(MER002676),蛋白酶体亚基β1(MER000551),蛋白酶体亚基β4(MER001711),Mername-AA230肽酶同系物(智人(Homosapiens))(MER047329),Mername-AA231假基因(智人(Homo sapiens))(MER047172),Mername-AA232假基因(智人(Homo sapiens))(MER047316),糖基天冬氨酰酶前体(MER003299),异天冬氨酰二肽酶(丝氨酸型)(MER031622),苏氨酸天冬氨酸酶(taspase)-1(MER016969),γ-谷氨酰基转移酶5(哺乳动物-型)(MER001977),γ-谷氨酰基转移酶1(哺乳动物-型)(MER001629),γ-谷氨酰基转移酶2(智人(Homo sapiens))(MER001976),γ-谷氨酰基转移酶-样蛋白4(MER002721),γ-谷氨酰基转移酶-样蛋白3(MER016970),与γ-谷氨酰基转移酶1前体相似(智人(Homo sapiens))(MER026204),与γ-谷氨酰基转移酶1前体相似(智人(Homo sapiens))(MER026205),Mername-AA211推定肽酶(MER026207),γ-谷氨酰基转移酶6(MER159283),γ-谷氨酰基转肽酶同系物(染色体2,智人(Homo sapiens))(MER037241),多囊蛋白(polycystin)-1(MER126824),KIAA1879蛋白(MER159329),多囊性肾病1-样3(MER172554),γ-谷氨酰基水解酶(MER002963),鸟嘌呤5″-单磷酸合成酶(MER043387),氨基甲酰-磷酸合成酶(智人(Homo sapiens)-型)(MER078640),二氢-乳清酸酶(N-端单位)(智人(Homo sapiens)-型)(MER060647),DJ-1推定肽酶(MER003390),Mername-AA100推定肽酶(MER014802),Mername-AA101非-肽酶同系物(MER014803),KIAA0361蛋白(智人(Homo sapiens)-型)(MER042827),FLJ34283蛋白(智人(Homosapiens))(MER044553),非-肽酶同系物染色体21开放阅读框33(智人(Homo sapiens))(MER160094),家族C56非-肽酶同系物(MER177016),家族C56非-肽酶同系物(MER176613),家族C56非-肽酶同系物(MER176918),含EGF-样模块粘液素样激素受体-样2(MER037230),CD97抗原(人型)(MER037286),含EGF-样模块粘液素样激素受体-样3(MER037288),含EGF-样模块粘液素样激素受体-样1(MER037278),含EGF-样模块粘液素样激素受体-样4(MER037294),钙粘蛋白EGF LAG七-跨G-型受体2前体(智人(Homo sapiens))(MER045397),Gpr64(小鼠(Mus musculus))-型蛋白(MER123205),GPR56(智人(Homo sapiens))-型蛋白(MER122057),蜘蛛毒素亲和蛋白(latrophilin)2(MER122199),蜘蛛毒素亲和蛋白-1(MER126380),蜘蛛毒素亲和蛋白3(MER124612),原钙粘素(protocadherin)Flamingo 2(MER124239),ETL蛋白(MER126267),G蛋白-偶联的受体112(MER126114),七跨膜螺旋受体(MER125448),Gpr114蛋白(MER159320),GPR126血管可诱导G蛋白-偶联的受体(MER140015),GPR125(智人(Homo sapiens))-型蛋白(MER159279),GPR116(智人(Homosapiens))-型G-蛋白偶联的受体(MER159280),GPR128(智人(Homo sapiens))-型G-蛋白偶联的受体(MER162015),GPR133(智人(Homo sapiens))-型蛋白(MER159334),GPR110 G-蛋白偶联的受体(MER159277),GPR97蛋白(MER159322),KPG_006蛋白(MER161773),KPG_008蛋白(MER161835),KPG_009蛋白(MER159335),未分配的同系物(MER166269),GPR113蛋白(MER159352),脑特异性血管生成抑制剂2(MER159746),PIDD自体-加工蛋白单位1(MER020001),PIDD自体-加工蛋白单位2(MER063690),MUC1自体-切割粘液素(MER074260), 肌营养不良蛋白聚糖(dystroglycan)(MER054741),前蛋白转化酶9(MER022416),位点-1肽酶(MER001948),弗林蛋白酶(MER000375),前蛋白转化酶1(MER000376),前蛋白转化酶2(MER000377),前蛋白转化酶4(MER028255),PACE4前蛋白转化酶(MER000383),前蛋白转化酶5(MER002578),前蛋白转化酶7(MER002984),三肽酰-肽酶II(MER000355),亚家族S8A非-肽酶同系物(MER201339),亚家族S8A非-肽酶同系物(MER191613),亚家族S8A未分配肽酶(MER191611),亚家族S8A未分配肽酶(MER191612),亚家族S8A未分配肽酶(MER191614),三肽酰-肽酶I(MER003575),脯氨酰寡肽酶(MER000393),二肽酰-肽酶IV(真核细胞)(MER000401),酰基氨基酰基-肽酶(MER000408),成纤维细胞激活蛋白α亚基(MER000399),PREPL A蛋白(MER004227),二肽酰-肽酶8(MER013484),二肽酰-肽酶9(MER004923),FLJ1推定肽酶(MER017240),Mername-AA194推定肽酶(MER017353),Mername-AA195推定肽酶(MER017367),Mername-AA196推定肽酶(MER017368),Mername-AA197推定肽酶(MER017371),C14orf29蛋白(MER033244),假定的蛋白(MER033245),假定的酯酶/脂酶/硫酯酶(MER047309),蛋白bat5(MER037840),假定的蛋白flj40219(MER033212),假定的蛋白flj37464(MER033240),假定的蛋白flj33678(MER033241),二肽酰肽酶同系物DPP6(MER000403),二肽酰肽酶同系物DPP10(MER005988),与小鼠(Mus musculus)染色体20开放阅读框135相似的蛋白(MER037845),犬尿氨酸甲酰胺酶(MER046020),甲状腺球蛋白前体(MER011604),乙酰胆碱酯酶(MER033188),胆碱酯酶(MER033198),羧基酯酶D1(MER033213),肝羧基酯酶(MER033220),羧基酯酶3(MER033224),羧基酯酶2(MER033226),胆酸盐-依赖性脂酶(MER033227),羧基酯酶-相关蛋白(MER033231),神经连接蛋白(neuroligin)3(MER033232),神经连接蛋白4,X-连接的(MER033235),神经连接蛋白4,Y-连接的(MER033236),酯酶D(MER043126),芳基乙酰胺脱乙酰基酶(MER033237),KIAA1363-样蛋白(MER033242),激素敏感性脂酶(MER033274),神经连接蛋白1(MER033280),神经连接蛋白2(MER033283),家族S9非-肽酶同系物(MER212939),家族S9非-肽酶同系物(MER211490),亚家族S9C未分配肽酶(MER192341),家族S9未分配肽酶(MER209181),家族S9未分配肽酶(MER200434),家族S9未分配肽酶(MER209507),家族S9未分配肽酶(MER209142),丝氨酸羧基肽酶A(MER000430),卵黄羧基肽酶-样蛋白(MER005492),RISC肽酶(MER010960),家族S15未分配肽酶(MER199442),家族S15未分配肽酶(MER200437),家族S15未分配肽酶(MER212825),溶酶体Pro-Xaa羧基肽酶(MER000446),二肽酰-肽酶II(MER004952),胸腺-特异性丝氨酸肽酶(MER005538),环氧化物水解酶-样推定肽酶(MER031614),Loc328574-样蛋白(MER033246),含自水解酶结构域的蛋白4(MER031616),环氧化物水解酶(MER000432),中胚层特异性转录蛋白(MER199890),中胚层特异性转录蛋白(MER017123),细胞溶质环氧化物水解酶(MER029997),细胞溶质环氧化物水解酶(MER213866),与假定的蛋白FLJ22408相似(MER031608),CGI-58推定肽酶(MER030163),Williams-Beuren综合症关键区蛋白21环氧化物水解酶(MER031610),环氧化物水解酶(MER031612),假定的蛋白flj22408(环氧化物水解酶)(MER031617),单甘油酯脂酶(MER033247),假定的蛋白(MER033249),伐昔洛韦水解酶(MER033259),Ccg1-相互作用因子b(MER210738),糖基天冬氨酸酶前体(MER003299),异天冬氨酰二肽酶(苏氨酸型)(MER031622),苏氨酸天冬氨酸酶-1(MER016969),γ-谷氨酰转移酶5(哺乳动物-型)(MER001977),γ-谷氨酰转移酶1(哺乳动物-型)(MER001629),γ-谷氨酰转移酶2(智人(Homo sapiens))(MER001976),γ-谷氨酰转移酶-样蛋白4(MER002721).γ-谷氨酰转移酶-样蛋白3(MER016970),与γ-谷氨酰转移酶1前体(智人(Homo sapiens))相似(MER026204),与γ-谷氨酰转移酶1前体(智人(Homo sapiens))相似(MER026205),Mername-AA211推定肽酶(MER026207),γ-谷氨酰转移酶6(MER159283),γ-谷氨酰转肽酶同系物(染色体2,智人(Homo sapiens))(MER037241),多囊蛋白-1(MER126824),KIAA1879蛋白(MER159329).