CN110922486B - 一种分离的结合抗原psma的蛋白及其用途 - Google Patents
一种分离的结合抗原psma的蛋白及其用途 Download PDFInfo
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Abstract
本申请提供一种分离的抗原结合蛋白,其包含氨基酸序列如SEQ ID NO:15所示的VH中的HCDR1、HCDR2和HCDR3;且其包含氨基酸序列如SEQ ID NO:16所示的VL中的LCDR1、LCDR2和LCDR3。本申请还提供包含所述分离的抗原结合蛋白的嵌合抗原受体和免疫耦联物、编码所述分离的抗原结合蛋白的核酸、包含所述分离的抗原结合蛋白的载体、包含所述核酸或所述载体的细胞、制备所述分离的抗原结合蛋白的方法以及所述分离的抗原结合蛋白的用途。
Description
技术领域
本申请涉及生物医药领域,具体的涉及一种分离的结合抗原PSMA的蛋白及其用途。
背景技术
对于男性而言,前列腺癌是最常诊断出的癌症,且为第三大致死癌症。据统计,2017年有16万患者被诊断有此肿瘤,且造成2万6千例死亡(Siegel RL et al., (2017) CA Cancer J Clin. 67:7–30)。患有局部癌症的患者通常接受手术治疗或放疗(Walsh PC et al., (2007) N Engl J Med. 357:2696–705)。然而,接受根治性前列腺切除术的患者中的20-40%,以及接受放疗的患者的30-50%会经历复发(Paller CJ et al., (2013) Clin Adv Hematol Oncol. 11:14–23)。转移性癌症的标准疗法通常为雄激素阻断,通过双侧睾丸切除或化学去势(如施用黄体生成素受体(LHR)激动剂或拮抗剂)的方式(Tannock IF et al., (2004) N Engl J Med. 351:1502–12)。尽管雄激素阻断很有效,但伴随产生明显的副作用,患者逐渐患上去势难治性前列腺癌(CRPC)(Petrylak DP et al., (2004) N Engl J Med. 351: 1513–20)。转移性的CRPC(mCRPC)目前还没有根治的方法,预后较差。
近年来,癌症疫苗、免疫检查点阻断和肿瘤靶向抗体对实体瘤的治疗具有重大的影响。2010年,以前列腺酸性磷酸酶为靶点的个性化癌症疫苗Sipuleucel-T称为第一个FDA批准的mCRPC免疫制剂(Kantoff PW et al., (2010) N Engl J Med. 363:411–22),其成功鞭策了靶向前列腺相关的其他抗原例如前列腺特异膜抗原(PMSA)和前列腺特异抗原(PSA)的疫苗的临床试验。
在已识别出的前列腺癌候选标记物中,前列腺特异膜抗原(PMSA)似乎是最突出的。PSMA是同型二聚的II类膜糖蛋白,在不同组织中表达,例如前列腺、肾脏、小肠、中央神经系统和周围神经系统,但主要在前列腺中表达。PSMA在前列腺癌中是上调的(Schulke Net al., (2003) Proc Natl Acad Sci USA. 100:12590-5; Ross JS et al., (2003)Clin Cancer Res. 9:6357-62),且随着疾病进展而增加,在转移性、去势难治性的前列腺癌中表达量最高(Su SL et al., (1995) Cancer Res. 55:1441-3)。此外,PSMA还在大多数其他实体瘤如肾癌、乳癌、肠癌等的新生血管中大量表达(Silver DA et al., (1997),Clin Cancer Res. 3:81-5; Liu H et al., (1997), Cancer Res. 57:3629-34; ChangSS et al., (1999) Cancer Res. 59:3192-8;Chang SS et al., (1999) Clin Cancer Res 5:2674-81; Chang SS et al., (2001), Urology 57:801-5)。最重要的是,PSMA快速且持续地内化,将与其结合的抗体、抗体药物偶联物等递送至细胞内部(Liu H et al.,(1998) Cancer Res. 58:4055-60; Henry MD et al., (2004) Cancer Res. 64:7995-8001)。这些特性使得PSMA成为了前列腺癌和其他癌症的免疫抗体疗法中的有吸引力的靶点之一。
在治疗前列腺癌的抗体中,研究最多的是靶向PSMA的单抗J591。早期试验表明,J591可以被很好地运送到骨骼和软组织的前列腺癌转移酶中(Nanus DM et al., (2003)J Urol. 170:S84–8)。J591与低剂量白介素-2(IL-2)的2期试验表明,这种疗法具有良好的耐受性,16名患者中的9名有稳定的PSA(− 50%< PSA变化 < 25%),但没有患者出现PSA降低超过50%。而标记有镥-177的J591的2期试验显示出更加鼓舞人心的结果,有59.6%的患者在治疗后出现PSA降低,12名患者中的1名具有部分缓解,8名病情稳定(Tagawa ST et al.,(2013) Clin Cancer Res. 19:5182–91)。此外,BAY2010112,对T细胞的CD3受体以及PSMA特异的双抗,也处于前列腺癌症治疗的研究中。在前列腺癌小鼠模型中进行的BAY2010112临床前研究发现,这种抗体的施用,可以快速减小肿瘤大小,达成完全缓解(Friedrich Met al., (2012) Mol Cancer Ther. 11:2664–73)。BAY2010112的临床试验目前正在进行中。此外,人源IgG1 PSMA抗体与微管破坏剂MMAE的偶联物正用于紫杉烷难治性mCRPC治疗的临床试验中。在1期临床试验中,约50%的治疗患者出现PSA降低或血液肿瘤细胞减少(Petrylak DP et al., (2013) J Clin Oncol. 31:119)。2期临床试验中,30%患者出现大于等于30%的PSA降低,14%患者出现大于等于50%的PSA降低,61%病情稳定,13%出现部分缓解,26%出现病情进展(Petrylak DP et al., (2015), J Clin Oncol. 33:144)。
此外,PSMA还被证实可以直接或间接地增加胞外谷氨酸盐的浓度,而由中枢或外周神经系统损伤引起的疼痛与增加的谷氨酸盐浓度相关。PSMA抑制可以降低谷氨酸盐浓度并从而减轻疼痛(Zhou J et al., (2005), Nature Reviews. Drug Discovery. 4(12):1015–26; Nagel J et al., (2006) Neuropharmacology. 51 (7–8): 1163–71; Chen SR et al., (2002) The Journal of Pharmacology and Experimental Therapeutics. 300(2): 662–7)。
尽管在PSMA靶点上有所进展,PSMA抗体存在较多不可忽视的缺陷,如抗体结合的抗原表位信息不详,缺少跨种系交叉反应性的数据等。因此,需要开发更多新的具有所需药学特性的PMSA抗体。
发明内容
一方面,本申请提供一种分离的抗原结合蛋白,其包含氨基酸序列SEQ ID NO: 15所示的VH中的HCDR1、HCDR2和HCDR3;且其包含氨基酸序列SEQ ID NO: 16所示的VL中的LCDR1、LCDR2和LCDR3。
在某些实施方式中,所述HCDR1包含SEQ ID NO: 1所示的氨基酸序列,所述HCDR2包含SEQ ID NO: 2所示的氨基酸序列,且所述HCDR3包含SEQ ID NO: 3所示的氨基酸序列。
在某些实施方式中,所述LCDR1包含SEQ ID NO: 4所示的氨基酸序列,所述LCDR2包含SEQ ID NO: 5所示的氨基酸序列,且所述LCDR3包含SEQ ID NO: 6所示的氨基酸序列。
在某些实施方式中,所述VH包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在某些实施方式中,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO: 7所示的氨基酸序列;所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO: 8所示的氨基酸序列;所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO: 9所示的氨基酸序列;所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4包含SEQ ID NO: 10所示的氨基酸序列。
在某些实施方式中,所述VL包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。
在某些实施方式中,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO: 11所示的氨基酸序列;所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO: 12所示的氨基酸序列;所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO: 13所示的氨基酸序列;所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4包含SEQ ID NO: 14所示的氨基酸序列。
在某些实施方式中,所述的分离的抗原结合蛋白包括抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
在某些实施方式中,所述抗体重链恒定区包含SEQ ID NO: 19所示的氨基酸序列。
在某些实施方式中,所述的分离的抗原结合蛋白包括抗体轻链恒定区,且所述抗体轻链恒定区包括人Igκ恒定区。
在某些实施方式中,所述抗体轻链恒定区包含SEQ ID NO: 20所示的氨基酸序列。
在某些实施方式中,所述的分离的抗原结合蛋白包含抗体重链HC,且所述HC包含SEQ ID NO : 21所示的氨基酸序列。
在某些实施方式中,所述的分离的抗原结合蛋白包含抗体轻链LC,且所述LC包含SEQ ID NO : 22所示的氨基酸序列。
在某些实施方式中,所述的分离的抗原结合蛋白包括抗体或其抗原结合片段,其中所述抗原结合片段包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在某些实施方式中,所述的分离的抗原结合蛋白具有下述性质中的一种或多种:
1)能够以4×10-10M或更低的KD与PSMA蛋白相结合,其中所述KD值通过Octet测定;
2)在FACS测定中,能够特异性结合过表达人PSMA的HEK293细胞、过表达猴PSMA的CHO-K1细胞或LNCAP细胞表面的PSMA蛋白;
3)能够内化到过表达人PSMA的HEK293细胞或LNCAP细胞中;
4)对LNCAP细胞具有ADCP活性。
在某些实施方式中,所述PSMA蛋白包含人PSMA蛋白或猴PSMA蛋白。
另一方面,本申请提供一种嵌合抗原受体,其包含所述的分离的抗原结合蛋白。
另一方面,本申请提供一种免疫耦联物,其包含所述的分离的抗原结合蛋白。
另一方面,本申请提供分离的一种或多种核酸分子,其编码所述的分离的抗原结合蛋白或所述的嵌合抗原受体。
另一方面,本申请提供一种载体,其包含所述的核酸分子。
