CN110799536B - 抗SIRPα抗体 - Google Patents
抗SIRPα抗体 Download PDFInfo
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- CN110799536B CN110799536B CN201880032714.7A CN201880032714A CN110799536B CN 110799536 B CN110799536 B CN 110799536B CN 201880032714 A CN201880032714 A CN 201880032714A CN 110799536 B CN110799536 B CN 110799536B
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Abstract
本发明涉及适用于抗癌治疗的针对SIRPα的抗体。本发明还涉及抗SIRPα抗体(任选地与其他抗癌治疗剂组合)在治疗人实体瘤和恶性血液病中的用途。该抗SIRPα抗体比已知的抗SIRPα抗体更具特异性,而它们对SIRPα1和SIRPαBIT二者均显示出优异的亲和力。在一个实施方案中,抗SIRPα抗体不与SIRPγ结合。在第二个实施方案中,抗SIRPα抗体不与SIRPγ结合并且不与SIRPβ1v1结合。在第三个实施方案中,抗SIRPα抗体不与SIRPγ结合并且不与SIRPβ1v2结合。在第四个实施方案中,抗SIRPα抗体不与SIRPβ1v1结合。
Description
技术领域
本发明涉及针对SIRPα的抗体,以及这些抗体(任选地与其他抗癌治疗剂组合)在治疗癌症中的用途。
背景技术
自20世纪90年代末以来,治疗性抗体已可用于治疗癌症。这些治疗性抗体可通过不同的途径对恶性细胞起作用。通过抗体与其恶性细胞上的靶标结合所触发的信号传导途径导致细胞增殖的抑制或凋亡。治疗性抗体的Fc区可触发补体依赖性细胞毒性(complement dependent cytotoxicity,CDC)、抗体依赖性细胞毒性(antibody-dependentcellular cytotoxicity,ADCC)和抗体依赖性细胞吞噬(antibody-dependent cellularphagocytosis,ADCP)。然而,治疗性抗体作为单一治疗通常不够有效。改善治疗性抗体效力的一种选择是通过改善ADCC和/或ADCP。这已通过改善Fc区对Fcγ受体的亲和力(例如通过氨基酸替换)(Richards等,Mol.Cancer Ther.2008,7(8),2517-2527)或通过影响Fc区的糖基化(Hayes等,J.Inflamm.Res.2016,9,209-219)实现。
改善治疗性抗体的ADCC和/或ADCP的另一种方法是通过将治疗性抗体与针对信号调节蛋白α的拮抗性抗体(抗SIRPα)或抗CD47抗体组合(WO2009/131453)。当CD47与在单核细胞、巨噬细胞、树突细胞和嗜中性粒细胞上表达的抑制性免疫受体SIRPα结合时,SIRPα传送防止通过吞噬作用或免疫效应细胞的其他Fc受体依赖性细胞破坏机制破坏癌细胞的抑制信号。
肿瘤细胞利用CD47的上调作为逃避由治疗性抗体诱导的抗肿瘤免疫应答的机制。抗CD47或抗SIRPα抗体阻断通过CD47-SIRPα轴产生的抑制性信号传导,导致ADCC和/或ADCP的提高。
与CD47-SIRPα相互作用相关的大多数临床研究都集中在抗CD47抗体作为单一治疗和作为与治疗性抗体组合的治疗二者上(Weiskopf.Eur.J.Cancer 2017,76,100-109)。尽管事实上CD47也在大多数正常组织中的细胞表面上表达,但有关抗CD47抗体作为抗癌治疗剂的研究正在增多。
对使用抗SIRPα抗体的抗癌单一治疗或组合治疗进行的研究很少。关于抗SIRPα抗体的大部分工作是有关CD47-SIRPα相互作用的机制研究并且已使用鼠抗SIRPα抗体进行;例如鼠12C4和1.23A提高嗜中性粒细胞介导的曲妥珠单抗(trastuzumab)调理的SKBR3细胞的ADCC(Zhao等,PNAS 2011,108(45),18342-18347)。WO2015/138600公开了提高i.a.西妥昔单抗(cetuximab)的体外吞噬的鼠抗人SIRPα抗体KWAR23及其嵌合Fab片段。WO2018/026600中公开了具有包含N297A突变的人IgG1 Fc部分的人源化KWAR23。WO2013/056352公开了IgG4 29AM4-5和其他IgG4人抗SIRPα抗体。IgG4 29AM4-5以8mg/kg每周给药三次,持续四周,降低了注射到NOD严重联合免疫缺陷病(scid)γ(NSG)小鼠右股骨中的原发性人AML细胞的白血病移植(engraftment)。
SIRPα是信号调节蛋白(signal regulatory protein,SIRP)家族的成员,该信号调节蛋白是存在于免疫效应细胞上具有胞外Ig样结构域的跨膜糖蛋白。SIRPα的NH2-末端配体结合结构域是高度多态的(Takenaka等,Nature Immun.2007,8(12),1313-1323)。然而,这种多态性不会显著影响与CD47的结合。SIRPαBIT(v1)和SIRPα1(v2)是两种最常见且最不同的(13个残基不同)多态物(polymorph)(Hatherley等,J.Biol.Chem.2014,289(14),10024-10028)。其他生物化学特征化的人SIRP家族成员是SIRPβ1和SIRPγ。
SIRPβ1不与CD47结合(van Beek等,J.Immunol.2005,175(12),7781-7787,7788-7789)并且至少两种SIRPβ1多态变体是已知的,SIRPβ1v1(ENSP00000371018)和SIRPβ1v2(ENSP00000279477)。尽管尚不清楚SIRPβ1的天然配体,但是使用抗SIRPβ1特异性抗体的体外研究显示,SIRPβ1的参与通过诱导DAP12、Syk和SLP-76的酪氨酸磷酸化以及随后MEK-MAPK-肌球蛋白轻链激酶级联的激活来促进巨噬细胞的吞噬作用(Matozaki等,J.Biol.Chem.2004,279(28),29450-29460)。
SIRPγ在T细胞和活化的NK细胞上表达,并且与SIRPα相比,SIRPγ以低10倍的亲和力结合CD47。CD47-SIRPγ相互作用参与抗原呈递细胞与T细胞之间的接触,共刺激T细胞活化并促进T细胞增殖(Piccio等,Blood 2005,105,2421-2427)。此外,CD47-SIRPγ相互作用在T细胞的跨内皮迁移中发挥作用(Stefanisakis等,Blood 2008,112,1280-1289)。
本领域中已知的抗SIRPα抗体不太适用于SIRPα指导的单一治疗或组合治疗,因为它们对人SIRPα不具有特异性,或者它们太具有特异性。现有技术抗体KWAR23、SE5A5、29AM4-5和12C4不具有特异性,因为它们也与人SIRPγ结合。与在T细胞上表达的SIRPγ结合可能会不利地影响T细胞增殖和募集。其他抗SIRPα抗体的特异性太有限,例如1.23A mAb仅识别人SIRPα多态变体SIRPα1且不识别在至少高加索人群(Caucasian population)中占主导地位的变体SIRPαBIT(X.W.Zhao等,PNAS 2011,108(45),18342-18347)。
除使用抗SIRPα抗体提高治疗性抗体的ADCC之外,这些抗体还可用于直接靶向表达SIRPα的癌症类型。包含野生型人-Fc的抗SIRPα抗体可能适合于治疗表达SIRPα的癌症,例如肾细胞癌和恶性黑素瘤,因为具有功能性Fc区的鼠抗SIRPα抗体在用Renca细胞和B16BL6黑素瘤细胞(二者均表达SIRPα)注射的小鼠中减慢了肿瘤形成(Yanagita等,JCIInsight 2017,2(1),e89140)。
总之,仍然需要这样的抗SIRPα抗体,其具有与SIRPγ的低结合,与SIRPα1和SIRPαBIT多态变体二者特异性结合并且适合单独或与治疗性抗体组合用于抗癌治疗。
发明简述
本发明涉及适合用于抗癌治疗的针对SIRPα的抗体。本发明还涉及该抗体在治疗人实体瘤(solid tumour)和恶性血液病(haematological malignancie)中的用途。
附图简述
图1.使用人嗜中性粒细胞作为效应细胞,在SKBR3 HER2阳性乳腺癌细胞上测量的对以下的%细胞毒性测量的ADCC的比较:单独的曲妥珠单抗(Tmab)、与鼠12C4抗SIRPα抗体(mu12C4)组合的曲妥珠单抗、与其中鼠12C4可变区被移植到人IgG1恒定区上的抗体(12C4huIgG1)组合的曲妥珠单抗,以及与其中鼠12C4可变区被移植到包含氨基酸替换L234A和L235A的人IgG1恒定区上的抗体(12C4huIgG1LALA)组合的曲妥珠单抗。
图2.在SKBR3细胞上,相对于曲妥珠单抗(设置为100%),对与以下组合的曲妥珠单抗的%ADCC的比较:具有包含氨基酸替换L234A和L235A的人IgG1恒定区的抗SIRPα抗体1至9,抗SIRPα抗体12C4huIgG1LALA(12C4LALA),以及抗CD47抗体B6H12huIgG1LALA(B6H12LALA)。实心正方形(■)是用具有SIRPαBIT变体之供体的嗜中性粒细胞测量的值,空心圆(○)是用具有SIRPα1变体的供体的嗜中性粒细胞测量的值。柱是所有供体的平均值;误差棒表示标准偏差。
图3.在SKBR3细胞上,相对于单独的曲妥珠单抗和与以下组合的曲妥珠单抗的%ADCC的比较:多种浓度(剂量响应曲线)的抗SIRPα抗体4、7、10、14(具有包含氨基酸替换L234A和L235A的人IgG1恒定区),以及抗SIRPα抗体12C4huIgG1LALA(12C4LALA)。具有SIRPαBIT变体的两个供体(△,○)的嗜中性粒细胞。柱是两个供体的平均值。
图4.在SKBR3细胞上,相对于单独的曲妥珠单抗和与以下组合的曲妥珠单抗的%ADCC的比较:抗SIRPα抗体4、7、10、13、14、15和16(具有包含氨基酸替换L234A和L235A的人IgG1恒定区),以及抗SIRPα抗体12C4huIgG1LALA(12C4LALA)。使用具有SIRPαBIT变体(△,◇)、具有SIRPα1变体(○,/>)的供体的嗜中性粒细胞和未确定变体(□)的供体的嗜中性粒细胞。柱是供体的平均值。
发明详述
没有可用的针对SIRPα的经批准治疗剂,尽管已显示该靶标在肿瘤免疫逃逸机制中发挥重要作用。另外,SIRPα在多种恶性细胞上表达,使其成为潜在的肿瘤相关抗原。
本发明涉及拮抗性抗SIRPα抗体,其对两种主要的SIRPα多态变体SIRPαBIT和SIRPα1表现出特异性结合,该抗SIRPα抗体不与SIRPγ结合并且提高治疗性抗体的ADCC和/或ADCP。
本说明书通篇使用的术语“抗体”是指包含两条重链和两条轻链的单克隆抗体(mAb)。抗体可以是任何同种型,例如IgA、IgE、IgG或IgM抗体。优选地,抗体是IgG抗体,更优选IgG1或IgG2抗体。抗体可以是嵌合的、人源化的或人的。优选地,本发明的抗体是人源化的。甚至更优选地,抗体是人源化的或人IgG抗体,最优选人源化或人IgG1 mAb。抗体可具有κ(kappa)或λ(lambda)轻链,优选κ(kappa)轻链,即人源化或人IgG1-κ抗体。抗体可包含经改造的恒定区,即,可引入一种或更多种突变以例如提高半衰期、和/或提高或降低效应物功能。
本文中使用的术语“单克隆抗体”和“mAb”是指从基本上同质的抗体群体中获得的抗体,即除可能以少量存在的可自然发生的突变之外,构成该群体的各抗体是相同的。可通过用代表所期望抗原的肽的混合物对动物进行免疫接种来产生抗体。将B淋巴细胞分离并与骨髓瘤细胞融合,或者将单个B淋巴细胞在存在条件培养基和饲养细胞的情况下培养数天。对包含产生的抗体的骨髓瘤或B淋巴细胞上清液进行测试以选择合适的B淋巴细胞或杂交瘤细胞。可通过由等,Nature 1975,256,495-497首先描述的杂交瘤方法从合适的杂交瘤细胞制备单克隆抗体。或者,可裂解合适的B细胞或淋巴瘤的RNA,可将RNA分离、反转录和测序。可通过在细菌、真核动物或植物细胞中的重组DNA方法来制备抗体(参见,例如,美国专利No.4,816,567)。还可使用本领域中例如在Clackson等,Nature 1919,352,624-628和Marks等,J.Mol.Biol.1991,222,581-597中描述的技术从噬菌体抗体文库分离“单克隆抗体”。
本说明书通篇使用的术语“抗原结合片段”包括Fab、Fab′或F(ab′)2片段、单链(sc)抗体、scFv、单结构域(sd)抗体、双抗体(diabody)或微抗体(minibody)。
在人源化抗体中,重链(HC)和轻链(LC)的可变区(VR)中的抗原结合互补决定区(CDR)来源于来自通常为小鼠、大鼠或兔的非人物种的抗体。这些非人CDR与HC和LC的可变区的人框架区(FR1、FR2、FR3和FR4)组合,以这样的方法保留抗体的功能特性,例如结合亲和力和特异性。在人FR中所选择的氨基酸可交换为相应的原始非人物种氨基酸以改善结合亲和力,同时保留低免疫原性。或者,原始非人物种FR中所选择的氨基酸交换为其相应的人氨基酸以降低免疫原性,同时保留抗体的结合亲和力。将如此人源化的可变区与人恒定区组合。
