CN111072780A - 白血病干细胞抑制剂及其在治疗慢性粒细胞白血病中的应用 - Google Patents
白血病干细胞抑制剂及其在治疗慢性粒细胞白血病中的应用 Download PDFInfo
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Abstract
本发明涉及白血病干细胞抑制剂及其在治疗慢性粒细胞白血病中的应用，所述白血病干细胞抑制剂为PAI‑1抗体，其能够以较高的亲和力结合PAI‑1蛋白，能够改善CML小鼠脾脏病变，能够延长CML小鼠生存期，能够用于预防或治疗慢性粒细胞白血病，有着广阔的应用前景。
Description
技术领域
本发明涉及生物医药领域，具体的涉及白血病干细胞抑制剂及其在治疗慢性粒细胞白血病中的应用。
背景技术
慢性粒细胞白血病（chronic myeloid leukemia，CML）是一种起源于造血干细胞（hematopoietic stem cell，HSC）的骨髓增殖克隆性疾病，正常的造血干细胞在各种内外因素的作用下，发生第 9 号染色体和 22 号染色体的易位，形成费城染色体（Philadelphia chromosome，Ph）,进而编码产生 BCR-ABL1 融合致癌蛋白，最终导致白血病干细胞（leukemia stem cell，LSC）的形成[1]。由于 BCR-ABL1 致癌蛋白具有持续激活的酪氨酸激酶活性，可诱导白血病细胞增殖失控、凋亡抑制，引起慢性粒细胞白血病的发生发展[2]。在不治疗的前提下，CML 会由慢性期逐渐进展到加速期，最后进入难治的急变期。
尽管已经有一些酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKIs）能够显著的改善CML的预后，例如imatinib。但停药后的临床试验结果显示在至少达到两年完全分子学缓解（complete molecular remission，CMR）患者中，停药后 12 个月的分子学复发达到 59%，而 65 个月的累积复发率上升到 61%[3]。后期陆续开展的各项 TKIs 停药试验，例如 TWISTER、HOVON等，都报道类似的复发率[4, 5]。由于CML易复发，导致病人在康复后仍然不能停止服用酪氨酸激酶抑制剂药物。经过研究发现，达到 CMR 后停药复发可能表明患者体内的白血病干细胞的持续存在，并没有被 TKIs 彻底清除掉。并且，白血病干细胞检测相关研究也显示，在持续深度分子学缓解的慢粒患者中仍能检测到白血病干细胞[6,7]。
白血病干细胞拥有独特的抵抗细胞毒性剂的能力，它拥有与正常造血干/族细胞一样的性能，包括自我更新、细胞周期静止以及抗传统化疗等[8, 9]。各项研究证明TKIs只能杀死处于分裂增殖状态的白血病细胞，并不能清除处于静止休眠期的慢粒白血病干细胞[7, 10-12]，这也是导致CML复发的关键原因。因此，清除白血病干细胞成为完全治愈慢性粒细胞白血病的关键点，也是当前慢性粒细胞白血病研究的热点[13]。现研究表明抑制纤溶酶原激活物抑制剂 1 (Plasminogen activator inhoibitor-1, PAI-1) 的活性能够促进白血病干细胞清除[14]。PAI-1是纤溶系统的一个重要的丝氨酸蛋白酶抑制蛋白，在造血干细胞中，PAI-1能够抑制原蛋白转化酶以及弗林蛋白酶的蛋白水解活性。原蛋白转化酶以及弗林蛋白酶能够促进I型膜金属蛋白酶的活性（membrane type-1 metalloprotease ，MT1-MMP）[15]，而MT1-MMP则通过破坏细胞周围基质蛋白以及粘附分子，致使造血干细胞脱离干细胞龛，增强造血干细胞运动性[16, 17]。抑制TGF-β-iPAI-1信号通路能够增加MT1-MMP依赖的细胞运动性，致使造血干细胞脱离干细胞龛，接受外来刺激[15, 18]。 因此阻断PAI-1活性，致使骨髓中的CML-LSCs脱离干细胞龛，使得CML-LSCs 对TKI敏感，达到清除CML-LSCs 以及完全治愈慢性粒细胞白血病的效果。
到目前为止，有许多PAI-1抗体在W02011139973、 W02015125904、WO2015023752、W02009033095、CN106029884、CN105705520等专利中提及，但一方面它们对PAI-1的结合能力还并不十分理想，另一方面，它们也并没有用来治疗慢性粒细胞白血病。