另一方面,本申请提供一种细胞,其包含所述的核酸分子或所述的载体。
另一方面,本申请提供一种药物组合物,其包含所述的分离的抗原结合蛋白、所述的嵌合抗原受体、所述的免疫耦联物、所述的核酸分子、所述的载体和/或所述的细胞,以及任选地药学上可接受的佐剂。
另一方面,本申请提供制备所述的分离的抗原结合蛋白的方法,所述方法包括在使得所述的分离的抗原结合蛋白表达的条件下,培养所述的细胞。
另一方面,本申请提供所述的分离的抗原结合蛋白、所述的嵌合抗原受体、所述的免疫耦联物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
在某些实施方式中,所述肿瘤包括前列腺癌。
另一方面,本申请提供一种检测样品中PSMA的方法,所述方法包括施用所述的分离的抗原结合蛋白。
本申请所述的分离的抗原结合蛋白与现有技术相比,至少具备下述有益效果中的一种:(1)本申请所述的分离的抗原结合蛋白能够以4×10-10M或更低的KD与PSMA蛋白相结合,其中所述KD值通过Octet测定;
(2)在FACS测定中,本申请所述的分离的抗原结合蛋白能够特异性结合HEK293细胞、CHO-K1细胞或LNCAP细胞表面的PSMA蛋白;
(3)本申请所述的分离的抗原结合蛋白能够内化到HEK293细胞或LNCAP细胞中;
(4)本申请所述的分离的抗原结合蛋白对LNCAP细胞具有ADCP活性;
(5)本申请所述的分离的抗原结合蛋白能够用于制备可以有效预防、缓解和/或治疗肿瘤的药物;
(6)本申请所述的分离的抗原结合蛋白能够用于检测样品中PSMA的存在或含量。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下:
图1A和图1B显示抗体与细胞表面的人PSMA蛋白的结合情况;
图2A和图2B显示抗体与细胞表面的猴PSMA蛋白的结合情况;
图3显示抗体与LNCAP细胞表面表达的PSMA蛋白的结合情况;
图4显示抗体处理下HEK293 hPSMA细胞的成活率;
图5示出抗体处理下LNCAP细胞的成活率;
图6显示抗体在巨噬细胞中介导的对LNCAP的吞噬作用。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
以下对本申请做进一步描述:在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
在本申请中,术语“分离的”通常指从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
在本申请中,术语“分离的抗原结合蛋白”通常指从天然状态下经人工手段获得的具有抗原结合能力的蛋白。该“分离的抗原结合蛋白”可以包含结合抗原的部分和任选地,允许抗原结合部分采用促进所述抗原结合部分结合抗原的构象的支架或构架部分。抗原结合蛋白可以包含例如抗体来源的蛋白支架或具有移植的CDR或CDR衍生物的备选蛋白支架或人工支架。此类支架包括,但不限于包含被引入例如以稳定抗原结合蛋白的三维结构的突变的抗体来源的支架以及包含例如生物相容性聚合物的完全合成的支架。参见例如Korndorfer等,2003,Proteins:Structure,Function,andBioinformatics,53(1):121-129(2003);Roque等,Biotechnol.Prog.20:639-654(2004)。此外,肽抗体模拟物("PAMs")以及利用纤连蛋白组分基于抗体模拟物的支架可以用作支架。
在本申请中,术语“KD”(同样地,“K D ”或“KD”)通常指“亲和常数”或“平衡解离常数”,并指在滴定测量中在平衡时、或者通过将解离速率常数(kd)除以结合速率常数(ka)所获得的值。使用结合速率常数(ka)、解离速率常数(kd)和平衡解离常数(KD)表示结合蛋白(例如本申请所述的分离的抗原结合蛋白)对抗原(例如PSMA蛋白)的结合亲和力。确定结合和解离速率常数的方法为本领域熟知。使用基于荧光的技术提供了高灵敏度以及在生理缓冲液中在平衡时检查样品的能力。例如,可以通过Octet测定所述K D 值,也可以使用其他实验途径和仪器例如BIAcore(生物分子相互作用分析)测定(例如,可以从BIAcoreInternationalAB,aGEHealthcarecompany,Uppsala,瑞典获得的仪器)。另外,也可以使用可以从SapidyneInstruments(Boise,Idaho)获得的KinExA(动态排阻测定(KineticExclusionAssay))测定所述K D 值,或者使用表面等离子共振仪(SPR)测定所述K D 值。
在本申请中,术语“EC50”,又叫半最大效应浓度,通常是指引起50%最大效应的抗体浓度。
在本申请中,术语“PSMA”通常是指前列腺特异膜抗原,也称二型谷氨酸羧肽酶(GCPII)或NAAG肽酶。该术语包括变体、同源物、类似物、直向同源物和/或平行同源物。例如,对人PSMA特异的抗体可以在某些情况下与另一物种例如猴的PSMA蛋白交叉反应。在其他实施方式中,对人PSMA蛋白特异的抗体可以完全地对人PSMA蛋白特异而不与其他物种或其他类型的蛋白交叉反应,或者可以与一些其他物种而非所有其他物种的PSMA蛋白交叉反应。
在本申请中,术语“人PSMA”通常是指具有人氨基酸序列的PSMA蛋白,例如具有Genbank登录号为NP_004467.1的氨基酸序列的PSMA蛋白。术语“猴PSMA”是指具有猴氨基酸序列的PSMA蛋白,例如具有Genbank登录号为XP_014970879.1的氨基酸序列的PSMA蛋白。
在本申请中,术语“特异性结合”或“特异性的”通常指可测量的和可再现的相互作用,比如靶标和抗体之间的结合,可在分子(包括生物分子)的异质群体存在的情况可决定靶标的存在。例如,特异性结合靶标(其可以为表位)的抗体是以比它结合其它靶标更大的亲和性、亲合力、更容易、和/或以更大的持续时间结合该靶标的抗体。在一个实施方案中,抗体结合无关靶标的程度小于抗体对靶标的结合的约10%,如例如通过放射免疫分析(RIA)测量的。例如,在本申请中,所述分离的抗原结合蛋白能够以<4x10-10M或更低的解离常数(KD)与PSMA蛋白相结合。在某些实施方案中,抗体特异性结合蛋白质上的表位,所述表位在不同种属的蛋白质中是保守的。在另一个实施方案中,特异性结合可以包括但不要求排他性地结合。
在本申请中,术语“肿瘤”通常指由异常细胞生长形成的赘生物或实体病变。在本申请中,肿瘤可以是实体瘤或血液瘤。例如,在本申请中,肿瘤可以是PSMA阳性的肿瘤,其中所述PSMA阳性的肿瘤可以包括前列腺癌。
在本申请中,术语“可变结构域”通常指抗体重链或轻链的氨基末端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”(或者分别称为“VH”和“VL”)。这些结构域通常是抗体的变化最大的部分(相对于相同类型的其它抗体),且包含抗原结合位点。
在本申请中,术语“可变”通常指在抗体之间可变结构域的某些区段在序列上存在很大差异的事实。V结构域介导抗原结合并决定特定抗体对其特定抗原的特异性。然而,可变性并非在整个可变结构域范围内均匀分布。相反,它集中在轻链和重链可变结构域中称为高变区(CDR或HVR)的三个区段中。可变结构域的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区,大多数采用β-折叠构型,通过三个CDR连接,其形成环形连接,并且在一些情况下形成β-折叠结构的一部分。每条链中的CDR通过FR区紧密靠近地保持在一起,并且来自另一条链的CDR一同促进抗体的抗原结合位点的形成(参见Kabat et al, Sequences of Immunological Interest, Fifth Edition,National Institute of Health, Bethesda, Md. (1991))。恒定结构域不直接参与抗体与抗原的结合,但显示出各种效应子功能,例如抗体参与抗体依赖性细胞毒性。
在本申请中,术语“抗体”通常指免疫球蛋白或其片段或其衍生物,涵盖包括抗原结合位点的任何多肽,无论其是在体外还是体内产生的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂化的、突变的和移植的抗体。除非另外被术语“完整的”修饰,如在“完整的抗体”中,为了本发明的目的,术语“抗体”也包括抗体片段,比如Fab、F(ab')2、Fv、scFv、Fd、dAb和保持抗原结合功能(例如,特异性结合PSMA)的其它抗体片段。通常,这样的片段应当包括抗原结合结构域。基本的4链抗体单元是由两个相同的轻(L)链和两个相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元与另外一个称为J链的多肽组成,且含有10个抗原结合位点,而IgA抗体包括2-5个可以与J链相结合聚合形成多价组合的基本4链单元。就IgG而言,4链单元一般为约150,000道尔顿。每个L链通过一个共价二硫键与H链连接,而两个H链通过一个或多个取决于H链同种型的二硫键相互连接。每个H和L链还具有规则间隔的链内二硫化桥键。每个H链在N末端具有可变结构域(VH),对于α和γ链各自继之以三个恒定结构域(CH)、对于μ和ε同种型继之以四个CH结构域。每个L链在N末端具有可变结构域(VL),在其另一端具有恒定结构域。VL与VH对应,且CL与重链的第一恒定结构域(CH1)相对应。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。VH和VL配对一起形成单个抗原结合位点。对于不同类别抗体的结构和性质,参见例如Basic and ClinicalImmunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G.Parsolw (eds), Appleton & Lange, Norwalk, Conn., 1994,第71页和第6章。来自任何脊椎动物物种的L链可以基于其恒定结构域的氨基酸序列被分为两种明显不同的类型中的一种,称为κ和λ。取决于其重链(CH)恒定结构域的氨基酸序列,可以将免疫球蛋白分为不同的类别或同种型。存在五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别被命名为α、δ、ε、γ和μ的重链。基于CH序列和功能方面的相对小的差异,将γ和α类进一步分成亚类,例如,人表达下述亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
在本申请中,术语“CDR”通常指抗体可变结构域的区域,其序列是高度可变的和/或形成结构定义环。通常,抗体包括六个CDR;在VH中三个(HCDR1、HCDR2、HCDR3),和在VL中三个(LCDR1、LCDR2、LCDR3)。在天然抗体中,HCDR3和LCDR3显示所述六个CDR的大多数多样性,并且特别地HCDR3被认为在赋予抗体的精细特异性方面起独特作用。参见,例如Xu etal, Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology248:1-25 (Lo, ed., Human Press, Totowa, N.J., 2003)。实际上,仅由重链组成的天然存在的骆驼抗体在缺乏轻链的情况功能正常且稳定。参见,例如 , Hamers-Casterman etal., Nature 363:446-448 (1993); Sheriff et al, Nature Struct. Biol. 3:733-736(1996)。