多囊性肾病1-样3(MER172554),γ-谷氨酰水解酶(MER002963),鸟嘌呤5″-单磷酸合成酶(MER043387),氨基甲酰-磷酸合成酶(智人(Homo sapiens)-型)(MER078640),二氢-乳清酸酶(N-端单体)(智人(Homo sapiens)-型)(MER060647),DJ-1推定肽酶(MER003390),Mername-AA100推定肽酶(MER014802),Mername-AA101非-肽酶同系物(MER014803),KIAA0361蛋白(智人(Homo sapiens)-型)(MER042827),FLJ34283蛋白(智人(Homo sapiens))(MER044553),非-肽酶同系物染色体21开放阅读框33(智人(Homosapiens))(MER160094),家族C56非-肽酶同系物(MER177016),家族C56非-肽酶同系物(MER176613),家族C56非-肽酶同系物(MER176918),含EGF-样模块粘液素-样激素受体-样2(MER037230),CD97抗原(人型)(MER037286),含EGF-样模块粘液素-样激素受体-样3(MER037288),含EGF-样模块粘液素-样激素受体-样1(MER037278),含EGF-样模块粘液素-样激素受体-样4(MER037294),钙粘蛋白EGF LAG七-跨G-型受体2前体(智人(Homosapiens))(MER045397),Gpr64(小鼠(Mus musculus))-型蛋白(MER123205),GPR56(智人(Homo sapiens))-型蛋白(MER122057),蜘蛛毒素亲和蛋白2(MER122199),蜘蛛毒素亲和蛋白-1(MER126380),蜘蛛毒素亲和蛋白3(MER124612),原钙粘素Flamingo 2(MER124239),ETL蛋白(MER126267),G蛋白-偶联的受体112(MER126114),七跨膜螺旋受体(MER125448),Gpr114蛋白(MER159320),GPR126血管可诱导G蛋白偶联的受体(MER140015),GPR125(智人(Homo sapiens))-型蛋白(MER159279),GPR116(智人(Homo sapiens))-型G-蛋白偶联的受体(MER159280),GPR128(智人(Homo sapiens))-型G-蛋白偶联的受体(MER162015),GPR133(智人(Homo sapiens))-型蛋白(MER159334),GPR110 G-蛋白偶联的受体(MER159277),GPR97蛋白(MER159322),KPG_006蛋白(MER161773),KPG_008蛋白(MER161835),KPG_009蛋白(MER159335),未分配的同系物(MER166269),GPR113蛋白(MER159352),脑特异性血管生成抑制剂2(MER159746),PIDD自体加工蛋白单位1(MER020001),PIDD自体加工蛋白单位2(MER063690),MUC1自体切割粘液素(MER074260),肌营养不良蛋白聚糖(MER054741),前蛋白转化酶9(MER022416),位点-1肽酶(MER001948),弗林蛋白酶(MER000375),前蛋白转化酶1(MER000376),前蛋白转化酶2(MER000377),前蛋白转化酶4(MER028255),PACE4前蛋白转化酶(MER000383),前蛋白转化酶5(MER002578),前蛋白转化酶7(MER002984),三肽酰-肽酶II(MER000355),亚家族S8A非-肽酶同系物(MER201339),亚家族S8A非-肽酶同系物(MER191613),亚家族S8A未分配肽酶(MER191611),亚家族S8A未分配肽酶(MER191612),亚家族S8A未分配肽酶(MER191614),三肽酰-肽酶I(MER003575),脯氨酰寡肽酶(MER000393),二肽酰-肽酶IV(真核细胞)(MER000401),酰基氨基酰基-肽酶(MER000408),成纤维细胞激活蛋白α亚基(MER000399),PREPL A蛋白(MER004227),二肽酰-肽酶8(MER013484),二肽酰-肽酶9(MER004923),FLJ1推定肽酶(MER017240),Mername-AA194推定肽酶(MER017353),Mername-AA195推定肽酶(MER017367),Mername-AA196推定肽酶(MER017368),Mername-AA197推定肽酶(MER017371),C14orf29蛋白(MER033244),假定的蛋白(MER033245),假定的酯酶/脂酶/硫酯酶(MER047309),蛋白bat5(MER037840),假定的蛋白flj40219(MER033212),假定的蛋白flj37464(MER033240),假定的蛋白flj33678(MER033241),二肽酰肽酶同系物DPP6(MER000403),二肽酰肽酶同系物DPP10(MER005988),与小鼠(Musmusculus)染色体20开放阅读框135相似的蛋白(MER037845),犬尿氨酸甲酰胺酶(MER046020),甲状腺球蛋白前体(MER011604),乙酰胆碱酯酶(MER033188),胆碱酯酶(MER033198),羧基酯酶D1(MER033213),肝羧基酯酶(MER033220),羧基酯酶3(MER033224),羧基酯酶2(MER033226),胆汁盐-依赖性脂酶(MER033227),羧基酯酶-相关蛋白(MER033231),神经连接蛋白3(MER033232),神经连接蛋白4,X-连接的(MER033235),神经连接蛋白4,Y-连接的(MER033236),酯酶D(MER043126),芳基乙酰胺脱乙酰基酶(MER033237),KIAA1363-样蛋白(MER033242),激素-敏感性脂酶(MER033274),神经连接蛋白1(MER033280),神经连接蛋白2(MER033283),家族S9非-肽酶同系物(MER212939),家族S9非-肽酶同系物(MER211490),亚家族S9C未分配肽酶(MER192341),家族S9未分配肽酶(MER209181),家族S9未分配肽酶(MER200434),家族S9未分配肽酶(MER209507),家族S9未分配肽酶(MER209142),丝氨酸羧基肽酶A(MER000430),卵黄羧基肽酶-样蛋白(MER005492),RISC肽酶(MER010960),家族S15未分配肽酶(MER199442),家族S15未分配肽酶(MER200437),家族S15未分配肽酶(MER212825),溶酶体Pro-Xaa羧基肽酶(MER000446),二肽酰-肽酶II(MER004952),胸腺-特异性丝氨酸肽酶(MER005538),环氧化物水解酶-样推定肽酶(MER031614),Loc328574-样蛋白(MER033246),含自水解酶结构域蛋白4(MER031616),环氧化物水解酶(MER000432),中胚层特异性转录蛋白(MER199890),中胚层特异性转录蛋白(MER017123),细胞溶质环氧化物水解酶(MER029997),细胞溶质环氧化物水解酶(MER213866),与假定的蛋白FLJ22408相似(MER031608),CGI-58推定肽酶(MER030163),Williams-Beuren综合症关键区蛋白21环氧化物水解酶(MER031610),环氧化物水解酶(MER031612),假定的蛋白flj22408(环氧化物水解酶)(MER031617),单甘油酯脂酶(MER033247),假定的蛋白(MER033249),伐昔洛韦水解酶(MER033259),Ccg1-相互作用因子b(MER210738)。
将认识到,对于给定的不需要的细胞类型,本领域技术人员可以容易地测定使用的合适蛋白酶切割位点,例如,通过翻阅科学文献来确定该细胞类型过表达哪种蛋白酶。Oncomine(https://www.oncomine.org)是在线癌基因表达数据库,并且因此将本发明的药剂用于治疗癌症时,本领域技术人员可以搜寻Oncomine数据库,以鉴定将适用于治疗给定癌症类型的特定蛋白酶切割位点。可替换的数据库包括欧洲生物信息研究院(http:// www.ebi.ac.uk),特别是(http://www.ebi.ac.uk/gxa)。蛋白酶数据库包括PMAP(http:// www.proteolysis.org)、ExPASy Peptide Cutter(http://ca.expasy.org/tools/peptidecutter)和PMAP.Cut DB(http://cutdb.burnham.org)。
注意到,希望筛选结合多个潜在切割位点的肽文库,并且评价用于给定的不需要的细胞(例如,肿瘤)的最佳切割位点。这样的肽可以用作连接物,以将T细胞抗原与靶向半体连接起来,如以下所讨论的。
表5:已经报道了其中ADAM过表达的肿瘤位点
蛋白 | 肿瘤表达 |
ADAM8 | 脑、肾、肺、胰腺 |
ADAM9 | 乳房、胃、肝、肺、胰腺、前列腺 |
ADAM10 | 结肠、胃、白血病、前列腺、子宫、卵巢 |
ADAM12 | 膀胱、脑、乳房、结肠、胃、肝 |
ADAM15 | 乳房、胃、肺、前列腺 |
ADAM17 | 脑、乳房、结肠、胃、肾、肝、肺、卵巢、胰腺、前列腺 |
ADAM19 | 脑、肾 |
ADAM28 | 乳房、肾、肺 |
在癌症中已经检测出多种蛋白水解ADAM(解聚素和金属蛋白酶),并且已经发现mRNA或蛋白水平相对于正常组织上调(改编自Nature Reviews Cancer 8,932-941(2008年12月)|doi:10.1038/nrc2459)。
在一个实施方案中,蛋白酶可以是酯酶。
其他切割位点包括在不需要的细胞附近在特定条件(例如,肿瘤微环境)下易分解的连接。例如,切割位点可以含有二硫键,其可以在含氧量低的肿瘤微环境中被还原,或可以含有pH敏感部分,其在酸性条件下断裂。然而,将理解,切割位点必须是在不需要的细胞附近选择性切割的,并且因此与需要的细胞附近相比,这样的连接必须在不需要的细胞附近更易分解,并且优选只在不需要的细胞附近分解。
或者,切割位点可以包含在不需要的细胞附近选择性切割(例如,通过核酸酶)的核酸(例如,DNA或RNA)。其他切割位点包括通过合适的酶可切割的含磷酸酯、脂质或二硫化物的部分。
本发明的药剂的合成
方便地,T细胞抗原通过连接物连接靶向半体。“连接物”包括将靶向半体连接T细胞抗原的化学部分的意思,并且如本文中所述,其包含在不需要的细胞附近选择性切割的切割位点。
认识到T细胞抗原可以与靶向半体共价结合或非共价结合。
优选地,T细胞抗原与靶向半体共价连接。
在一个实施方案中,T细胞抗原和靶向半体通过连接物共价连接。
