CN116836281A - B7h3抗体及包含其的双功能抗体 - Google Patents
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- CN116836281A CN116836281A CN202210306215.0A CN202210306215A CN116836281A CN 116836281 A CN116836281 A CN 116836281A CN 202210306215 A CN202210306215 A CN 202210306215A CN 116836281 A CN116836281 A CN 116836281A
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Abstract
本发明涉及生物医药技术领域,具体而言,涉及B7H3抗体及包含其的双功能抗体。本发明对B7H3的单克隆抗体8H9进行了人源化,人源化后的抗体能有效阻断B7H3引起的免疫抑制作用。此外,用人源化处理后的B7H3抗体或其抗原结合片段与4‑1BB单克隆抗体、VEGF‑Trap蛋白和SIPRα蛋白构建成融合蛋白,进一步提高了抗体对免疫细胞的激活作用。所述抗体在制备应用于抑制癌细胞及调节B7H3的作用、水平以及增强机体免疫力的相关药物,尤其是治疗癌症相关药物方面具有广阔的应用前景。
Description
技术领域
本发明涉及生物医药技术领域,具体而言,涉及B7H3抗体及包含其的双功能抗体。
背景技术
B7H3(CD276),是一种I型跨膜蛋白(Chapoval A.I.,et al.,(2001)Nat.Immunol.2:269)。B7H3存在于一些非免疫性成纤维细胞、内皮细胞和成骨细胞,以及一些免疫细胞,如B细胞,T细胞,单核细胞,树突状细胞(DC)或天然杀伤细胞(NK)。在许多恶性肿瘤中,B7H3的表达水平相当高。同时,B7H3具有较为广泛的调节免疫系统的功能。
专利US20020102264中的8H9克隆(Omburtamab)是一种针对B7H3的鼠源IgG1单克隆抗体。体外实验表明,8H9能与人的多种实体瘤结合(Modak S.,et al.,(2001)CancerRes.61:4048-54),并能促进NK细胞对B7H3阳性肿瘤细胞的杀伤作用(Cheung N,et al.,(2003)Hybrid Hybridomics 22:209-218)。动物实验显示,8H9能抑制肉瘤和脑瘤的生长(Modak S.,et al.,(2005)Cancer Biother.Radiopharm.20:534-546;Luther N.,(2008)Neurosurgery 63:1167-1174)。临床数据表明,8H9可以显著延长中枢神经系统实体瘤高危病人的生存期(Kramer K,et al.,(2007)J.Clin.Oncol.25,5465–70)。同位素镥Lu177标记的8H9(Omburtamab)最近刚在美国批准用于成神经管细胞瘤的治疗。由于8H9是鼠源抗体,在用于人体治疗过程中会因其免疫原性而产生抗药抗体,从而降低其疗效并可能产生负作用。Mahiuddin等对8H9进行人源化和亲和力成熟改造(Mahiuddin A,et al.,(2015)J.Biol.Chem.290,30018-29),但其轻重链人源化程度相对较低,分别为70.5%和76.5%。因此,设计人源化程度更高的8H9抗体,可以减少临床使用过程中产生的免疫副反应,更好地增加临床疗效。
近年来,双功能抗体的构建为抗体新药研发创造了一个新的途径。不少双功能抗体新药已陆续进入临床试验,显示了比相应的单抗更强的治疗效果。因此,用人源化的8H9抗体与其他抗体或者结合片段【例如4-1BB(CD137)抗体、VEGF-Trap蛋白或SIPRα蛋白】构建双功能抗体,将可进一步促进免疫细胞的功能,提高抗体的抗肿瘤效果。
发明内容
本发明涉及B7H3抗体或其抗原结合片段,其包含氨基酸序列依次如SEQ ID NO:1~3所示的重链互补决定区以及氨基酸序列依次如SEQ ID NO:4~6所示的轻链互补决定区。
本发明还涉及融合蛋白,其含有如上所述的B7H3抗体或其抗原结合片段。
本发明还涉及如上所述的B7H3抗体或其抗原结合片段及融合蛋白相关的核酸、载体及宿主细胞。
本发明还涉及如上所述的B7H3抗体或其抗原结合片段及融合蛋白的制备方法。
本发明还涉及药物组合物,其包括如上所述的B7H3抗体或其抗原结合片段,或如上所述的融合蛋白,或如上所述的偶联物。
本发明还涉及如上所述的B7H3抗体或其抗原结合片段,或如上所述的融合蛋白,或如上所述的偶联物在制备用以治疗B7H3阳性癌症或用以调节免疫系统的药物中的应用。
本发明对B7H3的单克隆抗体8H9的CDR区及FR区均进行了人源化,人源化后的抗体能有效阻断B7H3引起的免疫抑制作用。此外,用人源化处理后的B7H3抗体或其抗原结合片段与4-1BB单克隆抗体、VEGF-Trap蛋白和SIPRα蛋白构建成融合蛋白,进一步提高了抗体对免疫细胞的激活作用。所述抗体在制备应用于抑制癌细胞及调节B7H3的作用、水平以及增强机体免疫力的相关药物,尤其是治疗癌症相关药物方面具有广阔的应用前景。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1:用ELISA方法测定8H9人源化处理抗体与B7H3-his蛋白的结合特性;
图2:8H9人源化处理抗体对人的PBMC细胞IFN-γ分泌的促进作用;
图3:用ELISA方法测定B7H3/4-1BB双功能抗体与B7H3-his蛋白的结合特性;
图4:B7H3/4-1BB双功能抗体与Jurkat-B7H3细胞交联对NF-κB信号通路的激活作用;
图5:B7H3/4-1BB双功能抗体对人的PBMC细胞IFN-γ分泌的促进作用;
图6:用ELISA方法测定B7H3/VEGF-Trap双功能抗体与B7H3-his蛋白的结合特性;
图7:B7H3/VEGF-Trap双功能抗体对VEGF-NFAT信号通路的抑制作用;
图8:B7H3/VEGF-Trap双功能抗体对人的PBMC细胞IFN-γ分泌的促进作用;
图9:用ELISA方法测定B7H3/SIPRα双功能抗体与CD47-mFc蛋白的结合特性;
图10:用ELISA方法测定B7H3/SIPRα双功能抗体对SIPRα和CD47结合的阻断作用;
图11:B7H3/SIPRα双功能抗体对人的PBMC细胞IFN-γ分泌的促进作用。
具体实施方式
现将详细地提供本发明实施方式的参考,其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上,对本领域技术人员而言,显而易见的是,可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如,作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中,来产生更进一步的实施方式。