在本申请中,术语“FR”通常指抗体可变结构域的更高度保守的部分,其被称为框架区。通常,天然重链和轻链的可变结构域各自包含四个FR区,即在VH中四个(H-FR1,H-FR2,H-FR3,和H-FR4),和在VL中四个(L-FR1,L-FR2,L-FR3,和L-FR4)。例如,本申请所述的分离的抗原结合蛋白的VL可以包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。本申请所述的分离的抗原结合蛋白的VH可以包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,术语“抗原结合片段”通常指具有特异结合抗原(例如,PSMA蛋白)能力的一个或多个片段。在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在本申请中,术语“单克隆抗体”或“单抗”或“单克隆抗体组成”通常是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
在本申请中,术语“人源抗体”通常是指可变区框架和CDR区得自人种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自人种系免疫球蛋白序列。本申请的人源抗体可以包含不由人种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“人源抗体”不包括在人框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
在本申请中,术语“鼠源抗体”通常是指可变区框架和CDR区得自小鼠种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自小鼠种系免疫球蛋白序列。本申请的鼠源抗体可以包含不由小鼠种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“鼠源抗体”不包括在小鼠框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
在本申请中,术语“嵌合抗体”通常是指通过组合非人源遗传物质与人源遗传物质而得来的抗体。或者更笼统地说,嵌合抗体是指组合有一个物种的遗传物质与另一物种遗传物质的抗体。
在本申请中,术语“人源化抗体”通常是指来源于非人物种但其蛋白序列已经被修改以增加其与人天然生成抗体的相似度的抗体。
在本申请中,术语“识别抗原的抗体”以及“对抗原特异的抗体”在本文中与术语“特异结合抗原的抗体”交替使用。
在本申请中,术语“直接相连”与术语“间接相连”相对,术语“直接相连”通常是指直接连接。例如,所述直接相连可以为物质间没有间隔子而直接相连的情况。所述间隔子可以是连接子。例如,所述连接子可以为肽连接子。术语“间接相连”通常是指物质间不直接相连的情况。例如,所述间接相连可以为通过间隔子而连接的情况。例如,在本申请所述的分离的抗原结合蛋白中,所述L-FR1的C末端与所述LCDR1的N末端可以直接或间接相连。
在本申请中,术语“抗体依赖的细胞介导的吞噬作用”或“ADCP”可互换地使用,通常是指抗体与靶细胞上相应的抗原结合后,抗体的Fc段与效应细胞(如吞噬细胞)上的Fc受体结合,从而诱导效应细胞吞噬靶细胞的作用。
在本申请中,术语“分离的核酸分子”通常指任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物。
在本申请中,术语“载体”通常指可将编码某蛋白的多聚核苷酸插入其中并使蛋白获得表达的一种核酸运载工具。载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。举例来说,载体包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可能含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。载体还有可能包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
在本申请中,术语“细胞”通常指可以是或已经是受试者质粒或载体的接受者的单个细胞、细胞系或细胞培养物,其包括本发明所述的核酸分子或本发明所述的载体。细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。细胞可包括用本申请所述的载体在体外转染的细胞。细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、CHO-K1细胞、LNCAP细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞。在某些实施方案中,细胞为哺乳动物细胞。在某些实施方案中,哺乳动物细胞为HEK293细胞。
在本申请中,术语“药物组合物”通常指涉及适合施用于患者、优选人患者的组合物。例如,本申请所述的药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。此外,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下优选地对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在本申请中,术语“药学上可接受的佐剂”通常指与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂等,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在本申请中,术语“受试者”通常指人类或非人类动物,包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中,术语“包含”通常是指包括明确指定的特征,但不排除其他要素。
在本申请中,术语“约”通常是指在指定数值以上或以下0.5%-10%的范围内变动,例如在指定数值以上或以下0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、或10%的范围内变动。
一方面本申请提供了一种分离的抗原结合蛋白,其包含氨基酸序列如SEQ ID NO:15所示的VH中的至少一个CDR;且其包含氨基酸序列如SEQ ID NO: 16所示的VL中的至少一个CDR。
在本申请中,所述分离的抗原结合蛋白可以包含氨基酸序列如SEQ ID NO: 15所示的VH中的HCDR1。
在本申请中,所述分离的抗原结合蛋白可以包含氨基酸序列如SEQ ID NO: 15所示的VH中的HCDR2。
在本申请中,所述分离的抗原结合蛋白可以包含氨基酸序列如SEQ ID NO: 15所示的VH中的HCDR3。
在本申请中,所述分离的抗原结合蛋白可以包含氨基酸序列如SEQ ID NO: 16所示的VL中的LCDR1。
在本申请中,所述分离的抗原结合蛋白可以包含氨基酸序列如SEQ ID NO: 16所示的VL中的LCDR2。
在本申请中,所述分离的抗原结合蛋白可以包含氨基酸序列如SEQ ID NO: 16所示的VL中的LCDR3。
在本申请中,所述分离的抗原结合蛋白可以具有下述性质中的一种或多种:
1)能够以4×10-10M或更低的KD与PSMA蛋白相结合,其中所述KD值通过Octet测定;
2)在FACS测定中,能够特异性结合过表达人PSMA的HEK293细胞、过表达猴PSMA的CHO-K1细胞或LNCAP细胞表面的PSMA蛋白;
3)能够内化到过表达人PSMA的HEK293细胞或LNCAP细胞中;
4)对LNCAP细胞具有ADCP活性。
在本申请中,所述分离的抗原结合蛋白能够以4×10-10M或更低的KD与PSMA蛋白相结合,其中所述KD值通过Octet测定。例如,本申请所述的分离的抗原结合蛋白结合源自人的PSMA蛋白的KD值可以为≤4×10-10M、≤3.9×10-10M、≤3.8×10-10M、≤3.76×10-10M、≤3.7×10-10M、≤3.6×10-10M、≤3.5×10-10M、≤3.4×10-10M、≤3.3×10-10M、≤3.2×10-10M、≤3.1×10-10M、≤3×10-10M、≤2×10-10M、≤1×10-10M。又例如,本申请所述的分离的抗原结合蛋白结合源自鼠的PSMA蛋白的KD值可以为≤4×10-10M、≤3.9×10-10M、≤3.8×10-10M、≤3.76×10-10M、≤3.7×10-10M、≤3.6×10-10M、≤3.5×10-10M、≤3.4×10-10M、≤3.3×10-10M、≤3.2×10-10M、≤3.1×10-10M、≤3×10-10M、≤2×10-10M、≤1×10-10M。又例如,本申请所述的分离的抗原结合蛋白结合源自猴的PSMA蛋白的KD值可以为≤4×10-10M、≤3.9×10-10M、≤3.8×10-10M、≤3.76×10-10M、≤3.7×10-10M、≤3.6×10-10M、≤3.5×10-10M、≤3.4×10- 10M、≤3.3×10-10M、≤3.2×10-10M、≤3.1×10-10M、≤3×10-10M、≤2×10-10M、≤1×10-10M。
在本申请中,所述KD值还可以通过ELISA、竞争ELISA或BIACORE或KINEXA进行测定。
在本申请中,所述分离的抗原结合蛋白能够特异性结合HEK293细胞、CHO-K1细胞或LNCAP细胞表面的PSMA蛋白,所述特异性结合可以通过FACS测定。例如,可以通过FACS测定中的EC50来反映本申请所述分离的抗原结合蛋白特异性结合HEK293细胞、CHO-K1细胞或LNCAP细胞表面的PSMA蛋白的情况,例如,EC50越低说明特异性结合越好。例如,所述分离的抗原结合蛋白在FACS测定中结合HEK293细胞表面的PSMA蛋白的EC50值可以为0.01μg/ml-0.10μg/ml、0.01μg/ml-0.15μg/ml、0.01μg/ml-0.20μg/ml、0.01μg/ml-0.25μg/ml、0.01μg/ml-0.30μg/ml、0.01μg/ml-0.35μg/ml、0.01μg/ml-0.40μg/ml、0.01μg/ml-0.45μg/ml、0.01μg/ml-0.50μg/ml、0.01μg/ml-0.55μg/ml、0.01μg/ml-0.60μg/ml、0.01μg/ml-0.65μg/ml、0.01μg/ml-0.67μg/ml、0.01μg/ml-0.68μg/ml或0.01μg/ml-0.70μg/ml。又例如,所述分离的抗原结合蛋白在FACS测定中结合CHO-K1细胞表面的PSMA蛋白的EC50值可以为0.01μg/ml-0.10μg/ml、0.01μg/ml-0.15μg/ml、0.01μg/ml-0.16μg/ml、0.01μg/ml-0.20μg/ml、0.01μg/ml-0.25μg/ml、0.01μg/ml-0.30μg/ml、0.01μg/ml-0.35μg/ml、0.01μg/ml-0.40μg/ml、0.01μg/ml-0.45μg/ml、0.01μg/ml-0.50μg/ml、0.01μg/ml-0.55μg/ml、0.01μg/ml-0.60μg/ml、0.01μg/ml-0.65μg/ml或0.01μg/ml-0.70μg/ml。又例如,所述分离的抗原结合蛋白在FACS测定中结合LNCAP细胞表面的PSMA蛋白的EC50值可以为0.01μg/ml-0.09μg/ml、0.01μg/ml-0.10μg/ml、0.01μg/ml-0.11μg/ml、0.01μg/ml-0.12μg/ml、0.01μg/ml-0.15μg/ml、0.01μg/ml-0.20μg/ml、0.01μg/ml-0.25μg/ml、0.01μg/ml-0.30μg/ml、0.01μg/ml-0.35μg/ml、0.01μg/ml-0.40μg/ml、0.01μg/ml-0.45μg/ml、0.01μg/ml-0.50μg/ml、0.01μg/ml-0.55μg/ml、0.01μg/ml-0.60μg/ml、0.01μg/ml-0.65μg/ml或0.01μg/ml-0.70μg/ml。