因此,T细胞抗原(例如,肽)和靶向半体可以通过任何一种交联分子的便利途径来方便地连接,如通常在O′Sullivan等,Anal.Biochem.(1979)100,100-108中所述的和实施例2中所述的那些。例如,T细胞抗原(例如,肽)或靶向半体之一可以富含巯基而另一种则与能够与这些巯基反应的双功能试剂反应,例如,碘乙酸的N-羟基琥珀酰亚胺酯(NHIA)或N-琥珀酰亚胺-3-(2-吡啶二硫代)丙酸酯(SPDP)、在偶联的物质之间插入了二硫桥的杂双功能交联剂。酰胺和硫醚键,例如用m-马来酰亚胺苯甲酰-N-羟基琥珀酰亚胺酯获得的,通常在体内比二硫键更稳定。
已知双-马来酰亚胺试剂可以将巯基(例如,抗体的半胱氨酸残基的巯基)以按序或同时的方式连接另一个含巯基的部分(例如,T细胞抗原或连接物中间体的巯基)。除了马来酰亚胺以外的与巯基反应的其他官能团包括碘乙酰胺、溴乙酰胺、乙烯基嘧啶、二硫化物、吡啶基二硫化物、异氰酸酯和异硫氰酸酯。
更多的有用的交联剂包括S-乙酰基硫代乙醇酸N-羟基琥珀酰亚胺酯(SATA)(其是用于伯胺的巯化试剂,其允许巯基在温和条件下去保护(Julian等,(1983)Anal.Biochem.132,68))、二甲基辛二硝酸二盐酸酯和N,N’-o-亚苯基二马来酰亚胺。
特别优选的交联剂包括硫代琥珀酰亚胺4-[N-马来酰亚胺甲基]环己烷-1-羧酸酯(硫代-SMCC)、硫代琥珀酰亚胺6-(3’-[2-吡啶基二硫代]-丙酰胺基)己酸酯(硫代-LC-SPDP)和N-[β-马来酰亚胺丙酸]酰肼、三氟醋酸盐(BMHP)。
将理解,大量同型双功能和杂双功能交联化学物质适用于连接靶向半体和T细胞抗原,并且可以使用任何这样的化学物质。例如,可以使用使用Staudinger连接化学的点击化学(磷化氢-叠氮基化学)。
认识到,T细胞抗原和靶向半体不需要彼此直接交联,而是可以通过一个或多个间隔物半体来连接。例如,T细胞抗原可以与化学部分交联,其随后与靶向半体交联。在一个实施方案中,这样的间隔物半体可以包含在不需要的细胞附近选择性切割的切割位点,如以下所讨论的。将认识到,间隔物半体可以用于防止位阻和促进蛋白酶切割。
表6和7提供了合适的T细胞抗原肽以及怎样可以将它们结合至本发明的药剂中的实例。例如,T细胞抗原肽可以通过第一个间隔物半体连接蛋白酶切割位点,而蛋白酶切割位点随后通过第二个间隔物半体连接连接物半体。连接物可以用于将最后一个肽连接靶向半体。表6和7还列出了切割相应的蛋白酶切割位点的蛋白酶。
下表中还列出了可以结合(例如,通过连接合适的靶向半体,如抗体)至本发明药剂中的含有T细胞抗原和蛋白酶切割位点的肽的更多实例。
在特别优选的实施方案中,当T细胞抗原是肽时,将T细胞抗原肽在其N-端直接或间接通过间隔物半体连接靶向半体。在图9B中说明了这一点,其列出了包含T细胞表位和蛋白酶切割位点的三种肽。肽(i)和(ii)在N-端具有T细胞表位,使得表位通过连接到表位C端的间隔物半体连接靶向半体(包含蛋白酶切割位点和半胱氨酸偶联残基)。相反地,肽(iii)包含相同的T细胞表位,但表位通过连接到表位N-端的间隔物半体(包含蛋白酶切割位点和半胱氨酸偶联残基)连接靶向半体。在肽(i)和(ii)中,T-细胞表位的N-端离靶向半体更远(构造:N-端-(T细胞表位)-C-端-靶向半体),而在肽(iii)中,T-细胞表位的C-端离靶向半体更远(构造:C-端-(T细胞表位)-N-端-靶向半体)。换句话说,肽(iii)的构造与肽(i)和(ii)的相反。尽管两种构造都可以用于本发明的内容中,优选肽(iii)的构造。表7提供了合适的T细胞抗原以及怎样将其结合至本发明的药剂中的实例,使得T细胞抗原在其N-端直接或间接通过间隔物半体连接靶向半体。
鉴于以上内容认识到,本发明提供了用于预防或治疗特征在于存在不需要的细胞的病症的药剂,所述药剂包含(i)能够靶向不需要的细胞的靶向半体;(ii)T细胞抗原;和(iii)靶向半体和T细胞抗原之间的切割位点,其中切割位点可以在不需要的细胞附近选择性地切割。
在T细胞抗原和靶向半体共价连接并且其中抗原和靶向半体都是肽或多肽的特定实施方案中,认识到,两个成分可以是核酸分子编码的融合多肽的一部分。本发明包括这样的核酸分子以及含有所述核酸分子的宿主细胞。例如,使用本领域公知的遗传工程化技术,将抗体靶向半体进行遗传工程化来含有T细胞抗原。因此,将认识到,T细胞抗原可以包埋在靶向半体的多肽序列内,只要其可以释放,以使得能够在不需要的细胞上递呈来引发T细胞应答。例如,T细胞抗原可以位于靶向半体的多肽内,并且两侧为两个切割位点,其各自可以在不需要的细胞附近选择性切割。或者,T细胞抗原可以位于靶向半体的一端,并且通过待切割的一个切割位点来释放。合适地,T细胞抗原和靶向半体连接,使得两个部分保持其各自的活性,以使得可以将药剂靶向不需要的细胞,并且通过不需要的细胞来递呈T细胞抗原,以引发免疫应答。T细胞抗原和靶向半体的部分通常通过连接物肽连接,所述连接物肽包含如下所述的在不需要的细胞附近选择性切割的切割位点。合适的连接物肽是通常采用随机螺旋构象的那些,例如,多肽可以含有丙氨酸或脯氨酸或丙氨酸加脯氨酸残基的混合物。优选地,连接物含有2至100个氨基酸残基,更优选2至50个,再更优选4至20个。具有作为同一个多肽一部分的靶向半体和T细胞抗原的特定实例显示于图7,其中ScFv抗体-样片段、蛋白酶切割位点和T-细胞表位作为单个多肽链编码。将认识到这样的多肽包括在本发明的范围内,包括图7D中给出的特定实例的多肽。
编码合适靶向半体的多核苷酸是本领域已知的或可以从已知序列容易地设计出来,如从已知于不需要的细胞上表达的表面标记相互作用的蛋白的序列或包含在核苷酸序列数据库(如,GenBank、EMBL和dbEST数据库)中的序列。编码合适的T细胞抗原的多核苷酸是本领域已知的或可以从已知的序列容易地设计和制备出来。
编码合适的连接物肽的多核苷酸可以从连接物肽序列容易地设计和制备出来。
因此,使用公知的遗传工程化技术可以容易地构建编码本发明中所用药剂的多核苷酸。
然后在合适的宿主中表达核酸,以产生本发明的药剂。因此,可以根据已知技术来使用编码本发明药剂的核酸,鉴于本文中所含的教导进行适当修改,以构建表达载体,然后将其用于转化合适的宿主细胞和生产本发明的药剂。
认识到,编码本发明药剂的核酸可以连接多种用于引入合适宿主中的其他核酸序列。配偶体核酸将取决于宿主的性质、将核酸引入宿主中的方式和是否需要附加型维持或整合,如本领域公知的。
在可替换的实施方案中,T细胞抗原和靶向半体是非共价连接的。对于非共价连接,优选免疫结合或如各自通过生物素/抗生物素蛋白或抗生物素蛋白链菌素的结合。例如,靶向半体可以是双特异性抗体,其中一种特异性针对由不需要的细胞表达的实体,一种特异性针对T细胞抗原或其部分。此外,可以将T细胞抗原偶联对抗其的另一种物质,其依次将针对双特异性抗体的特异性。例如,T细胞抗原可以进一步含有被双特异性抗体识别的肽序列。另一种可能性涉及将靶向半体结合例如抗生物素蛋白链菌素,同时将T细胞抗原结合生物素,反之亦然。通过其可以形成非共价相互作用的其他方式包括亮氨酸拉链序列或亲和性键。在任一种情况中,在T细胞抗原和靶向半体之间,必须存在在不需要的细胞附近选择性切割的切割位点,使得T细胞抗原可以从靶向半体释放出来。
本文中所述的氨基酸残基通常是天然的“L”异构形式。然而,在特定的情况中,“D”异构形式的残基可以取代L-氨基酸残基,只要本发明的药剂仍然保持其功能,即预防或治疗特征在于存在不需要的细胞的病症。除非另外特意指出,定义还包括化学修饰的氨基酸,包括氨基酸类似物(如,青霉胺、3-巯基-D-缬氨酸)、天然产生的非成蛋白(proteogenic)氨基酸(如,正亮氨酸)、β-氨基酸、氮杂肽、N-甲基化氨基酸和具有本领域已知的氨基酸特征性性质的化学合成化合物。术语“成蛋白”表示可以通过公知的代谢途径整合入细胞中的蛋白中的氨基酸。定义还包括功能侧链基团已经被化学衍生的氨基酸。这样的衍生分子包括,例如,其中游离氨基已经衍生形成盐酸胺、p-甲苯磺酰基、苄氧羰基、t-丁氧基羰基、氯乙酰基或甲酸基的那些分子。游离羧基可以衍生形成盐、甲酯和乙酯或其他类型的酯或酰肼。游离羟基可以衍生形成O-酰基或O-烷基衍生物。衍生物还包括含有二十个标准氨基酸的一个或多个天然产生氨基酸衍生物的那些肽部分。
因此,认识到,本发明药剂的肽部分可以是肽“模拟物”,即,模拟肽的结构特征的肽模拟物,其包含如本文中所述的氨基酸序列或由本文中所述的氨基酸序列组成。肽模拟物在治疗用途、对抗降解、渗透性或可能的口服给药中甚至更有利。
肽模拟物设计中的主要目标是降低模拟物对肽酶引起的切割和失活的易感性。在一种方法中,如Sherman等(1990)中公开的,通过多种化学官能团,以基本上等排的方式,取代一个或多个酰胺键。这种逐步的方法已经获得了一些成功,因为已经获得了活性类似物。在一些情况中,这些类似物已经显示出具有比其天然产生的对应物更长的生物半衰期。在另一种方法中,多种未编码或未修饰的氨基酸,如D-氨基酸和N-甲基氨基酸,已经用于修饰哺乳动物肽。或者,通过共价修饰,如环化或通过引入γ-内酰胺或其他类型的桥,来稳定假定的生物活性构象(Veber等,1978)和Thorsett等,1983)。另一种方法,由Rich公开(1986),通过应用酶抑制剂设计中的过渡态类似物概念来设计肽模拟物。例如,已知statine的仲醇模拟胃蛋白酶底物的固定酰胺键的四面体过渡态。其他方法包括使用氮杂肽和β-氨基酸。
“肽模拟物”的定义中还包括逆反肽。逆反肽(也称为全-D-逆或逆-对映(enantio)肽),包括其中所有L-氨基酸被D-氨基酸取代并且肽键颠倒的肽的意思。因此,肽由以母体L-序列倒序形式装配的D-氨基酸组成。逆反肽可以通过本领域已知的方法合成,例如,如Meziere等(1997)J.Immunol.159 32303237中所述的那些。这种方法涉及制备假肽,其含有涉及主链的变化,而没有涉及侧链的方向,其保持与母体肽非常相似。逆反肽对蛋白水解的抵抗性更高。
因此,将认识到,当如本文中所述的靶向半体、T细胞抗原、切割位点、间隔物半体和靶向半体中的任何一个是肽或多肽时,那些肽或多肽中的任何一个或多个可以被相应的肽模拟物取代,所述肽模拟物保持母体肽或多肽各自的活性。这有助于给予本发明的药剂以蛋白酶抗性并且由此提高其稳定性。因此,例如,当T细胞抗原通过一个或多个肽间隔物半体连接靶向半体时,希望那些间隔物半体中的一个或多个是肽模拟物,例如,其中间隔物半体的一个或多个天然产生氨基酸被替代或修饰,例如,以提高稳定性。
另一种提高本发明药剂的肽部分稳定性的方法是在一端或两端具有稳定基团。典型的稳定基团包括酰胺基、乙酰基、苄基、苯基、甲苯磺酰基、烷氧羰基、烷基羰基、苄氧基羰基等末端基团修饰。其他的修饰包括使用“D”型氨基酸替代末端的“L”型氨基酸,以及酰胺而不是氨基或羧基端,或乙酰基而不是氨基端,以抑制外肽酶活性。因此,认识到,只要本发明的药剂具有暴露的肽末端,则末端可以具有加帽部分,优选小于200Da分子量的部分。更多的加帽部分包括萘基(naftyl)或聚乙二醇基。认识到逆反肽已经相对稳定,并且因此不需要其他的加帽部分。
优选地,本发明的药剂在37℃下具有至少24小时的血浆半衰期。
