CN111635459A - 抗cd47抗体及其在治疗癌症中的应用 - Google Patents
抗cd47抗体及其在治疗癌症中的应用 Download PDFInfo
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- CN111635459A CN111635459A CN202010593390.3A CN202010593390A CN111635459A CN 111635459 A CN111635459 A CN 111635459A CN 202010593390 A CN202010593390 A CN 202010593390A CN 111635459 A CN111635459 A CN 111635459A
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Abstract
本发明涉及一种特异性结合CD47的抗体，所述抗体能够以较高的亲和力结合CD47蛋白，阻断SIRPα与肿瘤细胞表面的CD47结合，促进巨噬细胞对肿瘤细胞的吞噬作用，发挥抗肿瘤作用，用于预防或治疗癌症，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，具体的涉及抗CD47抗体及其在治疗多种血液系统恶性肿瘤和实体瘤中的应用。
背景技术
CD47是一个分子量为50kD、广泛表达的膜表面受体，属于免疫球蛋白超家族成员。CD47具有一个V-型Ig-样胞外结构域和五次跨膜区以及短的胞内尾部；CD47可以结合多种蛋白，包括整合素、凝血栓蛋白-1(thrombospondin-1，TSP-1)，参与多种生理和病理过程，包括细胞迁移，T细胞和DC的激活以及轴突发育、细胞凋亡、增殖和炎症等。此外，CD47还可以结合信号调节蛋白α链(Signal-regulatory proteinα，SIRPα)。研究表明，在CD47-SIRPα信号通路中，CD47是一种“别吃我”(“don’t eat me”)信号，在机体正常生理状态下，可维持自身细胞的免疫耐受，而在病理状态下，CD47在多种血液系统恶性肿瘤和实体瘤细胞表面上高表达，通过与吞噬细胞(巨噬细胞、树突状细胞等)上的SIRPα受体结合进而启动一系列抑制性信号，这些抑制性信号可以转导到吞噬细胞内部，最终使吞噬细胞的吞噬功能消失，不能吞噬消除恶性增殖的细胞。
近年来，在众多的免疫治疗方案中，CD47是一个非常热门的靶点。而抗CD47抗体主要是通过以下几种机制清除肿瘤：首先，抗CD47抗体能够通过阻断肿瘤细胞上的CD47与吞噬细胞上的SIRPα的结合，促进吞噬作用。第二，抗CD47抗体通过ADCC和CDC效应清除肿瘤。第三，抗CD47抗体通过直接诱导凋亡清除肿瘤。
抗CD47治疗的基础研究涵盖了急性髓细胞白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤、多发性骨髓瘤、乳腺癌、非小细胞肺癌、肝细胞癌、黑色素瘤、卵巢癌、儿童脑瘤等多种疾病，现有技术中已有一些公开的CD47抗体，如CN110872348A、CN110615841A、CN110872350A等，但对新的抗CD47抗体仍然存在很大的需求。
发明内容
基于上述发现，本发明的首要目的在于提供一种新的、亲和力较高的CD47抗体。
本发明提供以下技术方案：
一种人源化抗CD47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，其中重链可变区选自SEQ ID NO:4，轻链可变区选自SEQ ID NO:8。
本发明所述CD47抗体重轻链可变区各有3个互补决定区(CDR)。所述CD47抗体的重链可变区3个CDR序列分别为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3；轻链可变区3个CDR序列分别为SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7。
本发明所述CD47抗体的重链和轻链进一步包含恒定区，所述抗体轻链恒定区进一步包含人源κ、λ链序列。所述抗体重链恒定区进一步包含人源IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM。
在一些实施方案中，所述抗体特异性结合CD47蛋白sema结构域，抑制CD47下游信号通路激活，预防或改善癌症的发展或转移。
在一些实施方案中，所述CD47抗体能够拮抗CD47活性，其中拮抗作用导致选自下列的至少一种活性：阻断SIRPα活性，促进巨噬细胞的吞噬作用和/或抑制肿瘤细胞生长。在一些实施方案中，可以将本发明CD47抗体拮抗剂用于治疗癌症，如急慢性髓系白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤以及膀胱癌、卵巢癌、乳腺癌、直肠癌、前列腺癌、肾癌、多发性骨髓瘤等多种实体肿瘤细胞或肿瘤干细胞等
