CN117730095A - 中度至重度成骨不全症的治疗 - Google Patents
中度至重度成骨不全症的治疗 Download PDFInfo
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- CN117730095A CN117730095A CN202280033273.9A CN202280033273A CN117730095A CN 117730095 A CN117730095 A CN 117730095A CN 202280033273 A CN202280033273 A CN 202280033273A CN 117730095 A CN117730095 A CN 117730095A
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Abstract
本公开文本提供了用于通过向受试者施用治疗有效量的结合并中和转化生长因子β(TGFβ)的药剂治疗和改善所述受试者的中度至重度成骨不全症(OI)的方法。
Description
相关申请的交叉引用
本申请要求于2021年5月7日提交的美国临时申请63/185,967的优先权。将该优先权申请的披露内容通过引用以其整体并入本文。
政府资助
本发明是在由美国国立卫生研究院授予的授权号AR068069下在政府支持下完成的。美国政府拥有本发明的某些权利。
序列表
本申请含有以ASCII格式电子提交并且通过引用以其整体并入本文中的序列表。创建于2022年5月3日的所述ASCII副本被命名为022548_WO026_SL.txt,并且大小为17,875字节。
联合研究协议
这项工作由与Sanofi Genzyme的研究协议支持。
背景技术
成骨不全症(OI)是一种遗传和表型异质性孟德尔型结缔组织障碍,其估计患病率为1/10,000-1/20,000名新生儿。OI的骨骼表现包括低骨量、骨脆性、反复发作性骨折、脊柱侧凸和骨畸形。骨骼以外表现包括减少的肌肉量、肌肉无力、牙质生成不全、听力损失和肺部疾病(Marini,Nat Rev Dis Primers(2017)3:17052;Marom等人,Am J Med Genet CSemin Med Genet.(2016)172(4):367-83;Patel等人,Clin Gen.(2015)87(2):133-40;Rossi等人,Curr Opin Pediatr.(2019)31(6):708-15;Tam等人,Clin Gen.(2018)94(6):502-11;DiMeglio等人J Bone Miner Res.(2006)21:132-40;Gatti等人,J Bone MinerRes.(2005)20(5):758-63);Gatti等人,Calcified Tissue Int.(2013)93(5):448-52)。患有OI的个体的管理通常涉及多学科方法。用于OI骨脆性的主要疗法涉及重新使用用于治疗骨质疏松症的药物(Adami等人,J Bone Miner Res.(2003)18(1):126-30;Bishop等人,EarHum Dev.(2010)86(11):743-6;Chevrel等人,J Bone Miner Res.(2006)21(2):300-6;Glorieux等人,NEJM(1998)339(14):947-52;Rauch等人,J Bone Miner Res.(2009)24(7):1282-9;Rauch等人,J Bone Miner Res.(2003)18(4):610-4;Orwoll等人,J Clin Invest(2014)124(2):491-8;Hoyer-Kuhn等人,J Musculoskelet Neuronal Interact/(2016)16(1):24-32;Anissipour等人,J Bone Joint Surg Am.(2014)96(3):237-43)。
二膦酸盐(BPN)作为一类减少骨重建的抗吸收药物已成为护理标准,尤其是在儿科OI中。在儿童中,BPN已被证明对面积和体积骨矿物质密度(aBMD和vBMD)、脊柱侧凸的进展、生活质量以及在一些研究中对骨折发生率具有有益作用(Bishop等人,Lancet(2013)382(9902):1424-32;Rauch等人,2003,同上;Bains等人,JBMR Plus(2019)3(5):e10118;Rauch等人,Bone(2007)40(2):274-80)。然而,鉴于OI的异质性和临床研究设计的可变性,BPN的作用是不一致的。在成年人中,不太确定长期使用二膦酸盐治疗的益处和后果(Adami等人,同上;Shi等人,Am J Ther.(2016)23(3):e894-904)。此外,在一项涉及患有OI的成年人的随机试验中,用合成代谢剂特立帕肽治疗导致患有轻度形式(I型OI)的个体的aBMD和vBMD增加,而在患有所述障碍的中度至重度形式的个体中并非如此。此外,这些重新利用的疗法都没有解决OI中的特定致病机制,因此,它们对骨骼以外表现没有影响。
因此,仍然存在对于靶向中度至重度形式的OI的有效疗法的显著未满足的需求。
发明内容
本公开文本提供了一种用于治疗有需要的人受试者的成骨不全症(OI)的方法,所述方法包括向所述受试者施用治疗有效量的抗TGFβ抗体或其抗原结合片段,其中所述抗体或抗原结合片段包含分别含有SEQ ID NO:4-6的重链互补决定区(CDR)1-3和分别含有SEQID NO:7-9的轻链CDR1-3,其中所述治疗有效量是1-10mg/kg(例如,1、2、3、4、5、6、7、8、9或10mg/kg)。
在一些实施方案中,所述抗体或抗原结合片段包含含有SEQ ID NO:10的重链可变结构域和含有SEQ ID NO:11的轻链可变结构域。在一些实施方案中,所述抗体包含人IgG4恒定区和/或人κ轻链恒定区。在某些实施方案中,所述人IgG4恒定区包含S228P突变(Eu编号)。在特定实施方案中,所述抗体包含含有SEQ ID NO:1的重链和含有SEQ ID NO:2的轻链。在其他特定实施方案中,所述抗体包含含有SEQ ID NO:3的重链和含有SEQ ID NO:2的轻链。
在一些实施方案中,所述抗体包含骨靶向部分,任选地其中所述骨靶向部分是聚精氨酸肽。在一些实施方案中,所述抗体包含一个或多个聚精氨酸肽,例如在所述抗体或抗原结合片段的重链的N末端或C末端或两端和/或轻链的C末端。在特定实施方案中,所述聚精氨酸肽是D10(SEQ ID NO:14)。
在一些实施方案中,所述OI是中度至重度OI或IV型OI。在一些实施方案中,所述人受试者是成年患者(≥18岁)或儿科患者(<18岁)。在一些实施方案中,所述人受试者具有COL1A1或COL1A2基因中的突变,任选地其中所述突变是所述COL1A1或COL1A2基因中的甘氨酸取代突变或所述COL1A2基因中的缬氨酸缺失。
