CN113874047A - Adc用于与多西他赛同时或随后治疗 - Google Patents
Adc用于与多西他赛同时或随后治疗 Download PDFInfo
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- CN113874047A CN113874047A CN202080033927.9A CN202080033927A CN113874047A CN 113874047 A CN113874047 A CN 113874047A CN 202080033927 A CN202080033927 A CN 202080033927A CN 113874047 A CN113874047 A CN 113874047A
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Abstract
本发明涉及一种具有下式(I)的ADC,其中Ab是抗IGF1R抗体,其特征在于其包含序列分别为SEQ ID No.9、5和11的轻链CDR和序列分别为SEQ ID No.7、2和3的重链CDR,并且n介于1和12之间,所述ADC用于治疗增殖性疾病如癌症,其特征在于所述ADC与多西他赛同时或随后施用。
Description
本发明涉及抗IGF1R ADC(ADC-A)用于治疗增殖性疾病(如癌症)的用途,其特征在于ADC-A与多西他赛同时或随后施用。
过度增殖性疾病(如癌症)是一个真正的公共卫生挑战。显然,需要寻找有效的一线抗肿瘤药物。但是,如果出现对这些一线治疗的耐药性(其是一种普遍现象)也需要提供长期解决方案。
多西他赛是一种二萜,用作癌症药物,其作用于癌细胞微管并导致阻止有丝分裂。多西他赛的有效性已在相当多的肿瘤中得到证实,尤其是在乳腺癌、肺癌和前列腺癌中。然而,大量患者随时间对多西他赛产生耐药性,导致治疗失败。
胰岛素样生长因子1受体,称为IGF-1R(或IGF1R),是一种具有酪氨酸激酶活性的受体,与胰岛素受体IR具有70%的同源性。IGF-IR是一种分子量约为350,000的糖蛋白。它是一种异源四聚体受体,其每个部分通过二硫键连接,所述每个部分由细胞外α亚基和跨膜β亚基组成。IGF-IR以非常高的亲和力(Kd#1nM)结合IGF1和IGF2,并且能够以低100至1000倍的亲和力结合胰岛素。
细胞质酪氨酸激酶蛋白通过配体与IGF-1R细胞外结构域的结合而激活。这些激酶的激活反过来导致各种细胞内底物的失活,包括IRS-1、IRS-2、She和Grb 10。通过激活众多下游效应子,IRS蛋白参与诱导细胞生长和分化的众多途径。此外,主要参与防止细胞凋亡的途径似乎是磷脂酰肌醇3-激酶(Pi3-激酶)途径。
IGF系统在致癌作用中的作用在过去十年中一直是深入研究的主题。实际上,已经确认IGF-IR的激活在许多种细胞中导致独立细胞的异常生长和肿瘤形成。因此IGF-IR在多种肿瘤和肿瘤系中表达。
为了治疗这种类型的癌症,已经开发了靶向IGF1R的治疗。因此已经确定,使用靶向IGF-1R的ADC(抗体药物偶联物)使得有可能减少甚至消除肿瘤生长。WO2015162291中已经特别描述了这样的ADC,特别是下面描述的ADC,称为ADC-A。
确实需要有效治疗过度增殖性疾病。因此,有必要确定治疗组合,使得有可能逃避肿瘤耐药现象的发生。
令人惊讶的是,本发明显示了抗IGF1R ADC与多西他赛的组合使用导致在肿瘤治疗中的协同效应。同样令人惊讶的是,表明了使用抗IGF1R ADC使得有可能治疗多西他赛治疗后产生耐药性的肿瘤。
附图说明
图1:在携带大约150mm3的MCF-7肿瘤的小鼠中,平均肿瘤体积(mm3)的进展作为时间(天)的函数:A.每两周一次用9mg/kg的多西他赛治疗,持续5个周期(三条合并的曲线是同时进行相同治疗的5只小鼠的三个系列)后;和B.治疗小鼠在第70天对多西他赛产生耐药性:第1组,每两周9mg/kg多西他赛(圆圈)和;第2组,注射3mg/kg的ADC-A(三角)。
因此,本发明的一个目的是用于增殖性疾病(如癌症)的抗IGF1RADC(ADC-A),其特征在于ADC-A与多西他赛同时或随后施用。
本发明还有一个目的是抗IGF1R ADC(ADC-A)用于治疗增殖性疾病(如癌症)的用途,其特征在于ADC-A与多西他赛同时或随后施用。
本发明还有一个目的是抗IGF1R ADC(ADC-A)用于制备旨在治疗增殖性疾病(如癌症)的药物的用途,其特征在于ADC-A与多西他赛同时或随后施用。
本发明还有一个目的是一种治疗增殖性疾病(如癌症)的方法,包括向有需要的患者施用有效量的抗IGF1R ADC(ADC-A)和多西他赛,其特征在于ADC-A与多西他赛同时或随后施用。
多西他赛
根据本发明,多西他赛是指下式的化合物:
以及其药学上可接受的盐和溶剂化物,尤其是其三水合物。
在本发明中,“药学上可接受的”是指可用于制备药物化合物的物质,其通常是安全的、无毒的并且在生物学上或其他方面不是不合需要的,并且对于兽医和人的药物用途均可接受。
化合物的“药学上可接受的盐或溶剂化物”是指如此处定义的药学上可接受的盐或溶剂化物,并且其具有母体化合物的所需药理学活性。
药学上可接受的盐尤其包括:
(1)药学上可接受的酸加成盐,其与药学上可接受的无机酸形成,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或与药学上可接受的有机酸形成,所述有机酸如:甲酸、乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚酸、葡糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、二苯甲酰-L-酒石酸、酒石酸、对甲苯磺酸、三甲基乙酸、三氟乙酸等,和