在本申请中,所述PSMA蛋白可以包含人PSMA蛋白或猴PSMA蛋白。例如,所述PSMA蛋白可以包含具有Genbank登录号为NP_004467.1的氨基酸序列的PSMA蛋白。又例如,所述PSMA蛋白可以包含具有Genbank登录号为XP_014970879.1的氨基酸序列的PSMA蛋白。
本申请中,所述分离的抗原结合蛋白能够内化到HEK293细胞或LNCAP细胞中。例如,本申请所述的分离的抗原结合蛋白可以通过结合PSMA的胞外尾部介导细胞表面表达的PSMA蛋白的内化。
在本申请中,所述分离的抗原结合蛋白可以对PSMA阳性的细胞(也可用“PSMA+细胞”表示)显示出ADCP活性。所述PSMA阳性的细胞可以是LNCAP细胞。例如,在某些实施方式中,所述分离的抗原结合蛋白能够通过诱导抗体依赖的细胞介导的细胞吞噬作用(ADCP)抑制肿瘤细胞的生长。所述肿瘤细胞可以是PSMA阳性的细胞,例如,LNCAP细胞。
在本申请中,所述分离的抗原结合蛋白可以包括抗体或其抗原结合片段。例如,本申请所述的分离的抗原结合蛋白可以包括但不限于重组抗体、单克隆抗体、人抗体、鼠源抗体、人源化抗体、嵌合抗体、双特异性抗体、单链抗体、双抗体、三抗体、四抗体、Fv片段、scFv片段、Fab片段、Fab'片段、F(ab')2片段和骆驼化单结构域抗体。
在本申请中,所述抗体可以为人源化抗体。换句话说,本申请所述的分离的抗原结合蛋白,其可以为免疫特异性结合至相关抗原(例如人类PSMA)且包含基本上具有人类抗体的氨基酸序列的框架(FR)区及基本上具有非人类抗体的氨基酸序列的互补决定区(CDR)的抗体或其变异体、衍生物、类似物或片段。此处的“基本上”在CDR的情况下是指CDR的氨基酸序列与非人类抗体CDR的氨基酸序列至少80%、优选至少85%、至少90%、至少95%、至少98%或至少99%同一。所述人源化抗体基本上可以包含所有至少一个且通常两个可变域(Fab、Fab′、F(ab′)2、FabC、Fv),其中所有或基本上所有CDR区对应于非人类免疫球蛋白(即抗体)的CDR区且所有或基本上所有框架区为具有人类免疫球蛋白共有序列的框架区。优选地,人源化抗体还包含至少一部分免疫球蛋白恒定区(例如,Fc),通常为人类免疫球蛋白的恒定区。在一些实施例中,人源化抗体含有轻链以及重链的至少可变域。抗体还可包括重链的CH1、铰链、CH2、CH3及CH4区。在一些实施例中,人源化抗体仅含人源化轻链。在一些实施例中,人源化抗体仅含人源化重链。在特定实施例中,人源化抗体仅含轻链和/或人源化重链的人源化可变域。
在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
抗体的CDR又称互补决定区,是可变区的一部分。该区域的氨基酸残基与抗原或抗原表位接触。抗体CDR可以通过多种编码系统来确定,如CCG、Kabat、Chothia、IMGT、综合考虑Kabat/Chothia等。这些编码系统为领域内已知,具体可参见http://www.bioinf.org.uk/abs/index.html#kabatnum。本领域技术人员可以根据抗体的序列和结构,用不同的编码系统确定出CDR区。使用不同的编码系统,CDR区可能存在差别。本申请所述的分离的抗原结合蛋白的CDR可以使用Kabat确定出来。
在本申请中,所述HCDR1可以包含SEQ ID NO: 1所示的氨基酸序列。
在本申请中,所述HCDR2可以包含SEQ ID NO: 2所示的氨基酸序列。
在本申请中,所述HCDR3可以包含SEQ ID NO: 3所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的HCDR1可包含SEQ ID NO: 1所示的氨基酸序列,HCDR2可包含SEQ ID NO: 2所示的氨基酸序列,HCDR3可包含SEQ ID NO: 3所示的氨基酸序列。
在本申请中,所述LCDR1可以包含SEQ ID NO: 4所示的氨基酸序列。
在本申请中,所述LCDR2可以包含SEQ ID NO: 5所示的氨基酸序列。
在本申请中,所述LCDR3可以包含SEQ ID NO: 6所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的LCDR1可包含SEQ ID NO: 4所示的氨基酸序列,LCDR2可包含SEQ ID NO: 5所示的氨基酸序列,LCDR3可包含SEQ ID NO: 6所示的氨基酸序列。
又例如,本申请所述的分离的抗原结合蛋白的HCDR1可包含SEQ ID NO: 1所示的氨基酸序列,HCDR2可包含SEQ ID NO: 2所示的氨基酸序列,HCDR3可包含SEQ ID NO: 3所示的氨基酸序列,且LCDR1可包含SEQ ID NO: 4所示的氨基酸序列,LCDR2可包含SEQ IDNO: 5所示的氨基酸序列,LCDR3可包含SEQ ID NO: 6所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述VH可以包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1可以包含SEQ ID NO: 7所示的氨基酸序列。
在本申请中,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2可以包含SEQ ID NO: 8所示的氨基酸序列。
在本申请中,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3可以包含SEQ ID NO: 9所示的氨基酸序列。
在本申请中,所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4可以包含SEQ ID NO: 10所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO: 7所示的氨基酸序列,H-FR2可包含SEQ ID NO: 8所示的氨基酸序列,H-FR3可包含SEQ ID NO: 9所示的氨基酸序列,H-FR4可包含SEQ ID NO: 10所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的VL可以包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。
在本申请中,所述L-FR1的C末端可以与所述LCDR1的N末端直接或间接相连,且所述L-FR1可以包含SEQ ID NO: 11所示的氨基酸序列。
在本申请中,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2可以包含SEQ ID NO: 12所示的氨基酸序列。
在本申请中,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3可以包含SEQ ID NO: 13所示的氨基酸序列。
在本申请中,所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4可以包含SEQ ID NO: 14所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO: 11所示的氨基酸序列,L-FR2可包含SEQ ID NO: 12所示的氨基酸序列,L-FR3可包含SEQ ID NO: 13所示的氨基酸序列,L-FR4可包含SEQ ID NO: 14所示的氨基酸序列。
又例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO: 7所示的氨基酸序列,H-FR2可包含SEQ ID NO: 8所示的氨基酸序列,H-FR3可包含SEQ ID NO: 9所示的氨基酸序列,H-FR4可包含SEQ ID NO: 10所示的氨基酸序列,且L-FR1可包含SEQ IDNO: 11所示的氨基酸序列,L-FR2可包含SEQ ID NO: 12所示的氨基酸序列,L-FR3可包含SEQ ID NO: 13所示的氨基酸序列,L-FR4可包含SEQ ID NO: 14所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可包含抗体轻链可变区VH和抗体重链可变区VL。例如,所述VH可包含SEQ ID NO: 15所示的氨基酸序列,所述VL可包含SEQ ID NO: 16所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG重链恒定区。在某些实施方式中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG1重链恒定区。例如,所述抗体重链恒定区可以包含SEQ ID NO: 19所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包括抗体轻链恒定区,且所述抗体轻链恒定区可以包括人Igκ恒定区。例如,所述抗体轻链恒定区可以包含SEQ ID NO: 20所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包含抗体重链HC,且所述HC可以包含SEQ ID NO : 21所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包含抗体轻链LC,且所述LC可以包含SEQ ID NO : 22所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可以包含抗体重链和抗体轻链。
例如,所述重链可包含SEQ ID NO: 21所示的氨基酸序列,所述轻链可包含SEQ IDNO: 22所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的重链可包含SEQ ID NO: 21所示的氨基酸序列,且轻链可包含SEQ ID NO: 22所示的氨基酸序列。其中,所述分离的抗原结合蛋白的HCDR1可包含SEQ ID NO: 1所示的氨基酸序列,HCDR2可包含SEQ ID NO: 2所示的氨基酸序列,HCDR3可包含SEQ ID NO: 3所示的氨基酸序列,且LCDR1可包含SEQ ID NO: 4所示的氨基酸序列,LCDR2可包含SEQ ID NO: 5所示的氨基酸序列,LCDR3可包含SEQ ID NO: 6所示的氨基酸序列。此外,所述分离的抗原结合蛋白的H-FR1可包含SEQ ID NO: 7所示的氨基酸序列,H-FR2可包含SEQ ID NO: 8所示的氨基酸序列,H-FR3可包含SEQ ID NO: 9所示的氨基酸序列,H-FR4可包含SEQ ID NO: 10所示的氨基酸序列,且L-FR1可包含SEQ ID NO:11所示的氨基酸序列,L-FR2可包含SEQ ID NO: 12所示的氨基酸序列,L-FR3可包含SEQ IDNO: 13所示的氨基酸序列,L-FR4可包含SEQ ID NO: 14所示的氨基酸序列。此外,所述VH可包含SEQ ID NO: 15所示的氨基酸序列,且所述VL可包含SEQ ID NO: 16所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为PR001331。