CDR可使用以下的方法来确定:Kabat(在Kabat,E.A.等,Sequences of Proteinsof Immunological Interest,第五版.Public Health Service,National Institutes ofHealth,Bethesda,MD.,NIH出版no.91-3242,第662、680、689页(1991)中)、Chothia(Chothia等,Nature 1989,342,877-883)或IMGT(Lefranc,The Immunologist 1999,7,132-136)。在本发明的上下文中,Eu编号用于指示抗体的重链和轻链恒定区中的位置。表述“Eu编号”是指Eu指数,如在Kabat E.A.等,Sequences of Proteins of ImmunologicalInterest,第五版.Public Health Service,National Institutes of Health,Bethesda,MD.,NIH出版号.91-3242,第662、680、689页(1991)中。
拮抗性抗体对特定抗原具有亲和力,并且抗体与其抗原的结合抑制受体上激动剂或反向激动剂的功能。在目前情况下,拮抗性抗SIRPα抗体与SIRPα的结合将防止CD47与SIRPα的结合或使由CD47-SIRPα结合触发的抑制信号中断。
拮抗性抗SIRPα抗体可与CD47结合的相同位点结合,防止CD47对SIRPα的连接并因此抑制负调节免疫效应细胞的Fc受体依赖性作用的信号传导。拮抗性抗SIRPα抗体还可与不同于CD47的结合位点的SIRPα的位点(即,别构位点(allosteric site))结合,并在不直接干扰物理的CD47-SIRPα相互作用的情况下抑制SIRPα的抑制性信号传导,例如,SIRPα的三维形状变化。这种三维形状变化阻止了在与CD47结合之后的(下游)信号传导。当SIRPα在别构位点结合时,CD47仍可以被SIRPα结合,这可导致CD47不那么可用于与血小板反应蛋白1(thrombospondin-1,TSP-1)结合。TSP-1与CD47的连接在例如T细胞活化的负调控中发挥作用(Soto-Pantoja等,Crit.Rev.Biochem.Mol.Biol.2015,50(3),212-230)。
本说明书通篇使用的术语“结合亲和力”是指特定抗原-抗体相互作用的解离常数(dissociation constant,KD)。KD是解离速率(koff)与结合速率(kon)的比值。因此,KD等于koff/kon并表示为摩尔浓度(M)。由此可见,KD越小,结合的亲和力越强。通常来说,KD值通过使用表面等离子体共振(surface plasmon resonance,SPR),通常使用生物传感器系统(例如,)使用本领域已知的方法来确定(例如,E.S.Day等,Anal.Biochem.2013,440,96-107)。术语“结合亲和力”还可以指用例如ELISA测定确定的或如通过流式细胞术确定的产生半最大结合的抗体浓度(EC50)。
本说明书通篇使用的术语“特异性结合”涉及抗体与其抗原之间以通常小于10-7M,例如10-8M、10-9M、10-10M、10-11M或甚至更低的KD的结合,如在25℃下由SPR确定的。
本说明书通篇使用的术语“低亲和力”可与术语“不结合”或“不与......结合”互换,并且是指抗体与其抗原之间以EC50大于1500ng/ml的结合亲和力,如使用ELISA测定确定的,或者其中在经固定的抗原与抗体之间未观察到特异性结合,如由SPR测定的。
本说明书通篇使用的术语“高亲和力”是指抗体与其抗原之间通常小于10-10M、10-11M或甚至更低的KD的结合亲和力,如在25℃由SPR确定的。
特别地,本发明涉及包含选自以下的重链(HC)和轻链(LC)可变区(VR)互补决定区(CDR)的抗SIRPα抗体或其抗原结合片段:
a.SEQ ID NO:1的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:2的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:3的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:4的CDR1、CDR2和CDR3氨基酸序列;
c.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
d.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;
e.SEQ ID NO:9的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:10的CDR1、CDR2和CDR3氨基酸序列;
f.SEQ ID NO:11的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:12的CDR1、CDR2和CDR3氨基酸序列;
g.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列;
h.SEQ ID NO:15的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:16的CDR1、CDR2和CDR3氨基酸序列;以及
i.SEQ ID NO:17的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:18的CDR1、CDR2和CDR3氨基酸序列,
其中CDR根据Kabat编号确定。
优选地,本发明涉及包含选自以下的重链(HC)和轻链(LC)可变区(VR)互补决定区(CDR)的抗SIRPα抗体或其抗原结合片段:
a.SEQ ID NO:3的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:4的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
c.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;
d.SEQ ID NO:9的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:10的CDR1、CDR2和CDR3氨基酸序列;
e.SEQ ID NO:11的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:12的CDR1、CDR2和CDR3氨基酸序列;
f.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列;
g.SEQ ID NO:15的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:16的CDR1、CDR2和CDR3氨基酸序列;以及
h.SEQ ID NO:17的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:18的CDR1、CDR2和CDR3氨基酸序列,
其中CDR根据Kabat编号确定。
更优选地,本发明涉及包含选自以下的HCVR CDR和LCVR CDR的抗SIRPα抗体或其抗原结合片段:
a.SEQ ID NO:3的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:4的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
c.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;
d.SEQ ID NO:9的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:10的CDR1、CDR2和CDR3氨基酸序列;以及
e.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列,
其中CDR根据Kabat编号确定。
甚至更优选地,本发明涉及包含选自以下的HCVR CDR和LCVR CDR的抗SIRPα抗体或其抗原结合片段:
a.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;以及
c.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列,
其中CDR根据Kabat编号确定。
最优选地,本发明涉及包含选自以下的HCVR CDR和LCVR CDR的抗SIRPα抗体或其抗原结合片段:
a.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;以及
b.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列,
其中CDR根据Kabat编号确定。
在一个优选实施方案中,本发明涉及如上文所限定的抗SIRPα抗体或其抗原结合片段,其中所述抗体显示出与SIRPαBIT和SIRPα1二者的特异性结合,并且不与SIRPγ结合。
在一个更优选的实施方案中,抗SIRPα抗体或其抗原结合片段以低于10-9M的KD与SIRPαBIT特异性结合,并且以低于10-7M的KD与SIRPα1结合,其中KD是在25℃下用SPR测量的。优选地,抗SIRPα抗体或其抗原结合片段以低于10-8M的KD与SIRPα1结合。
在另一个更优选的实施方案中,抗SIRPα抗体或其抗原结合片段以低于10-9M的KD与SIRPαBIT和SIRPα1特异性结合,其中KD是在25℃下用SPR测量的。
在一个甚至更优选的实施方案中,抗SIRPα抗体或其抗原结合片段以低于10-10M的KD与SIRPαBIT和SIRPα1特异性结合。优选地,抗SIRPα或其抗原结合片段抗体以低于10-10M的KD与SIRPαBIT特异性结合且以低于10-11M的KD与SIRPα1结合。通常来说,如上文所限定的抗SIRPα抗体是嵌合的、人源化的或人抗体。优选地,抗SIRPα抗体是人源化或人抗体。更优选地,抗SIRPα抗体是人源化抗体。在一个具体实施方案中,根据本发明的人源化的抗SIRPα抗体或其抗原结合片段包含选自以下的HCVR和LCVR:
a.SEQ ID NO:30的HCVR氨基酸序列和SEQ ID NO:31的LCVR氨基酸序列;
b.SEQ ID NO:32的HCVR氨基酸序列和SEQ ID NO:33的LCVR氨基酸序列;
c.SEQ ID NO:34的HCVR氨基酸序列和SEQ ID NO:8的LCVR氨基酸序列;
d.SEQ ID NO:35的HCVR氨基酸序列和SEQ ID NO:36的LCVR氨基酸序列;
e.SEQ ID NO:35的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列;
f.SEQ ID NO:13的HCVR氨基酸序列和SEQ ID NO:38的LCVR氨基酸序列;以及
g.SEQ ID NO:13的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列。
在一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:30的HCVR氨基酸序列和SEQ ID NO:31的LCVR氨基酸序列。
在另一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:32的HCVR氨基酸序列和SEQ ID NO:33的LCVR氨基酸序列。
在另一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:34的HCVR氨基酸序列和SEQ ID NO:8的LCVR氨基酸序列。
在另一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:35的HCVR氨基酸序列和SEQ ID NO:36的LCVR氨基酸序列。
在另一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:35的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列。
在另一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:13的HCVR氨基酸序列和SEQ ID NO:38的LCVR氨基酸序列。
在另一个优选实施方案中,人源化的抗SIRPα抗体或其抗原结合片段包含SEQ IDNO:13的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列。
除与人(hu)SIRPαBIT和(hu)SIRPα1二者结合之外,根据本发明的抗体还可与食蟹猴(cy)SIRPα结合,使得能够在相关动物模型中进行体内研究。
根据本发明的抗体可与不同于CD47的结合位点的SIRPα的位点(即,别构位点)结合,并在不直接干扰物理的CD47-SIRPα相互作用的情况下抑制SIRPα的抑制性信号传导。或者,抗体可与CD47结合的相同位点结合,防止CD47对SIRPα的连接并因此抑制负调节免疫效应细胞的Fc受体依赖性作用的信号传导。
如上文所述的抗SIRPα抗体或其抗原结合片段比已知的抗SIRPα抗体更具特异性,并且对SIRPαBIT和SIRPα1二者显示出良好的亲和力。同样地,根据本发明的抗SIRPα抗体不与SIRPγ结合。
在一个具体实施方案中,根据本发明的抗SIRPα抗体包含与人免疫效应细胞上存在的激活性Fc受体(activating Fc receptor)结合的Fc区。这样的抗SIRPα抗体适合于SIRPα阳性人实体瘤和恶性血液病的单一治疗,因为其可诱导ADCC和/或ADCP。人免疫效应细胞具有多种激活性Fc受体,其一经连接就触发吞噬作用、细胞因子释放、ADCC和/或ADCP等。这些受体的实例是Fcγ受体,例如FcγRI(CD64)、FcγRIIA(CD32)、FcγRIIIA(CD16a)、FcγRIIIB(CD16b)、FcγRIIC和Fcα受体FcαRI(CD89)。多种天然抗体同种型与这些受体结合。例如,IgG1与FcγRI、FcγRIIA、FcγRIIC、FcγRIIIA、FcγRIIIB结合;IgG2与FcγRIIA、FcγRIIC、FcγRIIIA结合;IgG3与FcγRI、FcγRIIA、FcγRIIC、FcγRIIIA、FcγRIIIB结合;IgG4与FcγRI、FcγRIIA、FcγRIIC、FcγRIIIA结合;以及IgA与FcαRI结合。