本发明提供一种治疗癌症的方法，其特征在于：使用本发明所述的抗CD47抗体，所述癌症选自急慢性髓系白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤以及膀胱癌、卵巢癌、乳腺癌、直肠癌、前列腺癌、肾癌、多发性骨髓瘤等多种实体肿瘤细胞或肿瘤干细胞等。
本发明所述的CD47抗体可应用于制备治疗和/或预防癌症的药物中，所述癌症选自急慢性髓系白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤以及膀胱癌、卵巢癌、乳腺癌、直肠癌、前列腺癌、肾癌、多发性骨髓瘤等多种实体肿瘤细胞或肿瘤干细胞等。
本文所用术语“抗体”包括具有免疫球蛋白样结合功能的任何部分。该术语包括完整的抗体分子和任何抗原结合片段(即“抗原结合部分”)或其单链，骆驼科抗体包括例如纳米抗体，噬菌体展示结合构建体等等。天然发牛的抗体是糖蛋白，其包含至少两条通过二硫键互联的至少两条重链(H)和两条轻链(L)。每条重链由重链可变区(在此缩写为VH)和重链恒定区组成.重链恒定区由三个结构域：CH1,CH2和CH3组成.只有两种类型的轻链：λ和κ。每条轻链由轻链可变区(在此缩写为VL)和轻链恒定区组成。轻链恒定区由一个结构域CL组成。VH区和VL区还可以细分为高变区，称作互补决定区(CDR)，其与更加保守的区，称为构架区(FR)的区域一起交替散布。如存自然中所发现的，每个VH和VL由三个CDR和四个FR组成，从氨基末端至羧基末端按以下顺序排布：FR1,CDR1,FR2，CDR2，FR3，CDR3，FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗休可以是单克隆或多克隆抗休。
本文所用术语“单克隆抗体”或“单克隆抗体组合物”指抗体分子的制品，其全部共有单一分子组分。因而单克隆抗体显示对特定表位单一的结合特性和亲和性。
本文所用术语“多克降抗体”指具有异质抗体群的抗体组合物。多克降抗体通常源自经免疫动物或源白选定人的收集的血清。
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。
本文所用术语“人源化抗体”通常是指一种嵌合抗体，其含有较少的来自非人免疫球蛋白的序列，从而降低异种抗体引入到人类中时的免疫原性，同时保持抗体的完全抗原结合亲和力和特异性。例如，可以使用CDR移植及其变体；包括“重塑”、“高度加成”、“贴面”、表面重建等技术手段，对非人源的结合域进行人源化。如果其他区域，例如铰链区和恒定区结构域也源自非人来源，则这些区域也可以被人源化。
本文所用的术语“亲和性”是旨在单一抗原性位点上抗体和称作“表位”的抗原部分之间相互作用的强度。在每一个抗原性位点内，抗体“臂”的可变区通过弱非共价力与抗原在抗体的多个原子位置或氨基酸残基原子上相互作用；一般地，这种相互作用的数目越大，抗体对抗原的亲和性就越强。免疫结合相互作用的强度或亲和力可以相互作用的平衡解离常数(KD)表示，其中KD值越小，表示亲和力越高。所选多肽的免疫结合性质可使用本领域中公知的方法定量。一种方法涉及测量抗原结合位点/抗原复合物形成和解离的速度。“结合速率常数”(kon)和“解离速率常数”(kdis)两者都可通过浓度及缔合和解离的实际速率而计算得出。kdis/kon的比率等于解离常数KD。可用任何有效的方法测量KD、kon和kdis值，如表面等离子共振技术(例如Biacore)或Kinexa来测量解离常数。
有益效果
本发明的有益效果主要体现在：所述抗体能够以更高的亲和力结合CD47蛋白，阻断SIRPα与肿瘤细胞表面的CD47结合，促进巨噬细胞对肿瘤细胞的吞噬作用，发挥抗肿瘤作用，为癌症的治疗和/或预防提供新的可能。
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巨噬细胞体外吞噬肿瘤细胞实验
图2人卵巢癌SKOV3裸小鼠皮下移植瘤模型
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CD47抗体制备及纯化
采用人CD47抗原蛋白(购自北京义翘神州生物技术有限公司)与佐剂共同免疫的方法免疫BALB/C品系的实验小鼠。采用皮下多点免疫，免疫剂量为100μg/只，每两周免疫1次，共免疫3次；第3次免疫后通过尾静脉取血，采用间接酶联免疫吸附法(ELISA)检测抗体滴度；选取抗体滴度高的小鼠，通过腹腔注射100μg CD47蛋白加强免疫1次；3d后处死小鼠取脾脏，进行细胞融合。取免疫后的Balb/c小鼠脾细胞，采用PEG法将其与骨髓瘤Sp2/0细胞株融合，将融合后的细胞加HAT铺板，采用HAT培养基加压筛选阳性克隆。以有限稀释法进行单克隆化，以ELISA方法进行筛选，经扩大培养后最终筛选出阳性杂交瘤细胞株m3D7。
实施例2.抗体人源化
利用TRIZOL法提取实施例1中杂交瘤细胞株m3D7的RNA。细胞计数1-3×107，用冷PBS洗一次。加入TRIZOL 1ml，吹打至细胞溶解，加入100μl氯仿振荡15秒，冰浴15分钟。4℃12000转离心，15分钟，取上层液体到新管中，加入等体积异丙醇,充分混匀，冰浴15分钟。4℃12000转离心15分钟，弃去上清液。用1ml 75％乙醇洗沉淀一次。短暂离心，弃去上清，真空干燥沉淀，加DEPC水50μl溶解沉淀。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为模板进行抗体可变区基因的PCR扩增，从而分别获得小鼠抗体轻链与重链可变区的基因片段，通过测序进一步获得可变区基因对应的核苷酸及氨基酸序列。
