CN111727058A - 靶向tag-72的t细胞疾病治疗 - Google Patents
靶向tag-72的t细胞疾病治疗 Download PDFInfo
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Abstract
本公开涉及通过靶向肿瘤相关糖蛋白72(TAG‑72)来治疗T细胞疾病,特别是T细胞淋巴瘤(TCL),特别包括皮肤T细胞淋巴瘤(CTCL),例如塞扎里综合征(SS)和蕈样肉芽肿病(MF)。
Description
对相关申请的交叉引用
本申请要求于2018年2月23日提交的美国临时申请号62/634,366的优先权权益,其全部内容通过引用并入本文。
发明领域
本公开涉及通过靶向肿瘤相关糖蛋白72(TAG-72)来治疗T细胞疾病,特别是T细胞淋巴瘤(TCL),特别包括皮肤T细胞淋巴瘤(CTCL),例如塞扎里综合征(SS)和蕈样肉芽肿病(MF)。
通过引用并入序列表
在2019年2月11日创建的、10KB的命名为10478的35478PCT_SequenceListing.txt的ASCII文本文件中的序列表通过引用并入本文。
发明背景
T细胞淋巴瘤和白血病是罕见的血液疾病。TCL是一类由T细胞突变引起的非何杰金淋巴瘤。它包括远离胸腺发展的T成淋巴细胞性淋巴瘤/白血病和外周T细胞淋巴瘤(PTCL)。PTCL包含许多子类,其中一些子类更具攻击性(增长更快),而其他子类是无痛性的(增长缓慢)。起源于皮肤的CTCL通常是PTCL的无痛性(缓慢生长)形式。在CTCL中,癌性T细胞在扩散到身体的其他部位之前形成皮肤损伤。SS是CTCL的一种特定形式,其中T细胞携带病理水平的粘多糖。SS的主要表现在皮肤中。目前,CTCL的治疗选项限于组蛋白脱乙酰基酶(HDAC)抑制剂、光疗和化学疗法。缓解率(remission rate)为约30%,但缓解并不持久。迫切需要新的治疗选项。免疫疗法的最新创新,例如单克隆抗体、抗体-药物缀合物(ADC)和CAR-T细胞,为TCL的治疗开辟了潜在的新方法。然而,此类治疗的发展取决于能够鉴定正常细胞上(基本上)不存在的TCL细胞上的特定标志物。
TAG-72已经建立为腺癌的标志物,并且还已经鉴定为某些实体瘤中CAR-T细胞的潜在靶标(Dotti et al.,Immunol Rev 257:1-35(2014))。已经在结肠直肠癌患者中进行了使用TAG-72靶向性CAR-T细胞的临床试验(Hege et al.,J Immunother Cancer 5:22(2017)。也已经鉴定出血液恶性(其包括CTCL)中CAR-T细胞的潜在靶标(Dotti等人,同上)。由于尚未报道TAG-72在此类恶性中的表达,尚未认为它是血液恶性的潜在靶标(Dotti等人,同上)。例如,在一项关于多种细胞类型的研究中,在10/10淋巴瘤样品中检测不到TAG-72(Rutter,Fleuren and Warnaar(编),Application of Monoclonal Antibodies inTumor Pathology,Martinus Nighoff Publishers(1987))。由于大多数淋巴瘤是B细胞淋巴瘤,可能的是这项研究中使用的大多数淋巴瘤样品是B细胞淋巴瘤。据报道,TAG-72在某些造血细胞系,例如Jurkat T细胞系中表达(Nicolet et al,Tumour Biol 18:356-366(1997))。然而,细胞系中肿瘤相关抗原(TAA)的表达不一定反映亲代肿瘤,并且也没有报道表明在从患有血源性癌症或与任何血液肿瘤相关的患者分离的肿瘤细胞上已检测到TAG-72。
发明概述
在一方面,本公开提供了治疗患者中的TCL的方法,所述TCL特别包括CTCL,该方法包括对患者施用靶向TAG-72的试剂。
在各个实施方案中,靶向TAG-72的试剂包含表达对TAG-72特异性的CAR的细胞。在一些实施方案中,细胞是T细胞,例如γδTCR T细胞、αβTCR T细胞、NKT细胞或MAIT(粘膜相关不变T)细胞;并且在其他实施方案中,该细胞是NK细胞。在一些实施方案中,CAR包含TAG-72识别部分,例如具有SEQ ID NO:2的氨基酸序列的scFv。在一些实施方案中,CAR包含含有CD3-zeta的胞内信号传导域的信号转导域;并且在具体的实施方案中,信号转导域还包含CD28、4-1BB或CD2的胞内共刺激域。如本文进一步所述,TAG-72识别部分可通过铰链和跨膜域连接至信号转导域。
在一些实施方案中,靶向TAG-72的试剂包含对TAG-72特异性的抗体或其抗原结合片段。在一些实施方案中,抗体或抗原结合片段与细胞毒剂缀合。在一些实施方案中,细胞毒剂是小分子化合物。在一些实施方案中,抗体与增强的ADCC活性相关。在一些实施方案中,抗体是双特异性抗体;例如,与T细胞、NK细胞或巨噬细胞上的受体结合的双特异性抗体。
在一些实施方案中,CTCL是塞扎里综合征(“SS”)。在一些实施方案中,CTCL是非SS形式,例如间变性大细胞淋巴瘤(anaplastic large-cell lymphoma)、红皮病性蕈样肉芽肿病(erythrodermic mycosis fungoides)和滤泡性营养性蕈样肉芽肿病。
在一些实施方案中,将本文公开的治疗方法给予患者,所述患者在治疗前已经鉴定为与对照相比具有血液中升高的表达TAG-72的T细胞水平或血液中升高的可溶性TAG-72水平。
在另一方面,本发明涉及TAG-72靶向剂,用于治疗TCL,特别包括CTCL。
在又一方面,本公开提供了诊断或表征TCL患者的方法,该方法包括检测患者血液中表达TAG-72的T细胞的水平或可溶性TAG-72的水平并且与对照水平进行比较。在一些实施方案中,通过从患者血液分离T细胞并评估分离的T细胞的TAG-72表达来测定患者中表达TAG-72的T细胞的水平。在一些实施方案中,通过使用针对TAG-72的抗体评估TAG-72的表达。在一些实施方案中,基于T细胞的CD3表达,从患者的血液中分离它们。在其他实施方案中,可以在从血液分离T细胞中包括其他标志物(例如,CD4+、CD45RO+和CD5+)。
附图简述
图1A-1M。如流式细胞术证明,塞扎里综合征PBMC表达与肿瘤相关的抗原TAG-72。与健康供体细胞(J-M)相比TAG-72在所有分析的患者样品(A-I)中过表达。除非另有说明,数字以分析的总事件的百分比(%T)表示群体频率。在对活的CD3+/CD4+/CD45RO+/CD5+细胞进行门控前,通过电子方式从分析排除细胞碎片,所述细胞最终分析TAG-72表达。
图1N-1V。T-ALL和B-ALL样品不表达肿瘤相关抗原TAG-72,如流式细胞术证明。T-ALL(N-R)或B-ALL(S-V)患者样品中的TAG-72水平未超过基线。除非另有说明,数字以分析的存活事件的百分比表示群体频率。在对单一活细胞进行门控前,通过电子方式从分析排除细胞碎片,所述细胞最终分析TAG-72与CD3(T-ALL)或CD19(B-ALL)的共表达。
图2。与正常个体相比,患有不同形式的TCL的患者显示增加的TAG-72+T细胞的频率。PBMC获自总共15位健康供体(HD)、21位塞扎里综合征(SS)患者、18位蕈样肉芽肿病(MF)患者和8位具有其他形式的TCL的患者(包括间变性大细胞淋巴瘤、外周T细胞淋巴瘤和滤泡性营养性蕈样肉芽肿病)。与健康供体细胞(蓝色)相比,TAG-72在SS(红色)、MF(绿色)和其他形式的TCL(紫色)PBMC中的CD3+T细胞亚组上以显著更高的程度表达,如通过流式细胞术证明(p<0.05)。数字以分析的总事件的百分比(%T)±SEM表示群体频率。进行的门控策略通过电子方式排除细胞碎片,并选择单一存活细胞。随后分析CD3+细胞的TAG-72共表达。