在一个优选实施方案中,根据本发明的抗SIRPα抗体包含IgA或IgG同种型的Fc区。更优选的是包含IgG1、IgG2、IgG3或IgG4同种型的Fc区的抗SIRPα抗体;甚至更优选IgG1、IgG2或IgG4同种型。最优选的是包含IgG1同种型的Fc区的抗SIRPα抗体。
尽管包含与人免疫效应细胞上存在的激活性Fc受体结合的Fc区的抗SIRPα抗体可能适合治疗表达SIRPα的癌症,但当与包含与人免疫效应细胞上存在的激活性Fc受体结合的人Fc区的其他抗体(即能够诱导ADCC和/或ADCP的抗体)组合在体外测试时,嵌合的抗SIRPα IgG1抗体没有显示出预期结果。体外ADCC测定的结果显示,基于使用鼠抗体的早期结果,嵌合的IgG1抗SIRPα抗体并未像预期那样多地提高这样的其他抗体的ADCC。
因此,本发明涉及对人免疫效应细胞上存在的激活性Fc受体表现出降低的结合或低亲和力的抗SIRPα抗体。这样的抗SIRPα抗体包含经修饰的Fc区,其中当与相似的未经修饰的Fc区相比,一个或更多个氨基酸已被其他氨基酸替换。降低的结合意味着包含经修饰的Fc区的抗SIRPα抗体对激活性Fc受体的亲和力小于具有包含相似的未经修饰的Fc区的相同可变区的抗SIRPα抗体的亲和力。通常使用表面等离子体共振(SPR)或流式细胞术,使用本领域已知的方法,例如Harrison等,在J.Pharm.Biomed.Anal.2012,63,23-28中的方法来测量抗体对激活性Fc受体的结合亲和力。与治疗性抗体组合的、对人Fcα或Fcγ受体表现出降低的结合或低亲和力的抗体,通过提高效应免疫效应细胞的ADCC和/或ADCP而在癌细胞的细胞破坏中特别有效。通常来说,根据本发明的抗SIRPα抗体的Fc区经修饰以降低与人免疫效应细胞上存在的激活性Fc受体的结合。
因此,根据本发明的抗SIRPα抗体包含对人Fcα或Fcγ受体表现出降低的结合或低亲和力的经修饰的Fc区。例如,通过替换选自L234、L235、G237、D265、D270、N297、A327、P328和P329(Eu编号)的一个或更多个IgG1氨基酸可降低IgG1与Fcγ受体的结合;通过引入例如一个或更多个以下氨基酸替换V234A、G237A、P238S、H268A、V309L、A330S和P331S,或者H268Q、V309L、A330S和P331S(与IgG1 Eu编号类似的编号)可降低IgG2结合(Vafa等,Methods2014,65,114-126);通过引入例如氨基酸替换L234A和L235A或氨基酸替换L234A、L235A和P331S可降低IgG3结合(Leoh等,Mol.Immunol.2015,67,407-415);以及通过引入例如氨基酸替换S228P、F234A和L235A((与IgG1 Eu编号类似的编号)可降低IgG4结合(Parekh等,mAbs2012,4(3),310-318)。通过引入例如氨基酸替换L257R、P440A、A442R、F443R和P440R(顺序编号)中的一个或更多个可降低IgA与Fcα受体的结合(Pleass等,J.Biol.Chem.1999,271(33),23508-23514)。
优选地,根据本发明的抗SIRPα抗体包含对人Fcγ受体表现出降低的结合或低亲和力的经修饰的Fc区。更优选地,经修饰的Fc区是IgG同种型的Fc区。甚至更优选地,经修饰的Fc区是IgG1、IgG2或IgG4同种型的Fc区。
在一个优选实施方案中,根据本发明的抗SIRPα抗体包含经修饰的人IgG1 Fc区,所述经修饰的人IgG1 Fc区包含在选自L234、L235、G237、D265、D270、N297、A327、P328和P329(Eu编号)中的一个或更多个位置处的一个或更多个氨基酸替换。
优选地,抗SIRPα抗体包含经修饰的Fc IgG1区,其不包含氨基酸替换N297A或N297G。更优选地,抗SIRPα抗体包含经修饰的Fc IgG1区,其不包含在位置N297处的氨基酸替换。
在一个实施方案中,经修饰的人IgG1 Fc区包含选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、D270A、D270E、D270N、N297A、N297G、A327Q、P328A、P329A和P329G的一个或更多个氨基酸替换。优选地,一个或更多个氨基酸替换选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、N297A、P328A、P329A和P329G。
在另一个实施方案中,经修饰的人IgG1 Fc区包含选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、D270A、D270E、D270N、A327Q、P328A、P329A和P329G的一个或更多个氨基酸替换。优选地,所述一个或更多个氨基酸替换选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、P328A、P329A和P329G。更优选地,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。甚至更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
在一个优选实施方案中,经修饰的人IgG1 Fc区包含氨基酸替换L234A和L235A、L234E和L235A、L234A、L235A和P329A或L234A、L235A和P329G。优选地,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
在另一个优选实施方案中,根据本发明的抗SIRPα抗体包含经修饰的人IgG1 Fc区,其包含氨基酸替换L234A和L235A或者L234E和L235A,优选氨基酸替换L234A和L235A。更优选地,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。甚至更优选地,经修饰的FcIgG1区不包含在位置N297处的氨基酸替换。
本发明还涉及包含如上文所述的抗SIRPα抗体和一种或更多种可药用赋形剂的药物组合物。治疗性蛋白质(例如,抗体)的典型药物制剂采用需要在静脉内输注之前(水性)溶解(即重构)的冻干块(冻干粉末)或者需要在使用之前解冻的冷冻(水性)溶液的形式。
通常来说,药物组合物以冻干块的形式提供。用于包含在根据本发明的药物组合物中(在冷冻干燥之前)的合适可药用赋形剂包括缓冲溶液(例如,在水中的包含柠檬酸盐、组氨酸或琥珀酸盐的盐)、冻干保护剂(例如,蔗糖、海藻糖)、张力调节剂(例如,氯化钠)、表面活性剂(例如,聚山梨酯)和填充剂(bulking agent)(例如,甘露醇、甘氨酸)。用于冷冻干燥的蛋白质制剂的赋形剂根据其在冷冻干燥过程期间和在储存期间防止蛋白质变性的能力进行选择。
本发明还涉及如上文所述的抗SIRPα抗体或药物组合物,其用作药物。
在一个实施方案中,本发明涉及如上文所述的抗SIRPα抗体或药物组合物,其用于治疗人实体瘤和恶性血液病。本发明的抗SIRPα抗体可用于治疗实体瘤,例如乳腺癌、肾癌或黑素瘤,或者恶性血液病例如急性髓性白血病(Acute Myeloid Leukaemia,AML)。
在第二个实施方案中,本发明涉及包含与人免疫效应细胞上存在的激活性Fc受体结合的Fc区的抗SIRPα抗体,其用于治疗SIRPα阳性人实体瘤和恶性血液病。优选地,与人免疫效应细胞上存在的激活性Fc受体结合的Fc区是IgA或IgG同种型的Fc区。更优选的是包含IgG1、IgG2、IgG3或IgG4同种型的Fc区的抗SIRPα抗体;甚至更优选IgG1、IgG2或IgG4同种型。最优选的是包含IgG1同种型的Fc区的抗SIRPα抗体,其用于治疗SIRPα阳性人实体瘤和恶性血液病。
在第三个实施方案中,本发明涉及如上文所述的抗SIRPα抗体或药物组合物,其与一种或更多种其他抗癌治疗剂的使用组合用于治疗人实体瘤和恶性血液病。合适的抗癌治疗是外科手术、化学治疗、放射治疗、激素治疗、靶向治疗和免疫治疗。如上文所述的抗SIRPα抗体或药物组合物可与一种或更多种其他抗癌治疗剂的使用组合地同时或依次用于治疗人实体瘤和恶性血液病。特别地,如上文所述的抗SIRPα抗体或药物组合物可在使用一种或更多种其他抗癌治疗剂之后用于治疗人实体瘤和恶性血液病。
优选地,本发明涉及如上文所述的抗SIRPα抗体或药物组合物,其与一种或更多种其他抗癌治疗剂的使用组合用于治疗人实体瘤和恶性血液病。特别地,如上文所述的抗SIRPα抗体或药物组合物可在使用一种或更多种其他抗癌治疗剂之后用于治疗人实体瘤和恶性血液病。
合适的抗癌治疗剂包括化学治疗剂、放射治疗剂、激素治疗剂、靶向治疗剂和免疫治疗剂。合适的化学治疗剂包括烷化剂,例如氮芥、亚硝基脲、四嗪类和氮丙啶类;抗代谢产物类,例如抗叶酸、氟嘧啶、脱氧核苷类似物和硫嘌呤;抗微管剂,例如长春花生物碱类和紫杉烷类;拓扑异构酶I和II抑制剂;以及细胞毒性抗生素,例如蒽环类和博来霉素(bleomycin)。
合适的放射治疗剂包括放射性同位素,例如131I-间碘苄胍(MIBG)、32P作为磷酸钠、223Ra氯化物、89Sr氯化物和153Sm二胺四亚甲基膦酸酯/盐(EDTMP)。
用作激素治疗剂的合适试剂包括激素合成抑制剂,例如芳香酶抑制剂和GnRH类似物;以及激素受体拮抗剂,例如选择性雌激素受体调节剂和抗雄激素。
靶向治疗剂是干扰参与肿瘤发生和增殖的特定蛋白质的治疗剂,并且可能是小分子药物;蛋白质,例如治疗性抗体;肽和肽衍生物;或者蛋白质-小分子杂合体,例如抗体-药物缀合物。靶向小分子药物的实例包括mTor抑制剂,例如依维莫司、替西罗莫司和雷帕霉素;激酶抑制剂,例如伊马替尼、达沙替尼和尼洛替尼;VEGF抑制剂,例如索拉非尼和瑞戈非尼;以及EGFR/HER2抑制剂,例如吉非替尼、拉帕替尼和厄洛替尼。肽或肽衍生物靶向治疗剂的实例包括蛋白酶体抑制剂,例如硼替佐米和卡非佐米。
免疫治疗剂包括诱导、增强或抑制免疫应答的试剂,例如细胞因子(IL-2和IFN-α);免疫调节酰亚胺药物,例如沙利度胺、来那度胺和泊马度胺(pomalidomide);治疗性癌症疫苗,例如talimogene laherparepvec;基于细胞的免疫治疗剂,例如树突细胞疫苗、过继性T细胞和嵌合抗原受体修饰的T细胞;以及当与癌细胞上的膜结合配体结合时可通过其Fc区触发ADCC/ADCP或CDC的治疗性抗体。
优选地,本发明涉及如上文所述的抗SIRPα抗体或药物组合物,其与一种或更多种其他抗癌治疗剂组合用于治疗人实体瘤和恶性血液病,其中所述抗癌治疗剂是靶向治疗剂或免疫治疗剂。根据本发明优选的靶向治疗剂是治疗性抗体或抗体-药物缀合物(antibody-drug conjugate,ADC)。最优选的靶向治疗剂是治疗性抗体。
本说明书通篇使用的术语“治疗性抗体”是指适用于人治疗的如上文所限定的抗体或其抗原结合片段。适用于人治疗的抗体是具有足够的品质、安全并有效用于治疗特定的人疾病的抗体。品质可使用已建立的良好操作规范(Good Manufacturing Practice,GMP)指南来评估;安全性和有效性通常使用已建立的药品监管当局(例如欧洲药品管理局(European Medicines Agency,EMA)或美国食品药品监督管理局(United States Foodand Drug Administration,FDA))指南来评估。这些指南是本领域公知的。
优选地,治疗性抗体是经药品监管当局例如EMA或FDA批准的抗体。可查阅大多数监管当局的在线数据库以确定抗体是否获得批准。
本说明书通篇使用的术语“ADC”是指经由接头与如上文所限定的抗体或其抗原结合片段缀合的细胞毒性药物。通常来说,细胞毒性药物是高度有效的,例如倍癌霉素(duocarmycin)、加利车霉素(calicheamicin)、吡咯并苯并二氮(PBD)二聚体、美登木素生物碱(maytansinoid)或奥瑞他汀(auristatin)衍生物。接头可以是可切割的,例如包含可切割的二肽缬氨酸-瓜氨酸(vc)或缬氨酸-丙氨酸(va);或者是不可切割的,例如琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)。
通常,与根据本发明的抗SIRPα抗体组合使用的治疗性抗体是包含与选自以下的靶标结合的至少一种HCVR和LCVR的单特异性或双特异性抗体或抗体片段:膜联蛋白A1、B7H3、B7H4、CA6、CA9、CA15-3、CA19-9、CA27-29、CA125、CA242、CCR2、CCR5、CD2、CD19、CD20、CD22、CD30、CD33、CD37、CD38、CD40、CD44、CD47、CD56、CD70、CD74、CD79、CD115、CD123、CD138、CD203c、CD303、CD333、CEA、CEACAM、CLCA-1、CLL-1、c-MET、Cripto、CTLA-4、DLL3、EGFL、EGFR、EPCAM、EPh(例如,EphA2或EPhB3)、内皮素B受体(ETBR)、FAP、FcRL5(CD307)、FGF、FGFR(例如,FGFR3)、FOLR1、GCC、GPNMB、HER2、HMW-MAA、整联蛋白α(例如,ανβ3和ανβ5)、IGF1R、TM4SF1(或L6抗原)、路易斯A类碳水化合物、路易斯X、路易斯Y、LIV1、间皮蛋白、MUC1、MUC16、NaPi2b、连接蛋白-4、PD-1、PD-L1、PSMA、PTK7、SLC44A4、STEAP-1、5T4抗原(或TPBG、滋养层糖蛋白)、TF(组织因子)、Thomsen-Friedenreich抗原(TF-Ag)、Tag72、TNF、TNFR、TROP2、VEGF、VEGFR和VLA。