修饰本发明的药剂是合乎需要的,以使得其可以更容易检测,例如,通过将其生物素化或通过插入本领域已知的任何可检测标记,如放射性同位素标记、荧光素-标记或酶标记。
本发明特别优选的实施方案提供了用于预防或治疗癌症的药剂,该药剂包含:
i)能够靶向癌症的靶向半体;和
ii)免疫原性T细胞肽,
其中T细胞肽可以通过癌症附近的选择性切割从靶向半体中释放出来。
癌症可以是任何癌症,如乳腺癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、肾癌、黑素瘤、肺癌、前列腺癌、睾丸癌、甲状腺癌、脑癌、食管癌、胃癌、胰腺癌、结直肠癌、肝癌、白血病、骨髓瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性骨髓性白血病、急性淋巴母细胞白血病、慢性淋巴母细胞白血病、淋巴增殖性失调、骨髓增生异常失调、骨髓增殖性疾病和癌变前疾病。
如上所述,发明人已经表明了本发明的药剂可以用于重现定向现有的免疫应答,以特异性的方式杀灭特定的不需要的细胞。由于以这种方式可以靶向任何不需要的细胞,本发明的药剂给予了显著的治疗潜能。
因此,本发明的第二个方面提供了预防或治疗特征在于存在不需要的细胞的病症的方法,该方法包括将根据本发明第一个方面的药剂给药于患者。
因此,该方法涉及鉴定患有病症或处于发展病症风险中的患者,所述病症的特征在于不需要的细胞(例如,癌症),将根据本发明第一个方面的药剂给药于患者,并且通过进行测试来测定不需要的细胞的数量或通过监控患者的临床症状,来监控患者体内不需要的细胞的水平。根据监控步骤的结果,可能需要给药更多的药剂。
相似地,本发明包括根据本发明第一个方面的药剂,其用于预防或治疗特征在于存在不需要的细胞的病症。
本发明还包括根据本发明第一个方面的药剂在制备用于预防或治疗特征在于存在不需要的细胞的病症的药物中用途。
对于病症和不需要的细胞的优选选择与以上关于本发明第一个方面的描述相同。优选地,不需要的细胞是肿瘤细胞,并且病症是肿瘤。
预防或治疗病症包括减轻或缓解病人症状(即,减缓用途)、防止症状恶化或进展、治疗失调(例如,通过抑制或消除病原体),或预防未患病患者体内的病症或失调的意思。
将认识到,本发明的药剂自身导致临床中的个体化医学,借此确定给药于病人的最合适药剂,并且在临床中选择或制备。例如,在将药剂给药于患者的步骤之前,可以测定以下的任一种情况:(i)患者的MHC等位基因,(ii)患者对T细胞抗原的细胞毒T细胞应答和(iii)不需要的细胞中可以是靶向半体目标的分子和/或能够切割本发明药剂中的切割位点的酶的表达特征。可以通过抗原水平的血清学试验或在遗传水平使用DNA试验来评价患者的MHC等位基因。可以通过将从患者分离的外周单核血细胞接触抗原并使用用于细胞增殖的标准试验来进行给定的抗原是否刺激患者体内的特异性细胞毒T细胞应答的测定。可以使用用于测量核酸(例如,DNA或RNA转录产物)或蛋白水平的常规试验,在活检样品上进行不需要的细胞的表达特征的评价。例如,可以使用转录组学或蛋白组学技术。这样,将可以鉴定特异性结合例如不需要的细胞表达的表面标记的定制靶向半体。还可以鉴定在不需要的细胞附近选择性切割的合适的蛋白酶切割位点。
因此,本发明的第二个方面的方法可以包括以下步骤:(i)鉴定患有病症或处于发展病症风险中的患者,所述病症的特征在于存在不需要的细胞(例如,癌症),(ii)从患者获取样品,(iii)分析样品来鉴定用于预防或治疗患者病症的最佳靶向半体、T细胞抗原和/或切割位点,(iii)制备本发明的药剂,(iv)将药剂给药于患者,和(v)通过进行测试来测定不需要的细胞的数量或通过监控患者的临床症状,来进行患者体内不需要的细胞的水平的监控。
认识到可以使用装置来选择和任选地制备用于特定病人的最适药剂。例如,装置可以进行来自患者的一个或多个样品的自动化分析,并且基于这种分析来选择和任选地制备用于该患者的定制药剂。因此,装置可以对样品进行血清学试验,以测定患者的MHC等位基因,并且基于此测试各种肽在引发细胞毒T细胞应答中的功效,以鉴定出用于该病人的最佳T细胞抗原。相似地,装置可以进行来自患者的不需要的细胞(例如,来自活检样品)的表达概况,以确定将结合不需要的细胞的合适靶向半体和/或确定将在不需要的细胞附近选择性切割的合适切割位点。
通过在临床中进行这些步骤中的任何一个或多个,可以制备针对特定患者定制的药剂。例如,药剂可以含有已知结合病人的MHC分子并且引发强烈T细胞应答的T细胞抗原、已知选择性结合不需要的细胞表达的表面标记的靶向半体和使T细胞抗原在不需要的细胞附近释放的蛋白酶切割位点。
在一个实施方案中,除了根据本发明的第一个方面的药剂,给患者给药另一种治疗剂。例如,当给药药剂来预防或治疗特定病症时,可以给药已知对于抗争该病症有用的另一种治疗剂。例如,当将药剂用于治疗癌症时,除了本发明的药剂以外,可以将另一种抗癌剂(例如,抗肿瘤化疗)给药于患者。相似地,另一种治疗剂可以是已知在过敏性疾病、炎性疾病、再生医学和神经再生性疾病中具有治疗应用的药剂。
认识到,可以与本发明药剂同时给予另一种治疗剂(即,任选在共同制剂中同时给药)或在本发明药剂的不同时间给予(即,按序给药)。
另一种治疗剂可以是疫苗;免疫刺激药物;抗癌剂;抑制对抗本发明药剂的抗体应答的药剂;和/或蛋白酶抑制剂中的任一种或多种。
例如,为了增强对抗所用的特定T细胞抗原的效应物免疫应答,希望给患者接种T细胞抗原;和/或给予免疫刺激剂,如IL-2、IL-7、IFNα、GM-CSF、甲福明、来那度胺(lenalidomide);和/或给予抗免疫调节剂,如依匹单抗;其全部都认为是其他治疗剂。
还认识到,如果患者给予了免疫抑制剂,则在给予本发明的药剂时或之前,从该患者撤除这些免疫抑制剂(例如,通过暂停治疗)。
相似地,使用旨在绕开涉及本发明药剂的、在体内引发不利抗体应答的任何免疫原性问题的方法是希望的。例如,患者还可以给予一种或多种已知抑制B细胞活性的药剂,如利妥昔单抗、环磷酰胺、Syk抑制剂、抗-BAFF抗体(例如,贝利木单抗(Belimumab))、抗-CD22抗体、抗-CD20抗体和抗-CD19抗体,其全部都认为是其他治疗剂。在这种情况中,如果在本发明的药剂之前将B细胞的抑制剂给予患者,例如,作为消除B细胞的预处理,则特别优选。
在另一个实施方案中,给予特定的蛋白酶抑制剂以提高本发明药剂的靶向选择性是合适的。例如,如果已知靶向半体结合心脏和乳房组织中的细胞,但只需要靶向乳房中的那些细胞,则给予选择性地抑制负责在心脏中而不是在乳房中释放T细胞抗原的蛋白酶的药剂是希望的。换句话说,给予药剂来抑制能够释放T细胞抗原的蛋白酶,但该蛋白酶停留在需要的细胞附近(例如,在需要的细胞的表面或表面附近)但不在不需要的细胞附近(例如,在不需要的细胞的表面或表面附近)。这在本发明的药剂的蛋白酶切割位点被多种蛋白酶切割的情况下特别有用,这些蛋白酶的一些停留在不需要的细胞附近,且一些停留在需要的细胞附近。在这种情况下,可以通过给予抑制停留在需要的细胞附近而且仍然能够切割切割位点并且因此从本发明的药剂中释放出T细胞抗原的蛋白酶的蛋白酶抑制剂来提高靶向特异性。给予抑制剂的作用将确保T细胞抗原在不需要的细胞附近偏向性地释放。例如,如果癌症患者也具有活跃的类风湿性关节炎,其中MMP2和其他蛋白酶是活跃的,并且通过包括MMP2的多种蛋白酶切割本发明药剂中的一个或多个切割位点,则抑制MMP2来防止药剂在关节炎关节处切割但仍然在癌症位点被另一种蛋白酶切割将是有益的。
因此,本发明包括一种组合物,其含有(i)根据本发明第一个方面的药剂和(ii)另一种治疗剂,其用于预防或治疗特征在于存在不需要的细胞的病症。鉴于本发明的药剂和另一种治疗剂可以同时或按序给药,将认识到,本发明包括根据本发明第一个方面的药剂,其用于预防或治疗特征在于给予了另一种治疗剂的患者体内存在不需要的细胞的病症。因此,本发明还包括用于预防或治疗特征在于给予了根据本发明第一个方面的药剂的患者体内存在不需要的细胞的病症的治疗剂。
相似地,本发明包括组合物在制备用于预防或治疗特征在于存在不需要的细胞的病症的药物中的用途,所述组合物含有(i)根据本发明第一个方面的药剂和(ii)另一种药剂。再次地,鉴于本发明的药剂和另一种药剂可以同时或按序给药,将认识到,本发明包括含有本发明第一个方面的药剂的组合物在制备用于预防或治疗特征在于给予了另一种治疗剂的患者体内存在不需要的细胞的病症的药物中的用途。因此,本发明还包括治疗剂在制备用于预防或治疗特征在于给予了根据本发明第一个方面的药剂的患者体内存在不需要的细胞的病症的药物中的用途。
本发明还提供了组合物,其含有(i)根据本发明第一个方面的药剂和(ii)适用于预防或治疗特征在于存在不需要的细胞的相同病症的另一种治疗剂。认识到,就在前两段中提及的治疗剂可以是适用于治疗特征在于存在不需要的细胞的、与利用本发明药剂可治疗的病症相同的病症的药剂。
本发明的第三个方面提供了根据本发明第一个方面的药剂,其用于医学中。
本发明的第四个方面是含有根据本发明第一个方面的药剂和药物学上可接受的载体、稀释剂或赋形剂的药物组合物。
同时,本发明的药剂单独给药是可能的,使其以与一种或多种可接受的载体共同存在的药物制剂提供是优选的。载体必须是“可接受的”是指与治疗剂相容,并且对其接受者无害。通常,载体将是水或盐水,其是无菌的并且无热原。
在合适的情况中,制剂可以方便地以单位剂量形式存在,并且可以通过药学领域中公知的任一种方法来制备。这样的方法包括将活性成分(用于治疗或预防特征在于不需要的细胞的病症的药剂)与组成一种或多种辅助成分的载体结合的步骤。通常,通过将活性成分与液体载体或细碎的固体载体或二者均匀且紧密地结合,并且然后,如果需要,将产品成型,从而制得制剂。
根据本发明的适用于口服给药的制剂可以作为分开的单位存在,如胶囊、扁囊剂或片剂,其各自含有预定量的活性成分;作为粉末或颗粒存在;作为含水液体或非水液体中的溶液或悬浮液存在;或作为水包油型液体乳液或油包水型液体乳液存在。
可以通过压制或模制来制备片剂,任选使用一种或多种辅助成分。可以通过在合适的机器中压制自由流动形式(如,粉末或颗粒)的活性成分来制备压缩片剂,任选与粘合剂(例如,聚维酮、明胶、羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟基乙酸淀粉钠、交联聚维酮、交联羧甲基纤维素钠)、表面活性剂或崩解剂混合。可以通过在合适的机器中模压用惰性液体稀释剂润湿的粉末状化合物来制得模压片剂。片剂可以任选有包衣或有压痕,并且可以进行配制,以提供其中的活性成分的缓慢或受控释放,通过使用,例如,不同比例的羟丙基甲基纤维素来提供所需的释放特征。
适用于口中局部给药的制剂包括在调味基料中含有活性成分的锭剂,所述调味基料通常是蔗糖和阿拉伯树胶或黄芪胶;在惰性基料(如,明胶和甘油,或蔗糖和阿拉伯树胶)中含有活性成分的软锭剂;和在合适的液体载体中含有活性成分的漱口水。