除非另有说明,用于披露本发明的所有术语(包括技术和科学术语)的意义与本发明所属领域普通技术人员所通常理解的相同。通过进一步的指导,随后的定义用于更好地理解本发明的教导。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
本文所使用的术语“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列项目中任一个项目,也包括相关所列项目的任意的和所有的组合,所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明的是,当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时,应当理解,在本申请中,该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案,还毫无疑问地包括均用“逻辑或”连接的技术方案。比如,“A及/或B”包括A、B和A+B三种并列方案。又比如,“A,及/或,B,及/或,C,及/或,D”的技术方案,包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案),也包括A、B、C、D的任意的和所有的组合,也即包括A、B、C、D中任两项或任三项的组合,还包括A、B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。
本发明中所使用的术语“含有”、“包含”和“包括”是同义词,其是包容性或开放式的,不排除额外的、未被引述的成员、元素或方法步骤。
本发明中用端点表示的数值范围包括该范围内所包含的所有数值及分数,以及所引述的端点。
本发明中涉及浓度数值,其含义包括在一定范围内的波动。比如,可以在相应的精度范围内波动。比如2%,可以允许±0.1%范围内波动。对于数值较大或无需过于精细控制的数值,还允许其含义包括更大波动。比如100mM,可以允许±1%、±2%、±5%等范围内的波动。涉及分子量,允许其含义包括±10%的波动。
本发明中,涉及“多个”、“多种”等描述,如无特别限定,指在数量上指大于等于2。
本发明中,以开放式描述的技术特征中,包括所列举特征组成的封闭式技术方案,也包括包含所列举特征的开放式技术方案。
本发明中,“抗体”此技术术语是结合特定抗原的蛋白,其泛指包含互补决定区(CDR区)的一切蛋白及蛋白片段,特别是全长抗体或抗体功能片段。“全长抗体”此用语包括多克隆抗体及单克隆抗体,术语“抗体功能片段”是包含抗体CDR的一部分或全部的物质,其缺乏至少一些存在于全长链中的氨基酸但仍能够特异性结合至抗原。此类片段具生物活性,因为其结合至靶抗原,且可与其他抗原结合分子(包括完整抗体)竞争结合至给定表位。
“框架”或“框架序列”是可变区的除了被定义为抗原结合位点的那些序列之外的其余序列。因为抗原结合位点可以由如上所述的不同术语定义,所以框架的精确氨基酸序列取决于如何定义抗原结合位点。
本发明中,术语“人源化”或“人源化处理”,是指将鼠源抗体序列替换为人源抗体序列,从而减轻或消除人抗鼠抗体(HAMA)反应。这种替换可以是框架替换,例如将可变区中的FR序列替换为人源的,和/或将抗体的恒定区(如果具有的话)替换为人源的。这种替换也可以是通过链更替将鼠单抗转换成完全人源性抗体,可用的手段例如噬菌体抗体库技术。需要注意的是,人源化的过程中,替换的人源序列可包含部分氨基酸的置换或增减,使得该替换的序列可能不是表达的人免疫球蛋白序列或种系基因序列的精确拷贝。如此产生的抗体可称为人鼠嵌合抗体(human-mouse chimeric antibody)、人源化抗体(humanizedantibody)或全人源抗体(human antibody)。
本发明中,术语“互补性决定区”或“CDR”是指免疫球蛋白的重链和轻链的高度可变区,如Kabat等人所定义(Kabat等人,Sequences of proteins of immunologicalinterest,5th Ed"US Department of Health and Human Services,NIH,1991,和后来的版本)。有三种重链CDR和三种轻链CDR。此处,取决于情况,术语“CDR”和“CDRs”用于指包含一种或多种或者甚至全部的对抗体与其识别的抗原或表位的结合亲和力起作用的主要氨基酸残基的区域。在另一具体实施方式中,CDR区或CDR是指IMGT定义的免疫球蛋白的重链和轻链的高度可变区。
如本文中所使用,短语“治疗剂”通常是指在投与生物体时引发所需药理学作用的任何药剂。在一些实施例中,药剂在其在适当人群中展示出统计学上显著的作用时被视为治疗剂。在一些实施例中,适当群体可以是模型生物体群体。在一些实施例中,适当群体可由各种准则界定,如某一年龄组、性别、遗传背景、先前存在的临床病状等。在一些实施例中,治疗剂是可用于对疾病、病症和/或病状的一或多种症状或特征进行缓解、改善、减轻、抑制、预防、延缓发作、降低严重度和/或降低发病率的任何物质。在一些实施例中,“治疗剂”是在其可市售用于向人类投药之前已经或需要由政府机构批准的药剂。在一些实施例中,“治疗剂”是用于向人类投药的医学处方所需要的药剂。
如本文所使用,术语“检测剂”是指任何可检测的成份、分子、官能团、化合物、片段或部分。在一些实施例中,单独提供或使用检测实体。在一些实施例中,检测实体与另一试剂结合(例如接合)提供和/或使用。检测实体的实例包括(但不限于):各种配位体、放射性核素(例如3H、14C、18F、19F、32P、35S、135I、125I、123I、64Cu、187Re、111In、90Y、99mTc、177Lu、89Zr等)、荧光染料(关于特定例示性荧光染料,参见下文)、化学发光剂(如吖啶酯、稳定化二氧杂环丁烷等)、生物发光剂、光谱可分辨的无机荧光半导体纳米晶体(即,量子点)、金属纳米粒子(例如金、银、铜、铂等)、纳米簇、顺磁金属离子、酶(关于酶的特定实例,参见下文)、比色标记(如染料、胶态金等)、生物素、地高辛(digoxigenin)、半抗原和抗血清或单克隆抗体可适用的蛋白质。
本发明中,“优选”、“更好”、“更佳”、“为宜”仅为描述效果更好的实施方式或实施例,应当理解,并不构成对本发明保护范围的限制。本发明中,“可选地”、“可选的”、“可选”,指可有可无,也即指选自“有”或“无”两种并列方案中的任一种。如果一个技术方案中出现多处“可选”,如无特别说明,且无矛盾之处或相互制约关系,则每项“可选”各自独立。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。除非和本申请的发明目的和/或技术方案相冲突,否则,本发明涉及的引用文献以全部内容、全部目的被引用。本发明中涉及引用文献时,相关技术特征、术语、名词、短语等在引用文献中的定义也一并被引用。本发明中涉及引用文献时,被引用的相关技术特征的举例、优选方式也可作为参考纳入本申请中,但以能够实施本发明为限。应当理解,当引用内容与本申请中的描述相冲突时,以本申请为准或者适应性地根据本申请的描述进行修正。
抗体及融合蛋白
本发明涉及一种B7H3抗体或其抗原结合片段,其包含氨基酸序列依次如SEQ IDNO:1~3所示的重链互补决定区以及氨基酸序列依次如SEQ ID NO:4~6所示的轻链互补决定区。