优选的是单特异性治疗性抗体。更优选的是针对肿瘤细胞表面上的膜结合靶标的抗体。
与根据本发明的抗SIRPα抗体组合使用的合适的治疗性抗体包括阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)和曲妥珠单抗。
与根据本发明的抗SIRPα抗体组合使用的合适的ADC包括曲妥珠单抗美坦新(trastuzumab emtansine)和本妥昔单抗(brentuximab vedotin)。
在一个优选实施方案中,本发明涉及如上文所述的抗SIRPα抗体,其用于与治疗性抗体组合的前述用途中,所述治疗性抗体针对肿瘤细胞表面上的膜结合靶标,其包含与人免疫效应细胞上存在的激活性Fc受体结合的人Fc区。
通过与上文所述的这些激活性Fc受体结合,包含与人免疫效应细胞上存在的激活性Fc受体结合的人Fc区的治疗性抗体可诱导ADCC和/或ADCP。人IgG、IgE或IgA同种型的治疗性抗体包含与人免疫效应细胞上存在的激活性Fc受体结合的人Fc区。
根据本发明使用的优选的治疗性抗体是IgG或IgA同种型的治疗性抗体。更优选的是IgG同种型的治疗性抗体,例如IgG1、IgG2、IgG3和IgG4抗体。甚至更优选的是IgG1或IgG2同种型的治疗性抗体。最优选的是IgG1同种型的治疗性抗体。
优选地,本发明涉及包含选自以下的HCVR CDR和LCVR CDR的人源化的抗SIRPα抗体:
a.SEQ ID NO:1的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:2的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:3的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:4的CDR1、CDR2和CDR3氨基酸序列;
c.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
d.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;
e.SEQ ID NO:9的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:10的CDR1、CDR2和CDR3氨基酸序列;
f.SEQ ID NO:11的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:12的CDR2和CDR3氨基酸序列;
g.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列;
h.SEQ ID NO:15的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:16的CDR1、CDR2和CDR3氨基酸序列;以及
i.SEQ ID NO:17的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:18的CDR1、CDR2和CDR3氨基酸序列,
所述抗SIRPα抗体与治疗性抗体的使用组合用于治疗人实体瘤和恶性血液病,所述治疗性抗体针对肿瘤细胞表面膜结合靶标,其包含与人免疫效应细胞上存在的激活性Fc受体结合的人Fc区,其中当与包含野生型Fc区的相同抗SIRPα抗体相比时,所述抗SIRPα抗体包含对人Fcα或Fcγ受体表现出降低的结合的经修饰的Fc区。
在一个优选实施方案中,与治疗性抗体组合用于治疗人实体瘤和恶性血液病的人源化的抗SIRPα抗体包含经修饰的人IgG1 Fc区,所述经修饰的人IgG1 Fc区在选自L234、L235、G237、D265、D270、N297、A327、P328和P329(Eu编号)的一个或更多个位置处包含一个或更多个氨基酸替换。
优选地,与治疗性抗体组合用于治疗人实体瘤和恶性血液病的人源化的抗SIRPα抗体包含经修饰的Fc IgG1区,其不包含氨基酸替换N297A或N297G。更优选地,抗SIRPα抗体包含经修饰的Fc IgG1区,其不包含在位置N297处的氨基酸替换。
在一个实施方案中,经修饰的人IgG1 Fc区包含选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、D270A、D270E、D270N、N297A、N297G、A327Q、P328A、P329A和P329G的一个或更多个氨基酸替换。
在另一个实施方案中,与治疗性抗体组合用于治疗人实体瘤和恶性血液病的人源化的抗SIRPα抗体包含经修饰的Fc IgG1区,所述经修饰的Fc IgG1区包含选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、D270A、D270E、D270N、A327Q、P328A、P329A和P329G的一个或更多个氨基酸替换。优选地,所述一个或更多个氨基酸替换选自L234A、L234E、L235A、G237A、D265A、D265E、D265N、P328A、P329A和P329G。更优选地,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。甚至更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
在一个优选实施方案中,经修饰的人IgG1 Fc区包含氨基酸替换L234A和L235A,L234E和L235A,L234A、L235A和P329A,或者L234A、L235A和P329G。优选地,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
在另一个优选实施方案中,与治疗性抗体组合用于治疗人实体瘤和恶性血液病的人源化的抗SIRPα抗体包含经修饰的人IgG1 Fc区,所述经修饰的人IgG1 Fc区包含氨基酸替换L234A和L235A或者L234E和L235A,优选氨基酸替换L234A和L235A。更优选地,经修饰的FcIgG1区不包含氨基酸替换N297A或N297G。甚至更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
在一个优选实施方案中,与治疗性抗体的使用组合用于治疗人实体瘤和恶性血液病的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区和HCVR CDR和LCVRCDR,所述治疗性抗体针对肿瘤细胞表面上的膜结合靶标,其包含与人免疫效应细胞上存在的激活性Fc受体结合的人Fc区,所述HCVR CDR和LCVR CDR选自以下:
a.SEQ ID NO:3的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:4的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
c.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;
d.SEQ ID NO:9的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:10的CDR1、CDR2和CDR3氨基酸序列;以及
e.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列。
在第二个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区和选自以下的HCVR CDR和LCVR CDR:
a.SEQ ID NO:5的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:6的CDR1、CDR2和CDR3氨基酸序列;
b.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;以及
c.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列。
在第三个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区和选自以下的HCVR CDR和LCVR CDR:
a.SEQ ID NO:7的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:8的CDR1、CDR2和CDR3氨基酸序列;以及
b.SEQ ID NO:13的CDR1、CDR2和CDR3氨基酸序列和SEQ ID NO:14的CDR1、CDR2和CDR3氨基酸序列。
在第四个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及
a.SEQ ID NO:30的HCVR氨基酸序列和SEQ ID NO:31的LCVR氨基酸序列;
b.SEQ ID NO:32的HCVR氨基酸序列和SEQ ID NO:33的LCVR氨基酸序列;
c.SEQ ID NO:34的HCVR氨基酸序列和SEQ ID NO:8的LCVR氨基酸序列;
d.SEQ ID NO:35的HCVR氨基酸序列和SEQ ID NO:36的LCVR氨基酸序列;
e.SEQ ID NO:35的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列;
f.SEQ ID NO:13的HCVR氨基酸序列和SEQ ID NO:38的LCVR氨基酸序列;或者
g.SEQ ID NO:13的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列。
在一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:30的HCVR氨基酸序列和SEQ ID NO:31的LCVR氨基酸序列。更优选地,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。甚至更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
在另一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:32的HCVR氨基酸序列和SEQ ID NO:33的LCVR氨基酸序列。
在另一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:34的HCVR氨基酸序列和SEQ ID NO:8的LCVR氨基酸序列。
在另一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:35的HCVR氨基酸序列和SEQ ID NO:36的LCVR氨基酸序列。
在另一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:35的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列。
在另一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:13的HCVR氨基酸序列和SEQ ID NO:38的LCVR氨基酸序列。
在另一个优选实施方案中,如上文所限定使用的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,以及SEQ ID NO:13的HCVR氨基酸序列和SEQ ID NO:37的LCVR氨基酸序列。
更优选地,如上文所限定使用的如上文所限定的人源化的抗SIRPα抗体包含含有氨基酸替换L234A和L235A的Fc区,经修饰的Fc IgG1区不包含氨基酸替换N297A或N297G。甚至更优选地,经修饰的Fc IgG1区不包含在位置N297处的氨基酸替换。
如上文所述当与包含野生型Fc区的相同抗SIRPα抗体相比时,包含经修饰的Fc区、对人Fcα或Fcγ受体表现出降低的结合的抗SIRPα抗体使用来自SIRPαBIT或SIRPα1纯合的不同供体的嗜中性粒细胞作为效应细胞增强了治疗性抗体的体外ADCC。所有这些抗体使用大多数供体的嗜中性粒细胞提高了体外ADCC,优选的抗体甚至使用所有供体的嗜中性粒细胞均提高了体外ADCC。
实施例
免疫接种方案和选择
将兔用表示人(hu)SIRPαBIT、人(hu)SIRPα1和食蟹猴(cy)SIRPα的细胞外结构域区的肽的混合物重复免疫接种。在不同的时间点收集血液,并富集淋巴细胞。将单一B细胞沉积在微量滴定板的单个孔中。将这些B细胞在存在条件化培养基和饲养细胞的情况下培养数天。在此期间其产生单克隆抗体并将其释放到培养基(B细胞上清液)中。分析这些单一B细胞的上清液的IgG产生;随后确定huSIRPαBIT和huSIRPα1与cySIRPα和与抗Fc抗体的特异性结合。合适的上清液是huSIRPαBIT和huSIRPα1二者均与cySIRPα结合的那些。在命中挑选步骤之后,测量与小鼠(mu)SIRPα和与huSIRPβ1v1、huSIRPβ1v2和huSIRPγ(作为反靶标)的结合。另外,确定与SIRPαBIT和SIRPα1过表达CHO细胞的结合。与亲代CHO细胞的结合用作对照测定。
选择合适的B细胞裂解物用于RNA分离、反转录和测序。对抗体轻链和重链的独特可变区进行基因合成并分别克隆到抗体恒定区序列(κLC SEQ ID NO:26和人IgG1HC-LALA格式SEQ ID NO:27)的前面。