图3A-3B。与健康供体相比,CTCL患者在其血浆中具有更高水平的可溶性TAG-72。通过ELISA评估了来自29位CTCL患者和14位健康供体的血浆样品的可溶性TAG-72。个别患者和供体的结果显示为条形图(A)和散点图(B)。CTCL患者中TAG-72的平均水平显著大于健康供体中的水平(P<0.05)。虚线表示在正常人AB血清中检测的TAG-72的水平。
图4A。来自一些CTCL患者的皮肤活组织检查显示TAG-72阳性细胞的存在。从11位诊断患有SS、MF或间变性T细胞淋巴瘤的个体获得受损伤影响的皮肤的打孔活组织检查。制备薄切片并通过H&E染色,并使用标准技术针对TAG-72或CD3表达染色。在图4A中显示每个切片和染色剂的代表性感兴趣区域,以及TAG-72和CD3染色切片的阳性对照。比例尺代表50um。
图4B。TAG-72可以在TCL患者中的循环和/或皮肤浸润细胞中表达。如先前所述进行循环T细胞的流式细胞术分析或皮肤活组织检查的免疫组织化学。图4B中总结了来自图4A的患者的比较表达水平。
图5A。三种TAG-72特异性CAR-T构建体的示意图,显示了与对TAG-72特异性的scFv连接的铰链、跨膜(TM)和信号传导域的不同组合。实施例中描述的研究利用表达这些构建体中的两个(命名为TAG-72(1)和TAG-72(3))的CAR-T细胞。
图5B。掺入TAG-72-特异性CAR构建体TAG-72(1)和TAG-72(3)的scFv域的核苷酸序列(SEQ ID NO:1)和氨基酸序列(SEQ ID NO:2)。TAG-72特异性scFV域的组件也表示为:TAG-72VH(重链可变区)、GS接头(粗体斜体)和TAG-72VL(轻链可变区)。
图6A-6B。TAG-72CAR(1)T细胞介导对表达TAG-72hi的靶标癌细胞(Ovcar 3)(A),而非对TAG-72-ve/低癌靶细胞(MESov)(B)的有力细胞杀伤。在以5:1(红色)、1:1(绿色)或1:5(紫色)的E:T比添加效应细胞(↓)之前,让靶细胞粘附于RTCA板达4h。在75小时内监测细胞阻抗(在此表示为标准化细胞指数)。也始终监测正常生长条件(蓝色)下的靶细胞增殖。
图6C-6D。TAG-72CAR(3)T细胞介导对表达TAG-72hi的靶细胞(Ovcar3)(C),而非TAG-72-ve/低癌靶细胞(MESov)(D)的有力细胞杀伤。在以5:1的E:T比添加NT T细胞(红色)或TAG-72CAR(3)(绿色)之前,让靶细胞粘附于RTCA板达4-6h。在20小时内监测细胞阻抗(表示为标准化细胞指数)。也始终监测正常生长条件(蓝色)下的靶细胞增殖。
图7A-7E。Jurkat细胞可以被体外悬浮培养中的TAG-72特异性CAR-T细胞杀死。在体外使用之前与同种型对照(蓝色)相比对Jurkat细胞系表征TAG-72表达(A;红色)。将Jurkat细胞维持在正常培养条件下(B),与未转导的T细胞(C)、TAG-72CAR(1)T细胞(D)或TAG-72CAR(3)T细胞(E)共培养48h,此时通过流式细胞术测定保留在培养物中的存活TAG-72+细胞的分析。数据表示为保留在培养物中的表达TAG-72的存活细胞的百分比。
图8A-8E。体外48小时暴露于TAG-72CAR(1)T细胞后,SS患者PBMC淋巴细胞群体内的TAG-72+细胞减少。小图A-D代表来自单个SS患者的结果。示例性的门控策略证明了在分析TAG-72表达(B-D)之前,通过对淋巴细胞群体(A)进行门控从分析消除碎片。E.来自图2的9位SS患者和4位正常受试者的汇总数据证明了当维持在正常扩增条件(蓝色)下时SS患者PBMC上TAG-72表达的体外持久性。在患者/NT PBMC培养物(红色)中可观察到略有减少,但是这没有达到显著性。当将患者PBMC与TAG-72CAR(1)T细胞(绿色)共培养时,观察到最大的变化。n.s.=不显著;*在t检验中表示p<0.05。
图9A-9H。相比于与非转导(NT)T细胞(蓝色)的共培养,与TAG-72CAR(3)T细胞(红色,B,D,F)共培养24小时后,TCL PBMC(随后称为疾病PBMC)中CD3+/TAG-72+的频率显著降低。使用健康供体(HD)PBMC(A,C,E)进行平行共培养,其中在测试条件下也观察到CD3/TAG-72+细胞减少(红色),尽管程度较小。使用5:1的E:T制备所有培养物。将每种靶细胞类型(疾病或健康受试者或Jurkat细胞系)与从至少两位不同供体分离的T细胞产生的CAR-T细胞共培养。在图9G和9H中,从来自图2的36位疾病患者(G)和10位健康个体(H)汇总数据。n.s.=不显著;**表示p<0.01;在配对t检验中,***表示p<0.001,并且****表示p<0.0001。
图10A-10E。使用抗TAG-72抗体-药物缀合物杀死TAG-72+细胞。暴露于抗TAG-72抗体-药物缀合物CC49-DM1后,表达TAG-72的塞扎里综合征患者PBMC减少。来自在48h内暴露于CC49-DM1的4位SS患者PBMC的汇总数据证明与在正常培养条件下维持的SS患者PBMC(蓝色)相比,表达TAG-72的细胞(A;红色)的总百分比的减少。暴露于此种抗体-药物缀合物也降低Jurkat培养物(B)中,而非健康供体PBMC(C)中表达TAG-72的细胞的频率。示例性FACS点图进一步证明了在不存在(D)和存在(E)抗体-药物缀合物的情况下,SS患者PBMC中此细胞亚群的变化。
发明详述
根据本发明已经鉴定TAG-72由TCL,特别是CTCL亚型,例如塞兹氏综合症(SS)和蕈样肉芽肿病(MF)中的细胞表达。本文已证明靶向TAG-72的CAR-T细胞在体外特异性杀伤TCLT细胞,并且TAG-72抗体-药物缀合物实质性降低来自SS患者的PBMC中TAG-72+细胞的百分比。因此,本文公开了通过施用TAG-72靶向剂来治疗TCL如SS和MF的方法。
TCL、CTCL和SS
本文公开的治疗方法有效治疗所有形式的TCL,包括CTCL亚型,包括例如SS、间变性大细胞淋巴瘤、红皮病性蕈样肉芽肿病和滤泡性营养性蕈样肉芽肿病。
TCL是由T细胞突变引起的一类非何杰金氏淋巴瘤。外周T细胞淋巴瘤(PTCL)远离胸腺起源。一种特定形式皮肤T细胞淋巴瘤(CTCL)指涉及皮肤的T细胞淋巴瘤。癌性T细胞在扩散到身体其他部位之前形成皮肤损伤。CTCL还可涉及血液、淋巴结和其他内部器官。症状可包括皮肤干燥、瘙痒、红疹和淋巴结肿大。大多数CTCL患者仅经历皮肤症状而没有严重并发症;然而,约10%的进展到较晚期阶段的人形成严重并发症。
CTCL的两种最常见的类型是蕈样肉芽肿病和SS。蕈样肉芽肿病是最常见的CTCL类型,皮肤症状可以以块、斑或肿瘤出现。SS是蕈样肉芽肿病的一种晚期的变体形式,并且特征是血液中淋巴瘤细胞(以一系列表面标志物并携带病理水平的粘多糖为特征的T细胞)的存在。SS的主要表现是在皮肤上,广泛的薄、红色、发痒的皮疹通常覆盖身体的80%。
TAG-72
TAG-72最初鉴定为对单克隆抗体B72.3有反应,该单克隆抗体已广泛表征其对多种癌与正常组织的反应性(Sheer et al.,Cancer Res 48,6811-6818,1988)。进一步的表征已将TAG-72建立为粘蛋白相关的截短的O-聚糖,其含有与GalNAcα-O-Ser/Thr以α-2,6连接的唾液酸,也称为唾液酸-Tn抗原(Munckley,Int.J.Mol.Sci.2016,17,275)。
靶向TAG-72的试剂
“靶向TAG-72的试剂”是指与癌性细胞表面上表达的TAG-72特异性结合并导致癌性细胞杀死的试剂。
抗原识别部分