适用于胃肠道外给药的制剂包括含水和非水无菌注射液,其可以含有抗氧化剂、缓冲剂、抑菌剂和溶质,其使得制剂与预计的接受者的血液等渗;以及含水和非水无菌悬浮液,其可以包括悬浮剂和增稠剂。制剂可以存在于单位剂量或多剂量容器中,例如,密封的安瓿和小瓶,并且可以存储于冷冻干燥(冻干)条件下,仅需要在使用前即刻添加无菌液体载体,例如,注射用水。临时注射液和悬浮液可以从之前所述种类的无菌粉末、颗粒和片剂制得。
可以以栓剂或阴道药栓的形式来给予本发明的药剂,或可以以洗液、溶液、霜剂、膏剂或爽身粉的形式来局部施用。药剂也可以经皮给药,例如,通过使用皮肤贴剂。
优选的单位剂型是含有日剂量或单位、日次剂量或其合适部分活性成分的那些。
应当理解,除了以上特别提及的成分以外,考虑到所讨论制剂的类型,本发明的制剂可以包括本领域中常规的其他药剂,例如,适用于口服给药的那些可以包括调味剂。
给与个体的药剂的量是有效抗争特定个体病症的量。量可以由医生来确定。
优选地,在本文中所述的本发明的任一个方面的内容中,待治疗的患者是人。或者,患者可以是动物,例如,家养动物(例如,狗或猫)、实验室动物(例如,实验室啮齿动物,例如,小鼠、大鼠或兔子)或农业中重要的动物(即,家畜),例如,马、牛、绵羊或山羊。
本发明提供了用于预防或治疗特征在于存在不需要的细胞的病症的试剂盒,该试剂盒包含:(i)能够靶向不需要的细胞并且连接第一个结合配偶体的靶向半体,和(ii)连接能够结合第一个结合配偶体的第二个结合配偶体的T细胞抗原,其中T细胞抗原可以通过第二个结合配偶体和T细胞抗原之间的切割位点的选择性切割在不需要的细胞附近从第二个结合配偶体释放出来。
病症、不需要的细胞、靶向半体和T细胞抗原的优先选择如上所述。如果试剂盒是用于预防或治疗癌症的,则特别优选。
第一个和第二个结合配偶体包括彼此选择性地结合的任何两个部分。最优选地,第一个和第二个结合配偶体只彼此结合,且不与任何其他部分结合。优选非共价结合,如生物素/抗生物素蛋白或抗生物素蛋白链菌素之间,或免疫结合。因此,第一个结合配偶体可以是生物素,且第二个结合配偶体可以是抗生物素蛋白,反之亦然。或者,第一个结合配偶体可以是抗原,且第二个结合配偶体可以是特异于该抗原的抗体,反之亦然。然而,可以使用彼此选择性结合的任何一对的第一个和第二个结合配偶体,并且合适的对是本领域技术人员已知的。
将认识到,试剂盒使得可以首先将靶向半体给予患者,并且在给予T细胞抗原之前建立靶向半体在患者体内的正确位置(例如,通过可检测地标记靶向半体(例如,放射性同位素标记的))。然后将T细胞抗原借助结合第一个结合配偶体的第二个结合配偶体靶向不需要的细胞。一旦位于不需要的细胞附近,T细胞抗原将通过第二个结合配偶体和T细胞抗原之间的切割位点的选择性切割从第二个结合配偶体中释放出来,使其在不需要的细胞表面上递呈,以将现有的免疫应答重新定向至不需要的细胞。
因此,本发明进一步提供了一种用于预防或治疗特征在于存在不需要的细胞的病症的方法,该方法包括给予患者(i)能够靶向不需要的细胞并且连接第一个结合配偶体的靶向半体,和(ii)连接能够结合第一个结合配偶体的第二个结合配偶体的T细胞抗原,其中T细胞抗原通过第二个结合配偶体和T细胞抗原之间的切割位点的选择性切割在不需要的细胞附近从第二个结合配偶体中释放出来。优选地,在T细胞抗原之前,给予靶向半体,例如,以使得靶向半体在待建立的不需要的细胞处正确定位。然而,靶向半体可以与T细胞抗原同时给予。
相似地,本发明提供了一种能够靶向不需要的细胞并且连接第一个结合配偶体的靶向半体,和连接能够结合第一个结合配偶体的第二个结合配偶体的T细胞抗原,其中T细胞抗原通过第二个结合配偶体和T细胞抗原之间的切割位点的选择性切割在不需要的细胞附近从第二个结合配偶体中释放出来,其用于预防或治疗特征在于患者体内存在不需要的细胞的病症。优选地,在T细胞抗原之前给予靶向半体,例如,以使得靶向半体在待建立的不需要的细胞处正确定位。然而,靶向半体可以与T细胞抗原同时给予。认识到靶向半体和T细胞抗原可以通过结合第一个和第二个结合配偶体彼此连接。
本发明提供的再一种试剂盒含有(i)能够靶向不需要的细胞的靶向半体,(ii)T细胞抗原,和(iii)一种或多种手段或试剂,以测定患者的(a)MHC等位基因,(b)针对T细胞抗原的细胞毒T细胞应答和(c)不需要的细胞在患者体内的表达特征中的一种或多种。
对于靶向半体和T细胞抗原的优先选择包括如本文中所述的那些。将认识到,这种试剂盒可以用于为给定的病人定制按照本发明第一个方面限定的特定药剂。可以用于评价患者的(a)MHC等位基因,(b)针对T细胞抗原的细胞毒T细胞应答和(c)不需要的细胞在患者体内的表达特征的合适手段或试剂是本领域公知的并且可以广泛地获得。在一个实施方案中,试剂盒含有本发明第一个方面的药剂,并且试剂盒可以用于测定药剂是否适合特定的病人。
本发明还提供了含有(i)T细胞抗原和(ii)切割位点的分子;其中切割位点含有连接部分,以使得分子连接靶向半体,该靶向半体能够靶向不需要的细胞,并且其中切割位点可以在不需要的细胞附近选择性切割。
认识到分子可以表示本发明第一个方面的药剂的一部分,而不是靶向半体。因此,对于T细胞抗原、切割位点、切割位点如何连接靶向半体(例如,通过含有巯基的连接物半体,如半胱氨酸残基)、靶向半体和不需要的细胞的优选选择包括以上关于本发明第一个方面限定的所有那些。
在特定的实施方案中,分子含有以上表6中所列的那些最终的肽,其中表6中所列的“表位”对应于分子的T细胞抗原,并且其中表6中所列的“切割序列”对应于切割位点。因此,分子可以包含以下任一种肽或由以下任一种肽组成:NLVPMVATVQKWNKWALSRASALASALC(SEQ ID No:283),NLVPMVATVQHSSKLQLGGGSGGGGSC(SEQ ID No:285),NLVPMVATVQGGGGFGGGGFGGGGFC(SEQ ID No:287),NLVPMVATVQKQSRKFVPGGGSGGGGSC(SEQ IDNo:288),NLVPMVATVQCPGRVVGGGGGSGGGGSC(SEQ ID No:289),NLVPMVATVQYLGRSYKVGGGSGGGGSC(SEQ ID No:290),NLVPMVATVQGPQGIASQGGGSGGGGSC(SEQID No:292),NLVPMVATVQPQG-IAGQGGGSGGGGSC(SEQ ID No:293)和NLVPMVATVQVLKVLKVLKGGGSGGGGSC(SEQ ID No:295)
在特定的实施方案中,分子含有以上表7中所列的那些最终的肽,其中表7中所列的“表位”对应于分子的T细胞抗原,并且其中表7中所列的“切割位点”对应于切割位点。因此,分子可以包含以下任一种肽或由以下任一种肽组成:CSGGGGSGGGGCPGRVVGGANLVPMVATV(SEQ ID No:297),CSGGGGSGGGGGGRANLVPMVATV(SEQ ID No:298),CSGGGGSGGGGYLGRSYKVANLVPMVATV(SEQ ID No:299),CSGGGGSGGGGSLGRKIQIANLVPMVATV(SEQ ID No:300),CSGGGGSGGGGLVPRGSANLVPMVATV(SEQ ID No:301),CSGGGGSGGGGRANLVPMVATV(SEQ ID No:304),CSGGGGSGGGGAAPVANLVPMVATV(SEQ ID No:305),CSGGGGSGGGGKQLRVVNGANLVPMVATV(SEQ ID No:306),CSGGGGSGGGGSSKYQANLVPMVATV(SEQ ID No:307)和CSGGGGSGGGGGGGGFANLVPMVATV(SEQ ID No:308)。
在另一个实施方案中,分子包含以下任一个肽或由以下任一个肽组成:KTPRVTGGGAMAIPVSLRSGGGGSGGGGSC(SEQ ID No:273),DDYSNTHSTRYVTIPVSLRSGGGGSGGGGSC(SEQ ID No:274),RNLVPMVATVQIPVSLRSGGGGSGGGGSC(SEQ ID No:275),YVLEETSVMLIPVSLRSGGGGSGGGGSC(SEQ ID No:277),NLVPMVATVQGALALALALC(SEQ ID No:278),NLVPMVATVQGPLGALALALALALALALALALALALC(SEQ ID No:279)或NLVPMVATVLPRSAKELRC(SEQ ID No:280)。
在一个实施方案中,本文中所述的靶向半体是西妥昔单抗(Cetuximab),T细胞抗原包含NLVPMVATV(SEQ ID NO:21),并且切割位点包含MMP14切割序列。
在一个实施方案中,本文中所述的靶向半体是Retuximab(利妥昔单抗),T细胞抗原包含DYSNTHSTRYV(SEQ ID NO:55),并且切割位点包含MMP2切割序列。
在一个实施方案中,本文中所述的靶向半体是Retuximab,T细胞抗原是TPRVTGGGAM(SEQ ID NO:31),并且切割位点包含MMP2切割序列。
在一个实施方案中,本文中所述的靶向半体是hP67.6(Gemtuzumab亲本抗体),T细胞抗原是TPRVTGGGAM(SEQ ID NO:31),并且切割位点包含MMP2切割序列。
在一个实施方案中,本文中所述的靶向半体是西妥昔单抗,T细胞抗原包含NLVPMVATV(SEQ ID NO:21),并且切割位点包含以下任一个切割序列:uPa/tPa切割序列(CPGR-VVGG)(SEQ ID No:254)、纤溶酶/TMPRSS2切割序列(GGR-X)(SEQ ID No:256)、C1s切割(YLGR-SYKV)(SEQ ID No:257)、MASP2切割序列(SLGR-KIQI)(SEQ ID No:259)、凝血酶切割序列(LVPRGS)(SEQ ID No:260)、胰蛋白酶切割序列(XXXR-X)(SEQ ID No:261)、弹性蛋白酶2切割序列(AAPV-X)(SEQ ID No:262)、MT-SP1/ST14切割序列(KQLR-VVNG)(SEQ IDNo:263)、PSA切割序列(SSKYQ)(SEQ ID No:265)或组织蛋白酶B切割序列(GGGG-F)(SEQ IDNo:267)。
附图说明
将借助以下附图和实施例来进一步详细描述本发明。
图1:用西妥昔单抗染色的MMP14转导的MDA.MB.231细胞,西妥昔单抗偶联含有NLVPMVATV(SEQ ID No:21)的MMP14切割序列(NLVPMVATVLPRSAKELRC(SEQ ID No:280),使用硫代-SMCC将MMP14切割序列连接西妥昔单抗。
图2:用利妥昔单抗将B-LCL细胞染色,利妥昔单抗偶联含有II类HLA肽DYSNTHSTRYV(SEQ ID No:55)的蛋白酶切割序列(DDYSNTHSTRYVTIPVSLRSGGGGSGGGGSC)(SEQ ID No:274)。