首先使用Ig Blast(http://www.ncbi.nlm.nih.gov/igblast/)分析与小鼠抗体m3D7的VH、VL基因最同源的人种系基因。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。将获得的人源化抗体可变区基因克隆进含有人IgG1表达载体中，表达并纯化。
最终，将人源化改造后的抗体命名为h3D7，测序结果显示，抗体h3D7的VH-CDR1、VH-CDR2、VH-CDR3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h3D7的VH链氨基酸序列如SEQ ID NO:4所示；h3D7的VL-CDR1、VL-CDR2、VL-CDR3的氨基酸序列分别如SEQ ID NO:5、SEQ ID NO:6和SEQ ID NO:7所示；抗体h3D7的VL链氨基酸序列如SEQ ID NO:8所示。
实施例3.人源化抗体的亲和力测定
将人Fc抗体捕获抗体(AHC)通过氨基偶联的方式包被在CM5芯片表面，参照氨基偶联试剂盒和人抗捕获试剂盒说明书，准备芯片活化缓冲液EDC/NHS、AHC和封闭用的乙醇胺，选择Biacore3000系统中的包被程序，将AHC氨基偶联在CM5芯片表面。将实施例2中获得的人源化CD47抗体h3D7抗体捕获于芯片表面。用HBS-EP+缓冲液将抗体稀释至1μg/mL，设置流速为5μL/min，包被至响应值达300RU。CD47抗原设置7个不同浓度梯度，用HBS-EP缓冲液依次进行2倍梯度稀释，浓度从200nM到3.125nM。设置CD47抗原的流速为30μL/min，结合时间为3min。设置HBS-EP+缓冲液流速为30μL/min，解离时间为10min。使用3M MgCl2作为再生缓冲液，按照再生程序对芯片进行再生。此外，按照相同的步骤对照抗体W3452-1.164.16-z11(通过CN110305214A专利说明书第14页第23行获得其轻重链可变区序列)进行了亲和力测定。用Bia-evaluation软件分析结果，计算结合动力学参数。结果如表一所示：与对照抗体相比，本发明的抗体亲和力较高，亲和力KD值达到1.02x10-11M。
表一
| 抗体 | Kon(1/Ms) | Kdis(1/s) | K<sub>D</sub>(M) |
| h3D7 | 1.59x10<sup>6</sup> | 1.61x10<sup>-5</sup> | 1.02x10<sup>-11</sup> |
| W3452-1.164.16-z11 | 4.11x10<sup>5</sup> | 3.84x10<sup>-5</sup> | 9.34x10<sup>-11</sup> |
实施例4.抗CD47抗体阻断活性的检测
主要采用细胞流式术的方法对抗CD47抗体h3D7以及huAbF46-H阻断SIRPα与人急性髓系细胞白血病(AML)细胞株U937细胞表面的CD47结合的活性进行检测。1×105个U937细胞重悬于100μL稀释液中。对应加入100μL稀释好的待测抗体，抗体浓度范围为0.03到50μg/mL。抗体与细胞4℃结合1h。移除一抗后，每个样品中加入100ng/mL FITC标记的SIRPα配体蛋白，4℃孵育40min。最后进行流式检测。结果如表二，表明抗CD47抗体h3D7的阻断活性优于huAbF46-H1。
表二
| 抗体 | SIRPαIC<sub>50</sub>(μg/mL) |
| h3D7 | 0.91 |
| W3452-1.164.16-z11 | 1.37 |
实施例5.巨噬细胞体外吞噬肿瘤细胞实验
体外分离人外周血单个核细胞(PBMCs)，用X-vivo15培养基重悬，并接种于12孔细胞培养板中，每孔接种1×106个细胞。将细胞培养板置于37℃,5％CO2孵箱中，使PBMC中的单核贴壁。细胞贴壁6hr后，去除未贴壁的细胞，洗涤细胞一次。在细胞培养基中加入100ng/mLGM-CSF，继续培养5-7天，激活单核细胞向巨噬细胞的分化。活化的巨噬细胞使用670-A染料进行标记：吸去细胞培养基,PBS洗涤一遍，加入1μM的670-A染料,37℃孵育10min；然后加入5倍体积的冰上预冷的X-Vivo15培养基，并将细胞置于冰上5min终止标记反应；最后用培养基洗细胞5次以彻底除去荧光染料。肿瘤细胞用CFSE染料进行标记，方法同上。将Raji肿瘤细胞加入巨噬细胞中，同时在对应孔中加入抗体，将细胞培养板在37℃孵育约4hr，期间在显微镜下观察细胞，当各处理组出现明显吞噬现象时,PBS反复冲洗除去悬浮的肿瘤细胞，然后将细胞用2.5％胰酶消化下来进行流式分析。670A+CFSE+双阳性细胞代表吞噬了肿瘤细胞的巨噬细胞，670A+CFSE-单阳性代表未吞噬肿瘤细胞的巨噬细胞，吞噬指标＝[670A+CFSE+个数/(670A+CFSE++670A+CFSE-)]个数比值。结果如图1所示，加入CD47抗体后，巨噬细胞的吞噬能力明显增强，且CD47抗体h3D7的促吞噬效果更优。