在一些实施方式中,其包含氨基酸序列如SEQ ID NO:7或8所示的重链可变区,以及氨基酸序列如SEQ ID NO:9或10所示的轻链可变区;其组合可以为下述任一种:SEQ IDNO:7、SEQ ID NO:9;SEQ ID NO:7、SEQ ID NO:10;SEQ ID NO:8、SEQ ID NO:9;SEQ ID NO:8、SEQ ID NO:10。
在一些实施方式中,所述重链可变区的第102位A突变为G。
在一些实施方式中,所述抗原结合片段为F(ab')2、Fab、scFv以及双特异抗体中的一种。
术语“F(ab')2”是由胃蛋白酶消化整个全长抗体去除大部分Fc区同时完整保留一些铰链区后得到的。F(ab')2片段具有通过二硫键连接在一起的两个抗原结合Fab部分,因此F(ab')2片段为双价抗体,以IgG抗体制备得到的F(ab')2为例,分子量为约110kDa。
术语“Fab”是仍可与抗原结合的抗体结构,其为单价并且不含Fc部分。木瓜蛋白酶消化全长抗体后得到两个Fab片段以及一个Fc片段,每个Fab片段均为约50kDa。
术语“scFv”意指包含通过接头连接的抗体重链可变结构域(或区域;VH)和抗体轻链可变结构域(或区域;VL)的分子。此类scFv分子可具有一般结构:NH2-VL-连接肽(linker)-VH-COOH或NH2-VH-连接肽(linker)-VL-COOH。
在本发明中,术语“连接肽”可以是为柔性或刚性的肽,例如由重复的GGGGS氨基酸序列或其变体组成,例如使用1~4个重复的变体(Holliger等人(1993),Proc.Natl.Acad.Sci.USA 90:6444-6448)。可用于本发明的其他连接肽由Alfthan等人(1995),Protein Eng.8:725-731,Choi等人(2001),Eur.J.Immunol.31:94-106,Hu等人(1996),Cancer Res.56:3055-3061,Kipriyanov等人(1999),J.Mol.Biol.293:41-56和Roovers等人(2001),Cancer Immunol.描述。
在一些实施方式中,所述连接肽的氨基酸数目为1~30个;可以是1,2,3,4,5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个;优选5~20个。
在一些实施方式中,所述连接肽的氨基酸是不具有除连接以外的额外功能(例如蛋白定位、酶切位点等)的无意义多肽。
在一些实施方式中,所述连接肽为柔性连接肽;
在一些实施方式中,所述连接肽的氨基酸序列选自Gly、Ser、Pro、Ala以及Glu中的一种或多种。
在一些实施方式中,所述连接肽的氨基酸序列选自(GGGGS)n、(GGGS)n、(GGS)n、(GS)n或(G)n,其中n选自1,2,3,4,5或6。
连接肽通常是柔性的,可以减少融合蛋白与目的蛋白之间的空间位阻,从而更有利于蛋白正确折叠。
在一些实施方式中,所述B7H3抗体或其抗原结合片段还包含抗体恒定区序列。
在一些实施方式中,所述重链恒定区序列选自IgG、IgA、IgM、IgE、IgD任意一种的恒定区序列。在一些实施方式中,所述重链恒定区序列可以选自人的重链恒定区,其中IgG可进一步分成亚类,如IgG1、IgG2、IgG3或IgG4。
在一些实施方式中,轻链恒定区为κ或λ链。
所述恒定区优选是人来源的。
根据本发明的再一方案,还涉及融合蛋白,其含有如上所述的B7H3抗体或其抗原结合片段。
在一些实施方式中,所述的融合蛋白包含靶向B7H3的第一蛋白功能区以及靶向第二抗原的第二蛋白功能区;
所述第一功能区具有如上所述的B7H3抗体或其抗原结合片段。
在一些实施方式中,所述第二蛋白功能区选自4-1BB抗体或其抗原结合片段、VEGF-Trap全长或其片段以及SIRPα全长或其片段。
4-1BB属于肿瘤坏死因子受体超家族(TNFRSF9)。T细胞表面的4-1BB与其配体4-1BBL(CD137L)结合后,能够促进T细胞的增殖和活化。4-1BB的激活抗体在多种肿瘤模型中显示了良好的抗肿瘤效果(Vinay DS,et al.,(2012)Mol.Cancer Ther.11:1062–70)。临床试验中,4-1BB抗体在黑色素瘤、肾癌和卵巢癌患者的治疗中显示出一定的疗效,但在部分病人中出现剂量依赖的肝脏毒性副作用(Sznol,et al.,(2008)J.Clin.Oncol.26(supp15):3007)。由于B7H3在肿瘤组织中高表达,而在正常细胞中表达水平较低;因此,将4-1BB抗体与B7H3抗体构建成双功能抗体,可以使4-1BB抗体对T细胞的激活作用限制在肿瘤部位,降低了对正常组织的毒副作用;另外,由于对4-1BB(激活)以及对B7H3(阻断)的双重影响,T细胞对肿瘤的杀伤功能得到了进一步增强。
VEGF是血管内皮生长因子,可通过与其内皮细胞表面受体(VEGFR)的相互作用,促进血管生长。目前临床癌症治疗的一个有效方法是通过抗体阻断VEGF/VEGFR的结合而抑制肿瘤新生血管的形成。VEGF-Trap是由VEGFR1和VEGFR2的活性功能区串联组成的融合蛋白,它比VEGFR的单克隆抗体具有更强的阻断作用(Jocelyn H.,et al.,(2002)PNAS 99:11393-98)。因此,将VEGF-Trap与B7H3抗体构建成双功能抗体,可以特异性的抑制肿瘤部位的血管生长,降低对正常组织中血管生长的影响,同时通过对B7H3的阻断,加强了T细胞对肿瘤细胞的毒杀活性。
CD47也称整联素关联蛋白,表达于多种肿瘤细胞及某些正常细胞中。SIPRα(CD172α)是CD47的受体,主要表达于骨髓细胞,包括单核细胞、巨噬细胞、中性粒细胞、树突状细胞等(Adams S.,et al.,(1998)J Immunol 161:1853-59)。巨噬细胞的吞噬活性受SIPRα/CD47信号通路的调节。肿瘤细胞通过CD47与巨噬细胞表面的SIPRα结合,抑制巨噬细胞对肿瘤细胞的吞噬作用。因此,将SIPRα与B7H3抗体构建成双功能抗体,可以特异性阻断肿瘤细胞的CD47与巨噬细胞的SIPRα结合,促进巨噬细胞对肿瘤细胞的吞噬作用(Chao MP.,etal.,(2010)Cell 142:699-713);另一方面,由于对B7H3的阻断作用,T细胞的活性得以增强,对肿瘤细胞施以另一维度的杀伤作用。
在一些实施方式中,所述4-1BB抗体或其抗原结合片段包含氨基酸序列依次如SEQID NO:11~13所示的重链互补决定区H-CDR1、H-CDR2、H-CDR3,以及氨基酸序列依次如SEQID NO:14~16所示的轻链互补决定区L-CDR1、L-CDR2、L-CDR3。
在一些实施方式中,所述4-1BB抗体或其抗原结合片段包含氨基酸序列如SEQ IDNO:17所示的重链可变区,以及氨基酸序列如SEQ ID NO:18所示的轻链可变区。
在一些实施方式中,所述第二蛋白功能区为4-1BB的scFv,优选其为SEQ ID NO:19所示的scFv。
在一些实施方式中,所述VEGF-Trap片段的氨基酸序列如SEQ ID NO:20所示。