图3:用利妥昔单抗将B-LCL细胞染色,利妥昔单抗偶联含有I类HLA肽TPRVTGGGAM(SEQ ID No:31)的蛋白酶切割序列(KTPRVTGGGAMAIPVSLRSGGGGSGGGGSC)(SEQ ID No:273),使用硫代-SMCC将蛋白酶切割序列连接Retuximab。
图4:(A)本发明的示例性实施方案的示意图。(B)显示了病毒肽传送的设计和机制的示意图。(i)由能够靶向肿瘤细胞的单克隆抗体组成的优选靶向分子,所述靶向分子共价连接含有蛋白酶识别结构域和T细胞肽抗原的合成肽。(ii)将肽偶联物通过特异性抗体传送至靶细胞,并且肽在肿瘤细胞附近切割。释放的较小的病毒肽被动地结合细胞表面上的空I类或II类MHC分子。然后MHC-肽复合物被识别并且通过特异性循环T细胞介导肿瘤细胞溶解。
图5:重新定向的病毒特异性T细胞的体外活性。(A)类淋巴母细胞淋巴瘤细胞系通过同源抗原TPRVTGGGAM(SEQ ID No:31)肽与利妥昔单抗(抗-CD20)的偶联被CD8+细胞巨化病毒特异性细胞毒T淋巴细胞识别。只有肽两侧为MMP2切割基序时,才存在识别。对照是单独的肿瘤细胞、单独的CTL和用游离TPR肽(KTPRVTGGGAMAIPVSLRSGGGGSGGGGSC)(SEQ IDNo:273)脉冲的肿瘤细胞,使用硫代-SMCC将所述游离TPR肽连接Retuximab。(B)HLA-DR7+限制性表位DYSNTHSTRYV(SEQ ID No:55)(DYSN)特异性的CD4+细胞巨化病毒特异性T细胞的重新定向。用利妥昔单抗或对照肽孵育类淋巴母细胞细胞系并洗涤,所述利妥昔单抗与不含切割位点(IPDDYSNTHSTRYVC)(SEQ ID No:309)的DYSN肽和含有蛋白酶切割位点(DDYSNTHSTRYVTIPVSLRSGGGGSGGGGSC)(SEQ ID No:274)的“DYSN-蛋白酶切割位点”交联。然后用DYSN-特异性CD4+T细胞将肿瘤细胞孵育过夜,并且通过ELISA,使用IFNγ释放测定T细胞识别。附近DYSN肽包含蛋白酶切割位点显著提高了CD4+T细胞对肿瘤细胞的识别。(C)朝向乳腺癌细胞系MDA-MB23、使用细胞巨化病毒pp65(NLVPMVATV)(SEQ ID No:21)表位特异性的细胞巨化病毒特异性的CD8+CTL的应用。与MMP14切割位点组合的肽的偶联介导了使用硫代-SMCC连接西妥昔单抗的细胞(NLVPMVATVLPRSAKELRC;SEQ ID No:28)的杀灭。更多未显示的数据表明缺乏MMP14切割位点的肽偶联物显示出与单独的西妥昔单抗相当的杀灭。
图6:使用APEC方法的肿瘤细胞系的体外和体内靶向。(A)两个乳腺癌细胞系MCF7和MB-MDA231上的EGFR表达。(B)使用含有NLVPMVATV(SEQ ID No:21)肽、与西妥昔单抗偶联的蛋白酶切割位点(CSGGGGSGGGGAIPVSLRANL VPMVATV;SEQ ID No:276)成功靶向EGFR+细胞系MDA-MB231。箭头表示APEC处理的细胞的T细胞的有效识别。(C)没有表达EGFR的MCF-7没有被西妥昔单抗免疫偶联物靶向。在(B)和(C)二者中,B-RPH是设计不被T细胞识别的HLA错配肽,并且VLE-蛋白酶切割肽是HLA相配的肽。这种肽设计为蛋白酶切割序列的对照,以确保T细胞不识别蛋白酶切割序列的一部分。因为对VLE-蛋白酶切割肽的应答是可以忽略的,用NLV-蛋白酶切割肽看到的应答是对抗NLVPMVATV(SEQ ID No:21)序列的而不是蛋白酶切割序列。
图7:使用APEC方法体内靶向肿瘤细胞系。(A)体内异种移植数据证明通过腹膜内注射给予西妥昔单抗-肽偶联物时,人MDA-MB-231乳腺癌细胞系可以通过CMV-特异性T细胞完全根除。西妥昔单抗-肽复合物单独不能控制肿瘤生长(上),而CMV-特异性T细胞也不能(中)。然而,两者的结合引起体内这种侵略性乳腺癌肿瘤的完全根除。(B)使用连接CMV-特异性T细胞表位和蛋白酶切割位点的抗-Muc1抗体成功靶向结直肠细胞系Colo205。GP1.4和SM3是充分表征的抗-MUC1特异性抗体。(C)这种抗-Muc1抗体-肽偶联物也能非常有效地靶向胰腺癌细胞系Panc1。MH1、SM3和GP1.4全部都是充分表征的MUC1特异性单克隆抗体。MH1对MUC1的胞质尾是特异性的,并且因此不结合完整的肿瘤细胞,而SM3和GP1.4结合MUC1糖蛋白的胞外部分。对于图7A,所用的肽是使用反向序列(CSGGGGSGGGGAIPVSLRA NLVPMVATV)(SEQ ID NO:276)的NLV肽,。在图7B和C中,肽如下:含有蛋白酶切割位点的NLVR(CSGGGGSGGGGAIPVSLRANLVPMVATV)(SEQ ID NO:276),含有与NLVR相同蛋白酶切割位点但病毒表位方向不同于NLV-R的RNLV(RNLVPMVATVQIPVSLRSGGGGSGGGGSC)(SEQ ID NO:275),并且将不含有蛋白酶切割位点的生物素肽(生物素-PFMRPHERNGFTVLC:SEQ ID No:320)用作对照肽。(D)编码与(A)中所用的肽序列相同但包含在scFv单多肽链内的单链片段V(scFv)蛋白构建体证明了在体外对抗MDA-MB-231细胞系的活性。ScFv构建体内的蛋白酶识别位点是IPVSLRS(SEQ ID NO:310)。
图8:抗体-肽偶联物的血浆稳定性和肿瘤B细胞的特异性靶向。(A)用偶联源自细胞巨化病毒的I类MHC肽的利妥昔单抗标记细胞后,CD8+细胞巨化病毒特异性细胞毒T细胞对类淋巴母细胞细胞系或健康B细胞的识别。在T细胞特异性的病毒肽的存在下,不存在健康B细胞的识别,而只存在靶向细胞的识别。该数据证明了与健康组织相比,APEC对恶性细胞的特异性。(B)将抗体肽-表位偶联物(APEC)在人血浆中在37℃下孵育,并且通过ELISA测试来测定肽偶联的稳定性。APEC的半衰期是~50分钟,并且通过在肽的C端添加乙酰基也不会被改变。在图8中,所用的肽序列是含有蛋白酶切割位点IPVSLRS(SEQ ID NO:310)的NLV-蛋白酶切割反向序列(CSGGGGSGGGGAIPVSLRANLVPMVATV)(SEQ ID NO:276)、含有蛋白酶切割位点IPVSLRS(SEQ ID NO:310)的VLE-蛋白酶切割序列(YVLEETSVMLIPVSLRSGGGGSGGGGSC)(SEQ ID NO:277)和用作对照肽的不含蛋白酶切割序列的生物素-RPH(生物素-PFMRPHERNGFTVLC:SEQ ID No:320)。
图9:(A)细胞巨化病毒pp65蛋白的氨基酸序列(SEQ ID NO:318);(B)实施例中参考的一些肽构建体的氨基酸序列。解释:粗体和下划线=T-细胞表位;加框=可变连接物;斜体=蛋白酶识别位点;加框和粗体=按照亲本pp65的表位延伸残基;双下划线=带有巯基的偶联残基。
图10:(A)外蛋白水解活性的依赖性:将靶细胞轻轻地固定在多聚甲醛中,或没有固定,然后用肽(NLVPMVATV)(SEQ ID No:21)或西妥昔单抗孵育,并用NLVPMVATV(SEQ IDNo:21)特异性T细胞孵育,所述西妥昔单抗与无关肽(VLE)或同源肽(NLVPMVATV:SEQ IDNo:21-蛋白酶切割位点)偶联。数据证明固定的细胞能够加工抗体-肽偶联物,并且内在化对于加工不是必需的。(B)数据证明受体肽激动剂(NLVPMVATVAIPVSLRSAAAFCDGFYACYMDV(SEQ ID NO:311)=Her2/neu激动剂肽[FCDGFYACYMDV](SEQ ID No:312)加上NLVPMVATV(SEQ ID No:21)和蛋白酶切割位点AIPVSLR(SEQ ID No:313);NLVPMVATVAIPVSLRSAAAYCRDYDYDGRYFDCY(SEQ ID No:314)=EGFR激动剂肽(YCRDYDYDGRYFDCY)(SEQ ID No:319)加上病毒肽NLVPMVATV(SEQ ID No:21)和蛋白酶切割位点AIPVSLR(SEQ ID No:313))可以用于重新定向对抗EGFR+肿瘤细胞的T细胞(Ponde等,Bioorg Med Chem Lett 21(8):2550-3)。
图11:(A)证明细胞因子可以用作靶向半体,IL-2(A)和IL-4(B)与II类HLA肽(DR7-限制的)PDDYSNTHSTRYVC(SEQ ID No:309)偶联并且使用生物素-RPH(生物素PFMRPHERNGFTVLC;SEQ ID No:320)作为对照肽。用细胞因子-肽复合物标记靶细胞并且与DYSN-特异性CD4T细胞培养4或24小时后,对用DR7-限制的肽(PDDYSN)标记的靶细胞存在强烈的T细胞应答,并且在4和24小时(A)以及24小时(B)后使用对照肽(生物素-RPH)时没有应答。
图12:通过多种肿瘤细胞系的T细胞识别。用同源抗原脉冲时,八个HLA-A*0201NCI-60细胞系全部被HLA-A*0201-限制的CMV-特异性T-细胞识别。
图13:使用抗体-肽-表位偶联物(APEC)方法体外靶向人癌细胞系。(A)早先的数据表明西妥昔单抗-肽偶联物可以用于靶向癌细胞系。阳性对照是同源病毒肽脉冲的肿瘤-如图12中所示。(B)在肽中引入蛋白酶切割位点对于肿瘤细胞的有效靶向是关键的。不带有切割序列的肽(PC)不切割并且因此不被T细胞识别。(C)使用西妥昔单抗-MMP2-NLVPMVATV(SEQ ID NO:21)APEC,我们可以成功地靶向7个HLA-A*0201 NCI-60细胞系中的4个。NCI-H522和Colo205也有微弱识别,而HCT-116没有识别。Caki-2不是HLA-A*0201,并且只用作对照。(D)我们已经基于西妥昔单抗序列和N-端连接的MMP2-NLVPMVATV(SEQ ID NO:21)产生了scFv蛋白。该制剂也能够在体外靶向MDA-MB-231肿瘤细胞(用红色显示)。(E)西妥昔单抗APEC的体外功效评价。这些实验表明EC50在2-5ug/ml(13-30nM)之间。在图13中,当肽表位是NLVPMVATV(SEQ ID NO:21)时,所用的肽是含有蛋白酶切割序列AIPVSLR(SEQ ID No:313)的CSGGGGSGGGGAIPVSLRANLVPMVATV(SEQ ID No:276)(‘NLVPMVATV-PC’),以及不含蛋白酶切割位点的CSGGGGSGGGGANLVPMVATV(SEQ ID No:315)(‘NLVPMVATV’)。