在一些实施方案中,所述施用改善选自以下的骨参数:骨矿物质密度(BMD)、骨体积密度(BV/TV)、总骨表面(BS)、骨表面密度(BS/BV)、骨小梁数量(Tb.N)、骨小梁厚度(Tb.Th)、骨小梁间隙(Tb.Sp)和总体积(Dens TV)。在其他实施方案中,所述骨参数是腰椎面积BMD(LS aBMD),任选地其中所述LS aBMD在所述施用后相对于基线水平增加了至少1%-10%。
在一些实施方案中,所述施用降低骨转换和/或骨细胞密度,任选地其中所降低的骨转换由血清CTX的降低或血清骨钙素(OCN)的增加指示。
在一些实施方案中,每月、每两个月、每三个月、每六个月、每九个月或每十二个月重复所述施用步骤,例如,以4mg/kg的剂量。所述抗体或抗原结合片段可以静脉内输注施用。
在一些实施方案中,所述方法进一步包括向所述受试者施用另一种治疗剂,如二膦酸盐(例如,阿仑膦酸盐、帕米膦酸盐、唑来膦酸盐和利塞膦酸盐)、甲状旁腺激素、降钙素、特立帕肽或抗骨硬化蛋白剂。
本文还提供了一种抗TGFβ抗体或其抗原结合片段,所述抗TGFβ抗体或其抗原结合片段用于在本文的所述治疗方法中治疗成骨不全症;以及抗TGFβ抗体或其抗原结合片段在制造用于在本文的所述治疗方法中治疗成骨不全症的药剂中的用途。
还提供了一种包含抗TGFβ抗体或其抗原结合片段的制品(例如,试剂盒),所述制品(例如,试剂盒)用于在本文的所述治疗方法中治疗成骨不全症。
本发明的其他特征、目的和优点在下面的详细描述中是清楚的。然而,应理解,虽然指示了本发明的实施方案和方面,但具体实施方式是通过仅说明而非限制的方式给出的。根据具体实施方式,在本发明范围内的各种变化和修改对于本领域技术人员而言将变得清楚。
附图说明
图1显示了用于组织学、RNA和蛋白质研究的人骨样本加工。图A:骨样本粉碎环境的图示,其显示将骨样本浸入双层液氮中并通过电钻粉碎。图B:在右上角显示了加工之前的骨样本的表示。在粉碎后,在液氮中收集杵底部的骨粉。加工紧邻粉碎区域的2-3mm3区域用于组织学和免疫化学。
图2显示了患有III型OI的个体和未受影响的对照的骨组织学。图A:收集的骨样本的H&E染色组织学切片的完整图像。来自未受影响的个体的大多数样本是皮质骨。III型OI样本更具异质性。大多数是皮质骨,但两个样本(OI62和OI83)仅含有小梁骨。一个样本(OI41)具有纤维软骨而一个样本(OI35)含有骨痂和小梁骨。比例尺:200μm。图B:未受影响的对照和III型OI骨的代表性更高放大倍数(10X)H&E染色图像。在对照骨中,观察到组织良好的哈弗氏管系统,而III型OI骨显示出具有较低组织化哈弗氏管的更高编织性皮质骨,以及更多可见的更具球形形状的骨细胞。比例尺:50μm。
图3显示了III型OI骨中增加的骨细胞密度。未受影响的对照(n=4)和III型OI(n=10)中骨细胞密度的定量。每个点代表一名个体的骨细胞密度。描绘了平均值和标准差。
图4显示了使用Nanostring和RNA Sequence平台所测的基因表达变化。分析中包括具有RNA-seq和NanoString数据二者的1个非OI对照和1个III型OI。使用满足NanoString质量控制的155个基因进行RNA-seq差异表达数据的验证。155个基因的RNA-seq和NanoString的倍数变化方向(与非OI对照相比增加或减少)表示为红色向上箭头(在III型OI中增加)或蓝色向下箭头(在III型OI中减少)。紫色背景:两个平台之间不一致的倍数变化方向。白色背景:两个平台之间一致的倍数变化方向。一致率是92%。
图5表示转录组学和生物信息学分析,其证明III型OI骨中TGFβ信号传导的激活。图A以3-PC维度显示了所有对照和III型OI的主成分分析(PCA)图。图B显示了使用所有对照和III型OI骨数据的RPKM进行的基于欧几里得距离的分层聚类。蓝色:下调;黄色:上调。图C显示了证明TGFβ信号传导激活的基因集富集图。NES:归一化富集得分。FDR:错误发现率。在分析数据库中TGFβ基因集中所涉及的基因的表达模式。蓝色:下调。红色:上调。C:对照。OI:III型OI。
图6显示了在III型OI骨中具有富集倍数变化的显著富集的基因本体论(GO)分析结果。提供了骨骼过程、骨细胞、胶原蛋白和骨骼相关的主要信号传导途径的类别下的Partek GO富集结果。显著性被定义为P值<0.05。
图7显示了III型OI和对照转录谱的前20个基因集富集测定(GSEA)结果。提供了III型OI或非OI对照中的前20个富集基因集。NES:归一化富集得分;FDR q-val:错误发现率调整后的q值。
图8显示了在RPPA分析中显著改变的蛋白质。所述表显示了在III型OI骨中基于标称P值<0.05的显著改变的蛋白质的完整列表。蛋白质表达水平表示为蛋白质阵列中的归一化强度。
图9显示了III型OI骨中磷酸化SMAD2(pSMAD2)水平的增加。图A显示了对照和III型OI骨切片中pSMAD2的免疫组织化学染色。在右下方的黑框处显示了更高放大倍数图像。在所有OI样品中、尤其是在骨细胞中检测到增加的pSMAD2信号。比例尺:20μm。图B显示了从对照和III型OI骨提取的蛋白质中磷酸化SMAD2(p-SMAD2)和总SMAD2(T-SMAD2)的蛋白质印迹。加载50μg的总蛋白。用小牛肠碱性磷酸酶(CIP)处理另外的OI62样品以去除磷酸化信号,并将其用作准确的pSMAD2信号的阴性对照(由箭头指示)。图C显示了(B)中蛋白质印迹的定量结果,显示为磷酸化(磷酸)与总SMAD2的比率。使用GAPDH作为加载对照。C:对照;OI:III型OI。
图10显示了来自评价患有OI的成年人中夫苏木单抗的安全性的试验的血液学安全性数据。注意到两名参与者(FR005和FR009)的血红蛋白下降,均分级为轻度。这两名个体具有被分级为与研究药物相关的鼻出血以及未被分级为与研究药物无关的月经出血。血小板计数和INR在正常范围内。
图11示出了夫苏木单抗对骨转换标记物和骨密度的影响。在1mg·kg体重-1队列的四名参与者中的三名中观察到骨钙素(Ocn)和C末端端肽(CTX)水平的增加,并且在治疗后第30天至第90天之间观察到峰值。在4mg·kg体重-1队列中,在第30天观察到Ocn的减少,并且这种抑制持续到第180天。在参与者中,FR012可能由于无法旅行而无法获得在第30天的骨转换标记物。在两个剂量队列中,两名患有IV型OI的个体具有L1-4aBMD的稳健增加。
图12示出了LS aBMD的两个中心读数之间的相关性和一致性。由两名对试验设计不知情的独立读者读取LS aBMD。在两个读数之间存在强相关性(R=0.995)。Bland-Altman图显示了两个读数之间的高度一致性。平均差异、一致性上限、一致性下限和置信区间分别用蓝色、绿色和红色描绘。
具体实施方式
本公开文本提供了一种通过施用结合并中和人TGFβ的所有亚型的单克隆抗体治疗人患者的中度至重度OI(例如,IV型OI)的方法。所述方法是基于以下出乎意料的发现:抗TGFβ抗体的不频繁给药(例如,每三个月或六个月)可能足以改善患者的OI症状。
用于OI骨脆性的护理治疗标准涉及重新使用用于治疗骨质疏松症的药物。然而,鉴于OI的异质性和临床研究设计的可变性,BPN的作用是不一致的。另外,在一项涉及患有OI的成年人的随机试验中,用合成代谢剂特立帕肽治疗导致患有轻度形式(I型OI)的个体的aBMD和vBMD增加,而在患有所述障碍的中度至重度形式的个体中并非如此。这些重新利用的疗法都没有解决OI中的特定致病机制,因此,它们对骨骼以外表现没有影响。诸位发明人已经出乎意料地发现,用1或4mg/kg单剂量的抗TFGβ抗体治疗的患有中度至重度OI的个体显示腰椎面积骨矿物质密度(LS aBMD)的稳健增加。