此外,需要说明的是,本申请所述分离的抗原结合蛋白可以包含与PR001331抗体存在一个或多个保守序列修饰的重链和/或轻链序列。所谓“保守序列修饰”是指不会显著影响或改变抗体结合特性的氨基酸修饰。这样的保守修饰包括氨基酸替换、添加和删除。可以通过领域内已知的标准技术,例如点突变和PCR介导的突变,将修饰引入本申请所述分离的抗原结合蛋白中。保守氨基酸替换是氨基酸残基用具有相似侧链的氨基酸残基进行替换。具有相似侧链的氨基酸残基组在领域内已知。这些氨基酸残基组包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。在某些实施方式中,本申请所述分离的抗原结合蛋白的CDR区中的一个或多个氨基酸残基可以用同侧链组的其他氨基酸残基替换。本领域内的技术人员知道,一些保守序列修改不会使抗原结合性消失,具体可以参见,例如,Brummell et al., (1993) Biochem 32:1180-8; de Wildt et al., (1997) Prot. Eng. 10:835-41; Komissarov et al.,(1997) J. Biol. Chem. 272:26864-26870; Hall et al., (1992) J. Immunol. 149:1605-12; Kelley and O'Connell (1993) Biochem.32:6862-35; Adib-Conquy et al.,(1998) Int. Immunol.10:341-6 and Beers et al., (2000) Clin. Can. Res. 6:2835-43。
另一方面,本申请提供了嵌合抗原受体,其可以包含本申请所述分离的抗原结合蛋白。
在某些实施方式中,本申请所述分离的抗原结合蛋白可以以scFv的形式包含在PSMA特异的CAR中。含有本申请所述分离的抗原结合蛋白的CAR可以包含于免疫细胞如T细胞、NK细胞中。
另一方面,本申请还提供了免疫耦联物,其可以包含本申请所述分离的抗原结合蛋白。
在某些实施方式中,可以将本申请所述分离的抗原结合蛋白与治疗剂交联,形成所述免疫耦联物。例如抗体-药物耦联物(ADC)。合适的治疗剂包括细胞毒素、烷化剂、DNA小沟结合分子、DNA嵌入剂、DNA交联剂、组蛋白去乙酰化酶抑制剂、核输出抑制剂、蛋白酶体抑制剂、拓扑异构酶I或II的抑制剂、热激蛋白抑制剂、酪氨酸激酶抑制剂、抗生素和抗有丝分裂剂,例如SN-38。在ADC中,抗体和治疗剂可以通过接头交联,该接头可切割,例如肽类接头、二硫类接头或腙类接头。在某些实施方式中,接头可以是肽类接头,例如Val-Cit、Ala-Val、Val-Ala-Val、Lys-Lys、Pro-Val-Gly-Val-Val、Ala-Asn-Val、Val-Leu-Lys、Ala-Ala-Asn、Cit-Cit、Val-Lys、Lys、Cit、Ser或Glu。ADC可以如美国专利7,087,600; 6,989,452;和7,129,261; PCT公开WO 02/096910; WO 07/038,658; WO 07/051,081; WO 07/059,404; WO 08/083,312;和WO 08/103,693; 美国专利公开20060024317; 20060004081;和20060247295中描述般进行制备。
此外,本申请所述分离的抗原结合蛋白还可以与其他功能分子(例如抗体或受体配体)融合形成双特异性分子。所述双特异性分子可以特异性结合至少两个不同结合位点或靶向分子。所述双特异性分子可以通过基因改造、体细胞杂交或化学法进行制备。具体可以参见,例如Kufer et al, cited supra; Cao and Suresh, Bioconjugate Chemistry,9 (6), 635-644 (1998); 和van Spriel et al., Immunology Today, 21 (8), 391-397(2000)。
另一方面,本申请还提供了分离的一种或多种核酸分子,其可以编码本申请所述的分离的抗原结合蛋白或本申请所述的嵌合抗原受体。本申请所述的分离的一种或多种核酸分子可以为任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物,但可以编码本申请所述的分离的抗原结合蛋白或本申请所述的嵌合抗原受体。
另一方面,本申请还提供了载体,其可以包含本申请所述的核酸分子。所述载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。例如,载体可以包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。又例如,所述载体可以含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,所述载体还可以含有复制起始位点。此外,所述载体还可以包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
另一方面,本申请还提供了细胞,其可以包含本申请所述的核酸分子或本申请所述的载体。所述细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。在某些实施方式中,所述细胞还可以包括用本发明所述的载体在体外转染的细胞。在某些实施方式中,所述细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、CHO-K1细胞、LNCAP细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞或骨髓瘤细胞。在某些实施方案中,所述细胞可以为哺乳动物细胞。在某些实施方案中,所述哺乳动物细胞可以为HEK293细胞。
另一方面,本申请还提供了药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的嵌合抗原受体、本申请所述的免疫耦联物、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。
在某些实施方案中,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下优选地对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在某些实施方案中,所述药学上可接受的佐剂可以包括与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在某些实施方案中,所述药物组合物可以包含肠胃外、经皮、腔内、动脉内、鞘内和/或鼻内施用或直接注射到组织中。例如,所述药物组合物可以通过输注或注射施用于患者或者受试者。在某些实施方案中,所述药物组合物的施用可以通过不同的方式进行,例如静脉内、腹膜内、皮下、肌肉内、局部或真皮内施用。在某些实施方案中,所述药物组合物可以不间断施用。所述不间断(或连续)施用可以通过患者佩戴的小泵系统来实现,以测量流入患者体内的治疗剂,如WO2015/036583所述。
所述药物组合物的给药方案可以是施用快速灌注剂,可以随时间推移施用多个分剂量,或者剂量可以随治疗情况的危急程度成比例降低或提高。在某些实施方式中,治疗方案可以是每周施用一次、两周一次、三周一次、四周一次、一个月一次、3个月一次、或3-6个月一次。在某些实施方式中,给药方案包括静脉内施用,1 mg/kg体重或3 mg/kg体重,抗体以下述给药时间表中的一个进行给药:(i)每四周给药六次,然后每三个月一次;(ii)每三周一次;(iii)3 mg/kg体重一次,之后1 mg/kg体重每三周一次。在某些实施方式中,剂量调整成实现约1-1000 µg/ml的血药浓度,例如可以为约25- 300 µg/ml。
另一方面,本申请还提供了制备本申请所述的分离的抗原结合蛋白的方法,所述方法可以包括在使得本申请所述的分离的抗原结合蛋白表达的条件下,培养本申请所述的细胞。
另一方面,本申请还提供了所述分离的抗原结合蛋白、所述的嵌合抗原受体、所述的免疫耦联物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
另一方面,本申请还提供了预防、缓解或治疗肿瘤的方法,所述方法可以包括向有需要的受试者施用本申请所述分离的抗原结合蛋白、所述的嵌合抗原受体、所述的免疫耦联物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物。在本申请中,所述施用可以通过不同的方式进行,例如静脉内、瘤内、腹膜内、皮下、肌肉内、局部或真皮内施用。
另一方面,本申请所述分离的抗原结合蛋白、所述的嵌合抗原受体、所述的免疫耦联物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物,其可以用于预防、缓解或治疗肿瘤。
在本申请中,所述肿瘤可以是实体瘤或血液瘤。
在本申请中,所述肿瘤可以包括PSMA阳性的肿瘤,所述PSMA阳性的肿瘤可以包括前列腺癌。
在本申请中,所述受试者可以包括人类和非人类动物。例如,所述受试者可以包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中,所述分离的抗原结合蛋白可以与一种或多种其他抗体一起施用,以便有效抑制受试者中的肿瘤生长。在某些实施方式中,可以向受试者施用所述分离的抗原结合蛋白以及一种或多种其他抗体,例如LAG-3抗体、PD-1抗体和/或CTLA-4抗体。
在本申请中,所述分离的抗原结合蛋白可以与化疗剂一起施用,所述化疗剂可以是细胞毒性剂,例如,SN-38、表阿霉素、奥沙利铂、和/或5-FU。
另一方面,本申请还提供了检测样品中PSMA的方法,所述方法包括施用本申请所述的分离的抗原结合蛋白。在本申请中,所述施用可以通过不同的方式进行,例如静脉内、瘤内、腹膜内、皮下、肌肉内、局部或真皮内施用。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的蛋白质分子、制备方法和用途等,而不用于限制本申请发明的范围。实施例不包括对传统方法的详细描述,如那些用于构建载体和质粒的方法,将编码蛋白的基因插入到这样的载体和质粒的方法或将质粒引入宿主细胞的方法。这样的方法对于本领域中具有普通技术的人员是众所周知的,并且在许多出版物中都有所描述,包括Sambrook, J., Fritsch, E.F. and Maniais,T.(1989) Molecular Cloning: A Laboratory Manual,2nd edition,Cold springHarbor Laboratory Press。
实施例
实施例1. 单克隆杂交瘤细胞的生成和筛选。
1.1 制备CHO-K1/cyno PSMA细胞稳转株。
包装有编码人PSMA的核酸序列的慢病毒颗粒(吉凯基因,cat#LVCON335)以M.O.I.=100((M.O.I. = (慢病毒颗粒滴度* 体积)/被感染细胞数量)的比例感染CHO-K1细胞(ATCC,cat# CCL-61)。感染48小时后的细胞以1:10的比例传代用含有8 µg/ml的筛选抗性和10%(w/v)胎牛血清的F2K 培养基1周左右至未感染的对照组CHO-K1被筛选抗性杀死。在96孔板内进行有限稀释成0.5细胞每孔,继续加含筛选抗性的培养基培养5天左右观察是否是单克隆,标记出来。继续在37度二氧化碳培养箱内培养1周左右至50%满,单克隆扩至6孔内。用Tab抗体(Pasotuxizumab)通过流式细胞仪检测其表达。高生长速度和FACS检测呈高荧光强度的克隆继续扩大培养,冻存至液氮中。