(2)药学上可接受的碱加成盐,其在母体化合物中存在的酸质子被金属离子取代时形成,所述金属离子例如碱金属离子、碱土金属离子或铝;或所述酸质子与药学上可接受的有机碱配位时形成,所述有机碱如二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等;或与药学上可接受的无机碱形成,所述无机碱如氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
用于根据本发明的化合物的药学用途的可接受的溶剂化物包括标准溶剂化物,如在根据本发明的化合物的制备方法的最后步骤与反应溶剂形成的那些。可以作为示例提及与水形成的溶剂化物(通常称为水合物)或与乙醇形成的溶剂化物。例如,它可以是三水合物。
ADC-A
ADC-A是下式的抗IGF1R ADC:
其中Ab是包含序列SEQ ID No.1、2和3的三个重链互补决定区(CDR)和序列SEQ IDNo.4、5和6的三个轻链CDR的抗IGF1R抗体,并且n包含在1和12之间,特别是等于2或4。
术语“抗体”、“ab”、“Ab”、“mAb”或“免疫球蛋白”在最广泛的意义上可互换使用,包括单克隆抗体、修饰的或重组的分离抗体(例如完全或完整的单克隆抗体)、多克隆抗体、多价抗体或多特异性抗体(例如双特异性抗体)以及其抗体片段,使得它们具有所需的生物活性,特别是其抗原结合片段。更特别地,它是单克隆抗体或可能是其抗原结合片段。
根据本发明的术语抗体的“抗原结合片段”旨在表示保留抗体与靶标(通常称为抗原)结合的能力的任何肽、多肽或蛋白质。
如在本说明书中所使用的,表述“抗IGF-1R抗体”是指能够结合IGF-1R的抗体,更特别地结合位于IGF-1R中的表位,优选IGF-1R的胞外域,更优选人IGF-1R(SEQ ID No.50),更优选人IGF-1R的胞外域(SEQ ID No.51),甚至更优选人IGF-1R胞外域的N-末端部分(SEQID No.52),或其任何一种天然变体序列。
根据本发明的一个具体实施方案,根据本发明的抗体包含三个重链CDR和三个轻链CDR,所述重链CDR包含或由以下组成:序列SEQ ID No.1、2和3,或与SEQ ID No.1、2或3具有至少80%、优选85%、90%、95%和98%同一性的任何序列;所述轻链CDR包含或由以下组成:序列SEQ ID No.4、5和6,或与SEQ ID No.4、5或6具有至少80%、优选85%、90%、95%和98%同一性的任何序列。
在本发明的公开内容中提及的百分比同一性是基于待比较序列的全局比对而确定的,即,使用任何本领域技术人员熟知的算法(如Needleman和Wunsch-1970的算法),基于在整个长度上完整获取的序列的比对而确定。这种序列的比较可以通过技术人员熟知的任何软件进行,例如Needle软件,使用“间隔开放(Gap open)”参数等于10.0、“间隔延伸(Gapextend)”参数等于0.5和“Blosum 62”矩阵。例如,可在ebi.ac.uk全球网站上以名称“Align”获得Needle软件。
当根据本发明的抗体具有的氨基酸序列与参考序列不是100%相同,但与这样的参考序列具有至少80%、优选85%、90%、95%和98%同一性时,它可能相对于该参考序列具有插入、缺失或取代。当涉及取代时,该取代优选用“等效”氨基酸进行,即任何结构与原始氨基酸相似的氨基酸,因此不太可能改变抗体的生物活性。这种取代的例子示于下表中:
原始氨基酸 | 取代 |
Ala(A) | Val,Gly,Pro |
Arg(R) | Lys,His |
Asn(N) | Gln |
Asp(D) | Glu |
Cys(C) | Ser |
Gln(Q) | Asn |
Glu(G) | Asp |
Gly(G) | Ala |
His(H) | Arg |
Ile(I) | Leu |
Leu(L) | Ile,Val,Met |
Lys(K) | Arg |
Met(M) | Leu |
Phe(F) | Tyr |
Pro(P) | Ala |
Ser(S) | Thr,Cys |
Thr(T) | Ser |
Trp(W) | Tyr |
Tyr(Y) | Phe,Trp |
Val(V) | Leu,Ala |
下表1说明了优选抗体的CDR序列:
表1
根据一个具体的方面,抗体是小鼠抗体,其特征在于它还包含源自与小鼠异源的物种(尤其是人)的抗体的轻链和重链恒定区。
根据本发明的一个具体的方面,抗体是嵌合抗体(c),其特征在于它还包含源自与小鼠异源的物种(尤其是人)的抗体的轻链和重链恒定区。
嵌合抗体是含有源自给定物种的抗体的天然可变区(轻链和重链)及与所述给定物种异源的物种的抗体的轻链和重链恒定区组合的抗体。
根据本发明的一个实施方案,抗体选自:
a)包含序列SEQ ID No.7、2和3的三个重链CDR,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;
b)包含序列SEQ ID No.7、2和3的三个重链CDR,和序列SEQ ID No.10、5和11的三个轻链CDR的抗体;
c)包含序列SEQ ID No.7、2和3的三个重链CDR,和序列SEQ ID No.9、5和12的三个轻链CDR的抗体;和
d)包含序列SEQ ID No.8、2和3的三个重链CDR,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体。
在本发明的一个优选但非限制性的实施方案中,抗体选自:
a)包含序列SEQ ID No.13或与SEQ ID No.13具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;
b)包含序列SEQ ID No.14或与SEQ ID No.14具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.10、5和11的三个轻链CDR的抗体;
c)包含序列SEQ ID No.15或与SEQ ID No.15具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和12的三个轻链CDR的抗体;