本文公开的靶向TAG-72的试剂包括特异性识别并结合TAG-72的抗原识别部分。TAG-72识别部分的特异性可以由至少在微摩尔范围内的解离常数(KD)反映,优选在纳摩尔或皮摩尔范围内的KD反映。
在各个实施方案中,抗原识别部分由特异性结合TAG-72的抗体的抗原结合片段组成。
如本文所用,术语“抗体”包括任何同种型的单克隆抗体,例如IgG、IgM、IgA、IgD和IgE,多克隆抗体,嵌合抗体,人源化抗体,多特异性抗体和单链抗体。典型的IgG抗体由通过二硫键连接的两条相同的重链和两条相同的轻链组成。每条重链和轻链均含有恒定区和可变区。每个可变区含有三个主要负责结合抗原的表位的“互补决定区”(“CDR”)。术语“VH”指抗体的免疫球蛋白重链的可变区,包括Fv、scFv、dsFv、Fab.Fab’或F(ab’)2片段的重链。术语“VL”是指抗体的免疫球蛋白轻链的可变区,包括Fv、scFv、dsFv、Fab、Fab’或F(ab’)2片段的轻链。可变区的更高度保守的部分称为“框架区”。
如本文所用,术语“嵌合抗体”是指恒定区或其部分和可变区具有不同起源的抗体。例如,可以克隆编码鼠单克隆抗体的重链和轻链可变区的DNA区段,并分别与编码人免疫球蛋白的重链和轻链恒定区的DNA区段连接,以产生鼠-人嵌合免疫球蛋白编码基因。
如本文所用,术语“人源化抗体”是指源自非人免疫球蛋白的抗体,其中非人免疫球蛋白的某些氨基酸已被人免疫球蛋白的氨基酸替代。人源化的目的是降低用于引入人接受体中的异种抗体(例如鼠抗体)的免疫原性,而保持抗体的完整抗原结合特异性。非人抗体的人源化可以使用本领域公知的技术进行,包括例如CDR植入(将非人免疫球蛋白的互补决定区植入人免疫球蛋白框架域中;参见例如WO 92/22653、EP 0 239 400、WO 91/09967、美国专利5,530,101和美国专利5,585,089),表面重修(基于分子建模、统计分析和诱变的组合来改变抗体可变区的非CDR表面,以类似于已知人抗体的表面;参见例如EP 0 592106,EP 0 519 596)和链改组(美国专利号5,565,332)。
术语“多特异性抗体”是指能够选择性结合两个或更多个表位或对两个或更多个表位具有特异性的抗体——所述表位在两个不同的分子(例如,抗原)或在相同的分子(例如,在相同的抗原上)。例如,多特异性抗体的实例是能够选择性结合两个或更多个表位的双特异性抗体。在本领域中充分记载了双特异性抗体的产生。
如本文所用,术语“抗体片段”包括保留结合全长抗体识别的表位的能力的抗体的任何部分。抗体片段的实例包括但不限于Fab、Fab’和F(ab’)2、Fd、单链Fv(scFv)、二硫化物连接的Fv(dsFv)和包含VL或VH区的片段。抗体的抗原结合片段可单独或与铰链区的一部分、CH1、CH2、CH3或其组合一起包含可变区。优选地,抗体片段含有整个抗体的所有六个CDR,尽管包含少于全部六个CDR的片段也可以是功能性的。
“单链FV”(“scFv”)是抗原结合片段,其含有单个多肽中与抗体的轻链可变区(VL)连接的抗体的重链可变区(VH),但缺少抗体的部分或全部恒定域。VH和VL之间的连接可以通过选择短的柔性肽来实现,所述肽经选择以确保VL和VH区发生适当的三维折叠,从而维持scFv来源的整个抗体的靶分子结合特异性。scFvs缺少部分或全部抗体恒定域。
对于本公开的TAG-72靶向剂的抗原识别部分,针对TAG-72的抗体是本领域可获得的,并且也可以使用已知技术制备。开发了针对TAG-72的多种第二代鼠单克隆抗体,尤其包括CC49和CC112(Molinolo et al.,Cancer Res 1990;50(4):1291-1298)。此类单克隆抗体及其嵌合或人源化形式可用于提供靶向TAG-72的试剂的抗原识别部分。从小鼠CC49抗体(muCC49)衍生的人源化TAG-72抗体(huCC49)已在美国专利8,835,167B2中进行了描述。
在具体的实施方案中,抗原识别部分包含小鼠单克隆抗体CC49的6个CDR。
在一些实施方案中,抗原识别部分包含6个CDR,其具有与SEQ ID NO:12-17具有至少95%、96%、97%、98%、99%或更高的同一性的氨基酸序列。在具体的实施方案中,抗原识别部分包含具有如SEQ ID NO:12-17所示氨基酸序列的6个CDR。
在一些实施方案中,抗原识别部分包含重链可变区(VH),其包含与SEQ ID NO:2的氨基酸Q1至S115的氨基酸序列具有至少95%、96%、97%、98%、99%或更高的同一性的氨基酸序列。
在一些实施方案中,抗原识别部分包含轻链可变区(VL),其包含与SEQ ID NO:2的氨基酸D131-R244的氨基酸序列具有至少95%、96%、97%、98%、99%或更高的同一性的氨基酸序列。
在一些实施方案中,抗原识别部分包含(i)重链可变区(VH),其包含与SEQ ID NO:2的氨基酸Q1至S115的氨基酸序列具有至少95%、96%、97%、98%、99%或更高的同一性的氨基酸序列;(ii)轻链可变区(VL),其包含与SEQ ID NO:2的氨基酸D131-R244的氨基酸序列具有至少95%、96%、97%、98%、99%或更高的同一性的氨基酸序列;并且其中VH和VL区包含具有如SEQ ID NO:12-17所示的氨基酸序列的6个CDR。
在一个具体的实施方案中,抗原识别部分包含由SEQ ID NO:2的氨基酸Q1至S115组成的重链可变区(VH)和由SEQ ID NO:2的氨基酸D131-R244组成的轻链可变区(VL)。
根据本公开,靶向TAG-72的试剂在试剂与此类癌细胞结合之后实现表达TAG-72的癌细胞的杀伤。取决于TAG-72靶向剂的形式,以各种方式实现杀伤,所述TAG-72靶向剂可包括药物偶联的抗体或抗原结合片段,具有增强的细胞毒性效应子功能的抗体,例如抗体依赖性细胞介导的细胞毒性(ADCC),双特异性抗体,以及表达嵌合抗原受体(CAR)的细胞。
药物缀合的抗体或抗原结合片段
在一些实施方案中,试剂是与细胞毒剂缀合,例如共价附接的抗TAG-72抗体或其抗原结合片段。
用于与抗TAG-72抗体或抗原结合片段缀合的细胞毒剂可以是导致细胞死亡,或诱导细胞死亡或以某种方式降低细胞存活力的任何化合物。在一些实施方案中,细胞毒剂是小分子化合物,特别包括具有抗癌特性的小分子化合物。术语“小分子化合物”包括具有简单且明确定义的化学结构的低分子量化合物(小于1500、1200、1000、800或甚至600道尔顿)。实例包括紫杉烷类(taxoid)、美登木素生物碱(maytansinoid)(例如DM1或DM4)、托马霉素(tomaymycin)衍生物、来普霉素(leptomycin)衍生物、多卡米星(duocarmycin)(例如CC-1065)或其类似物、Aurostatins和吡咯并苯并二氮杂卓(pyrrolobenzodiazepine)二聚体。其他药物如甲氨蝶呤、柔红霉素、多柔比星、长春新碱、长春碱、美法仑、丝裂霉素C、苯丁酸氮芥、加利车霉素、微管溶素(tubulysin)和微管溶素类似物、多拉司他汀(dolastatin)和多拉司他汀类似物也适用于本文制备缀合物的应用。
细胞毒剂可以直接或通过接头共价附接至抗体或其抗原结合片段。合适的接头是本领域公知的,包括二硫基、硫醚基、酸不稳定基团、光不稳定基团、肽酶不稳定基团和酯酶不稳定基团。例如,可以使用二硫化物交换反应或通过在抗体和小分子化合物之间形成硫醚键来构建缀合物。小分子还可以通过中间载体分子例如血清白蛋白与抗体分子连接。
具有改善的ADCC活性的TAG-72特异性抗体