使用Tecan Freedom Evo平台上的自动化程序,用包含抗体序列的质粒瞬时转染HEK 293细胞。在具有板自动进样器的Dionex Ultimate 3000 HPLC系统上使用亲和纯化(蛋白A)从细胞上清液纯化免疫球蛋白。产生的抗体在ELISA型测定中进行检测(ELISA:huSIRPα1、huSIRPαBIT、cySIRPα、muSIRPα、huSIRPβ1v1/β1v2/γ;细胞结合测定:huSIRPα1、huSIRPαBIT)。
抗体的瞬时表达
a)cDNA构建体和表达载体的制备
将抗体的HCVR氨基酸序列各自在N端与前导序列(对于抗体1至9、15、16为SEQ IDNO:28;对于抗体10至14为SEQ ID NO:39)连接,并且在C端与根据SEQ ID NO:27的人IgG1HC LALA的恒定结构域连接。将抗体12C4huIgG1LALA、12C4huIgG1或29AM4-5huIgG1LALA的HCVR氨基酸序列各自在N端与HAVT20前导序列(SEQ ID NO:29)连接,并且在C端与根据SEQID NO:27的人IgG1 HC LALA或野生型人IgG1 HC(SEQ ID NO:25)的恒定结构域连接。将所得到的嵌合氨基酸序列回译(back-translate)成用于在人细胞(智人(Homo sapiens))中表达的密码子优化的cDNA序列。类似地,通过如下获得构建体的LC的嵌合cDNA序列:将前导序列的序列(对于抗体1至9、12为SEQ ID NO:28,对于抗体10、11、13至16为SEQ ID NO:40,对于12C4huIgG1LALA、12C4huIgG1和29AM4-5huIgG1LALA为SEQ ID NO:29)在N端与抗体1至16、12C4huIgG1LALA和12C4huIgG1和29AM4-5huIgG1LALA的LCVR连接,并且在C端与人IgG1κ轻链恒定区(SEQ ID NO:26)连接。使用根据表1的HCVR和LCVR序列。
表1 抗体和参考抗体的HCVR和LCVR序列
抗体 | HCVR | LCVR |
1 | SEQ ID NO:1 | SEQ ID NO:2 |
2 | SEQ ID NO:3 | SEQ ID NO:4 |
3 | SEQ ID NO:5 | SEQ ID NO:6 |
4 | SEQ ID NO:7 | SEQ ID NO:8 |
5 | SEQ ID NO:9 | SEQ ID NO:10 |
6 | SEQ ID NO:11 | SEQ ID NO:12 |
7 | SEQ ID NO:13 | SEQ ID NO:14 |
8 | SEQ ID NO:15 | SEQ ID NO:16 |
9 | SEQ ID NO:17 | SEQ ID NO:18 |
29AM4-5huIgG1LALA | SEQ ID NO:19 | SEQ ID NO:20 |
12C4huIgG1LALA | SEQ ID NO:21 | SEQ ID NO:22 |
12C4huIgG1 | SEQ ID NO:21 | SEQ ID NO:22 |
KWAR23 | SEQ ID NO:23 | SEQ ID NO:24 |
人源化的10 | SEQ ID NO:30 | SEQ ID NO:31 |
人源化的11 | SEQ ID NO:32 | SEQ ID NO:33 |
人源化的12 | SEQ ID NO:34 | SEQ ID NO:8 |
人源化的13 | SEQ ID NO:35 | SEQ ID NO:36 |
人源化的14 | SEQ ID NO:35 | SEQ ID NO:37 |
人源化的15 | SEQ ID NO:13 | SEQ ID NO:38 |
人源化的16 | SEQ ID NO:13 | SEQ ID NO:37 |
b)载体构建和克隆策略
为了表达抗体链,使用哺乳动物表达载体,其包含CMV:BGHpA表达盒。将包含HC或LC表达盒的最终载体(分别为CMV:HC:BGHpA和CMV:LC-BGHpA)转移至大肠杆菌NEB 5-α细胞并在其中扩增。使用Maxi-或Megaprep试剂盒(Qiagen)进行用于转染的最终表达载体的大规模生产。
c)在哺乳动物细胞中的瞬时表达
使用ExpiFectamine转染剂根据制造商的说明如下用表达载体对市售Expi293F细胞(Thermo Fisher)进行转染:将75×107个细胞接种到300mL FortiCHO培养基中,将300μg表达载体与800μl ExpiFectamine转染剂组合并添加至细胞。转染之后一天,将1.5mlEnhancer 1和15ml Enhancer 2添加至培养物。转染之后六天,通过以4,000g离心15分钟并通过PES瓶过滤器/MF 75过滤器(Nalgene)过滤澄清的收获物来收获细胞培养物上清液。
抗体结合和特异性
实验
ELISA测定:将huSIRPα1、huSIRPαBIT、huSIRPβ1v1、huSIRPβ1v2、huSIRPγ和cySIRPα在磷酸盐缓冲盐水(PBS)中的溶液各自添加至ELISA的多孔黑色聚苯乙烯板中,并允许在室温下黏附1小时。使用标准洗涤缓冲液用三个洗涤步骤除去未结合的蛋白质。随后,向孔中添加封闭缓冲液。在室温孵育1小时之后,用标准洗涤缓冲液洗涤孔3次。将缓冲液中多种浓度的抗体添加至孔并在室温下孵育1小时。使用标准洗涤缓冲液用三个洗涤步骤除去未结合的抗体。向孔中添加缓冲液中的山羊抗人IgG(Fab′)2:辣根过氧化物酶(horse radishperoxidase,HRP)并在室温下孵育1小时。添加3,3′,5,5′-四甲基联苯胺(TMB)并在充分显色之后添加HCl。在450nm/620nm处读取吸光度。
表面等离子体共振(SPR)测定:在25℃下通过表面等离子体共振装置(BiacoreT200系统,GE Life Sciences)上的单周期动力学分析来进行亲和力分析。通过在以10μL/分钟注射链霉亲和素缀合物(20×稀释的生物素捕获试剂,GE Life Sciences)持续60秒之后以10μL/分钟将5μg/mlSIRP抗原注射到运行缓冲液(pH 7.4的10mM HEPES缓冲液,具有150mM NaCl,3mM EDTA和0.005%v/v聚氧乙烯(20)山梨醇单月桂酸酯(表面活性剂P20))中持续60秒,在适合用于生物素化分子的芯片表面(Sensor Chip CAP,GE Life Sciences)上捕获生物素化的SIRP抗原。将基线稳定设置为1分钟之后,将五种浓度递增的抗SIRP抗体注射到运行缓冲液(pH 7.4的具有150mM NaCl,3mM EDTA和0.005%v/v聚氧乙烯(20)山梨醇单月桂酸酯的10mM HEPES缓冲液)中。每个步骤使用150秒的结合时间,然后仅在最高浓度下解离时间为1200秒,全部以30μL/分钟的流量。用6M胍-HCl、0.25M NaOH溶液(60秒,流量为30μL/分钟)进行再生(regeneration)。使用非抗SIRP(空白)固定的参照流道和运行缓冲液注射对观察到的传感图进行双空白减法。对于所有测试的抗SIRP抗体,传感图用1∶1朗缪尔模型(Langmuir model)拟合。使用Biacore T200评价软件(v3.1)计算动力学参数(ka、kd和KD)。
流式细胞术:将内源性表达人SIRPαBIT抗原的U937细胞和来源于已从表达人SIRPα1、SIRPαBIT或cySIRPα抗原的CHO-S中国仓鼠卵巢细胞(ExpiCHO-S)中筛选和分离的非工程亚克隆的细胞(在96孔板中100,000细胞/孔)用包含0.2%v/w BSA(Sigma-Aldrich,St.Louis,MO)和0.02%v/w NaN3(Sigma-Aldrich)的冰冷的FACS缓冲液(1×PBS(LONZA))洗涤3次,随后添加在冰冷的FACS缓冲液中稀释的浓度范围的各第一mAb(50μL/孔)。在4℃下孵育30分钟时间之后,将细胞用冰冷的FACS缓冲液洗涤三次并添加50μL/孔的第二mAb(亲和纯F(ab′)2片段山羊抗人IgG-APC,1∶6,000稀释,Jackson Immuno Research)。在4℃下30分钟之后,将细胞洗涤两次并重悬于150μL FACS缓冲液中。通过流式细胞术(BDFACSVerse,Franklin Lakes,NJ)确定荧光强度,并表示为U937细胞和ExpiCHO-S细胞的中值荧光强度(MFI-中值)。在GraphPad Prism(Windows版本7.02,GraphPad,San Diego,CA)中使用具有可变斜率的S型剂量响应方程(四个参数),通过非线性回归拟合曲线。当使用4参数逻辑拟合时,EC50值计算为以μg/mL计的浓度,其给出在曲线的底部和顶部之间一半的响应。
结果
ELISA测定:表2中总结了用ELISA获得的抗体1至9和参照抗体与huSIRPα1、huSIRPαBIT、huSIRPβ1、huSIRPβ1v2、huSIRPγ、cySIRPα结合的EC50值。所有抗体与huSIRPα1和huSIRPαBIT结合。抗体29AM4-5huIgG1LALA和12C4huIgG1LALA与huSIRPβ1v1、huSIRPβ1v2和huSIRPγ结合。抗体2至6、8和9对huSIRPβ1v1和对huSIRPγ显示出低亲和力。抗体7与huSIRPβ1v1结合,但对huSIRPβ1v2和huSIRPγ具有低亲和力。抗体1与huSIRPβ1v2和huSIRPγ结合。
表2 抗SIRPα抗体和参照抗体的特异性
*huIgG1LALA
EC50值>100,000已调整至100,000。
SPR测定:表3中总结了与参照抗体KWAR23、huIgG112C4LALA和SE5A5(购自商业供应商)相比,抗体4、7、10至14与huSIRPα1、huSIRPαBIT和huSIRPγ结合的KD值。抗体4、7、10至14与huSIRPα1和huSIRPαBIT二者结合,且不与huSIRPγ结合。所有参照抗体均与huSIRPγ结合。
表3 SPR数据(KD以M计)
抗体 | KD(huSIRPαBIT) | KD(huSIRPα1) | KD(huSIRPγ) |
KWAR23小鼠IgG2a | <1.0E-111 | <1.0E-11 | <1.0E-11 |
KWAR23huIgG1LALA | <1.0E-111 | 1.1E-11 | <1.0E-11 |
12C4huIgG1LALA | 1.5E-11 | 8.7E-11 | 1.6E-11 |
SE5A5 | 2.6E-9 | 2.2E-9 | 4.9E-8 |
4 | <1.0E-11 | 2.6E-11 | N2 |
7 | <1.0E-11 | <1.0E-11 | N |
人源化的10 | <1.0E-11 | 3.2E-9 | N |
人源化的11 | 1.4E-10 | 4.1E-8 | N |
人源化的12 | <1.0E-11 | 5.9E-11 | N |
人源化的13 | 1.2E-11 | <1.0E-11 | N |
人源化的14 | 8.9E-11 | <1.0E-11 | N |
1<1.0E-11:KD超出范围,这意味着高亲和力
2N:未发现特异性结合
流式细胞术测定:通过流式细胞术确定多种抗体与细胞上表达的huSIRPα1、huSIRPαBIT和/或cySIRPα的结合。结合以表4中所示的EC50值来表示。抗体2、4、5、7、8、10至14与huSIRPα1、huSIRPαBIT和cySIRPα结合。抗体2、4、5、7、8、10至14在低μg/mL范围内与cySIRPα结合。
表4 流式细胞术数据
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-未确定值
CD47-SIRPα结合的抗体阻断
实验
将用SIRPα1或SIRPαBIT转染的CHO细胞或作为对照的亲本CHO细胞接种在具有透明底部的孔板中的20μl细胞培养基中并孵育过夜。向孔添加抗体1至9、29AM4-5huIgG1LALA或12C4huIgG1LALA参照抗体以及His标签CD47与抗His标签/>荧光检测抗体的混合物并孵育2小时。孵育之后,用细胞洗涤缓冲液洗涤细胞。使用筛选系统/> 确定荧光,并确定每个细胞的总荧光。
结果
抗体29AM4-5huIgG1LALA、12C4huIgG1LALA、3和7完全阻断CD47与表达huSIRPα1的CHO细胞和表达huSIRPαBIT的CHO细胞二者的结合,抗体1、2、4至6、8和9既不阻断CD47与表达huSIRPα1的CHO细胞的结合也不阻断与表达huSIRPαBIT的CHO细胞的结合。
ADCC测定
根据在Chao等PNAS 2011,108(45),18342-18347中的方法分离和培养SIRPα1或SIRPαBIT纯合的供体的嗜中性粒细胞。使用51Cr释放测定或非放射性铕TDA(Europium TDA,EuTDA)细胞毒性测定(DELFIA,PerkinElmer)确定ADCC。将SKBR3细胞用作靶细胞并在37℃下用100μCi51Cr(Perkin-Elmer)标记90分钟,或在37℃下用双(乙酰氧基甲基)2,2′:6′,2″-三联吡啶-6,6″-二羧酸盐(BATDA试剂Delfia)标记5分钟。用PBS洗涤2次之后,将每孔5×103个靶细胞在96孔U型底板中在补充有10%(v/v)胎牛血清(FCS)的IMDM培养基以及嗜中性粒细胞中(在存在适当抗体的情况下,效应细胞与靶细胞的比例为50∶1)在37℃和5%CO2下孵育4小时。孵育之后,收获上清液并在γ计数器(Wallac)中分析放射性,或者添加至铕溶液(DELFIA,PerkinElmer)并使用分光荧光计(Envision,PerkinElmer)确定铕2,2′:6′,2″-三联吡啶-6,6″-二羧酸(EuTDA)荧光。细胞毒性的百分比计算为[(实验释放-自发释放)/(总释放-自发释放)]×100%。所有条件以两次重复和/或三次重复测量。