1.2 老鼠免疫,杂交瘤细胞融合和抗体筛选。
H2L2转基因小鼠(WO2010/070263 Al)能够产生与野生型小鼠(如BALB/C)相当的免疫应答和抗体滴度。
用免疫原为重组PSMA ECD-his(Sino-Biological, cat# 15877-H07H)免疫6-8周龄的Harbour H2L2转基因小鼠,并将其养殖于无特定的病原条件(SPF)下。在第一次免疫中,每只小鼠分别在腹腔和腋下淋巴结及腹股沟淋巴结处共注射50 µg免疫原蛋白和0.22ml完全弗氏佐剂(CFA, Sigma, cat#F5881)。为了增强免疫应答,在第一次免疫接种两周后,将25 µg免疫原蛋白连同200 µl Ribi(Sigma佐剂系统, Sigma, cat#S6322),注射到每只小鼠的腹腔内和皮下淋巴结处,随后每只老鼠每隔2周注射一次25 µg免疫原和200 µlRibi佐剂,加上第一次免疫共计6次。分别在此免疫期间的第四针及第六针的一周后,采集小鼠血液,对血液进行10倍稀释取6个浓度(1:100、1:1000、1:10000、1:100000、1:1000000),在包被有人PMSA ECD 蛋白(Sino-Biological, cat# 15877-H07H)的ELISA板进行ELISA检测来确定小鼠血液中抗人PMSA的滴度,并经流式细胞术检测3个浓度的小鼠血液(1:100、1:1000、1:10000)对PSMA高表达的LNCAP细胞(Cobioer, Nanjing, China)的特异反应性。空白对照组(PB)为免疫前老鼠的血清。
在完成上述步骤之后,选择具有针对人PSMA的特异性免疫应答的小鼠进行融合之前,在会阴内注射100 µg纯化的PSMA ECD-his 加强免疫。三天后,处死小鼠,并收集其脾细胞和淋巴结细胞。将NH4OH添加到脾细胞和淋巴结样品中,最终浓度为1%(w/w),以溶解样品中的红细胞。样品以1000转/分的速度离心,用DMEM培养基洗涤三次,测定细胞的存活率和数量。小鼠骨髓瘤细胞sp2/0(ATCC, cat#CRL-1581)用无血清的DMEM洗涤两次,测定细胞的存活率和数量。然后用高效电融合法以5:1的比例将活脾细胞与小鼠骨髓瘤细胞sp2/0(ATCC, cat#CRL-1581)融合。
将融合细胞重新悬浮于并在含有20%超低IgG FBS( ultra-low IgG, FetalBovine Serum, cat#16250086, Life Technologies)并添加有1X 次黄嘌呤、氨蝶呤和胸苷(50X HAT supplement,cat#21060017, life technologies)的培养基(Hybridoma-SFM,cat#12045084,Life Technologies)将浓度调整为105个细胞/200 µl。在96孔板的每个孔中加入200 µl的融合细胞,在37摄氏度、5%二氧化碳条件下培养。细胞融合后14天,用酶联免疫吸附试验(ELISA)测定其与PSMA ECD his蛋白结合的能力来筛选杂交瘤上清液。
筛选出的阳性克隆(OD450>2)再通过流式细胞仪筛选与HEK293/hPSMA细胞(KYinno, Beijing, China)以及CHO-K1/cyno PSMA B6细胞特异结合的克隆。在荧光强度评分后,选择荧光强度最强的25个杂交瘤母克隆,通过有限稀释法进行亚克隆,经筛选生长起来的亚单克隆通过ELISA和流式细胞术筛选,找出与PSMA蛋白或细胞上的PSMA结合最强的亚单克隆。经小鼠Ig分型Ready-SET-GO!ELISA(Life technologies, cat#88-50640-88)确定为IgG亚型的亚单克隆将进行测序分析。
实施例2. 单克隆PSMA抗体的测序、表达和纯化。
对实施例1筛选到的单克隆PSMA抗体进行测序,氨基酸序列如表1所示。
表1. 单克隆PSMA抗体的测序结果
序列名称 | SEQ ID NO : |
HCDR1 | 1 |
HCDR2 | 2 |
HCDR3 | 3 |
LCDR1 | 4 |
LCDR2 | 5 |
LCDR3 | 6 |
V<sub>H</sub> | 15 |
V<sub>L</sub> | 16 |
将上述单克隆PSMA抗体的重链可变区序列亚克隆到含有信号肽和人重链IgG1恒定区(SEQ ID NO : 19)的pTT5表达载体中。将单克隆PSMA抗体的轻链可变区序列亚克隆到含有信号肽和人抗体轻链kappa恒定区(SEQ ID NO : 20)的表达载体中。重组质粒经测序证实后用大抽试剂盒(Macherey-Nagel,NucleoBond® Xtra Midi)抽提质粒,以提高重组质粒的纯度和质量,质粒通过0.22 µm过滤器(millpore)过滤。纯化后的质粒用于转染。
Epi 293F细胞(invitro gen, cat#A14527)在FreeStyle 293培养基(invitrogen, cat#12338026)中37˚C,130rpm,8%二氧化碳(v/v)培养。调整HEK293F细胞到1-1.5x106/ml细胞密度后进行转染。用重链质粒和轻链质粒通过PEI(sigma)共转染HEK293F细胞,持续一周。大约在第5-7天,测定抗体的滴度。约在第6-7天,对HEK293E培养物进行离心(30分钟,3500rpm),收集上清液,并通过0.22 µm过滤器过滤纯化。
蛋白A柱(GE)用0.1M NaOH洗涤30分钟或用5倍柱体积的0.5M NaOH洗涤以去除内毒素。长期未使用的蛋白A柱先在1 mNaOH中浸泡至少1小时,再用无内毒素水清洗至pH为中性值,最后用10倍柱体积的1%Triton X100进行清洗。然后用5倍柱体积的PBS(PBS磷酸盐缓冲液,pH7.4)平衡蛋白柱。将上述收集的上清液装载到柱上,必要时收集流过的液体。用5倍柱体积的PBS洗涤柱,然后用5倍柱体积的0.1 M甘氨酸-HCl (pH3.0)洗脱。含有单克隆PSMA抗体的洗脱液用0.5倍柱体积的1 M Tris-HCl(Nacl 1.5 M)pH 8.5中和。抗人PSMA的抗体(即上述单克隆PSMA抗体)在1X PBS中透析4小时,以避免内毒素污染。透析后用分光光度法或试剂盒测定抗PSMA抗体浓度,用高效液相色谱-质谱法测定抗体纯度,用内毒素检测试剂盒(lonza)测定内毒素含量。
经上述实验,得到单克隆PSMA抗体PR001331(即本申请所述的分离的抗原结合蛋白),其为IgG1亚型,其可变区的氨基酸序列如上表1所示。
此外,准备了两种对比例抗体,用于后续实施例,一种是对比例1抗体PR001086(自制),另一种是对比例2抗体Tab(Pasotuxizumab,自制)。
具体而言,对比例1抗体PR001086的恒定区序列与PR001331相同,可变区序列与PR001331不同,具体地,其VH的氨基酸序列如SEQ ID NO : 17所示,VL的氨基酸序列如SEQID NO : 18所示,重链的氨基酸序列如SEQ ID NO : 23所示,轻链的氨基酸序列SEQ IDNO: 24所示。
对比例2抗体Tab(Pasotuxizumab)是在Amgen公司的PSMA x CD3基础上自制的对比例抗体,其重链和轻链的氨基酸序列分别如SEQ ID NO: 25和26所示。
实施例3. 单克隆PSMA抗体与细胞表面PSMA的结合能力。
HEK293/hPSMA细胞或CHO-K1/cyno PSMA细胞或LNCAP细胞在T-75培养瓶中培养和扩增,达到90%的融合后吸取培养基,用PBS洗涤细胞两次。细胞用胰酶(Invitrogen,cat#15050065)处理1分钟左右,再用培养基中和胰酶。然后用PBS洗涤两次细胞,测定细胞计数,再用PBS再重悬细胞至2×106细胞/ml。将100 µl细胞悬浮液添加到96孔V型板的每个孔中。与不同浓度的纯化PSMA抗体或各同型对照抗体冰上孵育1小时。细胞用PBS洗涤两次后与山羊抗人(H+L)-Alexa Fluor 647(Life technology,cat#A21445)于4℃一起孵育30-45分钟。再次PBS洗涤后,在FACS CatonII 流式细胞仪上分析细胞的荧光强度中位值(MFI),对照组为人IgG1。
如图1A和图1B所示,图中IgG1,k或hIgG1k均表示对照组(即人IgG1),可以看出,本申请的PSMA抗体PR001331能特异性地结合人PSMA,且检测到的抗体结合能力与抗体浓度成正相关关系递增;与之相反,对比例1抗体PR001086与人PSMA的结合则很弱。与对比例2抗体Tab(Pasotuxizumab)相比,在相同浓度下,本申请的PSMA抗体PR001331表现出更高的Emax,表明了该抗体能在HEK293 hPSMA细胞上结合更多的hPSMA蛋白(即人PSMA蛋白)。此外,从表2和表3可以看出,本申请的PSMA抗体PR001331的EC50值比Tab低,说明该抗体能以较低的浓度更灵敏地结合人PSMA。
表2. 与图1A对应的EC50值。
抗体 | PR001086 | Tab | hIgG1k |
EC50(µg/ml) | 10.14 | 1.137 | 0.05266 |
表3. 与图1B对应的EC50值。
抗体 | PR001331 | Tab | IgG1,k |
EC50(µg/ml) | 0.6738 | 1.501 | 0.007228 |
如图2A、图2B以及表4和表5所示,图中IgG1,k或hIgG1,k均表示对照组(即人IgG1),可以看出,本申请的PSMA抗体PR001331能特异性地结合CHO-K1/cyno PSMA细胞表面表达的猴PSMA。且与对比例2抗体Tab(Pasotuxizumab)相比,该抗体的结合EC50值比对比例2抗体低得多,说明该抗体能以较低的浓度更灵敏地结合猴PSMA。而PR001086与猴PSMA结合则很弱。
表4. 与图2A对应的EC50值。
抗体 | PR001086 | Tab | hIgG1,k |
EC50(µg/ml) | 24.38 | 2.659 | 约0.01842 |
表5. 与图2B对应的EC50值
抗体 | PR001331 | Tab | IgG1,k |
EC50(µg/ml) | 0.1537 | 1.591 | 约0.02004 |
如图3和表6所示,图中IgG1,k表示对照组(即人IgG1),可以看出,本申请的PSMA抗体PR001331能特异性地结合LNCAP细胞表面表达的PSMA,且与对比例2抗体Tab(Pasotuxizumab)相比,抗体PR001331的EC50值低得多,说明该抗体能以较低的浓度更灵敏地结合肿瘤细胞株表达的PSMA。
表6. 与图3对应的EC50值。
抗体 | PR001331 | Tab | IgG1,k |
EC50(µg/ml) | 0.1056 | 0.6958 | 约11.12 |
实施例4. 抗体内化。
PSMA抗体可以通过结合PSMA的胞外尾部介导细胞表面表达的PSMA蛋白的内化。在本实施例中,测试本申请的PSMA抗体的内化程度以及PSMA+细胞对于PSMA抗体杀伤的易感性。