d)包含序列SEQ ID No.16或与SEQ ID No.16具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;和
e)包含序列SEQ ID No.17或与SEQ ID No.17具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和12的三个轻链CDR的抗体。
“与SEQ ID No.13至17具有至少80%、优选85%、90%、95%和98%同一性的任何序列”分别是指具有三个重链CDR SEQ ID No.1、2和3的序列和,此外,在对应于CDR的序列(即,SEQ ID No.1、2和3)以外,与完整序列SEQ ID No.13至17具有至少80%、优选85%、90%、95%和98%同一性。
根据本发明的一个实施方案,抗体选自:
a)包含序列SEQ ID No.13的重链可变结构域和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;
b)包含序列SEQ ID No.14的重链可变结构域和序列SEQ ID No.10、5和11的三个轻链CDR的抗体;
c)包含序列SEQ ID No.15的重链可变结构域和序列SEQ ID No.9、5和12的三个轻链CDR的抗体;
d)包含序列SEQ ID No.16的重链可变结构域和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;和
e)包含序列SEQ ID No.17的重链可变结构域和序列SEQ ID No.9、5和12的三个轻链CDR的抗体。
在另一个优选但非限制性的实施方案中,抗体选自:
a)包含序列SEQ ID No.18或与SEQ ID No.18具有至少80%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
b)包含序列SEQ ID No.19或与SEQ ID No.19具有至少80%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
c)包含序列SEQ ID No.20或与SEQ ID No.20具有至少80%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
d)包含序列SEQ ID No.21或与SEQ ID No.21具有至少80%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.8、2和3的三个重链CDR的抗体;和
e)包含序列SEQ ID No.22或与SEQ ID No.22具有至少80%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体。
“与SEQ ID No.18至22具有至少80%、优选85%、90%、95%和98%同一性的任何序列”分别是指具有轻链CDR SEQ ID No.4、5和6的序列和,此外,在对应于CDR的序列(即,SEQ ID No.4、5和6)以外,与完整序列SEQ ID No.18至22具有至少80%、优选85%、90%、95%和98%同一性。
根据本发明的一个实施方案,抗体选自:
a)包含序列SEQ ID No.18的轻链可变结构域和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
b)包含序列SEQ ID No.19的轻链可变结构域和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
c)包含序列SEQ ID No.20的轻链可变结构域和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
d)包含序列SEQ ID No.21的轻链可变结构域和序列SEQ ID No.8、2和3的三个重链CDR的抗体;和
e)包含序列SEQ ID No.22的轻链可变结构域和序列SEQ ID No.7、2和3的三个重链CDR的抗体;
根据本发明的一个实施方案,抗体是选自以下的抗体:
a)包含序列SEQ ID No.13或与SEQ ID No.13具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.18或与SEQ ID No.18具有至少80%同一性的任何序列的轻链可变结构域的抗体;
b)包含序列SEQ ID No.14或与SEQ ID No.14具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.19或与SEQ ID No.19具有至少80%同一性的任何序列的轻链可变结构域的抗体;
c)包含序列SEQ ID No.15或与SEQ ID No.15具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.20或与SEQ ID No.20具有至少80%同一性的任何序列的轻链可变结构域的抗体;
d)包含序列SEQ ID No.16或与SEQ ID No.16具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.21或与SEQ ID No.21具有至少80%同一性的任何序列的轻链可变结构域的抗体;和
e)包含序列SEQ ID No.17或与SEQ ID No.17具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.22或与SEQ ID No.22具有至少80%同一性的任何序列的轻链可变结构域的抗体。
此处描述的嵌合抗体也可以特征在于恒定结构域,更特别地,所述嵌合抗体可以选择或设计如,但不限于:IgG1、IgG2、IgG3、IgM、IgA、IgD或IgE。更优选地,在本发明的上下文中,所述嵌合抗体是IgG1或IgG4。