12C4huIgG1LALA相对于12C4IgG1的ADCC数据
图1示出了以%计的细胞毒性的ADCC测定的结果。使用嗜中性粒细胞作为效应细胞和单独的曲妥珠单抗在SKBR3细胞上测得的%细胞毒性小于与鼠12C4抗体(mu12C4)组合的曲妥珠单抗的%细胞毒性。与其中12C4可变区被移植到人IgG1恒定区上的抗体(12C4huIgG1)组合的曲妥珠单抗在低浓度的12C4huIgG1时,与单独的曲妥珠单抗相比显示出类似的%细胞毒性。在较高浓度的12C4huIgG1下,观察到%细胞毒性降低。与其中12C4可变区被移植到包含氨基酸替换L234A和L235A的人IgG1恒定区上的抗体(12C4huIgG1LALA)组合的曲妥珠单抗与单独的曲妥珠单抗的%细胞毒性相比显示出增加的%细胞毒性,并且与12C4huIgG1和曲妥珠单抗的组合相比显示出增加的%细胞毒性。
ADCC数据
图2比较了在存在具有包含氨基酸替换L234A和L235A(LALA)的人IgG1恒定区的抗体1至9与曲妥珠单抗组合的情况下,与12C4huIgG1LALA相比的人嗜中性粒细胞相对于曲妥珠单抗(设置为100%)的%ADCC。具有鼠抗CD47抗体的VR和包含氨基酸替换L234A和L235A的人IgG1恒定区的B6H12IgG1LALA和载剂(无曲妥珠单抗)分别用作阳性和阴性对照。实心正方形(■)是用具有SIRPαBIT变体(对SIRPαBIT纯合的)的供体嗜中性粒细胞测量的值,空心圆(○)是用具有SIRPα1变体(对SIRPα1纯合的)的供体的嗜中性粒细胞测量的值。对于所有抗体,与单独的曲妥珠单抗相比,平均ADCC提高。对于抗体1、2、4、5、7和8,平均ADCC提高增强,甚至多于12C4huIgG1LALA诱导的ADCC提高。当比较每个抗体的每个供体的ADCC提高时,抗体1、3至6、8和9在%ADCC提高上显示出比12C4huIgG1LALA更少的变化。
图3比较了在存在多种浓度的嵌合抗体4和7以及具有包含氨基酸替换L234A和L235A(LALA)的人IgG1恒定区的人源化抗体10和14与曲妥珠单抗组合的情况下,与单独的曲妥珠单抗和与多种浓度的12C4huIgG1LALA组合的曲妥珠单抗相比的人嗜中性粒细胞的%ADCC。使用SIRPαBIT纯合的两个供体的嗜中性粒细胞。即使在低浓度下,抗体4、7、10和14提高了ADCC。ADCC提高是浓度依赖性的。
图4比较了在存在抗体4、7、10、13、14、15和16与曲妥珠单抗(Tmab)组合的情况下,与单独的曲妥珠单抗和12C4huIgG1LALA的%ADCC相比的人嗜中性粒细胞的%ADCC。与单独的曲妥珠单抗相比,所有抗体提高了ADCC。与12C4huIgG1LALA组合曲妥珠单抗相比,在存在抗体4、7、10、13、14、15和16与曲妥珠单抗组合的情况下,大多数供体的嗜中性粒细胞的ADCC的提高相似或增加。
序列表,其中重链(HC)和轻链(LC)可变区(VR)氨基酸序列中的CDR1、CDR2和CDR3氨基酸序列具有下划线(使用Kabat方法确定)
SEQ ID NO:1(HC VR 1)
SEQ ID NO:2(LC VR 1)
SEQ ID NO:3(HC VR 2)
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SEQ ID NO:4(LC VR 2)
SEQ ID NO:5(HC VR 3)
SEQ ID NO:6(LC VR 3)
SEQ ID NO:7(HC VR 4)
SEQ ID NO:8(LC VR 4)
SEQ ID NO:9(HC VR 5)
SEQ ID NO:10(LC VR 5)
SEQ ID NO:11(HC VR 6)
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SEQ ID NO:12(LC VR 6)
SEQ ID NO:13(HC VR 7)
SEQ ID NO:14(LC VR 7)
SEQ ID NO:15(HC VR 8)
SEQ ID NO:16(LC VR 8)
SEQ ID NO:17(HC VR 9)
SEQ ID NO:18(LC VR 9)
SEQ ID NO:19(HC VR 29AM4-5)
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SEQ ID NO:20(LC VR 29AM4-5)
SEQ ID NO:21(HC VR 12C4)
SEQ ID NO:22(LC VR 12C4)
SEQ ID NO:23(HC VR KWAR23)
SEQ ID NO:24(LC VR KWAR23)
SEQ ID NO:25(人IgG1抗体HC恒定区)
SEQ ID NO:26(人IgG1抗体LCκ恒定区)
SEQ ID NO:27(人IgG1抗体HC恒定区LALA突变(突变具有下划线)
SEQ ID NO:28(前导序列HC 1至9、15+16、LC 1至9+12)
SEQ ID NO:29(HAVT20前导序列)
SEQ ID NO:30(HC VR 10)
SEQ ID NO:31(LC VR 10)
SEQ ID NO:32(HC VR 11)
SEQ ID NO:33(LC VR 11)
SEQ ID NO:34(HC VR 12)
SEQ ID NO:35(HC VR 13+14)
SEQ ID NO:36(LC VR 13)
SEQ ID NO:37(LC VR 14+16)
SEQ ID NO:38(LC VR 15)
SEQ ID NO:39(前导序列重链10至14)
SEQ ID NO:40(前导序列轻链10、11、13至16)
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序列表
<110> 拜奥迪斯私人有限公司
<120> 抗SIRPα抗体
<130> P1703PC00/PB-078
<140> PCT/EP2018/062473
<141> 2018-05-15
<160> 40
<170> PatentIn version 3.5
<210> 1
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:1 (HC VR 1)
<400> 1
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Pro
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Leu
85 90 95
Trp Ala Ala Ser Asn Tyr Tyr Met Ala Leu Trp Gly Pro Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 2
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:2 (LC VR 1)
<400> 2
Ala Ile Lys Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Ser Ile Asn Cys Gln Ala Ser Glu Asp Ile Glu Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Ser
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Asp Tyr Tyr Ser Ser Ser
85 90 95
Gly Asp Thr Gly Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 3
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:3 (HC VR 2)
<400> 3
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Ala
20 25 30
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Tyr Thr Gly Gly Ala Thr Ser Tyr Ala Thr Trp Ala Lys Gly
50 55 60
Gln Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Asp
85 90 95
Arg Asp Gly Tyr Ala Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 4
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:4 (LC VR 2)
<400> 4
Gln Ile Val Met Thr Gln Thr Pro Phe Ser Val Ser Ala Val Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser His Asn Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Glu Ser
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Ile Ser Tyr
85 90 95
Val His Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 5
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:5 (HC VR 3)
<400> 5
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Ala Cys Thr Val Ser Gly Phe Ser Leu Ile Ser Tyr Tyr
20 25 30
Ile Ser Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Ile Ile Asn Ile Gly Gly Gly Ala Ser Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Pro Thr Pro Glu Asp Thr Ala Thr Tyr Phe Cys Ala Met Ser Tyr
85 90 95
Gly Met Asp Thr Gly Ala Phe Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 6
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:6 (LC VR 3)
<400> 6
Ala Gln Val Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Glu Ser Val Tyr Lys Asn
20 25 30
Asn Phe Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu
65 70 75 80
Glu Ser Asp Asp Ala Ala Thr Tyr Phe Cys Gln Gly Gly Tyr Arg Thr
85 90 95
Asp Ile Tyr Pro Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 7
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:7 (HC VR 4)
<400> 7
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Gly Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val
20 25 30
Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly
85 90 95
Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 8
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:8 (LC VR 4)
<400> 8
Asp Ile Val Met Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asp Leu Glu Ser
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg
85 90 95
Ser Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105
<210> 9
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:9 (HC VR 5)
<400> 9
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val
20 25 30
Met Gly Trp Phe Arg Gln Ala Ala Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Tyr Ile Asn Ala Asp Gly Ser Pro Tyr Tyr Ala Thr Trp Val Asn Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Pro Thr Thr Met Asp Leu Lys Ile Asn