发明内容
为了克服现有技术的上述缺陷，本发明的目的在于提供一种新的且具有更高PAI-1结合能力的抗PAI-1抗体，为治愈慢性粒细胞白血病提供一种新可能性。
本发明提供以下技术方案：
一种PAI-1抗体，由重链和轻链组成，重链和轻链分别包括可变区和恒定区，其中重链可变区包含3个互补决定区，分别命名为VH-CDR1，VH-CDR2,VH-CDR3；同样地，轻链可变区也包含3个互补决定区，分别命名为VL-CDR1,VL-VDR2,VL-CDR3。所述PAI-1抗体的重链包含如SEQ ID NO:1所示的VH-CDR1氨基酸序列，和如SEQ ID NO:2所示的VH-CDR2氨基酸序列，和如SEQ ID NO:3所示的VH-CDR3氨基酸序列；所述PAI-1抗体的轻链包含如SEQ ID NO:4所示的VL-CDR1氨基酸序列，和如SEQ ID NO:5所示的VL-CDR2氨基酸序列，和如SEQ ID NO:6所示的VL-CDR3氨基酸序列。
本发明所述PAI-1抗体包含SEQ ID NO :7 所示的重链可变区和SEQ ID NO :8 所示的轻链可变区。
本发明所述PAI-1抗体的重链可变区和轻链可变区均包含框架区，所述抗体轻链可变区进一步包含人源κ、λ链或其变体的轻链框架区。所述抗体重链可变区进一步包含人源IgG1、IgG2a、IgG2b或IgG3或IgG4或其变体的重链框架区。
本发明所述PAI-1抗体包含恒定区,并且所述恒定区是人源化的，包含选自IgG1、IgG2、IgG3或IgG4的重链恒定区和包含选自kappa 或Lambda 亚型的轻链恒定区。
在一些实施方案中, 所述PAI-1抗体以5.7±1.2ng/ml的EC50值与PAI-1相结合。
在一些实施方案中，所述PAI-1抗体能够改善CML小鼠脾脏病变情况。
在一些实施方案中，所述PAI-1抗体能够延长CML小鼠生存期。
本发明提供一种治疗慢性粒细胞白血病的方法，其特征在于：将使用TKI抑制剂的与本发明所述的抗PAI-1抗体联合应用。
本发明所述的PAI-1抗体可应用于制备治疗慢性粒细胞白血病的药物中，优选为与TKI抑制剂联合应用。
本发明所使用的术语“ 抗体”指免疫球蛋白分子和免疫球蛋白分子的免疫活性部分，即含有特异性结合抗原的抗原结合位点的分子，涵盖全长抗体(例如，IgG1或IgG4抗体)、其各种功能性片段(例如可仅包含抗原结合部分，如Fab、Fab′、F(ab′)2)。抗体的实例包括但不限于多克隆抗体、单克隆抗体、嵌合抗体、人源化抗体、Fab、Fab′、F(ab′)2片段等。
术语“ 单克隆抗体”，指由单一的克隆细胞株得到的抗体，所述的细胞株不限于真核的，原核的或噬菌体的克隆细胞株。单克隆抗体或抗原结合片段可以用如杂交瘤技术、重组技术、噬菌体展示技术，合成技术(如CDR-grafting)，或其它现有技术进行重组得到。Fab片段”由一条轻链和一条重链的CH1及可变区组成。Fab分子的重链不能与另一个重链分子形成二硫键。“ Fab′片段”含有一条轻链和一条重链的VH结构域和CH1结构域以及CH1和CH2结构域之间的恒定区部分，由此可在两个Fab ′片段的两条重链之间形成链间二硫键以形成F(ab′)2分子。“ F(ab′)2片段”含有两条轻链和两条重链的VH结构域和CH1结构域以及CH1和CH2结构域之间的恒定区部分，由此在两条重链间形成链间二硫键。因此，F(ab′)2片段由通过两条重链间的二硫键保持在一起的两个Fab′片段组成。
本文所用术语“ 超变区”或“ CDR区”或“ 互补决定区”，是指负责抗原结合的抗体氨基酸残基。CDR区序列可以由Kabat、Chothia方法来定义或本领域熟知的任何CDR区序列确定方法而鉴定的可变区内的氨基酸残基。本发明所用的方法可利用或根据这些方法中的任一种所定义的CDR，包括但不限于Kabat定义、Chothia定义中的任一者来定义。具体地，本发明提供的CDR序列根据Kabat 定义。