根据本发明的一个实施方案,抗体是嵌合抗体,其包含重链可变结构域(VH)和轻链可变结构域(VL),如上文所述为IgG1形式。更优选地,所述嵌合抗体包含序列SEQ IDNo.43的VH的恒定结构域和序列SEQ ID No.45的VL的κ结构域。
根据本发明的一个实施方案,抗体是嵌合抗体,其包含VH和VL可变结构域,如上文所述为IgG4形式。更优选地,所述嵌合抗体包含序列SEQ ID No.44的VH的恒定结构域和序列SEQ ID No.45的VL的κ结构域。
在另一个优选但非限制性的实施方案中,抗体选自:
a)包含或由以下组成的抗体:序列SEQ ID No.23或与SEQ ID No.23具有至少80%同一性的任何序列的重链,和序列SEQ ID No.28或与SEQ ID No.28具有至少80%同一性的任何序列的轻链;
b)包含或由以下组成的抗体:序列SEQ ID No.24或与SEQ ID No.24具有至少80%同一性的任何序列的重链,和序列SEQ ID No.29或与SEQ ID No.29具有至少80%同一性的任何序列的轻链;
c)包含或由以下组成的抗体:序列SEQ ID No.25或与SEQ ID No.25具有至少80%同一性的任何序列的重链,和序列SEQ ID No.30或与SEQ ID No.30具有至少80%同一性的任何序列的轻链;
d)包含或由以下组成的抗体:序列SEQ ID No.26或与SEQ ID No.26具有至少80%同一性的任何序列的重链,和序列SEQ ID No.31或与SEQ ID No.31具有至少80%同一性的任何序列的轻链;和
e)包含或由以下组成的抗体:序列SEQ ID No.27或与SEQ ID No.27具有至少80%同一性的任何序列的重链,和序列SEQ ID No.32或与SEQ ID No.32具有至少80%同一性的任何序列的轻链。
为进一步清楚起见,下表2分别说明了优选嵌合抗体的VH和VL序列。
表2
根据本发明的另一个具体方面,抗体是人源化抗体,其特征在于源自人抗体的轻链和重链的恒定区分别是λ或κ区和γ-1、γ-2或γ-4区。
在一个优选的实施方案中,抗体包含重链可变结构域(VH),其具有:
i)分别为序列SEQ ID No.7、2和3的CDR-H1、CDR-H2和CDR-H3,和
ii)源自人种系IGHV1-46*01(SEQ ID No.46)的FR1、FR2和FR3,和
iii)源自人种系IGHJ4*01(SEQ ID No.48)的FR4。
在一个优选的实施方案中,抗体包含轻链可变结构域(VL),其具有:
i)分别为序列SEQ ID No.9、5和11的CDR-L1、CDR-L2和CDR-L3,和
ii)源自人种系IGKV1-39*01(SEQ ID No.47)的FR1、FR2和FR3,和
iii)源自人种系IGKJ4*01(SEQ ID No.49)的FR4。
在本发明的一个优选但非限制性的实施方案中,抗体包含:
a)重链,其具有分别为序列SEQ ID No.7、2和3的CDR-H1、CDR-H2和CDR-H3,和源自人种系IGHV1-46*01(SEQ ID No.46)的FR1、FR2和FR3,和源自人种系IGHJ4*01(SEQ IDNo.48)的FR4;和
b)轻链,其具有分别为序列SEQ ID No.9、5和11的CDR-L1、CDR-L2和CDR-L3,和源自人种系IGKV1-39*01(SEQ ID No.47)的FR1、FR2和FR3,和源自人种系IGKJ4*01(SEQ IDNo.49)的FR4。
在一个实施方案中,抗体包含序列SEQ ID No.33的重链可变结构域(VH)和序列SEQ ID No.35的轻链可变结构域(VL)。在下文中,所述人源化抗体将被称为hz208F2(“变体1(Variant 1)”或“变体1(Var.1)”)。
在另一个实施方案中,抗体包含序列SEQ ID No.33的重链可变结构域(VH),所述序列SEQ ID No.33包含至少1个选自残基20、34、35、38、48、50、59、61、62、70、72、74、76、77、79、82和95的回复突变。
在另一个实施方案中,抗体包含序列SEQ ID No.33的重链可变结构域(VH),所述序列SEQ ID No.33包含2、3、4、5、6、7、8、9、10、11、12、13、14、15、16或17个选自残基20、34、35、38、48、50、59、61、62、70、72、74、76、77、79、82和95的回复突变。
为了进一步清楚起见,下表3说明了优选的回复突变。
表3
在一个实施方案中,抗体包含序列SEQ ID No.35的轻链可变结构域(VL),所述序列SEQ ID No.35包含至少1个选自残基22、53、55、65、71、72、77和87的回复突变。
在一个实施方案中,抗体包含序列SEQ ID No.35的轻链可变结构域(VL),所述序列SEQ ID No.35包含2、3、4、5、6、7或8个选自残基22、53、55、65、71、72、77和87的回复突变。
在另一个实施方案中,抗体包含:
a)序列SEQ ID No.33的重链可变结构域(VH),其中所述序列SEQ ID No.33包含至少1个选自残基20、34、35、38、48、50、59、61、62、70、72、74、76、77、79、82和95的回复突变;和
b)序列SEQ ID No.35的轻链可变结构域(VL),其中所述序列SEQ ID No.35包含至少1个选自残基22、53、55、65、71、72、77和87的回复突变。
为了进一步清楚起见,下表4说明了优选的回复突变。
表4
残基编号 | 22 | 53 | 55 | 65 | 71 | 72 | 77 | 87 |
小鼠 | S | R | H | R | Y | S | N | F |
人 | T | S | Q | S | F | T | S | Y |