图14:(A)通过免疫组织化学显示CD8+T细胞的4个人腺癌的免疫组织化学揭示了人癌中大量CD8+T细胞浸润。(B)使用抗-Muc1(SM3)-(蛋白酶切割)-NLVPVATV(SEQ ID NO:21)APEC,我们可以成功地靶向胰腺癌细胞系Panc-1。(C)使用利妥昔单抗-蛋白酶切割-NLVPVATV(SEQ ID NO:21)APEC,我们有差别地靶向模型肿瘤B细胞系(LCL)(黑条)并避免靶向健康的B细胞(白条)。(D)使用利妥昔单抗-PC-DYSNTHSTRYV(SEQ ID NO:55)APEC,使用引发CD4+T细胞应答的II类HLA衍生的肽,我们可以成功地靶向模型肿瘤B细胞系(LCL)。(E)使用西妥昔单抗-MMP2-NLVPVATV(SEQ ID NO:21)APEC,我们可以以相似于未固定细胞(白条)中看到的水平成功地靶向之前固定的细胞(黑条)。(F)使用抗-CD138抗体来靶向骨髓瘤细胞系U266。PC=蛋白酶切割,“U266+NLVPVATV(SEQ ID NO:21)+T细胞”对应于单独的天然9氨基酸肽,其作为游离肽表位(即,没有连接物等),并且作为阳性对照,因为其基本上是最大可能的应答。在图14中,当肽表位是NLVPMVATV(SEQ ID No:21)时,所用的肽是含有蛋白酶切割序列AIPVSLR(SEQ ID No:313)的CSGGGGSGGGGAIPVSLRANLVPMVATV(SEQ ID No:276)(‘NLVPMVATV-PC’),以及不含蛋白酶切割位点的CSGGGGSGGGGANLVPMVATV(SEQ ID No:315)(‘NLVPMVATV’)。
具体实施方式
实施例1:通过西妥昔单抗-NLVMVATV(SEQ ID NO:21)偶联物刺激T细胞
概述
我们将乳腺癌细胞接触含有与具有和不具有切割位点的HLA-B7肽偶联的西妥昔单抗的药剂。随后,当乳腺癌细胞接触含有切割位点的药剂时,暴露于T细胞导致了T细胞应答的产生。
结果
用MMP14基因转导常常用作乳腺癌模型的MDA.MB.231细胞,以确保细胞内MMP14蛋白的表达。用未偶联(1)或与RPHERNGFTVL(SEQ ID No:32),HLA-B7肽偶联(2),与不含MMP14切割序列的NLVPMVATV(SEQ ID No:21)偶联(3)或与包括切割序列的NLVPMVATV(SEQ IDNo:21)偶联(4)的西妥昔单抗将靶细胞(1×105)染色后,将染色的细胞孵育过夜。第二天,洗涤细胞,并将NLV-特异性T细胞加入培养物中(1×104),并孵育过夜。收集上清液,并且使用ELISA来测定每个培养物中IFN-γ的存在,n=3。结果显示于图1中。
从与使用单独的西妥昔单抗和与错配的HLA-肽偶联的西妥昔单抗染色的细胞一起培养的T细胞中释放出非常少的IFN-γ。与使用偶联正确的肽但缺少MMP14切割位点的西妥昔单抗染色的细胞一起培养的T细胞也产生了非常少的IFN-γ,而与施用偶联含有MMP14切割位点的正确肽的西妥昔单抗染色的细胞一起培养的T细胞产生了大量的IFN-γ。
实施例2:通过Retuximab-DYSNTHSTRYV(SEQ ID NO:55)偶联物刺激CD4+T细胞
概述
我们将B-类淋巴母细胞细胞(B-LCL)接触含有与具有和不具有切割位点的细胞巨化病毒II类HLA限制肽DYSNTHSTRYV(SEQ ID NO:55)偶联的Retuximab的药剂。随后,当B-LCL细胞接触含有切割位点的药剂时,暴露于CD4+T细胞导致了T细胞应答的产生。
结果
用偶联不含蛋白酶切割序列的无关错配肽RPHERNGFTVL(SEQ ID No:32),HLA-B7肽(1),具有蛋白酶切割序列的无关错配I类HLA肽VLEEETSVML(SEQ ID No:316),HLAA-A2肽(2),不含蛋白酶切割序列的相关肽DYSNTHSTRYV(SEQ ID No:55)(3)或包括蛋白酶切割序列的相关肽DYSNTHSTRYV(SEQ ID No:55)(4)的利妥昔单抗将B-LCL细胞染色后,将染色的细胞孵育过夜。第二天,洗涤细胞,并将DYSN-特异性CD4+T细胞加入培养物中,并孵育过夜。收集上清液,测定每个培养物中IFN-γ的存在,n=3。从与使用偶联不含蛋白酶切割位点的错配HLA-肽的利妥昔单抗染色的细胞一起培养的CD4+T细胞释放出非常少的IFN-γ。与使用偶联正确的肽但缺乏蛋白酶切割位点的利妥昔单抗染色的细胞一起培养的CD4+T细胞也产生非常少的IFN-γ,而与使用偶联正确的肽且含有蛋白酶切割位点的利妥昔单抗染色的细胞一起培养的T细胞产生大量的IFN-γ。然而,用偶联含有蛋白酶切割位点的HLA-错配肽的利妥昔单抗培养T细胞时,不产生IFN-γ。结果显示于图2中。
图3中显示了通过Retuximab-TPRVTGGAM偶联物刺激CD4+T细胞的相似实施例。
实施例3:用于化学偶联半胱氨酰化肽和抗体的标准操作程序
1.将半胱氨酰化的肽溶解于DMSO中,至5mg/ml的终浓度。
2.称重1mg硫代琥珀酰亚胺4-[N-马来酰亚胺甲基]环己烷-1-羧酸酯(硫代-SMCC),并溶解于500μl磷酸盐缓冲盐水(PBS)中。
a.可以替代硫代-SMCC使用的其他杂双功能交联剂例如硫代琥珀酰亚胺6-(3’-[2-吡啶基二硫代]-丙酰胺基)己酸酯(硫代-LC-SPDP)和N-[β-马来酰亚胺丙酸]酰肼、三氟醋酸盐(BMHP)。
3.将20μl抗体(1mg/ml,20μg抗体)加入溶解的硫代-SMCC中,并且在室温下孵育1小时。
4.首先将柱子在13,000rpm下离心30秒来除去乙醇(存储缓冲液),从而洗涤蛋白G柱(GE Healthcare)。
5.加入500μl PBS并且将蛋白G珠充分混合,然后在13,000rpm下离心30秒。除去洗脱液,并且再重复两次。
6.将抗体-SMCC加入蛋白G柱中,充分混合,并且孵育5分钟。在13,000rpm下离心30秒,并除去洗脱液。
7.通过加入500μl PBS并且将珠子充分混合,然后在13,000rpm下离心30秒,并除去洗脱液来洗涤抗体。将该步骤再重复两次。
8.为了洗脱结合的抗体,将125μl 0.1M醋酸加入珠子中并且在室温下孵育2分钟。将柱子置于1.5ml eppendorf中并且在13,000rpm下离心30秒,并收集洗脱液。
9.重复步骤8。
10.加入250μl 0.2M Na2HCO3,并在室温下静置5分钟。
11.将2μl之前溶解于DMSO中的肽加入SMCC-激活的抗体中,并且在室温下孵育2小时。
12.重复步骤4至10,以从抗体除去过量的未结合肽。
13.加入250μl 0.2M Na2HCO3后,在存储前,再加入500μl PBS。抗体现在可以用于染色细胞了。
14.在4℃下存储抗体。
实施例4:乳腺癌的治疗
制备了含有西妥昔单抗的药剂,所述西妥昔单抗通过包含PRSA-KELR(SEQ ID NO:321)蛋白酶切割位点(基质金属蛋白酶14(MMP14)可切割)的连接物连接源自细胞巨化病毒的肽T细胞抗原,如NLVPMVATV(SEQ ID No:21)。将药剂与药学学上可接受的赋形剂一起配制,并且给予患有表皮恶性疾病(如,乳腺癌)的病人。药剂,西妥昔单抗,靶向乳腺癌细胞,并且结合时接触MMP14。蛋白酶切割位点的切割释放出T细胞抗原NLVPMVATV(SEQ ID No:21),其随后结合乳腺癌细胞表面上的HLA-A*0201分子。通过宿主免疫系统靶向表达T细胞抗原的乳腺癌细胞,通过效应物CD8T细胞进行细胞溶解。
实施例5:B-细胞淋巴瘤(例如,慢性淋巴细胞性白血病)的治疗
制备了含有利妥昔单抗的药剂,所述利妥昔单抗通过包含TIPV-SLRS(SIE ID No:317)蛋白酶切割位点(通过基质金属蛋白酶2(MMP2)可切割)的连接物连接源自细胞巨化病毒的II类HLA肽T细胞抗原,如DYSNTHSTRYV(SEQ ID No:55)。将药剂与药物学上可接受的赋形剂一起配制,并且给予患有B细胞淋巴瘤(例如,慢性淋巴细胞性白血病)的病人。药剂,利妥昔单抗,靶向B细胞,并且在结合时接触蛋白酶。随后蛋白酶切割位点的切割释放出T细胞抗原DYSNTHSTRYV(SEQ ID No:55),其随后结合B细胞表面上的HLA-DR*0107分子。然后,通过宿主免疫系统靶向表达T细胞抗原的B细胞,通过效应物CD4T细胞进行细胞溶解。
实施例6:肠癌的治疗
制备了含有西妥昔单抗的药剂,所述西妥昔单抗通过包含CPGR-VVGG(SEQ ID No:254)蛋白酶切割位点(通过uPA可切割)的连接物连接源自细胞巨化病毒的肽T细胞抗原。将药剂与药物学上可接受的赋形剂一起配制,并给予肠癌病人。
实施例7:B细胞淋巴瘤(例如,慢性淋巴细胞性白血病(CLL))的治疗
制备了含有Retuximab的药剂,所述Retuximab通过包含PQG-IAGQ(SIE ID No:269)蛋白酶切割位点(通过MMP2可切割)的连接物连接源自细胞巨化病毒的肽T细胞抗原。将药剂与药物学上可接受的赋形剂一起配制,并且给予B细胞淋巴瘤(例如,CLL)病人。
实施例8:通过利妥昔单抗-TPRVTGGGAM(SEQ ID No:31)偶联物刺激T细胞
概述
我们将B-类淋巴母细胞细胞(B-LCL)接触含有与具有和不具有切割位点的细胞巨化病毒肽TPRVTGGGAM(SEQ ID No:31)偶联的Retuximab的药剂。随后,当B-LCL细胞接触含有切割位点的药剂时,暴露于T细胞导致了T细胞应答的产生。
结果
用偶联RPHERNGFTVL(SEQ ID No:32),HLA-B7肽(1),含有蛋白酶切割序列的无关错配I类HLA肽VLEEETSVML(SEQ ID No:316)(HLAA-A2肽)(2),具有蛋白酶切割序列的相关肽TPRVTGGGAM(SEQ ID No:31)(3)或不具有蛋白酶切割序列的相关肽TPRVTGGGAM(SEQ IDNo:31)(4)的利妥昔单抗将细胞染色后,将染色的细胞在37℃下孵育过夜。第二天,洗涤细胞,并将TPR-特异性T细胞加入培养物中,并孵育过夜。收集上清液,测定每个培养物中IFN-γ的存在,n=3。结果显示于图3中。
从与使用偶联具有或不具有蛋白酶切割位点的错配HLA-肽的利妥昔单抗染色的细胞一起培养的T细胞释放出非常少的IFN-γ(1&2)。与使用偶联正确的肽但缺乏蛋白酶切割位点的利妥昔单抗染色的细胞一起培养的T细胞也产生非常少的IFN-γ(4),而与使用偶联正确的肽并含有蛋白酶切割位点(3)的利妥昔单抗染色的细胞一起培养的T细胞产生大量的IFN-γ。
实施例9:B细胞淋巴瘤(例如,慢性淋巴细胞性白血病)的治疗
制备了含有利妥昔单抗的药剂,所述利妥昔单抗通过包含TIPV-SLRS(SIE ID No:317)蛋白酶切割位点(通过基质金属蛋白酶2(MMP2)可切割)的连接物连接源自细胞巨化病毒的I类HLA肽T细胞抗原,如TPRVTGGGAM(SEQ ID No:31)。将药剂与药物学上可接受的赋形剂一起配制,并且给予患有B细胞淋巴瘤(例如,慢性淋巴细胞性白血病)的病人。药剂,利妥昔单抗,靶向B细胞,并且在结合时接触蛋白酶。蛋白酶切割位点的切割释放出T细胞抗原TPRVTGGGAM(SEQ ID No:31),其随后结合B细胞表面上的HLA-B*0702分子。然后,通过宿主免疫系统靶向表达T细胞抗原的B细胞,通过效应物CD8T细胞进行细胞溶解。