在一些实施方案中,TAG-72靶向剂是抗TAG-72抗体,其具有增强的介导细胞细胞毒效应子功能如抗体依赖性细胞介导的细胞毒性(ADCC)的能力。可以通过在抗体的恒定框架区中进行一个或多个氨基酸取代,从而改变抗体与细胞毒性效应细胞上的Fc受体的相互作用来获得此类抗体。参见例如Lazar et al.(Proc.Natl.Acad.Sci.USA.103(11):4005-4010,2006)。
在其他实施方案中,TAG-72靶向剂是对TAG-72和存在于细胞毒性效应细胞上的受体(例如,存在于NK细胞上的CD16)特异性的双特异性抗体。此类双特异性抗体可将细胞毒性效应细胞带到表达TAG-72的癌细胞附近,从而导致细胞毒性效应细胞更有效地杀死癌细胞。已经描述了针对肿瘤抗原和NK细胞受体的双特异性抗体(参见例如Schmohl et al.,Mol.Ther.24(7):1312-22,2016)。赋予对TAG-72的特异性的双特异性抗体的VH和VL区可以是上文描述的对TAG-72特异性的任何VH或VL区。
表达CAR的细胞
在其他实施方案中,试剂是表达嵌合抗原受体(CAR)的细胞,所述嵌合抗原受体包含对TAG-72特异性的抗原识别部分。
术语“嵌合抗原受体”(也称为“人工T细胞受体”、“嵌合T细胞受体”和“嵌合免疫受体”)是指将抗原结合部分植入免疫效应细胞上的工程化受体。这些受体在本文中用于将单克隆抗体的TAG-72特异性植入T细胞或NK细胞上。一般而言,CAR由对TAG-72特异性的抗原识别部分、跨膜域和免疫效应细胞上天然表达的受体的胞内/胞质信号传导域(也称为内域)组成,它们彼此可操作地连接,使得当免疫效应细胞表达此类CAR时,它们识别并杀死表达TAG-72的靶细胞。“可操作连接”是指个别域彼此连接,使得抗原识别部分与TAG-72结合后,通过胞内信号传导域诱导信号以激活表达CAR的细胞(例如,T细胞或NK细胞)并使得能够激活其效应子功能。
抗原识别部分:CAR的抗原识别部分是受体的胞外部分,其识别并结合靶抗原(即本文的TAG-72)的表位。抗原识别部分通常是scFv,由抗TAG-72单克隆抗体的重链和轻链可变区通过柔性接头相互融合而形成。在一些实施方案中,将CAR工程化改造成在抗原识别部分的N端末端具有信号肽。可以使用任何真核信号肽序列。通常,使用天然附接至氨基末端的信号肽(例如,在具有取向轻链-接头-重链的scFv中,使用轻链的天然信号)。
胞内信号传导域(或“内域”):抗原识别部分可操作连接至胞内信号传导域,其在抗原识别和结合后将信号传递至细胞(T细胞或NK细胞)的胞内部分以使实现其激活和效应子机制诱导。抗原识别部分可以可操作连接至天然TCR的亚基之一,或可操作连接至人工受体,例如嵌合抗原受体(CAR)。可以说T细胞活化是由两类不同的胞质信号传导序列介导的:通过TCR(初级胞质信号传导序列)启动抗原依赖性初级激活的序列和以抗原非依赖性方式起作用以提供刺激或共刺激信号的序列(次级胞质信号传导序列)。初级胞质信号传导序列以刺激性方式或以抑制性方式调节TCR复合物的初级激活。以刺激方式起作用的初级胞质信号转导序列可以含有信号转导基序,所述信号传导基序被称为基于免疫受体酪氨酸的激活基序或ITAM。特别有用的含有ITAM的初级胞质信号传导序列的例子包括那些衍生自TCRzeta、FcR gamma、FcR beta、CD3 gamma、CD3 delta、CD3 epsilon、CD5、CD22、CD79a、CD79b和CD66d的序列。在一些实施方案中,本文公开的CAR的胞内信号传导域包含来自CD3-zeta的胞质信号传导序列。在一些实施方案中,本文公开的CAR的胞内信号传导域包含CD3-zeta的胞内域,或包含含有存在于天然域中的3个ITAM的CD3-zeta的胞内域的部分。尽管通常可以使用天然受体的整个胞内信号传导域,但是在许多情况下,不必使用整个域。就使用天然细胞内信号传导域的截短部分而言,只要其转导效应子功能信号,就可以使用该截短部分代替完整域。在某些情况下,CD3-zeta可以不提供完全有效的激活信号,因此额外的共刺激信号是期望的。在一些实施方案中,CAR的胞内信号传导域可以包含与共刺激信号传导区域组合的CD3 zeta链部分。共刺激信号传导区可以包含共刺激分子的胞内域(或其功能部分)。合适的共刺激分子的例子包括CD27、CD28、4-lBB(CD137)、OX40、CD30、CD40、PD-1、TIM3、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3等。CAR的胞内信号传导域内的胞质信号传导序列(例如,CD3zeta链部分和共刺激信号传导区域)可以以随机或指定顺序彼此连接。任选地,短的寡肽或多肽接头,优选长度在2至10个氨基酸之间的短接头可以形成连接。甘氨酸-丝氨酸二联体提供了特别合适的接头。在一个实施方案中,将胞质域设计为包含CD3-zeta的信号传导域和CD28的信号传导域。
跨膜域:CAR的跨膜域通常是跨膜的典型疏水性alpha螺旋。在一些实施方案中,使用与CAR中的域之一天然缔合的跨膜域,例如,信号传导内域的原始分子,其突出到细胞中并传递期望的信号。在一些情况下,可以通过氨基酸取代来选择或修饰跨膜域,以避免此类域与相同或不同表面膜蛋白的跨膜域结合,以最小化与受体复合物的其他成员的相互作用。跨膜域可以源自天然或合成来源。若来源是天然的,则该域可衍生自任何膜结合蛋白或跨膜蛋白。例如,跨膜区可衍生自T细胞受体的alpha、beta或zeta链、CD28、CD3epsilon、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154,或可衍生自免疫球蛋白如IgG4。或者,跨膜域可以是合成的,在此情况下,其将主要包含疏水性残基,例如亮氨酸和缬氨酸。优选地,在合成的跨膜域的每个末端发现苯丙氨酸、色氨酸和缬氨酸三联体。任选地,短的寡肽或多肽接头,优选长度在2至10个氨基酸之间的短接头,可以形成CAR的跨膜域和胞质信号传导域之间的连接。甘氨酸-丝氨酸二联体提供了特别合适的接头。
间隔物:术语“间隔物”是指将多肽链中将跨膜域连接至胞外域或胞质域的任何寡肽或多肽。间隔物应当是足够柔性的,以允许抗原识别部分沿不同方向取向以促进抗原识别和结合。间隔物的一种简单形式是来自IgG1的铰链区。备选方案包括免疫球蛋白的CH2CH3区和CD3的部分。对于大多数基于scFv的CAR,IgG1铰链就足够。间隔物域可以包含多达300个氨基酸,优选10至100个氨基酸,最优选25至50个氨基酸。在又一个实例中,可以修饰铰链区域以改变其长度,从而实现额外的功能益处。例如,在包含CD8或CD28铰链的传统CAR中,单个半胱氨酸(Cys)可以留在铰链中以稳定T细胞表面的二聚化。因此,通常显示两个scFv(二价)。在另一个实例中,可以将Cys取代(取代为Ser),使得不能形成稳定的二硫键,从而防止二聚化并因此防止过早激活。也可以完全除去Cys。另一种设计是仅在一个CAR上显示VH域,在另一个CAR上显示VL域,因此Cys配对将使VH/VL对齐以形成功能性单价Fv,靶向目标抗原。
在图4A中描绘编码靶向TAG-72的CAR的核酸构建体的实例,并且SEQ ID NO:1-11提供了CAR和适用于CAR的各种域的示例性序列。
表达载体/构建体:用于在受体细胞中表达CAR的构建体或载体可以包含一个或多个包含与编码CAR的核苷酸序列可操作地连接的启动子的DNA区域和任选地编码选择标志物的第二DNA区。启动子可以是诱导型或组成型的。合适的组成型启动子的实例包括例如立即早期巨细胞病毒(CMV)启动子、延伸生长因子-1a(EF-1a)基因启动子、猿病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)启动子、人免疫缺陷病毒(HIV)长末端重复(LTR)启动子、MoMuLV启动子、禽白血病病毒启动子、埃巴病毒立即早期启动子、劳斯肉瘤病毒启动子以及人基因启动子,例如(但不限于)肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。诱导型启动子的实例包括但不限于金属硫氨酸启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