在一个这样的实施方案中,抗体包含所有上述回复突变,并且对应于包含序列SEQID No.34的重链可变结构域(VH)和序列SEQ ID No.36的轻链可变结构域(VL)的抗体;在下文中,所述人源化抗体将被称为hz208F2(“变体3”或“变体3(Var.3)”)。
在另一个实施方案中,变体1和变体3之间包含的所有人源化形式也涵盖在本发明中。换言之,抗体是包含共有序列SEQ ID No.41的重链可变结构域(VH)和共有序列SEQ IDNo.42的轻链可变结构域(VL)的抗体。整个人源化抗体在下文中将被称为hz208F2(“变体2”或“变体2(Var.2)”)。
在本发明的一个优选但非限制性的实施方案中,抗体选自:
a)包含序列SEQ ID No.33或与SEQ ID No.33具有至少80%、优选85%、90%、95%和98%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;和
b)包含序列SEQ ID No.34或与SEQ ID No.34具有至少80%、优选85%、90%、95%和98%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体。
“与SEQ ID No.33或34具有至少80%、优选85%、90%、95%和98%同一性的任何序列”分别是指具有三个重链CDR SEQ ID No.1、2和3的序列和,此外,在对应于CDR的序列(即,SEQ ID No.1、2和3)以外,与完整序列SEQ ID No.33或34具有至少80%、优选85%、90%、95%和98%同一性。
在本发明的一个实施方案中,抗体选自:
a)包含序列SEQ ID No.33或与SEQ ID No.33具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体;和
b)包含序列SEQ ID No.34或与SEQ ID No.34具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.9、5和11的三个轻链CDR的抗体。
如果在相关段落中未指示,在本说明书中应理解,具有特定序列的至少80%的任何序列或序列表示所述序列与参考序列具有至少80%、优选85%、90%、95%和98%同一性。无论这些序列是否含有CDR序列,应理解序列至少具有必须与参考序列的CDR相同的这些CDR,同一性应该为针对位于对应于这些CDR的序列以外的剩余序列计算的与完整序列的80%、优选85%、90%、95%和98%同一性。
在一个优选的实施方案中,抗体选自:
a)包含序列SEQ ID No.35或与SEQ ID No.35具有至少80%、优选85%、90%、95%和98%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体;和
b)包含序列SEQ ID No.36或与SEQ ID No.36具有至少80%、优选85%、90%、95%和98%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体。
“与SEQ ID No.35或36具有至少80%、优选85%、90%、95%和98%同一性的任何序列”是指具有三个轻链CDR SEQ ID No.4、5和6的序列,另外,序列在对应于CDR的序列(即,SEQ ID No.4、5和6)以外,与完整序列SEQ ID No.35或36具有至少80%、优选85%、90%、95%和98%同一性。
在本发明的一个实施方案中,抗体选自:
a)包含序列SEQ ID No.35或与SEQ ID No.35具有至少80%同一性的任何序列的轻链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体;和
b)包含序列SEQ ID No.36或与SEQ ID No.36具有至少80%同一性的任何序列的重链可变结构域,和序列SEQ ID No.7、2和3的三个重链CDR的抗体。
此处描述的人源化抗体也可以特征在于恒定结构域,更特别地,所述人源化抗体尤其可以选自IgG1、IgG2、IgG3、IgM、IgA、IgD或IgE。更优选地,在本发明的上下文中,所述人源化抗体是IgG1或IgG4。
根据本发明的一个实施方案,抗体是人源化抗体,其包含VH和VL可变结构域,如上文所述为IgG1形式。更优选地,所述人源化抗体包含序列SEQ ID No.43的VH的恒定结构域和序列SEQ ID No.45的VL的κ结构域。
根据本发明的一个实施方案,抗体是人源化抗体,其包含VH和VL可变结构域,如上文所述为IgG4形式。更优选地,所述人源化抗体包含序列SEQ ID No.44的VH的恒定结构域和序列SEQ ID No.45的VL的κ结构域。
根据本发明的另一个实施方案,抗体选自:
a)包含或由以下组成的抗体:序列SEQ ID No.37或与SEQ ID No.37具有至少80%同一性的任何序列的重链,和序列SEQ ID No.39或与SEQ ID No.39具有至少80%同一性的任何序列的轻链;和
b)包含或由以下组成的抗体:序列SEQ ID No.38或与SEQ ID No.38具有至少80%同一性的任何序列的重链,和序列SEQ ID No.40或与SEQ ID No.40具有至少80%同一性的任何序列的轻链。
为了进一步清楚起见,下表5a说明了人源化抗体hz208F2的变体1(Var.1)和变体3(Var.3)的VH和VL序列的非限制性示例。它还包含变体2(Var.2)的共有序列。
表5a
在另一个优选的实施方案中,抗体选自:
a)包含重链可变结构域和序列SEQ ID No.9、5和11的三个轻链CDR的抗体,所述重链可变结构域序列选自序列SEQ ID No.56、62、64、66、68、70、72、74、76、78和54或与SEQ IDNo.56、62、64、66、68、70、72、74、76、78和54具有至少80%、优选85%、90%、95%和98%同一性的任何序列;