在一些实施方式中,所述SIRPα片段的氨基酸序列如SEQ ID NO:21所示。
上述氨基酸序列的变体也在本发明范围内,本发明的B7H3抗体或其抗原结合片段,或4-1BB抗体或其抗原结合片段,或VEGF-Trap片段,或SIRPα片段所对应的变体,与SEQID NO:1~SEQ ID NO:210任一多肽相比,分别包含发生在CDR区域(如果具有)的至多3个氨基酸的突变;或者,变体相对于SEQ ID NO:1~SEQ ID NO:21整体序列而言,可包含3个以内或更多的突变,例如与SEQ ID NO:1~SEQ ID NO:21任一多肽相比具有至少80%、85%、90%、93%、95%、97%或99%同一性的序列。突变可以为氨基酸的置换、缺失或添加或其任意组合;优选地,所述突变为保守置换。
“保守置换”是指具有类似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚性等)的其它氨基酸置换蛋白中的氨基酸,使得可频繁进行改变而不改变蛋白的生物学活性。
通常视为保守置换的置换是在脂肪族氨基酸Ala、Val、Leu和Ile中的彼此置换、羟基残基Ser和Thr的互换、酸性残基Asp和Glu的交换、酰胺残基Asn和Gln之间的置换、碱性残基Lys和Arg的交换以及芳香残基Phe、Tyr间的置换。本领域技术人员知晓,一般而言,多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性(参见例如Watson等(1987)Molecular Biology of the Gene,The Benjamin/Cummings Pub.Co.,第224页,(第4版))。另外,结构或功能类似的氨基酸的置换不大可能破环生物学活性。
在一些实施方式中,所述第一蛋白功能区具有的抗体重链(例如包含IgG1恒定区的重链),且重链的C端和所述第二蛋白功能区的N端通过连接肽连接。
分离的核酸
本发明还涉及分离的核酸,其编码如上所述的B7H3抗体或其抗原结合片段,或如上所述的融合蛋白。
术语“分离的核酸”在本文中是指以单链或双链形式存在的脱氧核糖核酸或核糖核酸聚合物。所述分离的核酸包括RNA基因组序列,DNA(gDNA和cDNA)或从DNA转录的RNA序列,而且,除非特别指明,所述多肽还包括天然多核苷酸、糖、或碱基改变的类似物。根据本发明一个方面,所述多核苷酸是轻链多核苷酸。
所述分离的核酸包括编码蛋白复合物氨基酸序列的核苷酸序列,也包括与其互补的核苷酸序列。所述互补序列包括完全互补的序列和基本上互补的序列,这是指能在本领域已知的严谨条件下与编码蛋白复合物氨基酸序列的核苷酸序列杂交的序列。
而且,编码蛋白复合物氨基酸序列的核苷酸序列可以被改变或突变。所述改变包括添加、缺失、或非保守取代或保守取代。编码蛋白复合物氨基酸序列的多核苷酸可以被解释为,包括相对于该分离的核酸有实质性同一性的核苷酸序列。所述实质性同一性将该核苷酸序列与另外的随机序列以使得它们最大对应的方式进行比对,当用本领域常见的算法分析所比对的序列时,所述序列可显示大于80%的同源性,大于90%的同源性,或大于95%的同源性。
载体
本发明还涉及载体,其包含如上所述的核酸。
术语“载体(vector)”是指,可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(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。可用作载体的动物病毒包括但不限于,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)。在一些实施方式中,本发明所述载体中包含基因工程中常用的调控元件,例如增强子、启动子、内部核糖体进入位点(IRES)和其他表达控制元件(例如转录终止信号,或者多腺苷酸化信号和多聚U序列等)。
在本发明中,载体可以为组合物,例如为多种质粒的混合物,不同质粒负载抗体或其抗原结合片段的一部分。
宿主细胞
本发明还提供宿主细胞,其包含如上所述的核酸,或被如上所述的载体所转化。
适用于表达本发明的抗原结合蛋白的宿主细胞或细胞系包括:哺乳动物细胞诸如NS0、Sp2/0、CHO、COS、HEK、成纤维细胞和骨髓瘤细胞。可以使用人细胞,因而允许分子用人糖基化模式来修饰。或者,可以采用其他真核细胞系。合适的哺乳动物宿主细胞的选择,以及用于转化、培养、扩增、筛选和产物产生和纯化的方法,是本领域已知的。
可以证明,细菌细胞可用作宿主细胞,其适合表达本发明的蛋白或其他实施方案。但是,由于在细菌细胞中表达的蛋白倾向于未折叠的形式或不正确地折叠的形式或非糖基化形式,必须筛选在细菌细胞中产生的任何蛋白,以保留抗原结合能力。如果细菌细胞表达的分子以适当地折叠的形式产生,该细菌细胞将是期望的宿主,或者,在可替代的实施方案中,可以在细菌宿主中表达分子,随后进行重新折叠。例如,用于表达的各种大肠杆菌菌株,是生物技术领域中众所周知的宿主细胞。枯草芽孢杆菌、链霉菌属、其他芽孢杆菌属等的各种菌株,也可以用于该方法中。
如果需要,本领域技术人员已知的酵母细胞菌株以及昆虫细胞,例如果蝇和鳞翅目昆虫和病毒表达系统,也可用作宿主细胞。
在一些实施方式中,所述细胞基因组中插入有所述核酸,并且能稳定表达。
插入的方式可选用如上所述的载体,或者核酸不连入载体直接转入细胞内(例如脂质体介导的转染技术)。
制备方法
本发明还涉及一种制备如上所述B7H3抗体或其抗原结合片段,或如上所述的融合蛋白的方法,包括在合适的条件下培养如上所述的宿主细胞,以及从细胞培养物中回收目的产物。
本发明培养方法通常是无血清培养方法,通常通过无血清悬浮培养细胞。同样地,一旦产生本发明抗体,可将其根据本领域标准程序从细胞培养内容物纯化出,所述标准程序包括硫酸铵沉淀、亲和柱、柱层析、凝胶电泳等。这类技术在本领域技术范围内,不限定本发明。表达抗体的另一种方法可以利用在动物(特别是转基因动物或者裸鼠)中的表达。这涉及利用动物酪蛋白启动子的表达系统,当其被转基因地并入哺乳动物中时,允许雌性动物在其奶中产生希望的重组蛋白。分泌了抗体的培养液可以用常规技术纯化。比如,用含调整过的缓冲液的A或G Sepharose FF柱进行纯化。洗去非特异性结合的组分。再用pH梯度法洗脱结合的抗体,用SDS-PAGE检测抗体片段,收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体,也可以用常规方法去除,比如分子筛、离子交换。得到的产物需立即冷冻,如-70℃,或者冻干。
偶联物
本发明还涉及偶联物,其为与治疗剂或检测剂所结合的如上B7H3抗体或其抗原结合片段,或如上所述的融合蛋白。
治疗剂可以是或包含任何类别的化学实体,包括例如(但不限于)蛋白质、碳水化合物、脂质、核酸、小型有机分子、非生物聚合物、金属、离子、放射性同位素等。在一些实施例中,根据本发明使用的治疗剂可具有与治疗癌症的一或多种症状或起因相关的生物活性。在一些实施例中,根据本发明使用的治疗剂可具有与调节免疫系统和/或促进T细胞介导的细胞毒性和/或抑制B7H3对T细胞增殖和功能的抑制作用相关的生物活性。在一些实施例中,根据本发明使用的治疗剂具有一或多种其它活性。