靶向骨中TGFβ信号传导提供了显著的药效学优点。虽然在骨骼以外组织中调节这种关键途径需要持续的药理学抑制,但人骨重建单位为约3个月。因此,在单一时间点的药理学抑制可以具有超过药物在循环中的终末半衰期和持久性的延长效果。本文已经显示,即使用单剂量的泛特异性抗TGFβ抗体治疗也与第90天和180天的骨转换和aBMD的变化相关。此外,低给药频率由于更低的累积剂量而提供安全性优点,从而允许降低全身毒性。低频率给药的功效出乎意料,因为在OI小鼠的临床前研究中,以每周3次的频率用抗TGFβ抗体(鼠抗体1D11)治疗导致改善的检查结果,但当以更低频率(例如,以Q4W)向小鼠给药时所述改善削弱。
I.成骨不全症
OI涵盖一组以涉及骨基质沉积或内稳态的一种或多种蛋白质的缺陷为特征的先天性骨障碍。存在超过19种类型的OI,这些OI由它们的特定基因突变、所产生的蛋白质缺乏和受影响个体的表型来定义。分类包括X射线和其他成像测试的检查结果。主要OI类型如下(来自约翰·霍普金斯大学网站的信息)。
I型是最轻且最常见的类型。所有受影响的儿童中约50%患有这种类型。很少有骨折和畸形。
II型是最严重的类型。婴儿的手臂和腿很短,胸部很小,并且头骨柔软。他或她可能伴随骨折出生,也可能出生体重低,并且肺发育不良。患有II型OI的婴儿通常在出生后几周内死亡。
III型是婴儿中最严重的类型,他们不会作为新生儿死亡。出生时,婴儿的手臂和腿可能比正常情况略短,并且手臂、腿和肋骨骨折。婴儿也可能具有比正常情况大的头、三角形的脸、畸形的胸部和脊柱,以及呼吸和吞咽问题。
IV型是一种症状介于轻度与重度之间的OI类型。患有IV型的婴儿可以在出生时被诊断出来。他或她可能在爬行或行走之前没有任何骨折。手臂和腿的骨可能不直。他或她可能无法正常生长。
V型类似于IV型。症状可能是中度至重度。在大骨骨折的区域中通常具有扩大的增厚区域(肥大性骨痂)。
VI型非常罕见。症状中等,并且与IV型相似。
VII型可以类似于IV型或II型。通常比正常身高矮。比正常情况短的上臂和股骨也是常见的。
VIII型类似于II型和III型。患者具有非常软的骨和严重的生长问题。
尽管OI类型的表型不同,但常见的症状包括骨和牙齿的不完全骨化、减少的骨量、脆性骨和病理性骨折。具体症状包括容易断裂的骨、骨畸形(如腿的弯曲)、眼白(巩膜)变色、桶状胸部、弯曲的脊柱、三角形的脸、关节松动、肌肉无力、容易擦伤的皮肤、早期成年期听力损失和/或柔软变色的牙齿。OI的并发症包括呼吸道感染(例如,肺炎)、心脏问题(例如,心脏瓣膜功能不佳)、肾结石、关节问题、听力损失和异常眼睛病症(包括视力损失)。OI可以通过X射线、实验室测试(例如,血液测试和基因测试)、双能X射线吸收法扫描(DXA或DEXA扫描)和骨活检进行诊断或监测。
虽然多种致病基因突变可以引起OI的各种亚型,但超过90%是由COL1A1基因(其编码I型胶原蛋白α1链)或COL2A1基因(其编码II型胶原蛋白α1链)或者编码翻译后修饰I型胶原蛋白的蛋白质(CRTAP、PPIB和LEPRE1)的基因中的致病变体引起的(Patel等人,同上;Lim等人,Bone(2017)102:40-49)。
本公开文本的治疗方法有效地治疗中度至重度形式的OI,如IV型OI。在一些实施方案中,患者的OI是由COL1A1或COL1A2中的突变(例如,甘氨酸取代)或由CRTAP、PPIB或LEPRE1中的双等位基因致病变体引起的。参见例如,以下表1和表3中所示的突变。
II.抗TGFβ抗体
TGFβ是多功能细胞因子,其参与细胞增殖和分化、胚胎发育、细胞外基质形成、骨发育、伤口愈合、造血以及免疫和炎性应答。分泌的TGFβ蛋白被切割成潜伏相关肽(latency-associated peptide,LAP)和成熟TGFβ肽,并被发现有潜伏和活性形式。成熟TGFβ肽与其他TGFβ家族成员形成同二聚体和异二聚体二者。
有三种人(h)TGFβ亚型:TGFβ1、TGFβ2和TGFβ3(分别为UniProt登录号P01137、P08112和P10600)。TGFβ1与TGFβ2相差27个氨基酸,并且与TGFβ3相差22个氨基酸,主要是保守氨基酸。人TGFβ与小鼠TGFβ非常相似:人TGFβ1与小鼠TGFβ1具有仅一个氨基酸差异;人TGFβ2与小鼠TGFβ2具有仅三个氨基酸差异;并且人TGFβ3与小鼠TGFβ3相同。
TGFβ蛋白与同二聚体或异二聚体TGFβ跨膜受体复合物的结合激活由细胞内SMAD蛋白介导的经典TGFβ信号传导途径。TGFβ的失调导致病理学过程,所述病理过程在人体中与许多病症(如先天缺陷、癌症、慢性炎性疾病、自身免疫性疾病和纤维化疾病)有关(参见例如,Border等人,Curr Opin Nephrol Hypertens.(1994)3(4):446-52;Border等人,Kidney Int Suppl.(1995)49:S59-61)。
对于目前的OI治疗方法,抗TGFβ抗体可以是泛特异性抗体,即以高亲和力结合并中和TGFβ的所有三种亚型的抗体。在一些实施方案中,所述抗体是夫苏木单抗。夫苏木单抗是重组人抗体。其重链如下所示:
在上述序列中,位置1-120是重链可变结构域(VH),并且重链CDR(“HCDR”;根据Kabat定义)是加框的。该重链包含人IgG4恒定区。
夫苏木单抗的轻链如下所示:
在上述序列中,位置1-108是轻链可变结构域(VL),并且轻链CDR(“LCDR”;根据Kabat定义)是加下划线的。该轻链包含人Cκ恒定区。
在一些实施方案中,本文的抗TGFβ抗体是Ab1,一种夫苏木单抗的变体。Ab1的重链与夫苏木单抗的重链的不同之处仅是IgG4铰链区中的一个残基。所述残基是S228(Eu编号),其中Ab1在该位置具有脯氨酸,即相对于夫苏木单抗具有S228P取代。Ab1和夫苏木单抗具有相同的轻链。Ab1的重链如下所示:
在上述序列中,HCDR是加框的,并且S228P取代是加框并加粗的。
在一些实施方案中,所述抗TGFβ抗体包含夫苏木单抗的HCDR1-3和LCDR1-3中的一个或多个(例如,全部六个)。换句话说,所述抗体包含以下HCDR和LCDR中的一个或多个(例如,全部六个):
HCDR1 SNVI S(SEQ ID NO:4)
HCDR2 GVIPIVDIANYAQRFKG(SEQ ID NO:5)
HCDR3 TLGLVLDAMDY(SEQ ID NO:6)
LCDR1 RASQSLGSSYLA(SEQ ID NO:7)
LCDR2 GASSRAP(SEQ ID NO:8)
LCDR3 QQYADSPI T(SEQ ID NO:9)
在一些实施方案中,所述抗TGFβ抗体包含夫苏木单抗或Ab1的VH和/或VL。换句话说,所述抗体包含以下序列中之一或二者:
VH:
VL:
在一些实施方案中,所述抗TGFβ抗体是人IgG同种型,如人IgG4同种型。在某些实施方案中,所述人IgG4恒定区包含以下氨基酸序列:
在其他实施方案中,所述人IgG4恒定区在位置228(Eu编号)处具有突变。在一些实施方案(例如,Ab1)中,所述突变是丝氨酸至脯氨酸突变(S228P)。在上述序列中,所述S228丝氨酸是加框的。
在一些实施方案中,所述抗TGFβ抗体(例如,Ab1和夫苏木单抗)包含人κ轻链恒定区(Cκ)。在某些实施方案中,人Cκ包含以下氨基酸序列:
在一些实施方案中,还可以使用完整抗TGFβ抗体的抗原结合片段。术语“抗原结合片段”或类似术语是指抗体的包含如下氨基酸残基的部分,所述氨基酸残基与抗原相互作用并赋予结合剂其对于抗原的特异性和亲和力。抗原结合片段的非限制性例子包括:Fab片段、F(ab’)2片段、Fd片段、Fv片段、单链Fv(scFv)、dAb片段和由模拟抗体的高变结构域的氨基酸残基组成的最小识别单元。
在一些实施方案中,本文的抗体或抗原结合片段与骨靶向部分连接。在其他实施方案中,骨靶向部分是聚精氨酸(聚D)肽。如本文所用,术语“聚D肽”是指具有多个天冬氨酸或“D”氨基酸(如约2、3、4、5、6、7、8、9、10、20、30或更多个天冬氨酸氨基酸(残基))的肽序列。例如,聚D肽可以包含约2至约30、或约3至约15、或约4至约12、或约5至约10、或约6至约8、或约7至约9、或约8至约10、或约9至约11、或约12至约14个天冬氨酸残基。聚D肽可以仅包含天冬氨酸残基,或者可以包含一个或多个其他氨基酸或类似化合物。如本文所用,术语“D10”是指十个天冬氨酸氨基酸的连续序列,如SEQ ID NO:14中所示。在一些实施方案中,本发明的抗体或抗体片段可以包含1、2、3、4、5、6、7、8、9、10、11、12个或多于12个聚D肽。
聚D肽可以经由重组技术通过融合与所述抗TGFβ抗体或抗原结合片段连接,使得聚D通过肽键与所述抗体或片段连接(即,所述抗体或片段是融合蛋白)。例如,聚D肽可以与重链的N或C末端或二者和/或轻链的N或C末端或二者融合。聚D肽还可以使用或不使用接头部分(例如,马来酰亚胺官能团和聚乙二醇(PEG))通过化学缀合(例如通过与所述抗体或抗原结合片段上的半胱氨酸或赖氨酸残基的化学反应)与所述抗TGFβ抗体或抗原结合片段连接。参见例如,WO 2018/136698。
在某些实施方案中,所述抗体是在重链的N末端、C末端或两端与D10肽融合的夫苏木单抗。在一些实施方案中,所述抗体是在轻链的C末端与D10肽融合的夫苏木单抗。在特定实施方案中,所述抗体是在重链的两端和轻链的C末端与D10肽融合的夫苏木单抗。
在某些实施方案中,所述抗体是在重链的N末端、C末端或两端与D10肽融合的Ab1。在一些实施方案中,所述抗体是在轻链的C末端与D10肽融合的Ab1。在特定实施方案中,所述抗体是在重链的两端和轻链的C末端与D10肽融合的Ab1。
本公开文本的抗TGFβ抗体或其抗原结合片段可以通过本领域良好建立的方法来制备。可以将编码所述抗体的重链和轻链的DNA序列插入表达载体中,使得基因操作性地连接至必需的表达控制序列,如转录和翻译控制序列。表达载体包括质粒、逆转录病毒、腺病毒、腺相关病毒(AAV)、植物病毒(如花椰菜花叶病毒、烟草花叶病毒)、粘粒、YAC、EBV衍生的附加体等。抗体轻链编码序列和抗体重链编码序列可以插入单独的载体中,并且可以操作性地连接至相同或不同的表达控制序列(例如,启动子)。将编码本公开文本的抗体的表达载体引入宿主细胞中以用于表达。在适合于所述抗体表达的条件下培养宿主细胞,然后将所述宿主细胞收获并分离。宿主细胞包括哺乳动物、植物、细菌或酵母宿主细胞。可用作表达的宿主的哺乳动物细胞系是本领域熟知的,并且包括可从美国典型培养物保藏中心(ATCC)获得的许多永生化细胞系。这些细胞系尤其包括中国仓鼠卵巢(CHO)细胞、NS0细胞、SP2细胞、HEK-293T细胞、293 Freestyle细胞(Invitrogen)、NIH-3T3细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、非洲绿猴肾细胞(COS)、人肝细胞癌细胞(例如,Hep G2)、A549细胞和许多其他细胞系。细胞系可以基于它们的表达水平来选择。可以使用的其他细胞系是昆虫细胞系,如Sf9或Sf21细胞。用于宿主细胞的组织培养基可以包含或不含动物来源的组分(ADC),如牛血清白蛋白。在一些实施方案中,为了人的安全,无ADC的培养基是优选的。可以使用补料分批方法、连续灌注方法或适于宿主细胞和所需产率的任何其他方法进行组织培养。
III.药物组合物和用途
本文所述的方法包括向OI患者施用治疗有效量的抗TGFβ抗体或其抗原结合片段。如本文所用,短语“治疗有效量”意指一定剂量的与TGFβ结合的抗体,所述剂量的抗体导致与中度至重度OI(例如,IV型OI)相关的一种或多种症状的可检测的改善或者引起与导致中度至重度OI的病症或一种或多种症状的一种或多种潜在病理机制相关的生物效应(例如,特定生物标记物的水平降低)。
OI的改善可以表现为降低的骨转换、降低的骨重建率和/或降低的骨细胞密度。在一些实施方案中,OI的改善通过选自以下的骨参数的改善来指示:骨矿物质密度(BMD)、骨体积密度(BV/TV)、总骨表面(BS)、骨表面密度(BS/BV)、骨小梁数量(Tb.N)、骨小梁厚度(Tb.Th)、骨小梁间隙(Tb.Sp)和总体积(Dens TV)。
在某些实施方案中,改善的骨参数是如通过双能X射线吸收法测定的腰椎面积BMD(LS aBMD)。与治疗前的基线水平相比,LS aBMD值可以增加至少1%,例如至少1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%或更多百分比。
在一些实施方案中,在用治疗有效量的所述抗TGFβ抗体或片段治疗后,BMD、骨量和/或骨强度增加约5%至约200%。在某些实施方案中,在治疗后,BMD、骨量和/或骨强度增加约5%至约10%、10%至约15%、15%至约20%、20%至约25%、25%至约30%、30%至约35%、35%至约40%、40%至约45%、45%至约50%、50%至约55%、55%至约60%、60%至约65%、65%至约70%、70%至约75%、75%至约80%、80%至约85%、85%至约90%、90%至约95%、95%至约100%、100%至约105%、105%至约110%、110%至约115%、115%至约120%、120%至约125%、125%至约130%、130%至约135%、135%至约140%、140%至约145%、145%至约150%、150%至约155%、155%至约160%、160%至约165%、165%至约170%、170%至约175%、175%至约180%、180%至约185%、185%至约190%、190%至约195%或195%至约200%。