HEK293 hPSMA或LNCAP细胞在T-75培养瓶中培养和扩增,达到90%的融合后吸取培养基,用PBS洗涤细胞两次。细胞用胰酶(Invitrogen,cat#15050065)处理1分钟左右,再用培养基中和胰酶。将细胞转移到15 ml无菌离心管中,1000 rpm室温离心5分钟,使细胞成团。吸去培养基,将细胞重新悬浮于各自的培养基。轻柔地吹打细胞,得到单细胞混悬液。用细胞计数板进行计数,之后将2*103 LNCAP细胞或HEK293T hPSMA细胞加至黑色ViewPlate-96 TC(Perkin Elmer,cat#6005225)板中。37℃、5%CO2孵育箱中孵育过夜。
第二天,用不含FBS的培养基制备10X浓度(100 nM)的抗体溶液,5倍稀释,制备6个抗体浓度。将10 µl的各抗体样品移至上述细胞板内,各孔的终体积为100 µl。每孔加入2 µl的50 µg/ml αHFc-CL-MMAF培养基(αHFc-CL-MMAF试剂盒,Cat#:AH-102AF,moradec),使其终浓度为1 µg/ml。37℃、5%CO2孵育4天。
在第六天,每孔加入100 µl CellTiter-Glo®发光细胞活性试剂(Promega, USA,cat#G7570),在摇床上混合2分钟,诱导细胞裂解。96孔板在室温孵育10分钟来稳定光信号。使用PE Enspire酶标仪(Perkin Elmer, EnSpire)记录发光情况,确定EC50值。
图4示出抗体处理下HEK293 hPSMA细胞的成活率,图中hIgG1,k表示对照组(即人IgG1)。可以看到,在本申请的PSMA抗体PR001331的处理下,相比于对比例2抗体Tab(Pasotuxizumab),细胞成活率更低,且其EC50值远低于对比例2抗体(参见表7),说明其能够以较低浓度实现最大抗体内化效应。
图5示出抗体处理下LNCAP细胞的成活率,图中hIgG1,k表示对照组(即人IgG1)。可以看到,在本申请的PSMA抗体PR001331的处理下,相比于对比例2抗体Tab(Pasotuxizumab),LNCAP细胞成活率更低,且EC50值低于对比例2抗体(参见表8),说明其能够以较低浓度实现最大抗体内化效应。
表7. 与图4对应的EC50值。
抗体 | PR001331 | Tab | hIgG1,k |
EC50(µg/ml) | 0.1181 | 9.879 | 3.594 |
表8. 与图5对应的EC50值。
抗体 | PR001331 | Tab | hIgG1,k |
EC50(µg/ml) | 0.01924 | 0.3461 | 约0 |
实施例5. PSMA抗体对重组PSMA蛋白的结合亲和力和解离常数的测定。
按照制造商提供的详细操作和方法,使用Octet RED96仪器(Fortiebio)和抗人IgG Fc亲和素传感器(AHC传感器,Pall ForteBio ,cat#18-5060)测定亲和力。具体地,用含有0.1%(w/w)BSA和0.02%(v/v)吐温20的PBS缓冲液(pH7.4)将rhPSMA蛋白(SinoBiological,cat#15877-H07H)稀释至200 nM,与AHC传感器孵育。将40 nM的PSMA抗体与负载rhPSMA蛋白的AHC传感器在30℃孵育3分钟。该反应混合物在含有0.1%(v/w)BSA和0.02%(v/v)吐温20的PBS缓冲液(pH7.4)中于30℃继续孵育5分钟。Octet Red 96实时记录PSMA抗体与rhPSMA蛋白的结合和分离信号。亲和力、关联和解离常数由Octet使用软件确定,结果如表9所示。
从表9可以看出,PR001331抗体的KD值均低于对比例2抗体Tab(Pasotuxizumab),表明其更强的PSMA结合亲和力,KD值约低于对比例2抗体10倍。
表9. 抗体的结合亲和力。
抗体 | KD(M) | 应答 | Ka(1/Ms) | Kd(1/s) |
PR001331 | 3.76E-10 | 0.5758 | 4.88E+04 | 1.83E-05 |
Tab | 4.36E-09 | 0.3263 | 1.81E+04 | 7.90E-05 |
实施例6. PSMA抗体的ADCP活性。
从PBMC(Miaotong, cat#PB050F)中用人CD14分选磁珠(Meltenyi, 130-050-201))分离CD14+单核细胞,以密度为1*106/mL重悬于含10%FBS 的RPMI1640培养基,加入100 ng/ml GM-CSF(PeproTech, cat#300-03-A)。取2*106 个单核细胞每孔于6孔板内,37度二氧化碳培养箱培养9天,使其分化为巨噬细胞。每隔3-4天换一次液(含100 ng/ml GM-CSF)。9天后用胰酶消化巨噬细胞,用含10%FBS 的RPMI1640终止胰酶反应。收集细胞,用PBS洗涤一次,用PBS重悬为密度为1*106/ml。同样收集LNCAP细胞,用PBS重悬为密度为1*106/ml。用0.1 µM Far-red(溶于PBS)对巨噬细胞,用0.5 µM CFSE(溶于PBS)对LNCAP细胞在4度染色10分钟。离心染色后的细胞,用>20 ml的RPMI1640+10%FBS培养基洗涤一次。重悬洗涤后的细胞于1%BSA- RPMI1640培养基中,并调整细胞密度均为1.6*106 /ml。在96孔V型板内(Corning, cat#3894)每孔加入25 µl LNCAP细胞(每孔细胞数为4*104)和25 µl 巨噬细胞(每孔细胞数为4*104)。用1%BSA- RPMI1640稀释抗体至中间浓度20 nM,再从20 nM 5倍稀释成7个梯度。含有LNCAP和巨噬细胞的同一96孔V型板内每孔加入50 µl的稀释抗体,混匀完全。37℃孵育1小时。使用BD FACS Caton II(BD, Germany),经流式细胞术识别FITC+LNCAP细胞和Alexa647+巨噬细胞。数据用FlowJo软件(Tree Star, Ashland, OR)分析,双染细胞的百分比用于确定ADCP介导的细胞杀伤。
图6显示本申请的PSMA抗体PR001331在巨噬细胞中介导的对LNCAP的吞噬作用,图中IgG1,k表示对照组(即人IgG1),结合表10可以看出,PR001331抗体显示出对LNCAP细胞的ADCP效应。其中,在使用供体4051#的PBMC的情况下,从特异性杀伤率的均值和标准误看,抗体PR001331的最高杀伤%最接近于对比例2抗体Tab,其EC50值小于Tab,表明其能够在较低浓度下达到与对比例2抗体相当或更高的最大杀伤力。
表10. PSMA抗体PR001331对LNCAP的ADCP效果(供体4051#)。
抗体 | EC50(nM) | 最高吞噬% | 最低吞噬% |
Tab | 1.203 | 28.05 | 7.882 |
PR001331 | 0.1182 | 27.37 | 8.088 |
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方案的范围内。
序列表
<110> 和铂医药(上海)有限责任公司
<120> 一种分离的结合抗原PSMA的蛋白及其用途
<130> 0113-PA-008
<160> 26
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的HCDR1
<400> 1
Asn Tyr Gly Met Asn
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的HCDR2
<400> 2
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Arg
1 5 10 15
Gly
<210> 3
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的HCDR3
<400> 3
Gly Pro Gly Tyr Gly Gly His Ser Asp Ala Phe Asp Ile
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的LCDR1
<400> 4
Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的LCDR2
<400> 5
Thr Ala Ser Ser Leu Leu Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的LCDR3
<400> 6
Gln Gln Ser Phe Ser Thr Pro Tyr Thr
1 5
<210> 7
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的H-FR1
<400> 7
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ile
20 25 30
<210> 8
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的H-FR2
<400> 8
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
1 5 10
<210> 9
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的H-FR3
<400> 9
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 10
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的H-FR4
<400> 10
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
1 5 10
<210> 11
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的L-FR1
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 12
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的L-FR2
<400> 12
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 13
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的L-FR3
<400> 13
Gly Val Pro Ser Arg Phe Ser Ala Ser Gly Ser Trp Thr Asp Phe Ser
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 14
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的L-FR4
<400> 14
Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
1 5 10
<210> 15
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的VH
<400> 15
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ile Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Pro Gly Tyr Gly Gly His Ser Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 16