在本发明的一些实施例中,所结合的治疗剂是放射性同位素、药物结合物、纳米粒子、免疫毒素或任何其它治疗性负荷。
检测剂包含任何可使用分析来检测的部分,例如归因于其特定功能特性和/或化学特征。所述药剂的非限制性实例包括酶、放射性标记、半抗原、荧光标记、磷光分子、化学发光分子、发色团、发光分子、光亲和性分子、有色粒子或配位体(如生物素)。在本发明的一些实施例中,所结合的检测剂是诊断剂或成像剂。
药物组合物、医药用途与治疗方法
本发明还涉及药物组合物,其包含如上所述的B7H3抗体或其抗原结合片段,或如上所述的融合蛋白,或如上所述的偶联物。
本发明的B7H3抗体或其抗原结合片段或融合蛋白或偶联物可以应用于制备药物组合物或无菌组合物,例如,将它们中的任一种与药学上可接受的载体、赋形剂或稳定剂混合。
术语“药学上可接受的”指当分子本体、分子片段或组合物适当地给予动物或人时,它们不会产生不利的、过敏的或其他不良反应。可作为药学上可接受的载体或其组分的一些物质的具体示例包括磷酸,柠檬酸,和其它有机酸;抗氧化剂(例如,抗坏血酸和甲硫氨酸);抗菌剂(例如,十八烷基二甲基苯氯化铵,氯化六烃季铵,苯扎氯铵,酚,丁醇或苯甲醇,烷基尼泊金,邻苯二酚,间苯二酚,环己醇,3-戊醇,或间甲酚);低分子量(不到约10kDa)多肽;蛋白,例如,血清白蛋白,明胶,或免疫球蛋白;亲水性聚合物,例如,聚乙烯吡咯烷酮;氨基酸(例如,甘氨酸,谷氨酰胺,天冬酰胺,组氨酸,精氨酸,或赖氨酸);单糖,二糖和其它碳水化合物(包括例如,葡萄糖,甘露糖,或葡聚糖);螯合剂(例如,EDTA);糖(例如,蔗糖,甘露醇,海藻糖,或山梨醇);成盐反离子;金属复合物;和/或非离子型表面活性剂(例如,包括TWEENTM,PLURONICSTM,或聚乙二醇)。此外,根据配制方法,可以由本领域普通技术人员适当选择常用的填充剂,稀释剂,结合剂,增湿剂,崩解剂,和/或表面活性剂。
药物组合物中包含抗体或其功能片段的激活剂可以容纳在微胶囊中,或容纳在胶体性质的药物运送系统(如脂质体,白蛋白小球体,微乳剂,纳米颗粒及纳米胶囊)中,或者容纳在大乳剂(macroemulsions)中,所述微胶囊可以通过诸如凝聚(coacervation)技术或界面聚合作用来制备,例子分别有羟甲基纤维素或明胶微胶囊和聚-(异丁烯酸甲酯)微胶囊。
本发明的医药组合物可通过任何途径投与,如所属领域的技术人员将了解。在一些实施例中,本发明的医药组合物通过口服(PO)、静脉内(IV)、肌肉内(IM)、动脉内、髓内、鞘内、皮下(SQ)、心室内、经皮、皮内、皮内、经直肠(PR)、经阴道、腹膜内(IP)、胃内(IG)、局部(例如利用粉末、软膏、乳膏、凝胶、洗剂和/或滴剂)、粘膜、鼻内、颊内、经肠、玻璃体、舌下;通过气管内滴入、支气管滴入和/或吸入;作为口服喷雾、经鼻喷雾和/或气溶胶和/或经由门静脉导管投与。
本发明还涉及如上所述的B7H3抗体或其抗原结合片段,或如上所述的融合蛋白,或如上所述的偶联物在制备用以治疗B7H3阳性癌症或用以调节免疫系统的药物中的应用。
B7H3在多种实体肿瘤类型上广泛表达,包括例如黑色素瘤(Wang J.,et al.,(2013)J.Invest.Dermatol.133:2050)、白血病(Hu Y.,et al.,(2015)Hematology 20:187;Sun J.,et al.,(2014)Onco Targets Ther.7:1979)、前列腺癌(Zang X.,et al.,(2007)Proc.Natl.Acad.Sci.104:19458)、卵巢癌(Zang X.,et al.,(2010)Mod.Pathol.23:1104)、胰腺癌(Chen Y.,et al.,(2014)Onco.Targets Ther.7:1465-72)、肾细胞癌、尿道上皮细胞癌瘤(Crispen.,et al.,(2008),Clin Cancer Res.14:5150-157;Boorjian.,et al.,(2008),Clin Cancer Res.14:4800-4808)、神经胶母细胞瘤(Lemke.,et al.,(2012),Clin Cancer Res.18:105-117)、骨肉瘤(Wang.,et al.,(2013),PLoSOne.8:e70689)、神经母细胞瘤(Gregorio.,et al.,(2008),Histopathology.53:73-80)、弥漫性内源性脑桥神经胶质瘤(DIPG)(Zhou.,et al.,(2013),J.Neurooncol.111:257-264)、间皮瘤(Calabro.,et al.,(2011),J.Cell Physiol.226:2595-600)和胰脏癌(Yamato.,et al.,(2009),Br.J.Cancer.101:1709-1716)中。在一些较为优选的实施例中,B7H3阳性癌症选自神经母细胞瘤、子宫颈癌。
B7H3可显著抑制CD3抗体或同种异体DC细胞对T细胞的激活作用,而B7H3阻断抗体可有效逆转这种抑制作用(Prasad D.V.R.,et al.,(2004)J.Immunol.173:2500)。B7H3与NK细胞上的受体结合后,可抑制NK细胞对成神经细胞瘤的杀伤作用(Castriconi R.,etal.,(2004)Proc.Natl.Acad.Sci.101:12640)。B7H3对T细胞、NK和DC细胞的抑制作用能显著促进肿瘤细胞的免疫逃逸;另外,B7H3对肿瘤细胞的增殖、迁移、侵袭、血管生成、以及肿瘤细胞耐药性等也有重要影响。将肿瘤细胞移植在敲除B7H3的小鼠中或用B7H3抗体处理荷瘤小鼠,能够显著抑制肿瘤的生长(Cai D.,et al.,(2020)Cell.Mol.Immunol.17:227;LeeY.H.,et al.,(2017)Cell Res.27:1034),说明阻断B7H3的信号传导可用于肿瘤治疗。由于正常组织和肿瘤组织在B7H3表达水平上的显著差异,可以通过B7H3抗体的ADCC效应或毒素偶联来有效地杀死肿瘤细胞,而对正常组织不引起太大的副作用(Koenig S.,et al.,(2014)Medicographia 36:285)。
本发明所称癌症或肿瘤是指实体肿瘤和/或血液肿瘤,其可以是骨、骨连接、肌肉、肺、气管、心脏、脾脏、动脉、静脉、血液、毛细血管、淋巴结、淋巴管、淋巴液、口腔、咽、食管、胃、十二指肠、小肠、结肠、直肠、肛门、阑尾、肝、胆、胰腺、腮腺、舌下腺、泌尿肾、输尿管、膀胱、尿道、卵巢、输卵管、子宫、阴道、外阴部、阴囊、睾丸、输精管、阴茎、眼、耳、鼻、舌、皮肤、脑、脑干、延髓、脊髓、脑脊液、神经、甲状腺、甲状旁腺、肾上腺、垂体、松果体、胰岛、胸腺、性腺、舌下腺以及腮腺中任一处病变生成的肿瘤。具体如白血病、膀胱癌、结肠直肠癌、前列腺癌、胃癌、胰腺癌、肝癌、头颈部癌、肾癌、乳腺癌、卵巢癌、促纤维增生性小圆细胞肿瘤、非小细胞肺癌、黑色素瘤、肺泡横纹肌肉瘤、食管癌、淋巴癌、胚胎横纹肌肉瘤、神经母细胞瘤、宫颈癌、尤文肉瘤、肾母细胞瘤、神经母细胞瘤、弥漫性脑桥脑胶质瘤、神经节神经瘤、髓母细胞瘤、神经节神经母细胞瘤、高级别胶质瘤、具有多层玫瑰花结的胚胎肿瘤,优选为表达B7H3的癌症。