在一些实施方案中,治疗有效量可以导致降低的骨转换,例如,如通过血清或尿液生物标记物的降低所指示,所述血清或尿液生物标记物例如尿液羟脯氨酸、尿液总吡啶啉(PYD)、尿液游离脱氧吡啶啉(DPD)、尿液I型胶原蛋白交联N端肽(NTX)、尿液或血清I型胶原蛋白交联C末端端肽(CTX)、骨唾液蛋白(BSP)、骨桥蛋白(OPN)和抗酒石酸酸性磷酸酶5b(TRAP)。在某些实施方案中,与基线水平(例如,治疗前)相比的降低是在用与TGFβ结合的抗体治疗后降低约5%至约200%。例如,治疗后,所述降低可以是降低约5%至约10%、10%至约15%、15%至约20%、20%至约25%、25%至约30%、30%至约35%、35%至约40%、40%至约45%、45%至约50%、50%至约55%、55%至约60%、60%至约65%、65%至约70%、70%至约75%、75%至约80%、80%至约85%、85%至约90%、90%至约95%、95%至约100%、100%至约105%、105%至约110%、110%至约115%、115%至约120%、120%至约125%、125%至约130%、130%至约135%、135%至约140%、140%至约145%、145%至约150%、150%至约155%、155%至约160%、160%至约165%、165%至约170%、170%至约175%、175%至约180%、180%至约185%、185%至约190%、190%至约195%或195%至约200%。
在一些实施方案中,治疗有效量可以导致骨沉积的血清或尿液生物标记物(如总碱性磷酸酶、骨特异性碱性磷酸酶、骨钙素(OCN)和I型原胶原蛋白(C末端/N末端))的水平增加。在某些实施方案中,与基线水平(例如,治疗前)相比的增加是治疗后增加约5%至约200%。例如,治疗后,所述增加可以是增加约5%至约10%、10%至约15%、15%至约20%、20%至约25%、25%至约30%、30%至约35%、35%至约40%、40%至约45%、45%至约50%、50%至约55%、55%至约60%、60%至约65%、65%至约70%、70%至约75%、75%至约80%、80%至约85%、85%至约90%、90%至约95%、95%至约100%、100%至约105%、105%至约110%、110%至约115%、115%至约120%、120%至约125%、125%至约130%、130%至约135%、135%至约140%、140%至约145%、145%至约150%、150%至约155%、155%至约160%、160%至约165%、165%至约170%、170%至约175%、175%至约180%、180%至约185%、185%至约190%、190%至约195%或195%至约200%。
在一些实施方案中,治疗有效量促进骨沉积。在一些实施方案中,治疗有效量改善受OI影响的非骨骼器官的功能,如听力、视力、肺功能和肾功能。
治疗有效量可以是1-10mg/kg,例如1、2、3、4、5、6、7、8、9或10mg/kg。在一些实施方案中,OI患者通过静脉内注射用这种量的夫苏木单抗或Ab1治疗。治疗可以以医生认为适于患者的间隔重复。在一些实施方案中,用所述抗TGFβ抗体或其抗原结合片段的治疗可以每月、每两个月、每三个月、每四个月、每五个月、每六个月、每九个月、每12个月或每18个月重复。
患者可以是成年人(例如,18岁或更大的患者)。患者可以是儿科患者(小于18岁的患者,例如新生儿至6岁、6至12岁或12至18岁的患者)。
IV.组合疗法
在一些实施方案中,本发明的抗TGFβ抗体疗法可以与其他OI治疗组合。另外的治疗剂的例子包括但不限于二膦酸盐、降钙素、特立帕肽和已知治疗、预防或改善OI的任何其他化合物。一种或多种另外的治疗剂可以与结合TGFβ的抗体并行或依序施用。二膦酸盐的例子是依替膦酸盐、氯膦酸盐、替鲁膦酸盐、帕米膦酸盐、奈立膦酸盐、奥帕膦酸盐、阿仑膦酸盐、伊班膦酸盐、唑来膦酸盐和利塞膦酸盐。在一些实施方案中,另外的治疗剂是刺激骨形成的药物,如甲状旁腺激素类似物和降钙素。
除非本文另有定义,否则结合本公开文本所用的科学和技术术语应具有本领域普通技术人员通常所理解的含义。下文描述了示例性方法和材料,但在本公开文本的实践或测试中也可以使用与本文所述的方法和材料类似或等效的方法和材料。在矛盾的情况下,将以包括定义在内的本说明书为准。通常,本文所述的与细胞和组织培养、分子生物学、免疫学以及蛋白质和核酸化学和杂交结合使用的术语及其技术是本领域熟知并且一般使用的术语。酶促反应和纯化技术是根据制造商的说明书来进行的,如本领域通常所实现的或如本文所述的。此外,除非上下文另有要求,否则单数术语应包括复数,并且复数术语应包括单数。在整个本说明书和实施方案中,词语“具有(have)”和“包含(comprise)”或变型如“具有(has)”、“具有(having)”、“包含(comprises)”或“包含(comprising)”应被理解为暗示包括所陈述的整数或整数组,但是不排除任何其他整数或整数组。将本文提及的所有出版物和其他参考文献都通过引用以其整体并入。尽管本文引用了许多文件,但此引用并不意味着承认这些文件中的任一个构成本领域的公知常识的一部分。
为了可以更好地理解本发明,列出了以下实施例。这些实施例仅用于说明目的,而不被解释为以任何方式限制本发明的范围。
实施例
在以下实施例中,对从受OI影响(n=10)和未受OI影响(n=4)的儿童获得的骨进行组织学和RNA-seq。使用基因本体论(GO)富集测定、基因集富集测定(GSEA)和IngenuityPathway Analysis(IPA)鉴定关键的失调途径和调节因子。进行反相蛋白质阵列(RPPA)、蛋白质印迹(WB)和免疫组织化学(IHC)以确认蛋白质水平的变化。在八名患有III型和IV型OI的成年人中进行单次施用1或4mg/kg剂量的夫苏木单抗(一种泛抗TGFβ中和抗体)的1期研究。评估夫苏木单抗的安全性及其对腰椎面积骨矿物质密度(LS aBMD)和骨重建标记物的影响。用于研究的材料和方法的详细情况如下。
人骨样品收集和加工
根据由美国德克萨斯州休斯敦的贝勒医学院(BCM)的机构审查委员会(IRB)批准的方案,获得患有OI的儿童和未受OI影响的儿童的骨。骨样品是从由于医学原因已经接受手术的儿童获得的。收集并加工在手术过程中去除的原本将会被丢弃的骨碎片。在收集所有样品之前,从父母或法定监护人获得知情同意书。按照先前报道的方案(Chou等人,Osteoarthritis Cartilage(2013)21(3):450-61),如图1中所述在基于液氮的环境中加工骨样本。
RNA提取、RNA-seq、验证和数据分析
使用(ThermoFisher Scientific)从粉碎的骨提取总RNA,并将其通过氯化锂沉淀进一步纯化。通过Bioanalyzer(Agilent Technologies,美国加利福尼亚州圣克拉拉)测量RNA质量和数量。然后对总RNA进行RNA-seq,随后对途径和上游调节因子进行验证和生物信息学分析。
蛋白质提取、反相蛋白质阵列(RPPA)、蛋白质印迹(WB)和免疫组织化学(IHC)
通过使用在4℃下的裂解缓冲液(250mM EDTA、6M盐酸胍、50mM Tris-HCl,pH 7.4)从粉碎的骨过夜提取蛋白质。通过甲醇-水-氯仿沉淀浓缩提取物,并且将其溶解于4% SDS缓冲液(4SB;4% SDS、50mM Tris、5mM EDTA,pH 7.4)中以用于WB,或在SDS样品缓冲液中稀释至0.5mg/ml以用于RPPA。在WB中总共包括3个对照和5个III型OI骨样品;在RPPA和IHC中总共包括4个对照和8个III型OI骨样品(表1)。
表1.