b)包含轻链可变结构域和序列SEQ ID No.7、2和3的三个重链CDR的抗体,所述轻链可变结构域序列选自序列SEQ ID No.57或60或与SEQ ID No.57或60具有至少80%、优选85%、90%、95%和98%同一性的任何序列;和
c)包含重链可变结构域和轻链可变结构域的抗体,所述重链可变结构域序列选自SEQ ID No.56、62、64、66、68、70、72、74、76、78和54或与SEQ ID No.56、62、64、66、68、70、72、74、76、78和54具有至少80%、优选至少85%、90%、95%和98%同一性的任何序列;所述轻链可变结构域选自SEQ ID No.57或60或与SEQ ID No.57或60具有至少80%、优选至少85%、90%、95%和98%同一性的任何序列。
根据本发明的另一个实施方案,抗体选自:
a)抗体,其包含序列SEQ ID No.56、62、64、66、68、70、72、74、76、78和54或与SEQID No.56、62、64、66、68、70、72、74、76、78和54具有至少80%同一性的任何序列的重链,和SEQ ID No.57或与SEQ ID No.57具有至少80%同一性的任何序列的轻链;和
b)抗体,其包含序列SEQ ID No.56、64、68和78或与SEQ ID No.56、64、68和78具有至少80%同一性的任何序列的重链,和SEQ ID No.60或与SEQ ID No.60具有至少80%同一性的任何序列的轻链。
根据本发明的另一个实施方案,抗体选自:
a)包含或由以下组成的抗体:序列SEQ ID No.58或与SEQ ID No.58具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
b)包含或由以下组成的抗体:序列SEQ ID No.58或与SEQ ID No.58具有至少80%同一性的任何序列的重链,和序列SEQ ID No.61或与SEQ ID No.61具有至少80%同一性的任何序列的轻链;
c)包含或由以下组成的抗体:序列SEQ ID No.63或与SEQ ID No.63具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
d)包含或由以下组成的抗体:序列SEQ ID No.65或与SEQ ID No.65具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
e)包含或由以下组成的抗体:序列SEQ ID No.65或与SEQ ID No.65具有至少80%同一性的任何序列的重链,和序列SEQ ID No.61或与SEQ ID No.61具有至少80%同一性的任何序列的轻链;
f)包含或由以下组成的抗体:序列SEQ ID No.67或与SEQ ID No.67具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
g)包含或由以下组成的抗体:序列SEQ ID No.69或与SEQ ID No.69具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
h)包含或由以下组成的抗体:序列SEQ ID No.69或与SEQ ID No.69具有至少80%同一性的任何序列的重链,和序列SEQ ID No.61或与SEQ ID No.61具有至少80%同一性的任何序列的轻链;
i)包含或由以下组成的抗体:序列SEQ ID No.71或与SEQ ID No.71具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
j)包含或由以下组成的抗体:序列SEQ ID No.73或与SEQ ID No.73具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
k)包含或由以下组成的抗体:序列SEQ ID No.75或与SEQ ID No.75具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
l)包含或由以下组成的抗体:序列SEQ ID No.77或与SEQ ID No.77具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
m)包含或由以下组成的抗体:序列SEQ ID No.53或与SEQ ID No.53具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链;
n)包含或由以下组成的抗体:序列SEQ ID No.53或与SEQ ID No.53具有至少80%同一性的任何序列的重链,和序列SEQ ID No.61或与SEQ ID No.61具有至少80%同一性的任何序列的轻链;和
o)包含或由以下组成的抗体:序列SEQ ID No.55或与SEQ ID No.55具有至少80%同一性的任何序列的重链,和序列SEQ ID No.59或与SEQ ID No.59具有至少80%同一性的任何序列的轻链。
换言之,抗体可以是包含以下的抗体:
a)序列选自SEQ ID No.58、63、65、67、69、71、73、75、77、53和55或与SEQ IDNo.58、63、65、67、69、71、73、75、77、53和55具有至少80%同一性的任何序列的重链;和
b)序列选自SEQ ID No.59和61或与SEQ ID No.59和61具有至少80%同一性的任何序列的轻链。
在本发明的一个实施方案中,抗体选自:
a)序列选自SEQ ID No.58、63、65、67、69、71、73、75、77、53和55或与SEQ IDNo.58、63、65、67、69、71、73、75、77、53或55具有至少80%同一性的任何序列的重链;和
b)序列选自SEQ ID No.59和61或与SEQ ID No.59或61具有至少80%同一性的任何序列的轻链。