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly
85 90 95
Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 10
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:10 (LC VR 5)
<400> 10
Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Asn Arg Tyr
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Glu Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asp Leu Glu Ser
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Tyr Ile Ser Arg
85 90 95
Thr Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105
<210> 11
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:11 (HC VR 6)
<400> 11
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Thr
20 25 30
Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Ser
85 90 95
Ser Asp Gly Tyr Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 12
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:12 (LC VR 6)
<400> 12
Gly Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr His Phe Thr Leu Thr Ile Ser Asp Val Gln Ser
65 70 75 80
Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Thr Val Thr Ala Ala Ser
85 90 95
Asn Val Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 13
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:13 (HC VR 7)
<400> 13
Arg Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser His Gly
20 25 30
Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Thr Ile Gly Thr Gly Val Ile Thr Tyr Phe Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Gly Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Ser
85 90 95
Ala Trp Asn Asp Pro Phe Asp Pro Trp Gly Pro Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 14
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:14 (LC VR 7)
<400> 14
Ala Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Thr Lys Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln His Lys Pro Gly Gln Pro Pro Lys Leu
35 40 45
Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Thr Gly Val
65 70 75 80
Gln Ser Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp
85 90 95
Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 15
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:15 (HC VR 8)
<400> 15
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Val Asp Leu Ser Asn Tyr Ala
20 25 30
Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Tyr Ala Gly Gly Ser Thr Ser Tyr Ala Thr Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Thr
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg His Arg
85 90 95
Ser Asp Gly Tyr Asp Tyr Phe His Leu Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 16
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:16 (LC VR 8)
<400> 16
Ala Ile Asp Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Gln Ser
65 70 75 80
Asp Asp Ala Ala Ala Tyr Tyr Cys Gln Gln Gly Tyr Ala Val Ser Tyr
85 90 95
Val Glu Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 17
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:17 (HC VR 9)
<400> 17
Gln Ser Met Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asn Tyr Gly
20 25 30
Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Tyr Gly Gly Ser Asp Ile Thr Ala Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Thr Ile
65 70 75 80
Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Lys Ser
85 90 95
Tyr Thr Asn Gly Met Asp Tyr Tyr Asn Ile Trp Gly Pro Gly Thr Leu
100 105 110
Val Thr Val Ser Leu
115
<210> 18
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:18 (LC VR 9)
<400> 18
Ala Phe Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Pro Val Gly
1 5 10 15
Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Glu Thr Gln Phe Pro Leu Thr Ile Ser Asp Leu Glu Ser
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Arg Ser
85 90 95
Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105
<210> 19
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:19 (HC VR 29AM4-5))
<400> 19
Glu Val Gln Leu Val 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 Asn Ile Ser Tyr Tyr
20 25 30
Phe Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Val Tyr Ser Ser Phe Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Phe Thr Phe Pro Gly Leu Phe Asp Gly Phe Phe Gly Ala Tyr
100 105 110
Leu Gly Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 20
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:20 (LC VR 29AM4-5)
<400> 20
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 Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Val Asn Trp Val Gly
85 90 95
Ala Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 21
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:21 (HC VR 12C4)
<400> 21
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Met Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Ile Arg Asp Tyr Asp Tyr Asp Ala Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 22
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:22 (LC VR 12C4)
<400> 22
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser
20 25 30
Gly Tyr Asn Tyr Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Gly
85 90 95
Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 23
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:23 (HC KWAR23 )
<400> 23
Glu 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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Gln Gln Arg Thr Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 24
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:24 (LC VR KWAR23)
<400> 24
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Ser Tyr Phe Cys His Gln Trp Ser Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 25
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO 25: (人IgG1抗体HC恒定区)
<400> 25
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 Asp Glu
225 230 235 240
Leu 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> 26
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO 26: (人IgG 抗体LC恒定区)
<400> 26
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> 27