1期临床研究设计
作为美国国立卫生研究院罕见病临床研究网络脆性骨障碍协会(NationalInstitutes of Health Rare Disease Clinical Research Network’s Brittle BoneDisorders Consortium)的一部分,进行了一项在患有中度至重度形式的OI的成年人中评价夫苏木单抗的1期剂量递增临床试验。研究的第1阶段涉及单次输注夫苏木单抗(1mg/kg体重和4mg/kg体重;每个剂量队列中n=4)。总随访时间段是6个月。主要结局衡量指标是单剂量夫苏木单抗的安全性。次要结局是评估夫苏木单抗对通过双能X射线吸收法(DXA)测得的腰椎面积骨矿物质密度(LS aBMD)和血液中的骨转换标记物(Ocn和CTX)的影响。
募入18岁以上且基于以下情况被诊断为中度至重度OI的个体:已遭受20次或更多次骨折以及COL1A1或COL1A2中的甘氨酸取代突变或CRTAP、PPIB或LEPRE1中的双等位基因致病变体。
排除标准是:1)在LS和双髋处使用器械,妨碍aBMD评估,2)在筛选之前三个月长骨骨折,3)在筛选后6个月内用口服BPN治疗或在筛选后12个月内用静脉内BPN和特立帕肽治疗,4)预期的骨骼手术,5)具有可能影响安全性的特征,如自身免疫性疾病、结核病、癌症或癌前病变史、心脏瓣膜病和出血倾向。通过CLIA和CAP认证的实验室测量骨转换的标记物。在德克萨斯儿童医院使用经验证的临床机器进行DXA扫描。由两名对研究程序不知情的中心读者读取扫描。
组织学和骨细胞密度分析
将经加工的骨样本在4%多聚甲醛(Sigma-Aldrich,美国密苏里州圣路易斯)中固定48小时,并在10% EDTA(Sigma-Aldrich)中在4℃下脱钙14天。用苏木精和伊红对石蜡切片进行染色以用于形态学和骨细胞数量分析。使用BIOQUANT OSTEO(BIOQUANT ImageAnalysis Corporation,美国田纳西州那什维尔)计算骨细胞密度。
RNA-Seq和数据分析
对于RNA-Seq,将250ng的总RNA用于TureSeq Stranded mRNA文库(Illumina,美国加利福尼亚州圣地亚哥)制备,其中根据制造商的说明书施加ERCC掺入(ThermoFisherScientific)。将22pM等摩尔汇集的文库加载到高输出v4流通池的一个泳道上,以用于使用Illumina cBot机器进行桥式扩增。使用双端100循环运行在采用v4化学的高输出模式下的HiSeq 2500测序系统(FC-401-4003,Illumina)上对流动池进行测序。以按重量计2%掺入PhiX对照品v3衔接子连接的文库(Illumina),以确保平衡的多样性并监测聚类和测序性能。对于每个样品生成平均4250万个双端读段。使用HISAT2通过Genialis(https://www.genialis.com)并且用hg19-ERCC作为参考进行比对。然后使用基因组学套件(Partek,美国密苏里州圣路易斯)中的RNA-seq分析管线进行归一化、差异表达、分层聚类和基因本体论分析。通过建立在/>基因组学套件RNA-seq分析管线中的方差分析确定统计学显著性。然后将显著差异表达的基因(倍数变化>2且错误发现率<0.05)加载到途径分析(IPA)(Qiagen,德国希尔登)中以进行上游调节因子预测。根据研发者的说明书使用用于途径富集分析的基因集富集分析(GSEA)程序(布罗德研究所(BroadInstitute))。
通过进行RNA-seq验证
使用一个III型OI和一个对照样品及其RNA-seq数据运行NanoString(美国华盛顿州西雅图)人WNT nCounter检测组套以验证检测到的基因表达倍数变化。使用nSolverTM在常规模块下进行分析。读段计数低于20的基因被认为是背景,并从进一步分析中去除。验证了总共155个基因。通过显示出表达方向的相同变化的基因的百分比确定一致性。
反相蛋白质阵列(RPPA)
通过使用标准化方案(Marini等人,同上)进行RPPA。以3个技术重复实验测定每个样品,以说明技术变化。首先通过计算每个生物样品的技术上的一式三份实验样品的平均强度得出每个生物样品的蛋白质表达强度(PEI)。然后由所述组中每个样品的PEI的平均值计算对照组或III型OI组的平均表达强度。使用学生t检验确定对照与III型OI之间的统计学显著性。使用标称P值0.05确定显著性。
蛋白质印迹(WB)
使用50μg的总蛋白加载。在通过SDS-PAGE凝胶分离并转移到PVDF膜(MilliporeSigma,美国马萨诸塞州柏林顿)后,使用5%牛奶封闭膜,随后与一抗(磷酸-SMAD2(3108S,Cell Signaling)、SMAD2(5339S,Cell Signaling)和GAPDH(G9295,Sigma-Aldrich)一起在4℃下过夜孵育。在适当的二抗(Bio-Rad)后使用ChemiDocTM凝胶成像系统(Bio-Rad,美国加利福尼亚州赫拉克勒斯)捕获信号。
免疫组织化学(IHC)
脱蜡后,将切片在37℃下与0.05%胰蛋白酶一起孵育,以用于3%过氧化氢处理后的抗原修复。在用5%正常山羊血清封闭后,按照制造商的说明书,将切片与磷酸-SMAD2的一抗(44-244G,ThermoFisher Scientific,美国马萨诸塞州沃尔瑟姆)在4℃下一起孵育过夜。施加抗兔二抗(Vectastain ABC系统,Vector Laboratories,瑞士塞尔维翁),并使用0.1%3,39-二氨基联苯胺使印迹显影。
实施例1:在患有III型OI的儿童的骨中无组织的编织骨和增加的骨细胞密度
从10名患有III型OI的儿童(9名儿童具有COL1A1或COL1A2中的甘氨酸取代突变并且1名儿童具有与COL1A2中的缬氨酸缺失)和4名未受OI影响的儿童(表1)收集胫骨或股骨的骨碎片。在组织学上,对照样本主要包含皮质骨,而OI样本含有皮质骨和小梁骨二者。形态学检查揭示,与对照相比,OI骨展示无组织的哈弗氏系统,主要是编织骨(图2)。与早前的报道(Nijhuis等人,J Child Orthopaed.(2019)13(1):1-11)一致,与对照相比,在OI骨中的骨细胞密度高超过3倍(在OI中为686.44/mm2,而在对照中为221.94/mm2),并且陷窝看起来更具球形形状(图2和图3)。这些对于OI典型的数据暗示了样品的高质量。
实施例2:全转录组学分析证明增加的TGFβ信号传导是III型OI骨中的关键失调途径
为了以无偏倚的方式鉴定人OI骨中的关键失调途径,我们使用对照和III型OI骨进行RNA-seq。为了确保RNA-seq结果的准确性,我们通过验证155个基因并显示表达倍数变化的一致性为92%(图4)。转录组学数据的主成分分析(PCA)揭示在对照与OI骨之间的明显分离(图5,图A)。相比于OI骨,在对照中的基因表达谱更均一。全转录组RPKM的分层聚类显示在对照与OI骨之间不同的聚类,这表明OI中总体分子特征的变化(图5,图B)。在差异基因表达分析之后,进行GO富集分析。在GO生物学过程中,显著富集的骨骼相关功能捕获OI的分子特征,包括增加的骨形成、吸收和重建以及减少的骨小梁和骨成熟。一致地,在GO细胞过程中,在OI中鉴定出增加的成骨细胞和破骨细胞分化。在GO信号传导途径中,包括BMP-TGFβ、甲状旁腺激素途径、WNT和Notch信号传导在内的主要骨重建途径被上调。最有趣的是,SMAD蛋白磷酸化调节是所有途径中最显著上调的途径(P=1.78x10-15)(图6)。这些富集结果不仅与OI骨的已知分子病理学特征一致,而且无偏倚地揭示TGFβ下游事件SMAD磷酸化是III型OI骨中最受影响的靶标。
为了独立地探索OI骨中信号传导的变化,我们接下来使用对照和OI骨的RPKM进行GSEA(Subramanian等人,PNAS(2005)102(43):15545-50)。GSEA鉴定TGFβ信号传导为OI中最显著激活的途径(图5,图C;图7)。总之,这些结果表明,TGFβ信号传导是III型OI骨中主要且最一致的激活途径。
实施例3:TGFβ是III型OI的骨中的活性上游调节因子
为了研究从转录组学分析鉴定的TGFβ途径的激活是否确实由TGFβ配体导致,我们利用IPA进行基于3,722个显著改变的基因的上游调节因子预测。在所有潜在的上游调节因子中,TGFβ是所鉴定的最有活性的上游调节因子(Z得分=4.28,P=1.32x10-14)(表2)。为了确保这些转录组学检查结果导致蛋白质水平的变化,我们使用从骨提取的蛋白质进行靶向蛋白质组学RPPA。在检查的230种蛋白质中,29种蛋白质显示出在OI与对照骨之间标称的统计学上显著的强度变化(图8)。在该分析中,TGFβ通过IPA被鉴定为最显著激活的上游调节因子(Z得分=2.17,P=6.37x10-12)(表2)。
表2.
实施例4:III型OI骨中增加的SMAD2磷酸化
为了结论性地证明III型OI骨中原位增加的TGFβ信号传导,我们使用针对TGFβ下游靶标磷酸化SMAD2(pSMAD2)的抗体进行IHC。