为了进一步清楚起见,下表5b说明了人源化抗体hz208F2不同变体的VH和VL序列(可变结构域和全长)的非限制性示例。
表5b
根据本发明的另一方面,抗体由杂交瘤I-4757、I-4773、I-4775、I-4736或I-4774生产,其分别于2013年5月30日、2013年6月26日、2013年6月26日、2013年4月24日和2013年6月26日向法国巴斯德研究所CNCM提交。
抗体更特别地是208F2抗体(例如,嵌合或人源化,尤其是嵌合),并且更特别地是单克隆抗体(IgG1)c208F2抗体。该抗体特别描述于WO2015162291中,其特征在于它分别包含SEQ ID No.9、5和11的三个轻链CDR,以及分别包含SEQ ID No.7、2和3的三个重链CDR。该抗体的特征还在于它包含序列SEQ ID No.18的轻链可变结构域和序列SEQ ID No.13的重链可变结构域。该抗体的特征最后在于它包含序列SEQ ID No.28的轻链和序列SEQ IDNo.23的重链可变结构域。
抗体c208F2和ADC-A可以通过技术人员已知的用于获得抗体和ADC的任何方法获得。它们尤其通过WO2015162291(ADC-A优选为WO2015162291中称为c208F2-G-13的ADC)中描述的方法获得。
治疗
根据本发明,“耐药性”是指患者对治疗不再有反应,即癌症再次开始进展或稳定。
根据本发明,“治疗”尤其是指总生存期的增加和/或无进展生存期的持续时间的增加和/或无恶化生存期的增加和/或复发的减少和/或肿瘤大小的减小。
这些肿瘤反应标准(耐药性和治疗)的评估是技术人员众所周知的,尤其可以通过RECIST标准测量(Eisenhauer等人,Eur J Cancer,45(2009):228-247或其更新)。
增殖性疾病可以更特别地是癌症,尤其是对多西他赛耐药的癌症。
根据本发明的癌症尤其可以选自:乳腺癌、结肠癌、黑色素瘤、肺癌(包括非小细胞肺癌)、胃癌、上呼吸消化道癌、食道癌、结直肠癌、胃癌、神经胶质瘤、食道癌、卵巢癌、前列腺癌、肾癌、甲状腺癌、子宫癌、口腔鳞状细胞癌和间皮瘤。
在一个具体的实施方案中,根据本发明治疗的癌症将是通常用多西他赛治疗的癌症,尤其是胃癌、前列腺癌、肺癌(包括非小细胞)、乳腺癌和上呼吸消化道癌。
在一个具体的实施方案中,根据本发明治疗的癌症将是包含肿瘤细胞的癌症,所述肿瘤细胞表达或过表达全部或部分IGF-1R蛋白。表达IGF-1R的癌症可以是最初表达IGF-1R的癌症,或最初不表达IGF-1R但在对第一次(或之后)的治疗产生耐药性(如对多西他赛产生耐药性)后开始表达IGF-1R的癌症。
在一个实施方案中,ADC-A可以在对多西他赛产生耐药性之后施用。因此,ADC-A可以单独施用,在多西他赛之后施用,或与多西他赛和/或另一种化学疗法同时施用。ADC-A治疗的开始尤其可以在观察到耐药性发生后立即开始,或在观察到耐药性发生后1、2、3、4、5、6、7或甚至8周或更长时间后开始,尤其是观察到耐药性发生后的16周之前。
在另一个实施方案中,ADC-A可以在对多西他赛产生耐药性之前与多西他赛同时施用。ADC-A治疗可以在多西他赛治疗的同时开始,或在多西他赛治疗之后但在对多西他赛产生耐药性之前开始。
“同时”是指施用产品使得其同时存在于患者体内。产品可以同时或依次给药。
“随后”是指用第二种产品治疗之后开始用第一种产品治疗,例如在用多西他赛治疗之后用ADC-A治疗。因此,两种产物不同时存在于患者体内。
多西他赛的剂量方案将取决于严重程度、患者状况和待治疗的癌症类型。它也可能根据患者之前或同时接受的治疗而不同。通常,施用多西他赛的剂量为50mg/m2体表面积(BSA)和125mg/m2之间,尤其是75mg/m2至100mg/m2之间,每1至4周一次,尤其是每三周一次。
治疗周期数(即治疗施用发生的次数和两次施用之间的时间)将取决于患者的反应和对多西他赛的耐药性的发生。它尤其可以为3至12个或更多个周期。
ADC-A的剂量方案将取决于严重程度、患者状况和待治疗的癌症类型。它也可能根据患者之前或同时接受的治疗而不同。通常,ADC-A将以0.5至3mg/kg待治疗患者,尤其是0.9至2.5mg/kg待治疗患者的剂量施用,每1至4周一次,尤其是每三周一次。
ADC-A治疗的周期数将尤其取决于患者的反应。它尤其为1至18个或更多个周期,直到肿瘤恢复进展或其缓解。
根据本发明的治疗可以在多西他赛和/或ADC-A之前或同时与其他癌症治疗组合。特别地,癌症治疗是用选自以下的药物分子治疗:多柔比星、环磷酰胺、卡培他滨、顺铂、紫杉醇、卡铂、拉帕替尼、帕妥珠单抗、贝伐珠单抗、曲妥珠单抗、5-氟尿嘧啶、蒽环类、长春瑞滨、比美替尼(binimetinib)、康奈非尼(encorafenib)和来那替尼(neratinib)。根据本发明的治疗还可以与其他类型的药物组合,如皮质类固醇,尤其是地塞米松或泼尼松。
本发明还涉及包含ADC-A和至少一种药学上可接受的赋形剂的药物组合物,用于其根据本发明的用途。特别地,将配制ADC-A,使得能够静脉注射。
实施例:
材料与方法
细胞:MCF-7细胞获自ATTC(Manassas)。如供应商推荐的,细胞维持于标准细胞培养基中、5%CO2、90%湿度、37℃培养箱中。
抗体生成:生产抗体208F2如WO2015162291中描述。简而言之,使用杂交瘤技术生成抗IGF-1R抗体人源化c208F2(hz208F2(4))。用重组人IGF-1R蛋白(rhIGF-1R)(systèmesR&D)在弗氏佐剂存在下免疫Balb/c小鼠。小鼠与骨髓瘤SP2/0融合伴侣融合。通过有限稀释克隆后,确认抗体与MCF-7细胞的结合和内化,并确定同种型。通过ELISA验证对rhIGF-1R、重组人胰岛素受体(rhIR)和小鼠IGF-1R(mIGF-1R)(systèmes R&D)的结合特异性。然后通过移植互补决定区(CDR)将抗体m208F2人源化,并在中国仓鼠卵巢细胞中表达,以进行完整的药理学表征。