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO 27: (人IgG1 抗体HC恒定区LALA突变
(突变具有下划线)
<400> 27
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 Ala Ala 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 Asp Glu
225 230 235 240
Leu 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> 28
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:28 (抗体1至9的前导序列)
<400> 28
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 29
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:29 (HAVT20的前导序列)
<400> 29
Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu
1 5 10 15
Glu Phe Ser Met Ala
20
<210> 30
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:30 (HC VR 10)
<400> 30
Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
1 5 10 15
Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr Val Met
20 25 30
Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ile
35 40 45
Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly Arg
50 55 60
Phe Thr Ile Ser Lys Asp Asn Ser Glu Gly Met Val Tyr Leu Gln Met
65 70 75 80
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val
85 90 95
Gly Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 31
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:31 (LC VR 10)
<400> 31
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg
85 90 95
Ser Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 32
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:32 (HC VR 11)
<400> 32
Glu Val Lys Val Glu 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 Ser Leu Ser Ser Tyr
20 25 30
Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Gln Met
65 70 75 80
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val
85 90 95
Gly Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 33
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:33 (LC VR 11)
<400> 33
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 Gln Ala Gly Gln Ser Ile Asn Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg
85 90 95
Ser Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 34
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:34 (HC VR 12)
<400> 34
Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Ser Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val
20 25 30
Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn
65 70 75 80
Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly
85 90 95
Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 35
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:35 (HC VR 13 + 14)
<400> 35
Arg Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser His Gly
20 25 30
Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Thr Ile Gly Thr Gly Val Ile Thr Tyr Phe Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Gly Ser Lys Thr Ser Ser Thr Ala Tyr Met Glu Leu Ser
65 70 75 80
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg Gly Ser
85 90 95
Ala Trp Asn Asp Pro Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 36
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:36 (LC VR 13)
<400> 36
Ala 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 Gln Ala Ser Gln Ser Val Tyr Gly Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp
85 90 95
Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 37
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:37 (LC VR 14 +16)
<400> 37
Asp Ile Glu Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp
85 90 95
Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 38
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:38 (LC VR 15)
<400> 38
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp
85 90 95
Glu Ala Asp Asn Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 39
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:39 (重链10-14的前导序列)
<400> 39
Met Gly Trp Thr Leu Val Phe Leu Phe Leu Leu Ser Val Thr Ala Gly
1 5 10 15
Val His Ser
<210> 40
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:40 (轻链10, 11, 13-16的前导序列)
<400> 40
Met Val Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys
20
Claims (12)
1.包含重链(HC)和轻链(LC)可变区(VR)互补决定区(CDR)的抗SIRPα抗体或其抗原结合片段,其中:
(i)HC CDR1、2和3分别是氨基酸序列如SEQ ID NO:13所示的HC VR的CDR1、2和3;并且
(ii)LC CDR1、2和3分别是氨基酸序列如SEQ ID NO:14所示的LC VR的CDR1、2和3;
其中所述CDR根据Kabat编号确定。
2.根据权利要求1所述的抗SIRPα抗体或其抗原结合片段,其是嵌合的或人源化的。
3.根据权利要求2所述的抗SIRPα抗体或其抗原结合片段,其是人源化的。
4.根据权利要求3所述的抗SIRPα抗体或其抗原结合片段,其包含:
a.氨基酸序列如SEQ ID NO:35所示的HCVR和氨基酸序列如SEQ ID NO:36所示的LCVR;
b.氨基酸序列如SEQ ID NO:35所示的HCVR和氨基酸序列如SEQ ID NO:37所示的LCVR;
c.氨基酸序列如SEQ ID NO:13所示的HCVR和氨基酸序列如SEQ ID NO:38所示的LCVR;或者
d.氨基酸序列如SEQ ID NO:13所示的HCVR和氨基酸序列如SEQ ID NO:37所示的LCVR。
5.根据权利要求1至4中任一项所述的抗SIRPα抗体或其抗原结合片段,其包含经修饰的Fc区,所述抗SIRPα抗体与包含野生型Fc区的相同抗SIRPα抗体相比表现出与人Fcα或Fcγ受体的结合降低。
6.根据权利要求5所述的抗SIRPα抗体或其抗原结合片段,其包含经修饰的人IgG1 Fc区,所述经修饰的人IgG1 Fc区包含在选自根据Eu编号的L234、L235、G237、D265、D270、N297、A327、P328和P329的一个或更多个位置处的氨基酸替换。
7.根据权利要求6所述的抗SIRPα抗体或其抗原结合片段,其包含氨基酸替换L234A和L235A;L234E和L235A;L234A、L235A和P329A;或者L234A、L235A和P329G。
8.根据权利要求7所述的抗SIRPα抗体或其抗原结合片段,其包含氨基酸替换L234A和L235A;或者L234E和L235A。
9.药物组合物,其包含根据权利要求1至8中任一项所述的抗SIRPα抗体或其抗原结合片段和一种或更多种可药用赋形剂,所述药物组合物用于增强曲妥珠单抗对于人乳腺癌细胞的毒性。
10.根据权利要求9所述的药物组合物,其用作药物,所述药物用于增强曲妥珠单抗对于人乳腺癌细胞的毒性。
11.根据权利要求9所述的药物组合物在制备用于治疗人乳腺癌的药物中的用途。
12.根据权利要求1至8中任一项所述的抗SIRPα抗体或其抗原结合片段或者根据权利要求9所述的药物组合物与曲妥珠单抗的组合在制备用于治疗人乳腺癌的药物中的用途。
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MX2019013749A (es) | 2020-01-15 |
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US20210070874A1 (en) | 2021-03-11 |
RU2019141289A3 (zh) | 2021-09-17 |
WO2018210795A1 (en) | 2018-11-22 |
US20220195063A1 (en) | 2022-06-23 |
EP3625259B1 (en) | 2024-04-17 |
BR112019023754A2 (pt) | 2020-06-09 |
KR20200005659A (ko) | 2020-01-15 |
AR111630A1 (es) | 2019-07-31 |
AU2018268304A1 (en) | 2019-11-14 |
EP3625259A2 (en) | 2020-03-25 |
WO2018210793A3 (en) | 2018-12-20 |
JP7171617B2 (ja) | 2022-11-15 |
RU2019141289A (ru) | 2021-06-16 |
US11718681B2 (en) | 2023-08-08 |
CN110799536A (zh) | 2020-02-14 |
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WO2018210793A2 (en) | 2018-11-22 |
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