术语 “人源化抗体”是指抗体具有的人源框架、铰链区和恒定区与来自人基因组序列的框架和恒定区相同或基本上相同（基本上人源）。全人框架、铰链区和恒定区为那些人种系序列和具有自然发生的体细胞突变的序列。人源改造抗体可包含来自全人框架、铰链或恒定区的框架、铰链或恒定区，并在其中包含一个或多个氨基酸取代、缺失或添加。通常，人源改造抗体优选的在入中基本上没有免疫原性。在本发明的一优选实施方案中，所述的PAI-1人源化抗体的抗体轻链可变区进一步包含人源κ、λ链或其变体的轻链FR区。所述PAI-1人源化抗体的抗体重链可变区进一步包含人源IgG1、IgG2a、IgG2b或IgG3或IgG4或其变体的重链FR区。人源化抗体的恒定区可选自人源IgG1、IgG2、IgG3或IgG4或其变体的重链恒定区，优选包含人源的IgG1重链恒定区。所述人源化抗体抗体还包含选自kappa 或Lambda 亚型的轻链恒定区。
有益效果
本发明的PAI-1抗体具有下列性质：1)能够以较高的亲和力结合PAI-1蛋白；2)能够改善CML小鼠脾脏病变；3)能够延长CML小鼠生存期；4）能够抑制白血病干细胞；5)能够用于预防或治疗慢性粒细胞白血病。
附图说明
附图用来提供对本发明的进一步理解，并且构成说明书的一部分，与本发明的实施例一起用于解释本发明，并不构成对本发明的限制。
图1 h7C5抗体+imatinib及对照组处理后的CML小鼠脾脏重量。
图2 h7C5抗体+imatinib及对照组处理后的CML小鼠生存期变化。
具体实施方式
以下结合附图对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1.抗PAI-1抗体制备
将10μg重组活性型人PAI-1(购自Innovation公司)与引起免疫反应的弗氏完全佐剂一起注射到雌性Balb/c小鼠腹膜内，进行初次免疫，随后每2周再以相同量的抗原注射到上述雌性Balb/c小鼠腹膜内，继续免疫。最后在与骨髓瘤细胞融合前3天进行末次免疫，末次免疫以10μg重组活性型人PAI-1与免疫佐剂腹腔内免疫。取免疫后的Balb/c小鼠脾细胞，将其与骨髓瘤Sp2/0细胞株融合，将融合后的细胞用含有10%血清的Iscove培养基（0.1mM次黄嘌呤，0.4μM氨基蝶呤和16μM胸苷）稀释，稀释至适宜浓度后，加入96孔板内进行培养。10天后，取细胞上清，高通量ELISA法检测上清中与PAI-1 表现出阳性反应的原代培养物。再将此孔内的杂交瘤细胞进行稀释进行亚克隆，同样以ELISA方法进行筛选，最终获得阳性杂交瘤细胞株7C5。
实施例2.基因克隆和抗PAI-1抗体人源化改造
将培养的杂交瘤细胞株7C5用TRNzol-A+裂解后，置入离心管，每ml TRNzol-A+加入200μl氯仿，漩涡振荡15秒，放置3分钟。13000 rpm 4°C离心10分钟，Trizol-A+ 细胞溶液分为三层：上层无色水相、中层和下层黄色有机相，将溶有RNA的水相转移至离心管中，向水相中加入等体积异丙醇，混匀，室温静置25分钟。13000 rpm 4°C离心10分钟，弃去废液得到沉于底部的RNA沉淀。用75%乙醇洗涤RNA沉淀两次后，用PEDC水溶解RNA，-80℃保存。利用反转录试剂盒(购自北京全式金生物技术有限公司)制备编码抗体基因的cDNA；以cDNA为模板，利用PCR扩增出含有抗体重链可变区和轻链可变区的DNA产物，利用琼脂糖凝胶电泳分离并回收纯化含有抗体重链可变区和轻链可变区的目的片断。将其克隆到pGEM-T载体中，筛选阳性克隆测序，根据测序结果进一步获得可变区基因对应的氨基酸序列。
根据杂交瘤细胞株7C5分泌的抗体的可变区序列，采用CDR移植抗体人源化改造方法进行人源化改造，所述CDR区序列采用kabat方法定义。首先，用NCBI中提供的＂Blast forIg sequences"在线序列比对法，将杂交瘤细胞株7C5的VH区和VK 区与NCBI数据库中已有人源抗体序列进行比对，选出人胚胎系框架序列；之后利用SwissModel搭建鼠源抗体可变区三维结构，通过计算静电力，范德华力，亲疏水性和熵值，确定维持结合亲和力及维护空间构架的关键氨基酸，将其嫁接回已经选择的人胚胎系抗体框架。将获得的人源化改造后的抗体可变区基因克隆进含有人IgG恒定区基因的真核表达载体pCMV-163中，构建全抗体表达载体。真核表达载体pCMV-163的各个组成成分均为本领域已知的成分，按照所示次序重组而成。