本发明还涉及一种治疗、预防、减轻和/或诊断受试者的医学状况的方法,包括施用安全和有效量的如上所述的B7H3抗体或抗原结合片段,或如上所述的融合蛋白,或如上所述的偶联物的步骤,并且其中所述医学状况的特征在于B7H3抗原的表达。
优选其中所述医学状况为B7H3阳性癌症或免疫系统相关疾病。
短语“安全和有效量的”。如本文所用,意指在合理的医药调节范围内化合物或组合物的量大到足以明显有效地缓解所治疗的症状或病症,但小到足以避免严重的副作用(以合理的有益/危险比率)。本发明的方法所用的药物组合物中的活性成份的安全和有效量随所治疗的特定症状、年龄和所治疗患者的身体状况,疾病的严重性、治疗时间、同期治疗情况、使用的特定活性成份、使用的特定的药物学可接受的赋形剂及包括参与治疗医师的知识和技能在内的这类因素的不同而不同。
上述疾病的受试者或患者可选自人类、狗、猫、黑猩猩、猩猩、长臂猿、猕猴、狨猴、猪、马、熊猫和大象的群组。
下面将结合实施例对本发明的实施方案进行详细描述。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,优先参考本发明中给出的指引,还可以按照本领域的实验手册或常规条件,还可以参考本领域已知的其它实验方法,或者按照制造厂商所建议的条件。
下述的具体实施例中,涉及原料组分的量度参数,如无特别说明,可能存在称量精度范围内的细微偏差。涉及温度和时间参数,允许仪器测试精度或操作精度导致的可接受的偏差。
本发明将专利US20020102264中的鼠源8H9抗体(Omburtamab)进行了人源化改造;在显著提高抗体人源化程度的同时,保持了抗体的活性。双功能抗体B7H3/4-1BBab、B7H3/VEGF-Trap和B7H3/SIPRα中的抗体或受体分子均保留了各自的活性和功能。与8H9单克隆抗体相比,本发明构建的双功能抗体在促进人的免疫细胞产生和分泌细胞因子方面,表现出比更高的生物活性。本发明中的B7H3对照抗体MGA271(Enoblituzumab)来自专利US20180134790;CD47的对照抗体1F8来自专利CN201980001915;PD-L1-VEGF-Trap中PD-L1抗体序列来自专利CN201911023312。
实施例1
8H9抗体的人源化
8H9杂交瘤抗体的重链可变区序列为SEQ ID NO:22,轻链可变区序列为SEQ IDNO:23。采用互补决定簇嫁接法进行8H9杂交瘤抗体的人源化改造。首先,在IMGT数据库中分别搜寻与鼠源抗体的轻、重链可变区序列同源性最高的人胚系抗体(germline antibody)序列。重链可变区人源化选取IGHV1-18*01和IGHV1-8*01,抗体轻链可变区人源化选取的胚系为IGKV1-39*01和IGKV6-21*02。保留鼠源抗体的CDR区,将鼠源抗体的框架区(framework)序列用人胚系抗体的框架区序列置换。建立鼠源抗体的结构模型,逐个对比人源抗体与相应鼠源抗体框架区中每个位点的氨基酸,如果框架区的某个位点采用人的氨基酸序列没有导致CDR区域空间结构的破坏或改变,则该位点使用人的氨基酸序列,否则在该位点使用对应的鼠源序列(即回复突变为鼠源序列)。
根据结构模拟,将人源化处理抗体IGHV1-18*01重链的第48位Met回复突变为Ile,第67位Val回复突变为Ala,第69位Met回复突变为Leu。将人源化处理抗体IGHV1-8*01重链的第48位Met回复突变为Ile,第67位Val回复突变为Ala,第69位Met回复突变为Leu,第71位Arg回复突变为Thr。将人源化处理抗体IGKV1-39*01的第49位Tyr回复突变为Lys,第69位Thr回复突变为Ser。将人源化处理抗体IGKV6-21*02的第4位Leu回复突变为Met,第69位Thr回复突变为Ser。
人源化处理抗体重链(germline IGHV1-18*01)的可变区氨基酸序列号为SEQ IDNO:7,人源化程度为83.7%;人源化处理抗体重链(germline IGHV1-8*01)的可变区氨基酸序列号为SEQ ID NO:8,人源化程度为85.7%;人源化处理抗体轻链(germline IGKV1-39*01)的可变区氨基酸序列号为SEQ ID NO:9,人源化程度为87.4%;人源化处理抗体轻链(germline IGKV6-21*02)的可变区氨基酸序列号为SEQ ID NO:10,人源化程度为89.5%。将以上人源化处理抗体构建为IgG1亚型。本发明中构建的抗体轻、重链人源化程度显著高于文献报道的70.5%和76.5%(Mahiuddin A,et al.,(2015)J.Biol.Chem.290,30018-29)。
合成人源化处理抗体重链和轻链的核酸序列,并插入到表达载体pcDNA3.1。用0.1mg抗体轻链和0.1mg抗体重链表达质粒共转染200mL的293细胞(细胞密度为1×106/mL),在37℃摇瓶振摇培养6天,离心收集上清液,用Protein A纯化人源化处理抗体,纯化后的人源化处理抗体进行活性检测。8H9人源化处理抗体重链(germline IGHV1-18*01)与轻链(germline IGKV6-21*02)组合为hu8H9-V1(Version1),重链(germline IGHV1-18*01)与轻链(germline IGKV1-39*01)组合为hu8H9-V2(Version2),重链(germline IGHV1-8*01)与轻链(germline IGKV6-21*02)组合为hu8H9-V3(Version3),重链(germline IGHV1-8*01)与轻链(germline IGKV1-39*01)组合为hu8H9-V4(Version4)。发明人还在hu8H9-V4的基础上将重链可变区的第102位的丙氨酸突变为甘氨酸,得到hu8H9-V4(VH-A102G),以增强抗体的稳定性。
实施例2
人源化8H9抗体(hu8H9)与B7H3抗原结合的ELISA检测。
用50μL B7H3-his(终浓度:2μg/mL)包被96孔ELISA板(Corning,Cat.No.:9018),室温过夜;用洗涤缓冲液(PBS+0.05%Tween20)洗涤3次后,加入封闭缓冲液(PBS+2%BSA(Sigma,Cat.No.:V90093))室温孵育1小时,用洗涤缓冲液洗涤ELISA板3次;加入50μL不同浓度的抗体,室温孵育1小时,洗涤3次;每孔加入50μL HRP偶联羊抗鼠IgG二抗(Thermo,Cat.No.:31432),室温避光孵育1小时,洗涤3次;每孔加入100μL TMB(北京百奥赛博,Cat.No.:ES-002),室温孵育显色2分钟,加入100μL/孔的终止液(2N H2SO4)终止显色反应,用酶标仪(Tecan Spark)读取各孔OD450数值。结果如图1所示,与嵌合抗体相比,人源化8H9抗体及其突变体保持了对B7H3较高的亲和力。
实施例3
人源化8H9抗体(hu8H9)对PBMC的激活作用