表达构建体可以利用本领域已知且可用的一批载体,如质粒、噬菌体、杆状病毒、哺乳动物病毒、人工染色体等通过任何合适的方法,包括重组或合成技术产生。表达构建体可以是环形或线性的,并且应适合于复制和整合入真核生物中。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。已经开发了许多基于病毒的系统用于基因转移到哺乳动物细胞中。例如,逆转录病毒为基因递送系统提供了便利的平台。可以使用本领域已知的技术将选择的基因插入载体并包装在逆转录病毒颗粒中。然后可以分离重组病毒并递送至受试者干细胞。许多逆转录病毒系统是本领域已知的。
表达CAR的细胞:可以通过物理、化学或生物学方法将编码CAR的表达载体容易地引入宿主细胞(例如T细胞或NK细胞)中。用于将多核苷酸引入宿主细胞中的物理方法包括磷酸钙沉淀、脂转染、颗粒轰击、显微注射、电穿孔等。将病毒载体引入宿主哺乳动物细胞中的生物学方法是广泛使用的。用于将多核苷酸引入宿主细胞中的化学手段包括胶体分散系统,例如大分子复合物、纳米胶囊、微球、珠和基于脂质的系统,包括水包油乳液、胶束、混合胶束和脂质体。用作递送载体的示例性胶体系统是脂质体(例如,人工膜囊泡)。本文中使用的细胞,例如T细胞和NK细胞,可以使用已知方法获自人受试者,正常健康个体或待治疗个体。本文中使用的细胞,例如T细胞和NK细胞,也可以通过干细胞,例如诱导的多能干细胞(iPSC)的分化来产生,所述干细胞通过对从供体个体获得的细胞进行重编程而衍生。可以在临床使用之前评估含有CAR编码表达多核苷酸的所得细胞,例如,在体外评估CAR的表达、表达TAG-72的靶细胞的识别和杀死。
治疗和施用
根据本公开,可以将本文公开的TAG-72靶向剂施用于患有TCL,特别是CTCL,例如SS的患者以治疗癌性病况。
术语“治疗”是指有效抑制(例如减慢或消除)癌症的生长和/或转移。
本文公开的TAG-72靶向剂可以系统性施用(例如,通过胃肠外途径,例如静脉内、腹膜内、皮内、皮下或肌内途径),或通过直接注射到皮肤损伤中。待施用的药剂的剂量取决于药剂的性质、癌症的阶段和其他临床因素(例如受试者的体重和状况、制剂的类型和施用途径)。治疗有效且无害的精确剂量可以由本领域技术人员确定。
在一些实施方案中,治疗针对已鉴定为血液中升高的表达TAG-72的T细胞的水平或比例的TCL患者。“升高的水平”是指患者中表达TAG-72的T细胞的水平显著高于健康个体(即,对照水平)中,例如高至少50%、75%、100%、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍或更高。可以根据血液中TAG-72阳性的T细胞百分比确定水平,所述TAG-72阳性的T细胞可以通过使用T细胞标记物(例如CD3、CD4、CD5、CD7或CD45RO或其组合)的表面抗原染色和TAG-72染色通过例如FACS分析来鉴定。或者,可通过标准技术(例如ELISA)检测CTCL患者血浆或血清中的可溶性TAG-72。
因此,本文还公开了通过测定患者血液中表达TAG-72的T细胞的水平和/或血浆或血清中可溶性TAG-72的存在来对TCL患者进行分类或分亚型的方法。认为那些在血液中表达TAG-72的T细胞水平升高或可溶性TAG-72水平升高的患者响应基于本文公开的TAG-72靶向剂的治疗。
本文公开的TAG-72特异性治疗可以与TCL,特别是CTCL的其他治疗组合。CTCL的当前治疗选择通常取决于皮肤受累的程度、皮肤损伤类型以及癌症是否已经扩散到淋巴结或其他内部器官,并且可以针对皮肤或系统性。现有的针对皮肤的疗法可用于块和有限的斑疾病,包括局部治疗,例如皮质类固醇、类视色素(retinoids)或咪喹莫特(其激活免疫细胞)、氮芥凝胶(Valchlor)、局部化疗、局部放射、甲氨蝶呤、体外光化学疗法(photopheresis)、紫外线(光疗)。氮芥也被批准作为静脉内治疗。
通过以下实施例进一步说明本发明,所述实施例不应以任何方式解释为限制性的。所有引用的参考文献(包括本申请全文中引用的文献参考文献、公告专利和公布的专利申请)的内容在此明确地通过引用并入。
实施例1:通过FACS鉴定SS患者的血液中的TAG-72+T细胞。
通过静脉穿刺获得来自诊断为SS的供体的全血,并收集到柠檬酸右旋糖(ACD)管中。通过Ficoll密度离心分离外周血单个核细胞(PBMC),并立即表征或冷冻保存所得细胞。
简而言之,将分离的患者PBMC与8色抗体混合物在4℃避光温育15分钟(1x107细胞/100uL)。用FACS缓冲液洗涤细胞两次,然后重悬于终体积200uL中。在MACSQuant分析仪(Miltenyi Biotec)上进行流式细胞术分析。使用FlowLogic软件进行数据分析。
使用针对CD3、CD4、CD5、CD7和CD45RO或仅针对CD3的表面抗原染色,结合TAG-72表达的分析,通过FACS分析来分析T细胞(图1A-1M和图2B)。还可以在SS表型的表征中进行其他表面抗原如CD2、CD30、CD158k、CLA和CCR4的分析。
表1中总结了来自图2的结果。
表1.与来自正常个体的T细胞相比,TCL患者中TAG-72+表型T细胞的百分比汇总。
尽管在健康和TCL供体之间TAG-72+T细胞的频率重叠,但是在TCL患者中该频率升高。表2显示了对来自表1数据的分析,使用10%的频率作为健康和TCL供体之间的截留水平。
表2.来自健康供体或TCL患者的PBMC中高于或低于总存活T细胞的10%的TAG-72+T细胞百分比。
<10%TAG-72+ | >10%TAG-72+ | |
健康供体 | 14/15[93.3%] | 1/15[0.7%] |
TCL患者 | 27/49[55.1%] | 22/49[44.9%] |
两组之间的差异是统计学显著的[卡方=7.2911,p=0.00693]。
为了确定是否可以在来自白血病患者的细胞上检测到TAG-72,获得来自T-ALL(n=5)和B-ALL(n=4)患者的全血或骨髓(BM),其中如前所述,使用Ficoll密度离心分离出目的化合物。冷冻保存用于表征的所得细胞。将分离的患者PBMC或BM细胞(2x105细胞/测试)与CD3、CD19和TAG-72荧光缀合抗体的组合在4℃避光温育10分钟。用FACS缓冲液洗涤细胞两次,然后重悬于200uL终体积中。在BD Symphony分析仪(BD Biosciences)上进行流式细胞术分析。使用FlowLogic软件进行数据分析。
如图1N-1V所示,TAG-72水平未超过T-ALL(N-R)或B-ALL(S-V)患者样品中的基线,这表明异常的TAG-72似乎仅与来自TCL的T细胞相关。
实施例2:在多种形式的TCL中证明TAG-72表达。
使用流式细胞术分析来自TCL患者(包括SS、非SS CTCL和PTCL)的PBMC和HD PBMC的CD3和TAG-72表达。如前所述,使用Ficoll密度离心从全血分离PBMC。定量所得的PBMC,并将每个供体的等同数目的细胞(2x105细胞/100μL)与抗CD3和抗TAG-72荧光团缀合的抗体在4℃避光温育15分钟。将细胞用冷PBS洗涤两次,然后重悬至终体积200μL中。在分析之前立即将碘化丙啶添加到样品。使用MACSQuant(Miltenyi Biotec)分析样品。使用FlowLogic软件进行数据分析。