ADC-A的生产和表征:生产ADC-A如申请WO2015162291中描述(ADC-A是WO2015162291中称为c208F2-G-13的ADC)。如先前描述的(Sun等人,Bioconjug.Chem 2005;16:1282-90,Wagner-Rousset等人,mAbs 2014;6:173-84),进行mAb 208F2(hz208F2-4)的轻度还原和接头-有效载荷(linker payload)偶联。简而言之,为了达到DAR为4,用2.5摩尔当量的三(2-羧乙基)膦(TCEP)还原hz208F2-4。然后用7摩尔当量的接头-有效载荷(G-13)处理还原的抗体。偶联后,将ADC-A浓缩至5mg/mL(在25mM组氨酸pH 6.5,150mM NaCl和6%蔗糖的缓冲液中)。然后加入吐温(Tween)80以获得终浓度0.005%(v/v)。产物最终通过Stericup过滤器(GP Express PLUS膜,0.22μm,聚醚砜,Millipore)过滤并储存于4℃。
确定体内活性:在乳腺癌模型中测试体内活性:7周龄雌性裸鼠(Charles RiverLaboratories,n=15)皮下植入0.72mg释放17β-雌二醇(Innovative Research ofAmerica)60天的颗粒1天后,皮下移植5×106个MCF-7细胞。
小鼠随机分配,当肿瘤达到约150mm3大小后开始治疗。至少每周两次测量肿瘤体积(长度×宽度×高度×0.52),使用实体瘤反应标准(RECIST)定义治疗反应。
向携带MCF-7肿瘤的小鼠静脉注射9mg/kg多西他赛,每周两次,共5次注射。当肿瘤对多西他赛产生耐药性时,将小鼠分为2组,每组5只动物:组1每2周接受9mg/kg多西他赛,组2接受3mg/kg ADC-A单次注射。
使用以下公式计算消退百分比的值:
消退%=100×ΔT/T初始
其中,T=治疗组中的肿瘤体积,ΔT=研究当天治疗组中的肿瘤体积减去初始施用当天治疗组中的肿瘤体积,并且T初始=初始施用当天治疗组中的肿瘤体积。当肿瘤大小增加>20%时,认为疾病在进展。部分消退(RP)定义为肿瘤大小减少>30%。肿瘤不生长,或肿瘤大小轻微减小(<30%),或轻微增大(<20%)定义为稳定疾病(ET),没有明显的肿瘤块定义为完全消退(RC)。
结果
为了评估ADC-A在乳腺癌中的治疗潜力,在移植MCF-7细胞的小鼠模型中研究了多西他赛耐药发生后施用ADC-A的效果。70天后,肿瘤对多西他赛产生耐药性并复发(图1)。在患有多西他赛耐药性肿瘤的小鼠中施用3mg/kg的单剂量ADC-A,诱导了强烈且显著的肿瘤生长抑制(p<0.05)(图1)。在5只小鼠中,1只小鼠观察到RC,3只小鼠观察到RP。ADC-A和多西他赛表现出协同作用。我们可以得出结论,ADC-A是单独或与多西他赛联合治疗多西他赛耐药性肿瘤的良好治疗方法。鉴于所使用的有效载荷具有与紫杉烷类以及因此与多西他赛相似的作用机制(对微管蛋白的作用),这更加令人惊讶。
Claims (15)
2.根据权利要求1所述用途的ADC,其特征在于所述Ab是包含序列SEQ ID No.18的轻链可变结构域和序列SEQ ID No.13的重链可变结构域的抗体。
3.根据权利要求1或2所述用途的ADC,其特征在于所述ADC施用于对多西他赛产生耐药性的患者。
4.根据权利要求1至3中任一项所述用途的ADC,其特征在于使用ADC的治疗具有1个月至5年的持续时间。
5.根据权利要求1至4中任一项所述用途的ADC,其特征在于所述ADC在观察到对多西他赛的耐药性发生后立即施用,或在观察到耐药性发生后1、2、3、4、5、6、7或甚至8周或更长时间后施用,尤其是观察到耐药性发生后的16周之前施用。
6.根据权利要求1至5中任一项所述用途的ADC,其特征在于所述ADC以1至2mg/kg待治疗患者的剂量每2至4周周期施用。
7.根据权利要求1至6中任一项所述用途的ADC,其特征在于周期数为1至18个周期。
8.根据权利要求1至7中任一项所述用途的ADC,其特征在于癌症治疗通过以下来衡量:总生存期的增加和/或无进展生存期的持续时间的增加和/或无恶化生存期的增加和/或复发的减少和/或肿瘤大小的减小。
9.根据权利要求1至8中任一项所述用途的ADC,其特征在于所述ADC施用于以下患者:其在多西他赛和/或ADC之前或同时,经一种或多种其他化学疗法治疗,尤其是使用一种或多种选自以下的药物分子:多柔比星、环磷酰胺、卡培他滨、顺铂、紫杉醇、卡铂、拉帕替尼、帕妥珠单抗、贝伐珠单抗、曲妥珠单抗、5-氟尿嘧啶、蒽环类、比美替尼、康奈非尼和来那替尼。
10.一种药物组合物,其包含如权利要求1和2之一所定义的ADC和至少一种药学上可接受的赋形剂,用于其治疗增殖性疾病如癌症的用途,其特征在于包含ADC的药物组合物与多西他赛同时或随后施用。
11.根据权利要求10所述用途的药物组合物,其特征在于所述增殖性疾病是对多西他赛耐药的癌症。
12.根据权利要求10或11所述用途的药物组合物,其特征在于其在观察到对多西他赛的耐药性发生后立即施用,或在观察到耐药性发生后1、2、3、4、5、6、7或甚至8周或更长时间后施用,尤其是观察到耐药性发生后的16周之前施用。
13.根据权利要求10至12中任一项所述用途的药物组合物,其特征在于其以1至2mg/kg待治疗患者的剂量每2至4周周期施用,尤其是周期数为1至18个周期。
14.根据权利要求10至13中任一项所述用途的药物组合物,其特征在于使用所述药物组合物的治疗具有1个月至5年的持续时间。
15.根据权利要求10至14中任一项所述用途的药物组合物,其特征在于所述药物组合物施用于以下患者,其在多西他赛和/或ADC之前或同时,经一种或多种其他化学疗法治疗,尤其是使用一种或多种选自以下的药物分子:多柔比星、环磷酰胺、卡培他滨、顺铂、紫杉醇、卡铂、拉帕替尼、帕妥珠单抗、贝伐珠单抗、曲妥珠单抗、5-氟尿嘧啶、蒽环类、比美替尼、康奈非尼和来那替尼。
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