实施例10:在体外和体内通过重新定向抗病毒免疫应答靶向肿瘤
概述
我们已经显示,通过利用肿瘤相关蛋白水解环境,并且因此使停留的抗-病毒T细胞特异性地杀灭肿瘤细胞,可以将抗体工程化来传送病毒肽,并在肿瘤位点释放。我们筛选了15个HLA-A2+肿瘤细胞系(THP-1(急性单核细胞性白血病细胞系);A498(肾细胞癌);MDA-MB-231和MCF-7(乳房细胞腺癌);NCI-H522(非小细胞肺癌);Ovcar-3(卵巢腺癌);Colo205和HCT-116(结直肠癌))),并且显示出用同源病毒肽脉冲时,100%被人抗-病毒T细胞识别并杀灭(图12)。此外,我们使用了分子和细胞方法来证明免疫显性抗-病毒CD8+T细胞存在于各种人肿瘤中,给这样的方法提供了理论基础。
结果
通过将T细胞表位肽与临床上可用的抗体西妥昔单抗和利妥昔单抗共价连接,产生了抗体-肽表位偶联物(APEC)。溶液中的或平板结合的APEC都不能激活同源T细胞。健康CD20+B细胞结合Ritixumab-APEC(RPEC)但在体外不能激活T细胞。然而,通过结合肽的蛋白水解释放在体外被RPEC结合时,CD20+淋巴瘤细胞系能够被T细胞有效地靶向,这证明了差别性的肿瘤靶向(图5)。
使用乳腺癌作为实体肿瘤模型,使用西妥昔单抗-APEC(CPEC),在恶性细胞系MDA-MB-231上靶向EGF受体。结果证明了CPEC结合靶细胞时的T细胞识别(p<0.01)(图6)。图7B和7C也证明了使用抗-Muc1抗体肽偶联物成功靶向了结直肠腺癌细胞系和胰腺癌细胞系。
使用异种移植小鼠模型的体内数据证明了与用单独的T细胞或单独的CPEC治疗的小鼠相比,用CPEC和T细胞治疗的小鼠中显著的功效(参见图7A)。因为通过腹膜内注射给予偶联物,并且皮下给予肿瘤,这些数据还证明了体内的血浆稳定性。
图7D证明了使用含有作为多肽链一部分的病毒肽序列的蛋白成功靶向了T细胞。制备了单链片段V(scFv)抗体-样构建体,其编码蛋白酶识别结构域和T细胞表位,并且显示出在体外有效靶向MDA-MB-231细胞。
图8A显示了根据本发明的偶联物可以用于选择性地靶向癌细胞。用偶联病毒肽的利妥昔单抗标记类淋巴母细胞细胞或健康B细胞后,仅在存在T细胞特异性的病毒肽时,不识别健康的B细胞,而识别类淋巴母细胞细胞。
图8B证明了根据本发明的偶联物的血浆和血清稳定性。
图10A证明了在细胞表面产生的西妥昔单抗-肽复合物的作用机制,并且不是通过整个复合物的内在化。通过靶细胞的化学固定,抑制了复合物的内在化,并且使用固定化细胞的阳性IFN-γ应答证明了APEC的外部加工。结果表明,化学固定的靶细胞证明了用西妥昔单抗-NLVPMVATV-蛋白酶切割孵育时,与靶细胞没有化学固定时看到的相似的诱导T细胞产生IFN-γ的能力。相似地,化学固定的靶细胞用无关APEC(西妥昔单抗-VLEETSVML-蛋白酶切割)标记时,不能诱导INF-γ应答,与未处理靶细胞中看到的相似。
图10B证明了使用肽替代抗体作为靶向半体的能力。合成了直接结合EGF受体或Her2/neu受体的肽,其含有蛋白酶切割序列和称为受体肽的病毒表位(EGF-NLVPMVATV(NLVPMVATVAIPVSLRSAAAYCRDYDYDGRYFDCY)(SEQ ID No:314)Ponde等(2011)Bioorg Med ChemLett,21或Her2-NLVPMVATV(NLVPMVATVAIPVSLRSAAAFCDGFYACYMDV)(SEQ ID No:311)Park等(2000)Nat Biotech 18)。用任一种肽标记的靶细胞能够从病毒特异性的CD8+T细胞诱导IFN-γ应答,与靶细胞用外源病毒肽脉冲时看到的相似。除去任一个受体肽时,靶细胞就不能被T细胞识别。
图13显示了由抗-EGFR西妥昔单抗和肽形成的抗体肽表位复合物(APEC)能够重新靶向抗原特异性T细胞,以靶向这些恶性细胞系,但只有在肽含有蛋白酶切割位点时才可以。
图14显示了抗原特异性T细胞位于肿瘤位点,并且其他抗体可以用于该方法中(例如,抗-MUC1抗体SM3)。该图还证明了与健康细胞相比,恶性细胞的选择性靶向。例如,抗-CD20利妥昔单抗APEC有效地在体外靶向恶性淋巴瘤细胞,但不靶向源自外周血的健康B细胞(图14C)。该图还显示出使用CD4+细胞毒T细胞针对II类MHC限制肽的适用性(图14D),并且APEC方法不需要靶细胞的抗原加工能力(图14E),表明肽切割发生在细胞膜。
讨论
以这种方式靶向肿瘤绕开了对肿瘤细胞中完整抗原加工系统的需求。我们认为蛋白酶切割位点的加工以及随后的肽装载至I/II类MHC分子上发生在胞外,不需要经典的抗原加工部分。
此外,结果证明了将肽与不同抗体偶联可以靶向许多不同的恶性疾病,包括乳腺癌、多发性骨髓瘤、急性骨髓性白血病和胰腺癌。因此,这种机制的免疫治疗潜能是远大的。
异种移植研究
异种移植模型使用NOG小鼠(NOD Rag2-/-γc-/-)(M.Ito等Blood 100,3175(2002))。使用标准实验室组织培养技术使肿瘤细胞系生长,并且在基质胶中皮下注射,并使其保持移植~7天。使用标准技术来培养人CD4+和CD8+T细胞,并且从健康实验室捐献者培养。将106T细胞通过腹膜内注入每个研究小鼠中。将抗体或APEC注入腹膜内腔中。给小鼠每周注射120mg/kg荧光素,并且使用IVIS光谱(Caliper Lifesciences)监控细胞的生长和转移散播。定量了生长动力学并且在实验终点时通过测量来自每个器官的发光信号来定量转移。
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Claims (18)
1.一种药剂,其包含:
(i)能够靶向实体癌症肿瘤细胞的靶向半体,其中靶向半体是抗体或其抗原结合片段;
(ii)包含蛋白酶切割位点的肽连接物;和
(iii)T细胞抗原,其中T细胞抗原是能够结合I类MHC分子和/或II类MHC分子的病毒衍生的肽;
其中T细胞抗原可以通过可被蛋白酶选择性切割的连接物中的切割位点的切割在实体癌症肿瘤细胞附近从靶向半体中释放出来;
其中蛋白酶切割位点的选择性切割使得在实体癌症肿瘤细胞附近和之外释放T细胞抗原,并且其中药剂用于预防或治疗实体癌症肿瘤。
2.根据权利要求1的药剂,其中T细胞抗原能够引发患者体内现有T细胞应答。
3.根据权利要求1的药剂,其中实体癌症肿瘤选自上皮性肿瘤、前列腺肿瘤、卵巢肿瘤、肾细胞肿瘤、胃肠道肿瘤、肝脏肿瘤、结直肠肿瘤、肿瘤脉管系统、间质瘤肿瘤、胰腺肿瘤、乳腺肿瘤、肉瘤肿瘤、肺肿瘤、结肠肿瘤、脑肿瘤、黑素瘤肿瘤、小细胞肺肿瘤、神经母细胞瘤肿瘤、睾丸肿瘤、上皮癌肿瘤、腺癌肿瘤、胶质瘤肿瘤、精原细胞瘤肿瘤或骨肉瘤肿瘤。
4.根据权利要求1的药剂,其中切割位点的选择性切割能够在实体癌症肿瘤细胞表面上或接近实体癌症肿瘤细胞的细胞表面释放T细胞抗原。
5.根据权利要求1的药剂,其中抗体或其抗原结合片段对以下任何一种是特异性的:Her2/Neu;EpCAM(CD326);EGFR;PMSA;CA125;碳酸酐酶IX;c-met/HGFR;TRAIL-R1;DR5;DR5;IGF-1R;VEGF-R2;前列腺干细胞抗原(PSCA);MUC1;CanAg;间皮素;P-钙粘蛋白;肌肉生长抑制素(GDF8);Cripto(TDGF1);MUC5AC;CEACAM;SLC44A4;神经菌毛素1;磷脂酰肌醇聚糖;HER3/EGFR和EphA2。
6.根据权利要求1的药剂,其中抗体或其抗原结合片段特异于CEACAM。
7.根据权利要求1的药剂,其中抗体或其抗原结合片段是抗上皮生长因子受体抗体,抗-Her2抗体,抗-MUC1抗体,抗P-钙粘蛋白抗体,抗-EpCAM抗体,抗E-钙粘蛋白抗体,抗-CEA抗体或抗-FGFR3抗体。
8.根据权利要求7的药剂,其中抗上皮生长因子受体抗体是西妥昔单抗。
9.根据权利要求7的药剂,其中抗-MUC1抗体是GP1.4或SM3。
10.根据权利要求1的药剂,其中抗体或其抗原结合片段特异于CEA。
11.根据权利要求1的药剂,其中抗原源自水痘-带状疱疹病毒、单纯疱疹病毒、细胞巨化病毒、EB病毒、腺病毒、鼻病毒或流感病毒。
12.根据权利要求1的药剂,其中在实体癌症肿瘤细胞附近具有选择性的酶是肿瘤相关的蛋白酶。
13.根据权利要求1-12任一项的药剂在制备药物中的用途。
14.一种药物组合物,其包含根据权利要求1-12任一项的药剂和药物学上可接受的载体、稀释剂或赋形剂。
15.根据权利要求1-12任一项的药剂在制备用于预防或治疗患者中的实体癌症肿瘤的药物中的用途。
16.一种组合物,其包含(i)根据权利要求1-12任一项的药剂和(ii)适用于预防或治疗实体癌症肿瘤的另一种治疗剂。
17.根据权利要求16的组合物在制备用于预防或治疗实体癌症肿瘤的药物中的用途。
18.根据权利要求1-12任一项的药剂,或根据权利要求14或16的组合物,或根据权利要求15或17的用途,其中靶向半体和T细胞抗原由单个多肽链编码。
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CN103561771A (zh) | 2014-02-05 |
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US11236131B2 (en) | 2022-02-01 |
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WO2012123755A1 (en) | 2012-09-20 |
JP2017171665A (ja) | 2017-09-28 |
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CN110038135A (zh) | 2019-07-23 |
EP3138581A1 (en) | 2017-03-08 |
DK2686020T3 (en) | 2017-05-01 |
US9358282B2 (en) | 2016-06-07 |
AU2016259343A1 (en) | 2016-12-01 |
US20160106862A1 (en) | 2016-04-21 |
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EP2686020A1 (en) | 2014-01-22 |
CA2830349A1 (en) | 2012-09-20 |
AU2012228100A1 (en) | 2013-10-03 |
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