测试hu8H9对人PBMC细胞分泌细胞因子的影响:在96孔(Corning,Cat.No.:3799)加入用完全培养基(RPMI1640+10%FCS)重悬的PBMC细胞(TPCS,Cat.No.:PB025C),再加入40ng/mL OKT3(eBioscience,Cat.No.:16-0037-85),置37℃孵育72小时。活化的PBMC细胞计数后,用完全培养基重悬(2.5×105细胞/mL)。在96孔板中,每孔加入100μL PBMC细胞,50μL不同浓度的hu8H9抗体(起始浓度为20μg/mL,10倍系列稀释),将96孔细胞培养板(Corning,Cat.No.:3599)置于37℃,5%CO2培养箱中孵育48小时,收集上清液。用IFN-γELISA试剂盒(R&D Systems,Cat.No.:DY285)检测细胞因子的浓度。结果如图2所示,人源化8H9抗体及其突变体能够显著促进PBMC细胞分泌IFN-γ,优于对照抗体MGA271。
实施例4
双功能抗体hu8H9/4-1BBab的构建和功能检测
将4-1BB人源化处理抗体设计成单链形式scFv(序列见SEQ ID NO:19)通过Linker(G4S)4连接在hu8H9-V4重链C末端,与轻链载体共转染到293细胞。在37℃摇瓶振摇培养6天,离心收集上清液,用Protein A纯化,纯化后进行活性检测。
双功能抗体hu8H9/4-1BBab与B7H3抗原结合的ELISA检测。具体方法参考实施例2。结果如图3所示,hu8H9/4-1BBab双功能抗体对B7H3具有较高的亲和力。
采用报告基因方法检测双功能抗体hu8H9/4-1BBab对4-1BB信号通路的激活作用。在96孔板中加入50μl(5×104细胞/孔)Jurkat-4-1BB-NFkB-luc细胞以及50μl不同浓度的抗体,再加入Jurkat-B7H3细胞(2×104细胞/孔),混合后置37℃孵育4小时。加入25μlBright Glo(Promega,Cat No:E2620)室温孵育5分钟,用Tecan Spark酶标仪测定各样品的化学发光信号。结果如图4所示,在Jurkat-B7H3细胞存在时,双功能抗体hu8H9/4-1BBab能显著激活4-1BB信号通路。
双功能抗体hu8H9/4-1BBab对人PBMC细胞分泌细胞因子的影响,具体方法参考实施例3。如图5所示,相较于单抗,双功能抗体hu8H9/4-1BBab能够显著促进PBMC细胞IFN-γ的分泌。
实施例5
双功能抗体hu8H9/VEGF-Trap的构建和功能检测
将VEGF-Trap序列(SEQ ID NO:20)通过Linker(G4S)4连接在hu8H9-V4重链C末端,与轻链载体共转染到293细胞。在37℃摇瓶振摇培养6天,离心收集上清液,用Protein A纯化,纯化后进行活性检测。
双功能抗体hu8H9/VEGF-Trap与B7H3结合的ELISA检测,具体方法参考实施例2。如图6所示,hu8H9/VEGF-Trap双功能抗体对B7H3仍具有较高的亲和力。
采用报告基因方法检测双功能抗体hu8H9/VEGF-Trap对VEGF-NFAT信号通路的抑制作用。将50μl不同浓度的抗体与50μl 40ng/ml VEGF蛋白预孵育1小时。将50μl混合物加入50μl(5×104细胞/孔)293T-VEGFR-NFAT-luc细胞后,置37℃孵育4小时。加入25μlBright Glo(Promega,Cat No:E2620)室温孵育5分钟,用Tecan Spark酶标仪测定各样品的化学发光信号。如图7所示,双功能抗体hu8H9/VEGF-Trap能够显著抑制NFAT信号通路。
双功能抗体hu8H9/VEGF-Trap对人PBMC细胞分泌细胞因子的影响,具体方法参考实施例3。如图8所示,双功能抗体hu8H9/VEGF-Trap能够显著促进PBMC细胞分泌IFN-γ。
实施例6
双功能抗体hu8H9/SIPRα的构建和功能检测。
将SIPRα序列(见SEQ ID NO:21)通过Linker(G4S)4连接在人源化处理抗体hu8H9-V1重链C末端,与轻链载体共转染到293细胞。在37℃摇瓶振摇培养6天,离心收集上清液,用Protein A纯化,纯化后进行活性检测。
双功能抗体hu8H9/SIPRα与CD47结合的ELISA检测。用50μLCD47-mFc(终浓度:2μg/mL)包被96孔ELISA板(Corning,Cat.No.:9018),室温过夜;用洗涤缓冲液(PBS+0.05%Tween20)洗涤3次后,加入封闭缓冲液(PBS+2%BSA(Sigma,Cat.No.:V90093))室温孵育1小时,用洗涤缓冲液洗涤ELISA板3次;加入50μL不同浓度的抗体,室温孵育1小时,洗涤3次;每孔加入50μL HRP偶联羊抗鼠IgG二抗(Thermo,Cat.No.:31432),室温避光孵育1小时,洗涤3次;每孔加入100μL TMB(北京百奥赛博,Cat.No.:ES-002),室温孵育显色2分钟,加入100μL/孔的终止液(2N H2SO4)终止显色反应,用酶标仪(Tecan Spark)读取各孔OD450数值。结果如图9所示,hu8H9/SIPRα双功能抗体对CD47有较高的亲和力。
双功能抗体hu8H9/SIPRα阻断SIPRα与CD47结合的ELISA检测。用50μL CD47-mFc(终浓度:2μg/mL)包被96孔ELISA板(Corning,Cat.No.:9018),室温过夜;用洗涤缓冲液(PBS+0.05%Tween20)洗涤3次后,加入封闭缓冲液(PBS+2%BSA(Sigma,Cat.No.:V90093))室温孵育1小时,用洗涤缓冲液洗涤ELISA板3次;加入50μL不同浓度的抗体,室温孵育1小时,继续向样品孔中加入50μL SIPRα-Biotin,室温孵育1小时,洗涤3次;加入二抗AvidinHRP(Invitrogen,Cat No:18-4100-51),孵育30分钟,洗涤3次后加入TMB显色3分钟,用100μL/孔的终止液(2N H2SO4)终止反应,用酶标仪(Tecan Spark)读取各孔OD450数值。结果如图10所示,hu8H9/SIPRα双功能抗体能有效阻断SIPRα和CD47的结合。
双功能抗体hu8H9-SIPRα对人PBMC细胞分泌细胞因子的影响,具体方法参考实施例3。如图11所示,与hu8H9单抗相比,双功能抗体hu8H9/SIPRα对PBMC细胞分泌IFN-γ具有更强的促进作用。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准,说明书及附图可以用于解释权利要求的内容。
SEQUENCE LISTING
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115 120 125
Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His
130 135 140
Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser
145 150 155 160
Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg
165 170 175
Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr
180 185 190
Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
195 200
<210> 21
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> SIPRα
<400> 21
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser
115
<210> 22
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 8H9 heavy chain variable region
<400> 22
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Phe Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gln Thr Thr Ala Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 23
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 8H9 light chain variable region
<400> 23
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
Claims (20)
1.B7H3抗体或其抗原结合片段,其包含氨基酸序列依次如SEQ ID NO:1~3所示的重链互补决定区以及氨基酸序列依次如SEQ ID NO:4~6所示的轻链互补决定区。
2.根据权利要求1所述的B7H3抗体或其抗原结合片段,其包含氨基酸序列如SEQ IDNO:7或8所示的重链可变区,以及氨基酸序列如SEQ ID NO:9或10所示的轻链可变区。
3.根据权利要求2所述的B7H3抗体或其抗原结合片段,所述重链可变区的第102位A突变为G。
4.根据权利要求1~3任一项所述的B7H3抗体或其抗原结合片段,所述抗原结合片段为F(ab')2、Fab、scFv以及双特异抗体中的一种。
5.根据权利要求1~3任一项所述的B7H3抗体或其抗原结合片段,其具有恒定区,重链恒定区序列选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任意一种的恒定区序列;轻链恒定区为κ或λ链;所述恒定区优选是人来源的。
6.融合蛋白,其含有权利要求1~5任一项所述的B7H3抗体或其抗原结合片段。
7.根据权利要求6所述的融合蛋白,其包含靶向B7H3的第一蛋白功能区以及靶向第二抗原的第二蛋白功能区;
所述第一功能区具有权利要求1~5任一项所述的B7H3抗体或其抗原结合片段。
8.根据权利要求7所述的融合蛋白,所述第二蛋白功能区选自4-1BB抗体或其抗原结合片段、VEGF-Trap全长或其片段以及SIRPα全长或其片段。
9.根据权利要求8所述的融合蛋白,所述4-1BB抗体或其抗原结合片段包含氨基酸序列依次如SEQ ID NO:11~13所示的重链互补决定区H-CDR1、H-CDR2、H-CDR3,以及氨基酸序列依次如SEQ ID NO:14~16所示的轻链互补决定区L-CDR1、L-CDR2、L-CDR3。
10.根据权利要求9所述的融合蛋白所述4-1BB抗体或其抗原结合片段包含氨基酸序列如SEQ ID NO:17所示的重链可变区,以及氨基酸序列如SEQ ID NO:18所示的轻链可变区,优选其为SEQ ID NO:19所示的scFv。
11.根据权利要求8所述的融合蛋白,所述VEGF-Trap片段的氨基酸序列如SEQ ID NO:20所示。
12.根据权利要求8所述的融合蛋白,所述SIRPα片段的氨基酸序列如SEQ ID NO:21所示。
13.根据权利要求7~12任一项所述的融合蛋白,所述第一蛋白功能区具有的抗体重链,且重链的C端和所述第二蛋白功能区的N端通过连接肽连接。
14.分离的核酸,其编码权利要求1~5任一项所述的B7H3抗体或其抗原结合片段,或权利要求6~13任一项所述的融合蛋白。
15.载体,其包含权利要求14所述的核酸。
16.宿主细胞,其包含权利要求14所述的核酸,或被权利要求15所述的载体所转化。
17.制备权利要求1~5任一项所述的B7H3抗体或其抗原结合片段,或权利要求6~13任一项所述的融合蛋白的方法,包括在合适的条件下培养权利要求16所述的宿主细胞,以及从细胞培养物中回收目的产物。
18.偶联物,其为与治疗剂或检测剂所结合的权利要求1~5任一项所述的B7H3抗体或其抗原结合片段,或权利要求6~13任一项所述的融合蛋白。
19.药物组合物,其包含权利要求1~5任一项所述的B7H3抗体或其抗原结合片段,或权利要求6~13任一项所述的融合蛋白,或权利要求18所述的偶联物。
20.权利要求1~5任一项所述的B7H3抗体或其抗原结合片段,或权利要求6~13任一项所述的融合蛋白,或权利要求18所述的偶联物在制备用以治疗B7H3阳性癌症或用以调节免疫系统的药物中的应用。
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PCT/CN2023/081037 WO2023179392A1 (zh) | 2022-03-25 | 2023-03-13 | B7h3抗体及包含其的双功能抗体 |
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CN106535914B (zh) * | 2014-08-08 | 2021-08-27 | Alx 肿瘤生物技术公司 | SIRP-α变体构建体及其用途 |
CA2959356C (en) * | 2014-08-27 | 2024-02-20 | Memorial Sloan Kettering Cancer Center | Novel antibodies that bind to b7h3 |
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BR112020026862A2 (pt) * | 2018-06-29 | 2021-04-20 | Gensun Biopharma, Inc. | antagonistas antitumorais de reguladores de pontos de verificação imunológica |
CA3178510A1 (en) * | 2020-06-04 | 2021-12-09 | Ahmed Mahiuddin | Anti-b7h3 antibodies for the treatment of cancer |
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