与对照相比,我们发现III型OI骨中增加的pSMAD2染色(图9,图A)。通过使用来自对照和III型OI骨的蛋白质裂解物进行的WB,我们观察到在所有检查的OI样品中pSMAD2的增加(图9,图B)。进一步的定量展示OI骨中pSMAD2/总SMAD2比率的显著增加(图9,图C)。总之,这些结果表明TGFβ激活是患有OI的人的驱动致病机制。
实施例5:作为OI的治疗干预的夫苏木单抗
为了翻译这些检查结果,我们进行了一项评价中和所有哺乳动物TGFβ亚型的夫苏木单抗(一种人IgG4κ单克隆抗体)的安全性的I期临床试验。为了与我们已生成的临床前数据和人数据一致,只有患有由COL1A1或COL1A2中的甘氨酸取代突变或CRTAP、PPIB或LEPRE1中的双等位基因致病变体引起的临床中度至重度OI的个体才被募入。总共募入了8名个体(表3)。
表3.
四名接受剂量为1mg/kg体重的夫苏木单抗的单次施用,并且四名接受4mg/kg体重的夫苏木单抗。使用夫苏木单抗的治疗耐受性良好。在两个队列中没有严重的不良事件(AE),并且没有观察到临床上显著的实验室变化(图10)。在1mg/kg队列中,仅两个AE被分级为可能/很可能与研究药物相关:在施用药物后恶心以及鼻出血。在4mg/kg队列中,有7个AE被分级为可能/很可能与药物相关:不适、头痛、鼻出血、尿液中的隐血、从皮肤结痂出血以及在一名参与者中在第180天校正的QT间期为457ms。
用1mg/kg的夫苏木单抗的治疗与骨转换的标记物Ocn和CTX的增加相关。在治疗后第30天与第90天之间观察到骨重建的增加峰值。从治疗后第30天开始,用4mg/kg剂量的治疗与Ocn的持续减少相关(图11)。LS aBMD的两个中心读数(掩蔽于测量的时间点)具有高度的相关性(r=0.995)和一致性(图12)。因此,来自两个读数的平均aBMD用于计算相比于基线的百分比变化。在1mg/kg剂量下,两名IV型OI参与者显示LS aBMD的稳健增加,而患有VIII型OI的个体未展示任何变化。显示出aBMD下降的患有III型OI的参与者具有显著的脊柱侧凸,这在分析来自DXA扫描的结果时构成了挑战。
在4mg/kg队列中,在第90天和180天评估LS aBMD。到第90天,两名患有IV型OI的参与者具有aBMD的稳健增加。显示出aBMD急剧下降的患有III型OI的个体遭受股骨骨折,导致长期不能移动;其aBMD是在远程设施下测量的,使得比较不太理想。
总而言之,在本研究中,我们以不偏倚的方式全面检查了OI(一种孟德尔形式的骨质疏松症)中的总体信号传导异常。这些检查结果和“组学尺度(omic-scale)”数据不仅影响OI的治疗,而且还可能与其他低骨量的障碍有关。此外,本研究导致出乎意料的发现,即在我们的研究中,即使使用单剂量夫苏木单抗治疗也与第90天和180天的骨转换和aBMD的变化相关。此外,骨生物学的独特特征提供了潜在的安全性优点,因为更低的累积剂量和施用频率允许降低全身毒性。实际上,与在针对黑色素瘤、特发性肺纤维化、系统性硬化病和局灶节段性肾小球硬化症的试验中给予的那些相比,本文所施用的夫苏木单抗剂量更低。使用单剂量施用时未观察到严重AE。此外,我们观察到这两种试验剂量对骨转换标记物不同的影响。在1mg/kg剂量下,夫苏木单抗与骨重建的轻度增加相关。然而,如血浆Ocn水平所示,4mg/kg夫苏木单抗治疗导致骨转换的持续抑制。对LS aBMD的影响更具变化性,这取决于疾病严重程度。两名患有IV型OI的参与者在1mg/kg单剂量下LS aBMD增加了6.8%和8.6%。在4mg/kg队列中,在输注之后3个月,一名参与者具有7.6%的增加并且两名参与者显示出2.9%和1.3%的增加。与合成代谢剂特立帕肽相比,这些增加更高,特立帕肽在患有轻度而非重度OI的个体中在6个月时展示2%增加,并且与每月高剂量塞曲单抗(setrusumab)是可比较的,后者在6个月试验时间段内与III型和IV型OI中LS aBMD增加5.4%相关(Eric等人,JBMR Plus(2021)5(S1):增刊:e10455)。两名患有III型OI的参与者(FR005和FR012)具有aBMD降低。
序列
下表显示了本公开文本中提及的氨基酸序列。
SEQ ID NO | 描述 |
1 | 夫苏木单抗重链 |
2 | 夫苏木单抗或Ab1轻链 |
3 | Ab1重链 |
4 | 夫苏木单抗或Ab1 HCDR1 |
5 | 夫苏木单抗或Ab1 HCDR2 |
6 | 夫苏木单抗或Ab1 HCDR3 |
7 | 夫苏木单抗或Ab1 LCDR1 |
8 | 夫苏木单抗或Ab1 LCDR2 |
9 | 夫苏木单抗或Ab1 LCDR3 |
10 | 夫苏木单抗或Ab1 VH |
11 | 夫苏木单抗或Ab1 VL |
12 | 人IgG4恒定区 |
13 | 人κ轻链恒定区 |
14 | D10氨基酸序列 |
序列表
<110> 贝勒医学院
<120> 中度至重度成骨不全症的治疗
<130> 022548.WO026
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<141>
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<151> 2021-05-07
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Asn
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Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Val Ile Pro Ile Val Asp Ile Ala Asn Tyr Ala Gln Arg Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Thr Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Ser Thr Leu Gly Leu Val Leu Asp Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
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Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
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Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 2
<211> 215
<212> PRT
<213> 人工序列
<220>
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<400> 2
Glu Thr Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Asp Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 3
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
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<400> 3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Asn
20 25 30
Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Val Ile Pro Ile Val Asp Ile Ala Asn Tyr Ala Gln Arg Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Thr Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Thr Leu Gly Leu Val Leu Asp Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 4
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<400> 4
Ser Asn Val Ile Ser
1 5
<210> 5
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 5
Gly Val Ile Pro Ile Val Asp Ile Ala Asn Tyr Ala Gln Arg Phe Lys
1 5 10 15
Gly
<210> 6
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 6
Thr Leu Gly Leu Val Leu Asp Ala Met Asp Tyr
1 5 10
<210> 7
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 7