图2显示SS、非SS CTCL和PCTL CD3+T细胞以明显高于HD CD3+T细胞的频率表达TAG-72。
实施例3:在CTCL患者血浆中证明可溶性TAG-72。
从29位CTCL患者(24例SS和5例蕈样肉芽肿病)和14位健康供体获得血浆样品。使用根据制造商的产品说明书(IBL International,CA 72-4ELISA,RE54111)操作的商业ELISA试剂盒,对样品的可溶性TAG-72水平进行测定。包括正常人AB血清作为另外的正常对照。
图3A-3B显示,CTCL患者血浆中的可溶性TAG-72的水平显著大于健康供体血浆中的水平。
实施例4:在来自CTCL患者的皮肤活组织检查中检测携带TAG-72的细胞。
从11位患者获得皮肤活组织检查——5位SS、3位MF、1位间变性T细胞淋巴瘤和2位经初步诊断的MF患者——并立即进行了福尔马林固定。从活组织检查中切下4um切片,然后用苏木精和曙红(H&E)染色,或使用标准免疫组织化学技术针对TAG-72或CD3(T细胞标志物)表达染色。有经验的组织学家(对样品的身份盲的)将载玻片评分为TAG-72或CD3阳性或阴性。
图4A显示了每个切片的样品显微视野(以40倍放大率)。四个患者样品评分为TAG-72阳性(患者1、2、10和11),而11个样品中的所有10个样品评分为CD3阳性(1个样品不可用)。CTCL患者皮肤中T细胞的存在是公知的。TAG-72阳性细胞(与CD3,因此推测TAG-72阳性T细胞共定位)的存在是先前尚未知的。如表2所示,在相对较小的样品数目的限度内,CTCL患者皮肤中TAG-72阳性T细胞的检测频率(36%)与TCL患者中TAG-72阳性T细胞水平升高的频率(45%)充分相关。
图4B总结了在可得的来自匹配供体的浸润T细胞和循环T细胞上的TAG-72表达。TAG-72表达不限于疾病表型的一方面,因为在2/11样品(其中四个样品不可用)中循环和浸润T细胞两者都被识别为TAG-72+。
实施例5:靶向TAG-72的CAR-T细胞的创建。
产生靶向TAG-72的CAR构建体,并且在图5A中以图形描绘。CAR各由对具有图5B描绘的氨基酸序列的TAG-72特异性的单链Fv(scFv)组成。将这些CAR构建体克隆到用于转导T细胞的慢病毒载体中。在随后的实施例中显示的结果利用了TAG-72(1)或TAG-72(3)构建体,其转导至供体衍生的T细胞中,以分别产生TAG-72CAR(1)或TAG-72CAR(3)T细胞。两种构建体具有相同的TAG-72scFv(SEQ ID NO:2),但是在它们的铰链、跨膜和信号传导域序列中不同,如图5A所示。
为了制备慢病毒,将293T细胞铺到经聚L-赖氨酸(Sigma)包被的175cm2烧瓶中。转染前2小时,将培养基替换为补充有10%FCS的DMEM。将慢病毒转移载体DNA以及包装和包膜质粒DNA组合在一起,并与Lipofectamine2000混合。将溶液短暂涡旋振荡并在室温温育30分钟。此后,再次混合溶液,然后滴加到细胞。将烧瓶放回培养箱。6小时后,添加新鲜的生长培养基。48小时后收集病毒上清液,并通过在4℃下以1500rpm离心5分钟进行澄清,然后通过0.45μm孔的PVDF Millex-HV滤器(Millipore)。使用超速离心浓缩慢病毒通过使用AH-629转子的Sorval Discovery 100SE离心机进行。将30mL过滤的病毒上清液添加至36mL的异质同晶聚合物(polyallomer)锥形管(Beckman)。在20,000g下离心90分钟。完全去除上清液,并且将病毒团粒重悬于300μLPBS中,并保存在-80℃直至使用。
T细胞的最佳慢病毒转导涉及它们在TCR和共刺激受体处的激活。因此,在第0天,通过单采血成分术(apheresis)从健康的供体中收集新鲜的PBMC,使用与顺磁珠(Dynabeads ClinExVivo CD3/CD28,Invitrogen,Camarillo,CA,USA)结合的抗CD3和抗CD28抗体以比率3:1(珠:细胞)富集活化的T细胞。将细胞和珠在室温共温育1小时,并使用磁体(Invitrogen)进行CD3+细胞富集。将CD3+级份中的细胞在含有100IU/ml IL-2的T细胞扩增培养基中以1x 106细胞/ml的浓度重悬于启动培养基中。在第1天,使用RetroNectin在PBS中的10mg/mL溶液中以2mg/cm2的浓度于4℃包被细胞培养皿过夜。在第2天,吸出RetroNectin溶液,并将相同体积的封闭溶液(由PBS中的0.5%人血清白蛋白组成)添加到每个皿,并在室温温育30分钟。吸出封闭溶液,并用PBS洗涤每个皿。将慢病毒上清液快速融化,并添加到具有含300IU/ml IL-2的T细胞扩增培养基的每个皿中。将培养物放回培养箱中,并且放置至少24小时。在第4天,停止转导;将细胞以0.5-1x106细胞/mL的浓度重悬于新鲜的T细胞扩增培养基中。将培养物维持到第14天,并每隔一天用新鲜的扩增培养基补料,以将细胞浓度维持于1x 106细胞/mL。
实施例6:使用TAG-72靶向性CAR-T细胞在体外特异性杀死TAG-72+粘附细胞系。
采用实时细胞监测系统(xCELLigence)测定CAR-T细胞的体外杀伤效率。将10,000个靶细胞/100μL(例如卵巢癌细胞系Ovcar3)重悬于补充有10%-20%胎牛血清的培养基(例如RPMI-1640培养基)中,并沉积到RTCA板中。将靶细胞在37℃,5%CO2下维持3-20小时,以使细胞附着。靶细胞附着后,以范围为1:5-5:1的可变的效应子与靶标比率添加来自实施例3的TAG-72-特异性CAR-T效应细胞。在一些情况下,在使用前,通过FACS基于GFP或FLAG表达分离效应细胞。在最佳生长条件下维持共培养至少12小时。始终监测细胞阻抗;阻抗降低指示细胞脱离,最终指示细胞死亡。
TAG-72CAR(1)和TAG-72CAR(3)T细胞介导对TAG-72hi表达性靶癌细胞(Ovcar 3)而非TAG-72-ve/低癌靶细胞(MESov)的有力细胞杀伤(图6A-6D)。
实施例7:使用TAG-72靶向性CAR-T细胞在体外特异性杀死TAG-72+非粘附Jurkat细胞。
使用流式细胞术证实T细胞白血病细胞系Jurkat为表达TAG-72的细胞系。Jurkat细胞是非粘附性的,因此代表了测试来自SS患者的细胞的良好模型。以效应子与靶标比率5:1将Jurkat细胞与TAG-72CAR-T(1)、TAG-72CAR(3)或来自同一供体的未转导(NT)的PBMC共培养。在一些情况下,在使用前,通过FACS基于GFP或FLAG表达分离效应细胞。将培养物在37℃,5%CO2下维持48小时。此时,再次通过流式细胞术分析共培养物的TAG-72表达。另外,在共培养物中进行膜联蛋白和PI染色以区分死亡与早期凋亡细胞。鉴于CAR-T细胞不表达TAG-72,可以在FACS分析中区分靶细胞和效应细胞的死亡。
图7A-7E显示Jurkat细胞表达TAG-72,并且可以在体外悬浮培养中被靶向TAG-72的CAR-T细胞杀死。
实施例8:使用TAG-72靶向性CAR-T细胞在体外杀死患有塞扎里病的患者的T细胞。
SS患者的PBMC在从全血中分离后立即使用或在使用当天从冷冻原种中融化。将TAG-72CAR-T(1)效应细胞以5:1的效应子与靶标比率在多孔板中添加至患者PBMC。在某些情况下,在使用前通过FACS基于GFP或FLAG表达分离效应细胞。将细胞悬浮液在补充有人血清的T细胞扩增培养基中于37℃,5%CO2维持48小时,此时进行表型分析。TAG-72的染色在4℃避光进行15分钟(1x107个细胞/100uL)。用FACS缓冲液洗涤细胞两次,然后重悬于终体积200uL中。流式细胞术分析在MACSQuant(Miltenyi Biotec)上进行。使用FlowLogic软件进行数据分析。维持健康供体PBMC并进行平行分析。