最终，将人源化改造后的抗体命名为h7C5，测序结果显示，抗体h7C5的VH-CDR1-3的氨基酸序列分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示；抗体VH的氨基酸序列如SEQ ID NO:7所示；h7C5的VL-CDR1-3的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示；抗体VL的氨基酸序列如SEQ ID NO：8所示。
实施例3. 抗PAI-1抗体与PAI-1结合能力测定
将实施例2中获得的抗体质粒转染CHO-K1细胞筛选高表达克隆，并用无血清培养基扩大培养，用Protein A 亲和柱分离纯化人源化抗体h7C5。将纯化抗体用PBS进行透析，获得纯度较高的PAI-1人源化抗体h7C5。将通过WO2011/139973A2专利获得抗PAI-1抗体MEDI-579，即PICK147_A01(CAT-1001)（其轻重链序列参见该专利说明书第212-214页）的序列且通过上述中的方法获得抗体MEDI-579，作为对照抗体。通过ELISA 实验评估上述获得的人源化抗PAI-1抗体h7C5、对照抗体-MEDI-579与PAI-1蛋白在50%有效浓度时(EC50)的结合亲和力。将重组人PAI-1蛋白用PBS稀释1000ng/mL，以每孔100μL添加到96板中，4℃过夜包被。通过反向离心除去固相液，以每1孔200μL添加封闭剂，在室温下静置30分钟。将上述PAI-1固相化板用TBS洗涤后，以每孔100μl添加PAI-1抗体。将PAI-1抗体h7C5以及对照抗体MEDI-579用培养基稀释成1000ng/ml，250ng/ml，62.5ng/ml，15.63ng/ml，3.91ng/ml，0.98ng/ml的浓度梯度，4℃孵育2h，吸出培养基，加入戊二醛室温孵育10min，用PBS洗涤3次后加入100ul抗人IgG抗体，室温孵育2h。用PBS洗涤3次后加入50μl显色液，室温避光孵育15min，加入终止液终止显色反应，用酶标仪检测样品在450nm波长处的吸光度值，并用620nm波长处的吸光度值校正。处理数据，最终确定各样品EC50值，结果如表一所示。结果表明，人源化的抗PAI-1抗体h7C5与对照抗体MEDI-579相比，展现出更强的结合能力。
表一 抗PAI-1抗体与PAI-1结合能力测定
| 名称 | EC50（ng/ml） |
| h7C5 | 5.7±1.2 |
| 对照抗体-MEDI-579 | 12.3±3.5 |
实施例4. 抗PAI-1抗体对CML小鼠脾脏的影响
取5周大小的雄性BALB／c小鼠，尾静脉注射5-氟尿嘧啶(150mg/kg)。5天后取5-氟尿嘧啶处理过的供体小鼠股骨和胫骨，取出骨髓细胞，用BCR/ABL1-ires GFP逆转录病毒感染，培养24h后，再次用BCR/ABL1-ires GFP逆转录病毒二次感染， 继续培养24h。收集经逆转录病毒感染的骨髓细胞，1XPBS洗涤3遍，1XPBS重悬细胞，调至密度为2×106/ml，将上述小鼠骨髓细胞植入经致死剂量x射线照射的受体小鼠体内，每个小鼠尾静脉注射200μl (4×105个细胞)。移植7天后，若小鼠外周血中出现成熟粒细胞异常增殖，表明小鼠造模成功。取造模成功小鼠，随机分组，每组6只。取造模成功小鼠，对小鼠进行药物处理。共分为4组，A组小鼠仅注射IgG（不具有结合PAI-1的能力）,B组小鼠注射TKI抑制剂imatinib处理和IgG，实验组小鼠注射TKI抑制剂imatinib和抗PAI-1抗体h7C5，对照组小鼠注射TKI抑制剂imatinib和抗PAI-1抗体MEDI-579。各组小鼠连续注射7天药物，其中imatinib剂量为400 mg/kg，抗PAI-1抗体及IgG抗体剂量为1mg/kg。10天后，取小鼠脾脏称重。结果如图1所示:仅注射imatinib的小鼠、注射imatinib和抗PAI-1抗体h7C5组的小鼠、注射imatinib和抗PAI-1抗体MEDI-579组的小鼠与注射IgG的小鼠相比，脾脏重量不同程度的减轻；注射imatinib和抗PAI-1抗体h7C5组的小鼠与仅注射imatinib的小鼠相比，脾脏重量明显减轻，且效果明显优于注射imatinib和抗PAI-1抗体MEDI-579组的小鼠。脾脏重量反映出CML疾病病情，脾脏重量越大，证明小鼠病情越严重。脾脏重量结果表明将imatinib与抗PAI-1抗体h7C5联用能够有效治疗慢性粒细胞白血病，且明显优于单独使用imatinib及imatinib与对照抗体联用的效果。