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的VL
<400> 16
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Ala
50 55 60
Ser Gly Ser Trp Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105
<210> 17
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 对比例1抗体PR001086的VH
<400> 17
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 Ile Phe Arg Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Asn Ile Val Ser Thr Trp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Arg Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Arg Ala Ala Val Asp Leu Trp Gly Gln Gly Thr Met Val Thr
100 105 110
Val Ser Ser
115
<210> 18
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 对比例1抗体PR001086的VL
<400> 18
Glu Lys Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331/对比例1抗体PR001086的重链恒定区
<400> 19
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 20
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331/对比例1抗体PR001086的轻链恒定区
<400> 20
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 21
<211> 452
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的重链
<400> 21
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ile Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Pro Gly Tyr Gly Gly His Ser Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 22
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PR001331的轻链
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Ala
50 55 60
Ser Gly Ser Trp Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 23
<211> 445
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 对比例1抗体PR001086的重链
<400> 23
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 Ile Phe Arg Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Asn Ile Val Ser Thr Trp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Arg Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Arg Ala Ala Val Asp Leu Trp Gly Gln Gly Thr Met Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 24
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 对比例1抗体PR001086的轻链
<400> 24
Glu Lys Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 25
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 对比例2抗体Tab的重链
<400> 25
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 26
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 对比例2抗体Tab的轻链
<400> 26
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (24)
1.分离的抗原PSMA结合蛋白,其包含氨基酸序列SEQ ID NO: 15所示的VH中的HCDR1、HCDR2和HCDR3;且其包含氨基酸序列SEQ ID NO: 16所示的VL中的LCDR1、LCDR2和LCDR3。
2.根据权利要求1所述的分离的抗原PSMA结合蛋白,其中所述HCDR1的氨基酸序列如SEQ ID NO: 1所示,所述HCDR2的氨基酸序列如SEQ ID NO: 2所示,且所述HCDR3的氨基酸序列如SEQ ID NO: 3所示。
3.根据权利要求1所述的分离的抗原PSMA结合蛋白,其中所述LCDR1的氨基酸序列如SEQ ID NO: 4所示,所述LCDR2的氨基酸序列如SEQ ID NO: 5所示,且所述LCDR3的氨基酸序列如SEQ ID NO: 6所示。
4.根据权利要求1所述的分离的抗原PSMA结合蛋白,其中所述VH包括框架区H-FR1,H-FR2,H-FR3和H-FR4。
5.根据权利要求4所述的分离的抗原PSMA结合蛋白,其中所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO: 7所示的氨基酸序列;所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO: 8所示的氨基酸序列;所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO: 9所示的氨基酸序列;所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4包含SEQ ID NO: 10所示的氨基酸序列。
6.根据权利要求1所述的分离的抗原PSMA结合蛋白,其中所述VL包括框架区L-FR1,L-FR2,L-FR3和L-FR4。
7.根据权利要求6所述的分离的抗原PSMA结合蛋白,其中所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO: 11所示的氨基酸序列;所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO: 12所示的氨基酸序列;所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO: 13所示的氨基酸序列;所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4包含SEQ ID NO: 14所示的氨基酸序列。
8.根据权利要求1所述的分离的抗原PSMA结合蛋白,其包括抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
9.根据权利要求8所述的分离的抗原PSMA结合蛋白,其中所述抗体重链恒定区包含SEQID NO: 19所示的氨基酸序列。
10.根据权利要求1所述的分离的抗原PSMA结合蛋白,其包括抗体轻链恒定区,且所述抗体轻链恒定区包括人Igκ恒定区。
11.根据权利要求10所述的分离的抗原PSMA结合蛋白,其中所述抗体轻链恒定区包含SEQ ID NO: 20所示的氨基酸序列。
12.根据权利要求1所述的分离的抗原PSMA结合蛋白,其包含抗体重链HC,且所述HC包含SEQ ID NO : 21所示的氨基酸序列。
13.根据权利要求1所述的分离的抗原PSMA结合蛋白,其包含抗体轻链LC,且所述LC包含SEQ ID NO : 22所示的氨基酸序列。
14.根据权利要求1所述的分离的抗原PSMA结合蛋白,其包括抗体或其抗原结合片段,其中所述抗原结合片段包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv和/或di-scFv。
15.根据权利要求1-14中任一项所述的分离的抗原PSMA结合蛋白,其具有下述性质中的一种或多种:
1)能够以4×10-10M或更低的KD与PSMA蛋白相结合,其中所述KD值通过Octet测定;
2)在FACS测定中,能够特异性结合过表达人PSMA的HEK293细胞、过表达猴PSMA的CHO-K1细胞或LNCAP细胞表面的PSMA蛋白;
3)能够内化到过表达人PSMA的HEK293细胞或LNCAP细胞中;
4)对LNCAP细胞具有ADCP活性。
16.根据权利要求15所述的分离的抗原PSMA结合蛋白,所述PSMA蛋白包含人PSMA蛋白或猴PSMA蛋白。
17.嵌合抗原受体,其包含权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白。
18.免疫耦联物,其包含权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白。
19.分离的一种或多种核酸分子,其编码权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白或权利要求17所述的嵌合抗原受体。
20.载体,其包含权利要求19所述的核酸分子。
21.细胞,其包含权利要求19所述的核酸分子或权利要求20所述的载体。
22.药物组合物,其包含权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白、权利要求17所述的嵌合抗原受体、权利要求18所述的免疫耦联物,以及任选地药学上可接受的佐剂。
23.制备权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白的方法,所述方法包括在使得权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白表达的条件下,培养权利要求21所述的细胞。
24.权利要求1-16中任一项所述的分离的抗原PSMA结合蛋白、权利要求17所述的嵌合抗原受体、权利要求18所述的免疫耦联物、和/或权利要求22所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗前列腺癌。
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