实施例6.人卵巢癌SKOV3裸小鼠皮下移植瘤模型
裸小鼠皮下接种SKOV3细胞,5×106/只/100ml,待肿瘤生长至90-100mm3，将小鼠随机分组，每组8只。通过尾静脉给药，分别注射抗CD47抗体h3D7、抗CD47抗体W3452-1.164.16-z11以及阴性对照抗体IgG(不结合c-Met)，抗体注射浓度为40mg/kg。小鼠每三天注射一次抗体,同时测量肿瘤长、短径，并计算肿瘤大小，肿瘤体积计算公式为体积＝(长径×短径×短径)/2。结果如图2所示，对小鼠进行抗CD47抗体处理后，小鼠肿瘤生长速度明显变缓，表明抗CD47抗体h3D7能够抑制肿瘤生长。
序列表
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<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Gly Ser Ser Arg Ala Thr Lys Cys Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Glu Gly Thr Leu Lys Leu Leu Ile
35 40 45
Tyr Arg Ser Val Lys Asn Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Leu Ala Gly Asp Ser Pro Gln Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
Claims (7)
1.一种抗CD47抗体，由重链和轻链组成，其特征在于：所述抗体的重链可变区3个CDR序列分别为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3；轻链可变区3个CDR序列分别为SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7。
2.根据权利要求1所述的抗CD47抗体，其特征在于：所述重链包含如SEQ ID No:4所示的重链可变区；所述轻链包含如SEQ ID No:8所示的轻链可变区。
3.根据权利要求1-2任一项所述的抗CD47抗体，其特征在于：所述抗体重链恒定区为IgG1。
4.原核或真核细胞系中复制的表达载体，其特征在于：其编码权利要求1-3任一项所示的抗体。
5.一种药物组合物，其特征在于包含权1-3任一项所述的抗体。
6.权利要求1-3任一项的抗CD47抗体在制备用于治疗癌症的药物中的用途。
7.根据权利要求6所述的用途，其中所述癌症选自急慢性髓系白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤以及膀胱癌、卵巢癌、乳腺癌、直肠癌、前列腺癌、肾癌、多发性骨髓瘤等多种实体肿瘤细胞或肿瘤干细胞等。
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| CN112851810A (zh) * | 2021-01-23 | 2021-05-28 | 北京广未生物科技有限公司 | Cd20抗体及其治疗癌症的应用 |
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| US20140363442A1 (en) * | 2012-12-12 | 2014-12-11 | William A. Frazier | Therapeutic cd47 antibodies |
| CN110305214A (zh) * | 2018-03-20 | 2019-10-08 | 上海药明生物技术有限公司 | 新型抗cd47抗体 |
| CN110872350A (zh) * | 2018-08-31 | 2020-03-10 | 南京圣和药业股份有限公司 | 抗cd47抗体及其应用 |
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| US20140363442A1 (en) * | 2012-12-12 | 2014-12-11 | William A. Frazier | Therapeutic cd47 antibodies |
| CN110305214A (zh) * | 2018-03-20 | 2019-10-08 | 上海药明生物技术有限公司 | 新型抗cd47抗体 |
| CN110872350A (zh) * | 2018-08-31 | 2020-03-10 | 南京圣和药业股份有限公司 | 抗cd47抗体及其应用 |
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| CN112851810A (zh) * | 2021-01-23 | 2021-05-28 | 北京广未生物科技有限公司 | Cd20抗体及其治疗癌症的应用 |
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