实施例5. 抗PAI-1抗体对CML小鼠存活率的影响
取5周大小的雄性BALB／c小鼠，尾静脉注射5-氟尿嘧啶(150mg/kg)。5天后取5-氟尿嘧啶处理过的供体小鼠股骨和胫骨，取出骨髓细胞，用BCR/ABL1-ires GFP逆转录病毒感染，培养24h后，再次用BCR/ABL1-ires GFP逆转录病毒二次感染， 继续培养24h。收集经逆转录病毒感染的骨髓细胞，1XPBS洗涤3遍，1XPBS重悬细胞，调至密度为2×106/ml，将上述小鼠骨髓细胞植入经致死剂量x射线照射的受体小鼠体内，每个小鼠尾静脉注射200μl (4×105个细胞)。移植7天后，若小鼠外周血中出现成熟粒细胞异常增殖，表明小鼠造模成功。取造模成功小鼠，随机分组，每组8只。取造模成功小鼠，对小鼠进行药物处理。共分为4组，A组小鼠仅注射IgG（不具有结合PAI-1的能力）,B组小鼠注射TKI抑制剂imatinib处理和IgG，实验组小鼠注射TKI抑制剂imatinib和抗PAI-1抗体h7C5，对照组小鼠注射TKI抑制剂imatinib和抗PAI-1抗体MEDI-579。其中imatinib剂量为400 mg/kg，抗PAI-1抗体及IgG剂量为1mg/kg，连续注射7天，随后观察小鼠死亡率。结果如图2所示: 仅注射imatinib的小鼠、注射imatinib和抗PAI-1抗体h7C5组的小鼠、注射imatinib和抗PAI-1抗体MEDI-579组的小鼠与注射IgG的小鼠相比，生存期不同程度的延长；其中注射imatinib和抗PAI-1抗体h7C5组的小鼠的生存期延长时间最高，明显高于仅注射imatinib及注射imatinib和抗PAI-1抗体MEDI-579组的小鼠的生存率。结果表明将imatinib与抗PAI-1抗体h7C5联用能够有效治疗慢性粒细胞白血病，延长CML生存期，且明显优于单独使用imatinib及imatinib与对照抗体联用的效果。
参考文献
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序列表
<110> 北京岳昊科技发展有限公司
<120> 白血病干细胞抑制剂及其在治疗慢性粒细胞白血病中的应用
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Claims (9)
1.一种抗PAI-1抗体，由重链和轻链组成，重链和轻链分别包括可变区和恒定区，其中重链可变区中VH-CDR1的序列如SEQ ID NO:1所示，VH-CDR2的序列如SEQ ID NO:2所示，VH-CDR3的序列如SEQ ID NO:3所示；轻链可变区中VL-CDR1的序列如SEQ ID NO:4所示，VL-CDR2的序列如SEQ ID NO:5所示，VL-CDR3的序列如SEQ ID NO:6所示。
2.根据权利要求1 所述的抗PAI-1抗体，其特征在于：所述重链可变区序列为SEQ IDNo :7的氨基酸序列；所述轻链可变区序列为SEQ ID No :8的氨基酸序列。
3.根据权利要求1-2任一项所述的抗PAI-1抗体，其特征在于：所述抗体为全长抗体或嵌合抗体、人源化抗体、Fab、Fab′或F(ab′)2片段。
4.根据权利要求1 -2任一项所述的抗PAI-1抗体，其特征在于：所述抗体还包含选自IgG1、IgG2、IgG3或IgG4的重链恒定区和包含选自kappa 或Lambda 亚型的轻链恒定区，所述抗体重链恒定区进一步优选为IgG1。
5.权利要求1-4任一项的抗PAI-1抗体在制备用于抑制白血病干细胞的药物中的用途。
6.权利要求1-4任一项的抗PAI-1抗体在制备用于治疗慢性粒细胞白血病的药物中的用途。
7.权利要求1-4任一项的抗PAI-1抗体在制备用于检测PAI-1蛋白的制剂中的用途。
8.一种用于治疗慢性粒细胞白血病的药物组合物，其特征在于：包含权利要求1-4任一项所述的抗体以及一种TKI抑制剂。
9.如权利要求8所述的药物组合物，其特征在于：所述TKI抑制剂为imatinib。
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