Arg Ala Ser Gln Ser Leu Gly Ser Ser Tyr Leu Ala
1 5 10
<210> 8
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 8
Gly Ala Ser Ser Arg Ala Pro
1 5
<210> 9
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<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
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<400> 9
Gln Gln Tyr Ala Asp Ser Pro Ile Thr
1 5
<210> 10
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<213> 人工序列
<220>
<223> 人工序列的描述:合成
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Asn
20 25 30
Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Val Ile Pro Ile Val Asp Ile Ala Asn Tyr Ala Gln Arg Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Thr Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
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1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
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100 105
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Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser 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 Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
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305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 13
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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
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85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
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1 5 10
Claims (25)
1.一种用于治疗有需要的人受试者的成骨不全症(OI)的方法,所述方法包括向所述受试者施用治疗有效量的抗TGFβ抗体或其抗原结合片段,其中所述抗体或抗原结合片段包含
分别含有SEQ ID NO:4-6的重链互补决定区(CDR)1-3和
分别含有SEQ ID NO:7-9的轻链CDR1-3,
其中所述治疗有效量是1-10mg/kg。
2.根据权利要求1所述的方法,其中所述抗体或抗原结合片段包含含有SEQ ID NO:10的重链可变结构域和含有SEQ ID NO:11的轻链可变结构域。
3.根据权利要求1或2所述的方法,其中所述抗体包含人IgG4恒定区和/或人κ轻链恒定区。
4.根据权利要求3所述的方法,其中所述人IgG4恒定区包含S228P突变(Eu编号)。
5.根据权利要求3所述的方法,其中所述抗体包含含有SEQ ID NO:1的重链和含有SEQID NO:2的轻链。
6.根据权利要求3所述的方法,其中所述抗体包含含有SEQ ID NO:3的重链和含有SEQID NO:2的轻链。
7.根据前述权利要求中任一项所述的方法,其中所述抗体包含骨靶向部分,任选地其中所述骨靶向部分是聚精氨酸肽。
8.根据权利要求7所述的方法,其中所述抗体包含一个或多个聚精氨酸肽。
9.根据权利要求8所述的方法,其中所述抗体在所述抗体或抗原结合片段的重链的N末端或C末端或两端和/或轻链的C末端与聚精氨酸肽融合。
10.根据权利要求7-9中任一项所述的方法,其中所述聚精氨酸肽是D10(SEQ ID NO:14)。
11.根据前述权利要求中任一项所述的方法,其中所述OI是中度至重度OI或IV型OI。
12.根据前述权利要求中任一项所述的方法,其中所述人受试者是成年患者(≥18岁)或儿科患者(<18岁)。
13.根据前述权利要求中任一项所述的方法,其中所述人受试者具有COL1A1或COL1A2基因中的突变,任选地其中所述突变是所述COL1A1或COL1A2基因中的甘氨酸取代突变或所述COL1A2基因中的缬氨酸缺失。
14.根据前述权利要求中任一项所述的方法,其中所述施用改善选自以下的骨参数:骨矿物质密度(BMD)、骨体积密度(BV/TV)、总骨表面(BS)、骨表面密度(BS/BV)、骨小梁数量(Tb.N)、骨小梁厚度(Tb.Th)、骨小梁间隙(Tb.Sp)和总体积(Dens TV)。
15.根据权利要求14所述的方法,其中所述骨参数是腰椎面积BMD(LS aBMD),任选地其中所述LS aBMD在所述施用后相对于基线水平增加了至少1%-10%。
16.根据前述权利要求中任一项所述的方法,其中所述施用降低骨转换和/或骨细胞密度,任选地其中所降低的骨转换由血清CTX的降低或血清骨钙素(OCN)的增加指示。
17.根据权利要求1-16中任一项所述的方法,其中所述治疗有效量是1mg/kg。
18.根据权利要求1-16中任一项所述的方法,其中所述治疗有效量是4mg/kg。
19.根据前述权利要求中任一项所述的方法,所述方法进一步包括每月、每两个月、每三个月、每六个月、每九个月或每十二个月重复所述施用步骤。
20.根据前述权利要求中任一项所述的方法,其中将所述抗体或抗原结合片段通过静脉内输注施用。
21.根据前述权利要求中任一项所述的方法,所述方法进一步包括向所述受试者施用二膦酸盐、甲状旁腺激素、降钙素、特立帕肽或抗骨硬化蛋白剂。
22.根据权利要求21所述的方法,其中所述二膦酸盐选自阿仑膦酸盐、帕米膦酸盐、唑来膦酸盐和利塞膦酸盐。
23.一种抗TGFβ抗体或其抗原结合片段,所述抗TGFβ抗体或其抗原结合片段用于在根据权利要求1-22中任一项所述的方法中治疗成骨不全症。
24.抗TGFβ抗体或其抗原结合片段在制造用于在根据权利要求1-22中任一项所述的方法中治疗成骨不全症的药剂中的用途。
25.一种包含抗TGFβ抗体或其抗原结合片段的制品或试剂盒,所述制品或试剂盒用于在根据权利要求1-22中任一项所述的方法中治疗成骨不全症。
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PCT/US2022/027666 WO2022235796A1 (en) | 2021-05-07 | 2022-05-04 | Treatment of moderate-to-severe osteogenesis imperfecta |
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FR9F (fr) | 1960-07-11 | 1962-03-09 | A Castaigne Lab | Applications thérapeutiques de l'arginase (corps 45-25c). |
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WO2022235796A1 (en) | 2022-11-10 |
US20240238415A1 (en) | 2024-07-18 |
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MX2023013184A (es) | 2023-12-05 |
KR20240018471A (ko) | 2024-02-13 |
BR112023022742A2 (pt) | 2024-01-02 |
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