图8A-8E显示,在体外暴露于TAG-72CAR(1)T细胞48小时后,SS患者PBMC的淋巴细胞群体中TAG-72+细胞的百分比显著降低。
实施例9:使用TAG-72CAR(3)T细胞在体外杀死来自CTCL患者的T细胞
SS患者的PBMC在从全血中分离后立即使用或在使用当天从冷冻原种融化。将TAG-72(3)CAR-T效应细胞(含有4-1ββ胞内信号传导域,无GFP报告物的CAR-T细胞)在多孔板中以效应子与靶标比率5:1添加到患者PBMC。将细胞悬浮液在补充有人血清的T细胞培养基中于37℃,5%CO2维持24小时,此时进行表型分析。TAG-72和CD3的染色在4℃避光进行15分钟(2x105个细胞/测试)。将细胞洗涤两次,然后重悬至终体积200uL。使用MACSQuant(Miltenyi Biotec)进行流式细胞术分析。使用FlowLogic进行数据分析。维持健康的供体PBMC并进行平行分析。使用从三个独立的健康供体获得的T细胞生成的CAR-T细胞,证明CAR-T细胞的杀伤能力不是供体依赖性的。
图9A-9H证明在体外暴露于TAG-72(3)T细胞24小时后,TAG-72+T细胞的频率降低。
实施例10:使用抗TAG-72抗体-药物缀合物杀死TAG-72+细胞。
使用Ficoll密度离心从全血中分离SS患者和正常对照供体PBMC。所得细胞立即使用或在使用当天从冷冻原种融化。在37℃,5%CO2将细胞悬浮液维持于补充有5%人AB血清和20U IL-2的T细胞扩增培养基中。将细胞暴露于抗TAG-72抗体-药物缀合物CC49-DM1达48小时,此时进行表型分析,以相对于未处理的对照测定保留于SS亚群(CD3+/CD4+/CD7neg/CD45RO+)以及正常PBMC内的TAG-72+细胞的水平。平行分析了表达TAG-72的T细胞白血病细胞系Jurkat,其中监测总存活TAG-72+细胞的变化。
图10A-10E显示,TAG-72抗体-药物缀合物能够显著降低来自SS患者的PBMC中和培养的Jurkat细胞中TAG-72+细胞的百分比。没有看到对来自健康供体的PBMC的影响。
序列表
<110> 卡瑟里克斯私人有限公司
<120> 靶向TAG-72的T细胞疾病治疗
<130> 35478PCT
<150> 62/634366
<151> 2018-02-23
<160> 17
<170> PatentIn version 3.5
<210> 1
<211> 732
<212> DNA
<213> 人工序列
<220>
<223> 编码TAG-72 scFV的DNA
<400> 1
caggtgcagc tgcagcagag cgacgccgag ctggtgaagc ccggcgccag cgtgaagatc 60
agctgcaagg ccagcggcta caccttcacc gaccacgcca tccactgggt gaagcagaac 120
cccgagcagg gcctggagtg gatcggctac ttcagccccg gcaacgacga cttcaagtac 180
aacgagcgct tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240
ctgcagctga acagcctgac cagcgaggac agcgccgtgt acttctgcac ccgcagcctg 300
aacatggcct actggggcca gggcaccagc gtgaccgtga gcagcggcgg cggcggcagc 360
ggcggcggcg gcagcggcgg cggcggcagc gacatcgtga tgacccagag ccccagcagc 420
ctgcccgtga gcgtgggcga gaaggtgacc ctgagctgca agagcagcca gagcctgctg 480
tacagcggca accagaagaa ctacctggcc tggtaccagc agaagcccgg ccagagcccc 540
aagctcctga tctactgggc cagcacccgc gagagcggcg tgcccgaccg cttcaccggc 600
agcggcagcg gcaccgactt caccctgagc atcagcagcg tggagaccga ggacctggcc 660
gtgtactact gccagcagta ctacagctac cccctgacct tcggcgccgg caccaagctg 720
gtgctgaagc gc 732
<210> 2
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 scFV的蛋白序列
<400> 2
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Ala Ile His Trp Val Lys Gln Asn Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Phe Ser Pro Gly Asn Asp Asp Phe Lys Tyr Asn Glu Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Leu Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Thr Arg Ser Leu Asn Met Ala Tyr Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Pro Val Ser
130 135 140
Val Gly Glu Lys Val Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu
145 150 155 160
Tyr Ser Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser
180 185 190
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Ser Ile Ser Ser Val Glu Thr Glu Asp Leu Ala Val Tyr Tyr Cys
210 215 220
Gln Gln Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
225 230 235 240
Val Leu Lys Arg
<210> 3
<211> 60
<212> PRT
<213> 人工序列
<220>
<223> CD8铰链蛋白序列
<400> 3
Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu
1 5 10 15
Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
20 25 30
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
35 40 45
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
50 55 60
<210> 4
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> CD8 TM蛋白序列
<400> 4
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 5
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> CD28铰链蛋白序列
<400> 5
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 6
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> 具有C至S取代的CD28铰链蛋白序列
<400> 6
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Ser Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 7
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> CD28 TM蛋白序列
<400> 7
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 8
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> 具有C至S取代的CD28 TM
<400> 8
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Ser Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 9
<211> 41
<212> PRT
<213> 人工序列
<220>
<223> CD28信号传导域蛋白序列
<400> 9
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 10
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 4-1BB信号传导域蛋白序列
<400> 10
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 11
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> TCR zeta信号传导域蛋白序列
<400> 11
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 12
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 VH CDR1
<400> 12
Asp His Ala Ile His
1 5
<210> 13
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 VH CDR2
<400> 13
Tyr Phe Ser Pro Gly Asn Asp Asp Phe Lys Tyr Asn Glu Arg Phe Lys
1 5 10 15
Gly
<210> 14
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 VH CDR3
<400> 14
Ser Leu Asn Met Ala Tyr
1 5
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 VL CDR1
<400> 15
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 16
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 VL CDR2
<400> 16
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 17
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> TAG-72 VL CDR3
<400> 17
Gln Gln Tyr Tyr Ser Tyr Pro Leu Thr
1 5
Claims (22)
1.治疗T细胞相关疾病的方法,其中所述疾病涉及表达TAG-72的T细胞,包括对所述患者施用靶向TAG-72的试剂。
2.权利要求1的方法,其中所述T细胞相关疾病是T细胞淋巴瘤(TCL)。
3.权利要求1或2的方法,其中所述试剂包含表达对TAG-72特异性的CAR的细胞。
4.权利要求3的方法,其中所述细胞是T细胞,例如γδTCR T细胞、αβTCR T细胞、NKT细胞或MAIT(粘膜相关不变T)细胞。
5.权利要求3的方法,其中所述细胞是NK细胞。
6.权利要求3的方法,其中所述CAR包含scFv,所述scFv包含:
(i)以SEQ ID NO:12-17所示的6个CDR;
(ii)VH,其包含SEQ ID NO:2的Q1至S115或与SEQ ID NO:2的Q1至S115具有至少90%同一性的氨基酸序列;和VL,其包含SEQ ID NO:2的D131至R244或与SEQ ID NO:2的D131至R244具有至少90%同一性的氨基酸序列;或
(iii)SEQ ID NO:2的氨基酸序列。
7.权利要求6的方法,其中所述CAR包含CD3-zeta的胞内信号传导域。
8.权利要求7的方法,其中所述CAR还包含CD28、4-1BB或CD2的胞内共刺激域。
9.权利要求1或2的方法,其中所述试剂包括对TAG-72特异性的抗体或其抗原结合片段。
10.权利要求9的方法,其中所述抗体或抗原结合片段与细胞毒剂缀合。
11.权利要求10的方法,其中所述细胞毒剂是小分子化合物。
12.权利要求9的方法,其中所述抗体与增强的ADCC活性相关。
13.权利要求12的方法,其中所述抗体是双特异性抗体。
14.权利要求13的方法,其中所述双特异性抗体与T细胞、NK细胞、NKT细胞、MAIT细胞或巨噬细胞上的受体结合。
15.权利要求2的方法,其中所述TCL是T成淋巴细胞性淋巴瘤/白血病、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤/T细胞淋巴瘤(鼻型)、与肠病相关的肠道T细胞淋巴瘤(EATL)、塞扎里综合征、间变性大细胞淋巴瘤、红皮病性蕈样肉芽肿病或滤泡性营养性蕈样肉芽肿病。
16.权利要求1或2的方法,其中在所述治疗之前已经将所述患者鉴定为具有升高的表达TAG-72的T细胞的水平。
17.TAG-72靶向剂,用于治疗TCL。
18.诊断或表征患有T细胞相关疾病的患者的方法,其包括检测所述患者血液中表达TAG-72的T细胞的水平或可溶性TAG-72的水平,并与对照水平进行比较。
19.诊断或表征TCL患者的方法,其包括检测所述患者血液中表达TAG-72的T细胞的水平或可溶性TAG-72的水平,并与对照水平进行比较。
20.权利要求18或19的方法,其中通过从患者血液中分离T细胞并评估分离的T细胞的TAG-72表达来测定表达TAG-72的T细胞的水平。
21.权利要求20的方法,其中通过使用针对TAG-72的抗体评估所述TAG-72表达。
22.权利要求21的方法,其中基于CD3的表达从所述患者的血液分离所述T细胞。
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